melphalan and Amyloidosis

Systemic Light chain (AL) amyloidosis is a monoclonal plasma cell proliferative disorder characterized by deposition of amyloidogenic monoclonal light chain fragments causing organ dysfunction. It is a fatal disease and if not diagnosed and treated early can lead to organ failure and potentially death. The renal system along with the cardiovascular system are the most common organs involved but other organs such as gut and liver can be involved as well. The initial evaluation of patients requires confirming the diagnosis with tissue biopsy and staining with Congo red followed by confirmatory typing with mass spectrometry of the Congo red positive tissue. Then establishing the extent of the organs involvement by various staging and biomarkers testing. The treatment options and the tolerability of therapy depend on the disease staging, frailty, and co-morbidities. The autologous hematopoietic cell transplantation (HCT) after high dose melphalan therapy is an effective strategy which is usually done after initial bortezomib induction therapy. Unfortunately, most systemic AL amyloidosis patients are not candidate for HCT due to frailty, old age, multi-organ involvement, renal and heart failure at the time of diagnosis. While it is widely accepted that the patients need to be treated until they achieve complete hematologic response, the maintenance therapy after HCT is not well established in AL amyloidosis. In this review, we report the literature on the latest treatment updates of AL amyloidosis and the ongoing clinical trials highlighting the future treatments.

Topics: Amyloidosis; Congo Red; Frailty; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Paraproteinemias

The management of immunoglobulin light chain (AL) amyloidosis is complex. Emerging data have shown promising results for several novel agents. We review the management of AL amyloidosis, including factors that determine transplant eligibility, treatment options for transplant-ineligible patients, and treatment options for relapsed/refractory AL amyloidosis. For carefully selected patients, high-dose melphalan and stem cell transplantation is recommended. Transplant eligibility criteria generally include biopsy-proven amyloidosis, evidence of a plasma cell dyscrasia, involvement of at least one major organ, and adequate performance status. For transplant-ineligible patients, bortezomib-based regimens are recommended, including: 1) bortezomib, oral melphalan, and dexamethasone (BMDex); 2) bortezomib, cyclophosphamide, and dexamethasone (CyBorD or VCd); and 3) subcutaneous daratumumab (DARA SC) and VCd. The latter option is based on a landmark trial that led to the first US Food and Drug Administration-approved therapy for AL amyloidosis. For relapsed/refractory disease, novel therapeutics including proteosome inhibitors, immunomodulatory agents, and monoclonal antibodies have shown promising results. In this review, we summarize data for various therapeutics in different clinical scenarios of AL amyloidosis.

Topics: Amyloidosis; Bortezomib; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Stem Cell Transplantation

High-dose melphalan followed by autologous stem cell transplant (ASCT) has been transformative in treating AL amyloidosis since the early nineties. Recently, the European Hematology Association (EHA) and International Society of Amyloidosis (ISA) have developed a combined guideline for the management of patients undergoing an ASCT for AL amyloidosis.. In this practitioner's perspective, we review the guideline, focusing on 6 major areas and offer practical advice for its application. We provide a perspective on the optimal use of ASCT and its potential application in the future.. The EHA-ISA guideline comprehensively outlines the practicalities of performing an ASCT in AL amyloidosis. The critical aspect is careful patient selection. Vigilant fluid balance assessments are crucial as associated complications are common and dangerous. The role of ASCT is changing with improving hematological responses associated with novel agents. Evidence is limited for the use of ASCT in patients who achieve a complete hematological response (CR). Therefore, ASCT should be considered for those who only achieve a very good partial response (VGPR)/partial response (PR) and fulfil the strict selection criteria. Future research identifying the cohort who would benefit most from ASCT in the era of novel therapies is warranted.

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Retrospective Studies; Transplantation, Autologous; Treatment Outcome

Immunoglobulin light chain (AL) amyloidosis, the most common of the systemic amyloidosis, is characterized by the deposition of amyloid fibrils that derive from the aggregation of misfolded monoclonal immunoglobulin light chains. Amyloid fibrils disrupt tissue architecture and the pre-fibril oligomers are directly toxic to myocardiac cells, causing cardiac dysfunction. The lethal consequences of AL amyloidosis are due to the toxic product and not due to the malignant behaviour of the plasma cell clone; however, the characteristics of this clone are associated with long-term prognosis. Early and accurate diagnosis is the key to effective management, but is challenging. Modern chemotherapy options (including autologous transplantation, bortezomib, lenalidomide) have improved the outcomes of patients at low or intermediate risk, but the prognosis of patients with severe cardiac dysfunction is still poor. Therapies targeting amyloid deposits and the amyloidogenic process are under investigation and offer promise for better future treatments.

Topics: Amyloidosis; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Melphalan; Myeloablative Agonists; Plasma Cells; Risk Assessment; Stem Cell Transplantation; Treatment Outcome

Topics: Amyloidosis; Antineoplastic Agents; B-Lymphocytes; Clinical Trials as Topic; Drug Administration Schedule; Gene Rearrangement, B-Lymphocyte, Light Chain; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Patient Selection; Precision Medicine; Remission Induction; Survival Analysis; Transplantation, Autologous; Treatment Outcome

Immunoglobulin (Ig) light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of Ig light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/ autonomic neuropathy. The diagnosis can be challenging, requiring a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains which can result in organ improvement and extend patient survival. Standard treatment approaches include high dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (SCT) or oral melphalan with dexamethasone (MelDex). The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored.

Topics: Amyloidosis; Biopsy; Dexamethasone; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Melphalan; Stem Cell Transplantation

Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma.. Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory.. N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months.. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT-proBNP <5,000 ng/mL, troponin T <0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone or cyclophosphamide-bortezomib-dexamethasone. Other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide have documented activity. Future Challenges: Late diagnosis remains a major obstacle to initiating effective therapy. Recognizing the presenting syndromes is necessary for improving survival.

Topics: Age Factors; Amyloidosis; Antineoplastic Agents; Biomarkers; Bone Marrow; Boronic Acids; Bortezomib; Creatinine; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulin Light Chains; Melphalan; Pyrazines; Stem Cell Transplantation; Subcutaneous Fat; Survival Analysis; Troponin T

AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. It is often difficult to recognize because of its many manifestations. Recent diagnostic and prognostic advances include the serum-free light chain assay, cardiac MRI, and serologic cardiac biomarkers. Treatment strategies that have evolved during the past decade are prolonging survival and preserving organ function. This article outlines the role of high-dose melphalan and stem cell transplantation. This year marks the 20th anniversary for the first patient who underwent successful stem cell transplantation for this disease at Boston Medical Center.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Peripheral Blood Stem Cell Transplantation; Remission Induction; Survival Analysis; Transplantation, Autologous; Treatment Outcome

Light-chain amyloidosis is a plasma cell dyscrasia characterized by the production of fibrillar proteins comprised of monoclonal light chains, which deposit in tissues causing multiorgan dysfunction and death. The diagnosis is challenging and requires a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains, which improve organ function and extend survival. Standard treatment approaches have included high-dose melphalan followed by autologous hematopoietic SCT or oral melphalan with dexamethasone. The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk-adapted approach to SCT followed by novel agents as consolidation, reduces treatment-related mortality with promising activity. Immunotherapy targeting pathologic plasma cells and amyloid fibrils is being developed and could potentially eliminate visceral amyloid deposits. Improved understanding of the biology that renders light-chains amyloidogenic and a commitment to refer patients to specialized centers conducting well-designed clinical trials is essential to improve patient outcomes.

Topics: Amyloidosis; Animals; Boronic Acids; Bortezomib; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Immunologic Factors; Immunosuppressive Agents; Immunotherapy; Lenalidomide; Melphalan; Pyrazines; Survival Analysis; Thalidomide

Systemic amyloid light-chain (AL) amyloidosis is a protein conformation disorder caused by clonal plasma cell dyscrasias. Symptoms result from fibrillar extracellular deposits in various tissues. The deposits disrupt organ function and ultimately lead to death. The prognosis is poor and depends mostly on the severity of cardiac involvement. The treatment is derived from the therapy of multiple myeloma with the main goal being to reach a complete hematological remission (CR). High-dose melphalan (HDM) and autologous hematopoietic cell transplantation can induce CR rates in about 40%. The main concern was the high transplant-related mortality of up to 40% due to organ dysfunction, which could be reduced to <12% by careful patient selection in experienced centers. However, >50% of patients in CR survive longer than 10 years, suggesting that HDM has the potential to change the natural course of the disease. As there is evidence that 'graft-versus-plasma-cell-dyscrasia' effects are active in AL amyloidosis, allogeneic hematopoietic cell transplantation might be an option for younger patients with preserved organ functions who have relapsed after HDM.

Topics: Amyloidosis; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Prognosis

Light-chain (AL) amyloidosis may present with features suggesting vasculitis, including giant-cell arteritis (GCA). We describe a case of an 80-year-old man, who initially presented with bilateral jaw claudication, bi-temporal headache and arthralgia, however a temporal-artery biopsy then revealed AL amyloidosis. A diagnosis of AL amyloidosis complicating multiple myelome simulates GCA and polymyalgia rheumatica was established. The patient was successfully treated with melphalan and dexamethasone: the free kappa light chains decreased, the patient's jaw claudication and headache disappeared. Then we discuss similarities between GCA and AL amyloidosis and potential confusion in diagnosis. We suggest that, in patients with clinical features of GCA without any temporal-artery typical findings, specimens are stained with Congo red, which then results in a different diagnosis and treatment.

Topics: Aged, 80 and over; Amyloid; Amyloidosis; Antineoplastic Agents; Biopsy; Comorbidity; Dexamethasone; Diagnosis, Differential; Giant Cell Arteritis; Humans; Male; Melphalan; Multiple Myeloma; Polymyalgia Rheumatica; Temporal Arteries; Treatment Outcome

Various renal disorders are associated with monoclonal gammopathies, secondary to tissue deposition or precipitation of a monoclonal immunoglobulin (Ig) or a fragment thereof (isolated Ig light chain or heavy chain). They are classified according to the localization of renal lesions, either glomerular or tubular and to the pattern of ultrastructural organization of Ig deposits. Renal disease in monoclonal gammopathies may be isolated, or associated with various systemic symptoms particularly in AL amyloidosis, Randall-type monoclonal Ig deposition disease and monoclonal cryoglobulinemias. Except for myeloma cast nephropathy, which occurs in the setting of high-mass myeloma and is recognized after electrophoretic analysis of proteinuria and AL amyloidosis, which diagnosis is usually made after pathological examination of non-invasive tissue specimens (i.e. abdominal fat or minor salivary glands), a kidney biopsy is required to identify the other types of renal disorders associated with monoclonal gammopathies and to estimate renal prognosis. Renal pathological diagnosis is difficult and relies on careful examination of kidney biopsy samples, by light microscopy, immunofluorescence studies using conjugates specific for Ig light and heavy chains, IgG sub-classes and heavy chain constant domains and by electron microscopy. In some cases, additional studies are required to identify the nature of deposits, such as immuno-electron microscopy or mass spectrometric-based proteomic analysis after laser dissection. In patients with renal disorders related to Ig light chain precipitation or deposition (myeloma cast nephropathy, AL amyloidosis, Randall-type light chain deposition disease), measurement of serum free light chains at baseline and throughout follow-up is mandatory to evaluate clonal response to chemotherapy. A more than or equal to 50% decrease in serum free light chain levels is associated with increased renal and patient survival. In AL amyloidosis, serum levels of markers of cardiac disease (NT-proBNP and troponin) are also closely associated with prognosis. Efficient chemotherapy, tailored to the underlying plasma cell or lymphoproliferative disorder and adapted to renal function, should be promptly introduced, even in the absence of overt malignant haematological disease. Renal prognosis and patient survival (particularly in AL amyloidosis and cast nephropathy) are closely associated with the rapid achievement of an haematological response. The combi

Topics: Amyloidosis; Biopsy; Boronic Acids; Bortezomib; Dexamethasone; Heart Transplantation; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Kidney; Kidney Diseases; Kidney Transplantation; Melphalan; Paraproteinemias; Plasma Exchange; Pyrazines

AL amyloidosis is a systemic disease characterised by pathogenetic proteins produced by malignant plasma cells and the deposition of them in different organs of the body. Amyloidogenic protein is the light chain of the monoclonal immunoglobulin, which becomes water insoluble, precipitates and deposites in the extracellular space resulting damage of organ function. AL amyloidosis belongs to plasma cell dyscrasias or it can associate to other monoclonal B-cell diseases. Diagnosis - such as in case of other types of amyloidosis - is based on histology. Identification of the amyloidogenic protein often needs special examinations. The goal of the therapy is the eradication of the malignant cell clone. Therapeutical armamentarium has been largely flared in the past few decades, several drugs with new mechanisms of action are available (thalidomide, lenalidomide, bortezomib). The standard treatment is high dose chemotherapy followed by autologous stem cell transplantation in case of eligible patients. Transplantation uneligible patients can be treated with a low dose alkylating agent with or without dexamethasone, or with the new agents. The therapeutical decision must be preceded by very thorough risk assessment. Early diagnosis and the prompt beginning of the treatment has great significance because the evolving functional abnormalities of parenchymal organs (mainly cardiac failure) prevents the effectivity of the treatment. Amyloidosis is an orphan disease, special centers play a significant role in the field of clinical trials.

Topics: Algorithms; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Diagnosis, Differential; Heart Failure; Humans; Lenalidomide; Melphalan; Myocardium; Palliative Care; Patient Selection; Prognosis; Pyrazines; Quality of Life; Risk Assessment; Risk Factors; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous

Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.

Topics: Aged; Amyloidosis; Bence Jones Protein; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney; Lenalidomide; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Pyrazines; Renal Insufficiency; Thalidomide

Systemic AL amyloidosis is a rare complication of monoclonal gammopathies. Renal manifestations are frequent, mostly characterized by heavy proteinuria, with nephrotic syndrome and renal failure in more than half of the patients at diagnosis. Without treatment, median survival does not exceed 12 months. Amyloid heart disease and diffusion of amyloid deposits are associated with reduced survival. Treatment of systemic AL amyloidosis has been profoundly modified with the introduction of international criteria for the definition of organ involvement and hematologic response, and with the use of sensitive tests for the measurement of serum-free light chain levels. Melphalan plus dexamethasone is now established as the gold standard for first line treatment of systemic AL, with similar efficacy and reduced treatment-related mortality compared to high-dose therapy. Modern chemotherapy regimens, based on the use of novel agents such as bortezomib and lenalidomide, might further improve patient survival.

Topics: Amyloid; Amyloidosis; Biomarkers; Boronic Acids; Bortezomib; Cardiomyopathies; Consensus Development Conferences as Topic; Dexamethasone; Drug Therapy, Combination; Heart Transplantation; Humans; Immunoglobulin Light Chains; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Lenalidomide; Melphalan; Natriuretic Peptide, Brain; Paraproteinemias; Paraproteins; Peptide Fragments; Prognosis; Pyrazines; Randomized Controlled Trials as Topic; Renal Dialysis; Thalidomide

Light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the pathologic production of fibrillar proteins comprised of monoclonal light chains which deposit in tissues and cause organ dysfunction. The diagnosis can be challenging, requiring a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains which can result in organ improvement and extend patient survival. Standard treatment approaches include high dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (SCT) or oral melphalan with dexamethasone (MDex). The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk adapted approach to SCT followed by novel agents as consolidation reduces treatment related mortality with promising outcomes. Immunotherapeutic approaches targeting pathologic plasma cells and amyloid precursor proteins or fibrils are being developed. Referral of patients to specialized centers focusing on AL amyloidosis and conducting clinical trials is essential to improving patient outcomes.

Topics: Amyloidosis; Animals; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Melphalan; Paraproteinemias

During the past 10 to 15 years, there has been substantial progress in developing new treatments for the systemic amyloidoses. These advances have improved patient outcomes but have also raised new questions with direct clinical implications. For example, development of less intensive treatments for AL amyloidosis has made less certain the role of autologous stem cell transplantation, and new quantitative assays should now allow determination of the importance of fully eliminating amyloidogenic light chain production in AL disease. Additionally, observations from a clinical trial in AA amyloidosis have generated hypotheses about the relative contributions of amyloid precursors and mature fibrils to amyloidosis-associated kidney disease.

Topics: Amyloid; Amyloidosis; Humans; Kidney Diseases; Melphalan; Myeloablative Agonists; Stem Cell Transplantation; Transplantation, Autologous

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Biomarkers; Dexamethasone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Humans; Melphalan; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Remission Induction; Stem Cell Transplantation; Survival Analysis; Time Factors; Treatment Outcome

Treatment of amyloidosis is a substantial challenge. Various types of amyloidosis are associated with a broad spectrum of organ manifestations and considerable morbidity and mortality.. The present paper is based on a review of international literature, retrieved through a PubMed search on amyloidosis, and the author's clinical experience.. Current treatment of amyloidosis is first and foremost aimed at reducing the level of amyloid precursor proteins; e.g. immunosuppression in AA amyloidosis, chemotherapy in AL amyloidosis and supportive treatment of diminished or lost organ function. Aggressive immunomodulating treatment increases survival in AA amyloidosis associated with rheumatic disease, and high-dose melphalan with autologous stem-cell transplantation (HMAS) has in selected studies shown increased survival in AL amyloidosis. More recent knowledge on mechanisms of amyloid formation has given rise to novel therapeutic targets that may be useful for all amyloidoses. Examples of this are immunotherapy and inhibition of the interaction of extrafibrillary components, which have shown benefit in animal models for AA, AL and Abeta amyloidosis as well as in the first human studies. More studies are needed to define their place in treatment of amyloidosis.

Topics: Amyloid; Amyloid beta-Protein Precursor; Amyloidosis; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Humans; Immunotherapy; Melphalan; Stem Cell Transplantation; Transplantation, Autologous

We reviewed the literature in 2007 on 3 groups of systemic diseases affecting the kidney: lupic nephropathy (LN), small vessel vasculitis (SVV) and renal amyloidosis. A systematic review of 268 patients with LN pooled from 4 studies found that mycophenolic acid (MPA) in the induction phase caused more remissions and achieved greater renal survival than cyclophosphamide (CP), confirming it as a valid alternative to CP. Using a protocol including rituximab and MPA in the induction phase (14 days), MPA alone without corticoids is effective and safe in the maintenance phase. Rituximab has also been successfully used in CP-resistant forms of LN, where it reduces clinical activity and mesangial proliferation. Plasma exchanges achieve better results than bolus corticoids in SVS with severe renal failure. Complications are severe. Anti- TNF-alpha agents provide no benefit in this indication. Prolonged administration of low-dose corticoids reduces the incidence of relapses. MPA is an alternative to CP if this drug cannot be administered. Good results are achieved with rituximab in CP-resistant forms. According to a controlled trial, treatment of AL amyloidosis with dexamethasone and melphalan has equivalent results to highdose melphalan and rescue with hematopoietic stem cell transplant. In AA amyloidosis, eprosidate slows the rate of progression of renal failure.

Topics: Adrenal Cortex Hormones; Amyloidosis; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Combined Modality Therapy; Cyclophosphamide; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Lupus Nephritis; Melphalan; Mycophenolic Acid; Plasma Exchange; Randomized Controlled Trials as Topic; Recurrence; Rituximab; Vasculitis

Light chain (AL) amyloidosis is the most frequently diagnosed form of systemic amyloid in the western world. The historically poor prognosis of AL amyloidosis appears to be improving with currently reported median survival of c. 40 months compared to 13 months in the early 1990s when low-dose oral melphalan was the mainstay of treatment. Autologous stem cell transplantation (ASCT) achieves the highest rates of complete clonal response but is confounded by substantial treatment-related mortality in AL amyloidosis unless it is restricted to highly selected patients. Newer chemotherapy regimens appear to have a balance of better safety and respectable efficacy with overall outcomes nearly similar to ASCT, but which may be used more widely. There are few data comparing durability, depth of clonal response, rate of organ response and overall survival following ASCT or chemotherapy, but a recent small, randomized trial did not suggest superiority of ASCT to oral melphalan and dexamethasone. There is a compelling need for further and larger randomized trials in this context. At the same time, various new specific anti-amyloid drugs have shown (in early phase studies or animal models) some very promising results. This review attempts to highlight the challenges, controversies and progress in AL amyloidosis.

Topics: Amyloidosis; Humans; Immunosuppressive Agents; Melphalan; Organ Transplantation; Prednisone; Stem Cell Transplantation

Amyloidoses are a heterogeneous group of multisystem disorders, which are characterized by an extracellular deposition of amyloid fibrils. Typically affected are the heart, liver, kidneys, and nervous system. More than half of the patients die due to cardiac involvement. Clinical signs of cardiac amyloidosis are edema of the lower limbs, hepatomegaly, ascites and elevated jugular vein pressure, frequently in combination with dyspnea. There can also be chest pain, probably due to microvessel disease. Dysfunction of the autonomous nervous system or arrhythmias may cause low blood pressure, dizziness, or recurrent syncope. The AL amyloidosis caused by the deposition of immunoglobulin light chains is the most common form. It can be performed by monoclonal gammopathy. The desirable treatment therapy consists of high-dose melphalan therapy twice followed by autologous stem cell transplantation. Due to the high peritransplantation mortality, selection of appropriate patients is mandatory. The ATTR amyloidosis is an autosomal dominant disorder caused by the amyloidogenic form of transthyretin, a plasmaprotein that is synthesized in the liver. Therefore, liver transplantation is the only curative therapy. The symptomatic treatment of cardiac amyloidosis is based on the current guidelines for chronic heart failure according to the patient's New York Heart Association (NYHA) state. Further types of amyloidosis with possible cardiac involvement comprise the senile systemic amyloidosis caused by the wild-type transthyretin, secondary amyloidosis after chronic systemic inflammation, and the beta(2)-microglobulin amyloidosis after long-term dialysis treatment.

Topics: Adult; Aged; Amyloidosis; Amyloidosis, Familial; Biopsy; Cardiomyopathies; Echocardiography; Female; Humans; Immunoglobulin Light Chains; Magnetic Resonance Imaging; Male; Melphalan; Myocardium; Practice Guidelines as Topic; Prognosis; Radionuclide Imaging; Stem Cell Transplantation; Transplantation, Autologous

Systemic amyloidosis is characterized by the involvement of multiple organs and the presence of an amyloid precursor protein in serum. This disorder is classified into four major forms: immunoglobulin light chain-derived (AL), reactive AA, dialysis-related (beta2M) and hereditary transthyretin (ATTR) type. Heart, kidney, gastrointestinal tract and peripheral nerves are commonly affected by amyloid deposition in systemic amyloidosis and histopathological demonstration of amyloid deposits on any of affected organs is the first step leading to the diagnosis of this disease. Immunohistochemical analysis of amyloid protein on tissue amyloid deposits is necessary to make classification of the disease and DNA testing is also useful in a hereditary form. Amyloidosis had been considered to be an incurable disease but during the past one decade several therapeutic approaches have been employed for the amyloidosis patients with diverse pathogenetic backgrounds: intravenous large dose of melphalan accompanied by autologous peripheral blood stem cell transplantation for AL amyloidosis and liver transplantation for hereditary ATTR type amyloidosis. As a result some amyloidosis patients have been rescued and are now enjoying their own social lives. It is likely that recent advance on the research of amyloidosis has changed the concept of this disease.

Topics: Amyloid; Amyloidosis; Humans; Immunohistochemistry; Liver Transplantation; Melphalan; Mutation; Peripheral Blood Stem Cell Transplantation; Prealbumin

We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. Two of the patients were considered to be classifiable as primary systemic AL amyloidosis based on the presence of M-protein in serum and abnormal plasma cells or lymphoplasmacytoid cells in the bone marrow probably producing the precursor immunoglobulin, although no visceral organs were affected. The size of the involved lymph nodes in these two patients increased gradually, and one was treated with rituximab and VAD (vincristine, doxorubicin and dexamethasone) followed by high-dose melphalan with autologous peripheral blood stem cell transplantation (auto-PBSCT). The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.

Topics: Aged; Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Diagnosis, Differential; Female; Humans; Lymph Nodes; Lymphatic Diseases; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous

Amyloidosis is a disease in which abnormal proteins form toxic intermediates and fibrillar tissue-deposits that compromise key viscera and lead to early death. In order to treat amyloidosis, the type of abnormal protein must be identified. The most common type is monoclonal immunoglobulin light chain or AL amyloidosis. One-third to one-half of patients with systemic AL amyloidosis has renal involvement in the form of glomerular, vascular and interstitial deposits of amyloid causing progressive proteinuria. Less than 5% of AL patients present with renal failure requiring dialysis; patients with renal involvement usually present with fatigue, peripheral edema, proteinuria and hypoalbuminemia. The aim of therapy in systemic AL amyloidosis is to reduce the amyloid-forming monoclonal light chains, measured with the serum free light chain assay, by suppressing the underlying plasma cell dyscrasia, while using supportive measures to sustain organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor light chain is eliminated. The most effective treatment for systemic AL is risk-adapted melphalan with peripheral blood stem cell transplant; oral melphalan and dexamethasone is the most effective therapy for patients who are not stem cell transplant candidates although it carries a risk of myelodysplasia and leukemia. Novel therapies currently under study include thalidomide, bortezomib and lenalidomide. With therapy, a majority of patients can achieve long-term durable remissions with stabilization or recovery of organ function. The use of novel antibody-based approaches for imaging amyloid and possibly for accelerating removal of deposits is under active investigation.

Topics: Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Humans; Immunoglobulin Light Chains; Immunologic Factors; Kidney; Kidney Transplantation; Melphalan

Amyloidosis is a rare disease in which a specific protein is deposited as aggregated interstitial fibrils that can compromise organ function and lead to death. Immunoglobulin (Ig) light-chain amyloidosis (AL), caused by the monoclonal gammopathy of a plasma cell dyscrasia, is the most common type. A hereditary type is also caused by mutant transthyretin and other proteins. Rarely, a patient with amyloid has both a monoclonal gammopathy and a hereditary protein. In AL, circulating monoclonal Ig light chains can be measured with the free light-chain (FLC) assay and provide a target for therapy to eliminate the underlying plasma cell dyscrasia while supporting the patient's organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor FLC is eliminated. For patients with limited organ involvement, intravenous melphalan in doses from 100 to 200 mg/m2 with autologous stem cell support (SCT) is an effective approach and, when followed at 3 months post-SCT with adjuvant thalidomide and dexamethasone for persistent plasma cell disease, has a 1-year hematologic response rate of 77%. Monthly oral melphalan and dexamethasone for 1 year can also be effective therapy for patients too sick for SCT (67% response rate). Hematologic complete responses are usually durable and result in long-term survival and a variable degree of organ recovery. For patients with advanced cardiac involvement, the prognosis remains guarded even with treatment. Drugs effective in multiple myeloma are usually active in AL, depending on side effects. New agents such as bortezomib and lenalidomide have shown promising activity, and novel antibody-based approaches for imaging amyloid and accelerating removal of deposits are being actively investigated.

Topics: Amyloidosis; Combined Modality Therapy; Glucocorticoids; Humans; Immunoglobulin Light Chains; Immunosuppressive Agents; Melphalan; Myeloablative Agonists; Organ Transplantation; Paraproteinemias; Stem Cell Transplantation

AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. This review outlines an overview of high-dose intravenous melphalan and stem cell transplantation in the treatment of AL amyloidosis. An algorithm of our recommendations for the treatment of AL amyloidosis is also outlined.

Topics: Algorithms; Amyloidosis; Dose-Response Relationship, Drug; Humans; Melphalan; Myeloablative Agonists; Practice Guidelines as Topic; Stem Cell Transplantation

Renal involvement is common in multiple myeloma. Although several types of renal disease are observed, most of them are considered to be specifically related to monoclonal immunoglobulin light chains. Myeloma cast nephropathy is the most frequent and sometimes associated with acute renal failure. AL amyloidosis and monoclonal immunoglobulin deposit disease are often presented as a nephrotic syndrome. In this review, we describe the pathogenesis and diagnosis of these three renal diseases. We also focus on the treatment of renal disease in multiple myeloma, in the view points of the chemotherapy to reduce M-protein and the prevention to reduce the risks of promoting renal injury.

Topics: Amyloidosis; Biomarkers; Combined Modality Therapy; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Hypergammaglobulinemia; Immunoglobulin Light Chains; Kidney Diseases; Melphalan; Multiple Myeloma; Myeloma Proteins; Plasma Exchange; Prednisolone

Topics: Amyloid; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Dexamethasone; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Remission Induction

Topics: Aged; Amyloidosis; Anti-Inflammatory Agents; Dexamethasone; Diagnosis, Differential; Disease Progression; Early Diagnosis; Fatal Outcome; Female; Heart Failure; Humans; Immunosuppressive Agents; Mass Screening; Melphalan; Myeloablative Agonists; Nurse's Role; Patient Education as Topic; Pleural Effusion; Proteinuria; Rare Diseases; Stem Cell Transplantation; Thalidomide

The optimal treatment of immunoglobulin light chain amyloidosis (AL) patients requires early diagnosis, correct amyloid typing, effective treatment and careful supportive therapy. In the last few years the therapeutic arsenal for the management of AL has been considerably enriched. Cardiac dysfunction can be accurately monitored by measuring the serum concentration of natriuretic peptide type-B and cardiac troponins and the quantitative test for circulating free light chains allows an easy assessment of haematological response to chemotherapy. These new tools can be combined in order to maximise the improvement of organ dysfunction and minimise toxicity, adapting the intervention to each patient.

Topics: Amyloidosis; Dexamethasone; Glucocorticoids; Humans; Immunosuppressive Agents; Melphalan; Myeloablative Agonists; Prednisone; Stem Cell Transplantation; Thalidomide

Primary systemic (AL) amyloidosis is a rare plasma cell disorder characterized by soft-tissue deposition of monoclonal light chain fragments. High-dose melphalan followed by autologous stem cell transplantation currently has become the treatment of choice. Favorable outcome is ensured with achievement of hematologic response, but little is known about organ response. This study was undertaken to determine the prognostic importance of renal response after high-dose melphalan and stem cell transplantation.. All patients with AL amyloidosis who underwent autologous stem cell transplantation between 1996 and December 2002 were selected for study. Renal response is defined as a 50% or greater reduction in proteinuria with less than 25% decline in renal function. Exclusion criteria included pretransplantation dialysis therapy or dialysis dependence posttransplantation, treatment mortality, lack of proteinuria assessment posttransplantation, and baseline proteinuria with protein less than 1 g/d.. Of 105 patients, 47 were excluded for stated reasons. Renal response was achieved in 60.3% of evaluated patients. Proteinuria was reduced by greater than 90% in 37.9% and returned to normal in 15.5%. Median response time was 12 months. Renal response was associated with a greater increase in serum albumin level (P = 0.001), maintenance of renal function (P < 0.001), and better survival (P = 0.0003). Renal responders had better survival regardless of hematologic response (P = 0.01 to 0.05).. Currently, high-dose melphalan followed by stem cell transplantation is the most effective treatment for AL amyloidosis for those who are eligible. Our data show that renal response after high-dose melphalan followed by stem cell transplantation is associated with improved survival. Renal response is an independent marker of treatment success and can be used in cases in which determination of hematologic response is difficult.

Topics: Adult; Aged; Amyloidosis; Cohort Studies; Combined Modality Therapy; Female; Humans; Kidney; Kidney Function Tests; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Proteinuria; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Focal and segmental glomerulosclerosis (FSGS) is a common histological finding in patients with proteinuria. The natural history of the condition varies, and although it may be responsive to therapy, FSGS is an important cause of end-stage renal disease. FSGS can be caused by a variety of conditions, but it has been reported rarely in association with a plasma cell disorder.. Mayo Clinic databases were queried and cross-referenced for FSGS and plasma cell disorders. The diagnoses were confirmed, and relevant clinical and laboratory data were abstracted.. A cohort of 13 patients with "idiopathic" FSGS and a monoclonal plasma cell disorder were identified. Four patients had myeloma, and 9 patients had monoclonal gammopathy of undetermined significance. Patients treated for myeloma experienced improvement in their renal lesion, and the latter relapsed when the myeloma relapsed.. We show that FSGS and plasma cell disorders are temporally and epidemiologically linked. Therapy for the underlying plasma cell disorder can lead to resolution of FSGS. The emerging molecular pathogenesis of both FSGS and myeloma also provides potential mechanisms that link the 2 conditions together. Thus, physicians must rule out a plasma cell proliferative disorder in patients with FSGS before concluding that the renal lesion is idiopathic. Moreover, FSGS may respond favorably after the underlying plasma cell disorder is controlled.

Topics: Aged; Amyloidosis; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cohort Studies; Combined Modality Therapy; Comorbidity; Cytokines; Databases, Factual; Dexamethasone; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunoglobulin Light Chains; Kidney; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Multiple Myeloma; Myeloma Proteins; Paraneoplastic Syndromes; Paraproteinemias; Peripheral Blood Stem Cell Transplantation; Prednisone; Prevalence; Proteinuria; Recurrence; Remission Induction; Retrospective Studies; Time Factors; Vasculitis

Autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Gene Expression Profiling; History, 20th Century; History, 21st Century; Humans; Immunotherapy; Melphalan; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prognosis; Renal Insufficiency; Salvage Therapy; Thalidomide; Transplantation, Autologous; Transplantation, Homologous

Topics: Amyloidosis; Antibodies, Monoclonal; Apolipoproteins; Bence Jones Protein; Colchicine; Combined Modality Therapy; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Hemodiafiltration; Humans; Immunoglobulin Light Chains; Infliximab; Melphalan; Membranes, Artificial; Micropore Filters; Prealbumin; Prednisolone; Renal Dialysis; Serum Amyloid A Protein

Amyloidosis is a rare disease characterized by extracellular protein deposits in various tissues and vital organs of the body, which often leads to severe and debilitating chronic health problems and death. Early recognition of symptoms, prompt diagnosis and treatment, and nursing care are essential in decreasing the morbidity and improving the quality of life of the patient with this disease.

Topics: Amyloidosis; Anti-Inflammatory Agents; Causality; Diagnosis, Differential; Disease Progression; Humans; Incidence; Information Services; Internet; Mass Screening; Melphalan; Nurse's Role; Nursing Assessment; Patient Education as Topic; Prednisone

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Humans; Immunoglobulin Light Chains; Kidney Diseases; Melphalan; Multiple Myeloma; Paraproteinemias; Stem Cell Transplantation

High-dose melphalan with autologous blood stem cell transplantation (SCT) can reverse the disease process in selected patients with primary systemic amyloidosis (AL); however, SCT for AL remains controversial because of the treatment-related mortality in patients with cardiac and multisystem organ involvement. In this review, we briefly discuss recent advances in AL, such as the free light-chain assay and the role of immunoglobulin light-chain variable region germline genes in the disease, and then we discuss the current status of SCT for AL with emphases on patient selection, approaches to stem cell mobilization, and peri-SCT management. It is clear that patients with AL who have advanced amyloid cardiomyopathy or more than 2 major viscera involved with disease are poor candidates for SCT. Therefore, the importance of patient selection cannot be overemphasized, and patients with 1 or 2 involved organs or with early cardiac involvement are usually appropriate candidates for SCT. Because the toxicity of melphalan is dose-related and survival with AL may be age-related, patient age and the extent of organ involvement can provide a basis for patient stratification. We discuss such a risk-adapted approach to melphalan dosing in detail and conclude with a brief overview of current research using SCT to treat patients with AL.

Topics: Amyloidosis; Clinical Trials as Topic; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Risk Assessment; Transplantation, Autologous

Primary amyloidosis is a plasma cell dyscrasia in which insoluble immunoglobulin light chain fragments are produced and polymerize into fibrils that deposit extracellularly, causing visceral organ dysfunction and death. The disorder is rare. Its recognition requires understanding the association between nephrotic syndrome, cardiomyopathy, peripheral neuropathy, and hepatomegaly with amyloidosis. The most important screening test for amyloidosis is immunofixation of the serum and urine to detect a monoclonal immunoglobulin light chain. All patients need the diagnosis confirmed histologically. The least invasive source of tissue for amyloid detection is the subcutaneous fat. The most important prognostic factor is whether there is cardiac involvement, which is best assessed by echocardiography with Doppler studies. Therapies used include oral melphalan/prednisone and high-dose corticosteroids. High-dose chemotherapy followed by stem cell reconstitution seems to provide the highest reported response rates. Transplant is associated with unique morbidities not seen in the transplantation of patients with other hematologic malignancies.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Heart Transplantation; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Prednisone; Prognosis; Survival Rate

Primary or AL amyloidosis results from a plasma cell dyscrasia in which fibrillar light chain protein deposition leads to organ failure and death. Standard treatment for AL amyloidosis has been oral melphalan and prednisone. However, this form of treatment modifies the natural history of this lethal disease only marginally, extending median survival from 13 months following diagnosis to 17 months. At Boston University Medical Center, we have developed treatment protocols using high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT) to treat AL amyloidosis, and we have treated over 200 patients with HDM/SCT during the past six years. This extensive experience has shown that patients with AL amyloidosis, despite multisystem involvement and compromised organ function can tolerate this aggressive form of treatment. Furthermore, HDM/SCT results in durable hematologic responses in a substantial proportion of patients, and such responses are associated with clinical improvement, decreased amyloid-related organ dysfunction, and prolonged survival. However, toxicity from treatment is high (overall peri-transplant mortality, 14%), particularly for those patients with clinically significant cardiac involvement. For this reason, we believe a multidisciplinary management approach is essential when using HDM/SCT for treatment of AL amyloidosis. Based on our experience, we believe that HDM/SCT is the treatment of choice for patients with AL amyloidosis who have a good performance status and limited cardiac involvement at the time of diagnosis. HDM/SCT offers the best chance for hematologic remission, prolongation of survival, and reversal of amyloid-related disease. At the same time, we believe that HDM/SCT should continue to be examined in the context of clinical trials, directed at developing approaches to broaden the applicability of this therapy by minimizing toxicity and to increase the likelihood of complete hematologic responses.

Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Alkylating Agents; Amyloidosis; Boston; Cardiomyopathies; Case Management; Clinical Trials as Topic; Combined Modality Therapy; Factor X Deficiency; Female; Forecasting; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Male; Melphalan; Middle Aged; Multicenter Studies as Topic; Multiple Organ Failure; Nephrotic Syndrome; Patient Care Team; Patient Selection; Pilot Projects; Remission Induction; Renal Dialysis; Survival Analysis; Survival Rate; Transplantation Conditioning; Treatment Outcome

Mucocutaneous involvement occurs predominantly in primary systemic amyloidosis as well as in myeloma-associated systemic amyloidosis. It is rarely observed in other types of amyloidoses. Signs of such involvement may aid in the early diagnosis of the disease process. Herein, we describe a 64-year-old white male patient with myeloma-associated systemic amyloidosis in whom the disease presented with unique cutaneous lesions consisting of chronic paronychia and palmodigital erythematous swelling and induration of the hands. Following weekly regimens with prednisone (20 mg/day) and melphalan (2 mg/day) administered every 16 weeks, almost complete resolution of the cutaneous lesions was observed after 1 year of therapy. Also, in response to chemotherapy, modest regression of the myelomatous bone lesions and complete resolution of the underlying gammopathy occurred.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Chronic Disease; Drug Therapy, Combination; Erythema; Glucocorticoids; Hand Dermatoses; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Paronychia; Prednisone; Recurrence; Time Factors

Primary systemic AL (amyloid light-chain) amyloidosis is a plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure. The prognosis of primary amyloidosis is generally poor, with a median survival of 1-2 years. There is no available treatment which improves impaired organ function by induction of amyloid mobilization. Since amyloidosis is a dynamic process, measures that reduce the supply of the amyloid fibril precursor protein can result in a major regression of the deposits. Conventional-dose melphalan can prolong the median duration of survival from 8.5 to 18 months, but the clinical response rates with improvement of impaired organ function are low and the response is slow. Preliminary data suggest that VAD is effective in AL amyloidosis. Up-front high-dose chemotherapy with autologous peripheral blood stem cell transplantation can result in an improvement of the patient's clinical condition, but the treatment-related toxicity can be high, owing to impaired organ function. The use of VAD followed by high-dose chemotherapy is the concept of a German trial. The improvement of the patient's condition prior to high-dose chemotherapy by induction of a remission with VAD might reduce the transplantation-related morbidity and mortality in amyloidosis.

Topics: Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Dose-Response Relationship, Drug; Humans; Melphalan

Nephrotic syndrome represents a constellation of symptoms including hyperalbuminuria, hypoalbuminemia, edema formation, hypercholesterolemia, hypertension, hypercoagulopathy, and increased infection risk. The hallmark of this syndrome is proteinuria greater than 3.5 grams per 24 hours, and the clinical features are secondary manifestations of an underlying primary glomerular or systemic disease. The objectives of treatment are threefold: correcting the primary disease, decreasing the symptoms and secondary effects associated with this syndrome, and preventing complications. This article presents a case report of a man diagnosed with nephrotic syndrome secondary to amyloidosis. The clinical aspects of the disease processes, the diagnostic evaluation, the treatment course, and disease management are discussed.

Topics: Adult; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Biopsy; Combined Modality Therapy; Diagnosis, Differential; Hematopoietic Stem Cell Transplantation; Humans; Male; Medical History Taking; Melphalan; Nephrotic Syndrome; Physical Examination; Prednisone; Referral and Consultation

Primary (AL, amyloid light-chain) amyloidosis is a plasma cell disorder in which deposits of amyloid light-chain protein cause progressive organ failure. It is important to recognise that amyloidosis is a dynamic process and chemotherapy-induced reduction of the activity of the plasma cell clone reduces the supply of the amyloid precursor protein and can result in a major regression of the deposits. The most common target organ is the kidney and renal amyloidosis manifests as proteinuria or nephrotic syndrome. Proteinuria is seen in three quarters of patients. Amyloid related nephrotic syndrome and renal failure are potentially reversible. Fatigue, congestive heart failure, hepatomegaly, peripheral neuropathy, orthostatic hypotension, carpal tunnel syndrome and macroglossia are other common features. The median survival is one to two years. Conventional-dose melphalan as standard treatment can prolong the median duration of survival by about ten months, but the clinical response rates with improvement of impaired organ function are low. Up-front high-dose chemotherapy with autologous peripheral blood stem cell transplantation is much more effective and can result in a major improvement in the clinical condition of patients. However, the toxicity related to this treatment can be relevant due to impaired organ function. Conventional-dose chemotherapy consisting of vincristine, doxorubicin and dexamethasone or high-dose dexamethasone or interferon-alpha are other possible approaches to treatment. The improvement of patient condition with an effective conventional-dose chemotherapy may increase the tolerability of high-dose chemotherapy and reduce transplantation related problems.

Topics: Amyloidosis; Animals; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Prednisone; Vincristine

AL amyloidosis is a plasma cell disorder characterized by the tissue accumulation of immunoglobulin light chains. The prognosis of AL amyloidosis is poor, with a median survival inferior to two years. Amyloid deposits, responsible for the clinical manifestations of this disease, can regress at least partially after the suppression of the production of amyloid precursors. Therefore, current treatment strategies in AL amyloidosis aim at reducing the plasma cell clones, using chemotherapy regimens applied in multiple myeloma. A combination of melphalan and prednisone is the standard therapy of AL amyloidosis, but its results remain disappointing. Intensive chemotherapy regimens, with high-dose melphalan followed by peripheral blood stem cell transplantation, lead to increased response rates and improved survival, but are complicated by severe short term morbidity and mortality. These regimens offer the best clinical perspectives for selected patients, until the introduction of innovative agents capable of interfering with amyloid fibril formation.

Topics: Amyloid; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Morbidity; Prednisone; Prognosis; Remission Induction; Survival Analysis; Treatment Outcome

Patients with unexplained heart failure, hepatomegaly, nephrotic syndrome, or peripheral neuropathy should be evaluated for primary systemic (amyloid light-chain, or AL) amyloidosis by first seeking evidence of a clonal plasma cell disorder with serum and urine immunofixation studies, as well as a bone marrow biopsy. Immunostaining of the marrow biopsy for lambda and kappa isotypes will usually demonstrate a dominant clonal population of plasma cells if immunofixation studies are negative (less than 10% of cases). Tissue diagnosis of amyloidosis should be sought by biopsy of the abdominal fat or an involved organ. In addition, patients with stable myeloma or monoclonal gammopathy of undetermined significance who develop such conditions or become progressively ill should be evaluated for amyloidosis. We recommend that newly diagnosed patients with AL amyloidosis, who meet criteria for autologous hematopoietic cell transplantation, be considered for high-dose melphalan with stem cell support. Criteria usually include adequate cardiac, pulmonary, and hepatic function. AL amyloidosis patients treated with autologous transplantation frequently achieve durable complete remissions of the plasma cell disease and marked improvement in amyloid-related organ dysfunction. AL amyloidosis patients with dominant cardiac amyloid, who are without symptomatic pleural effusions and have no history of cardiac syncope or symptomatic arrhythmias, may be considered for autologous transplantation but are at increased risk of peritransplant mortality. Autologous transplantation should not routinely be offered to patients with dominant cardiac amyloid with recurrent effusions or histories of syncope or arrhythmias or to patients older than 50 years of age with more than two major organ systems involved (eg, heart, kidneys, liver, and peripheral nerves). We recommend that AL patients with isolated advanced cardiac or hepatic amyloidosis be considered for solid organ replacement followed by autologous transplantation. Otherwise, AL patients who are elderly or ineligible for autologous transplantation may be treated with oral melphalan (Alkeran, GlaxoWellcome, Middlesex, UK) and prednisone; however, because the response rate is only about 25% and the prognosis poor, such patients might also be enrolled on clinical trials of emerging therapies.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Heart Transplantation; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Palliative Care; Prednisone; Prognosis; Survival Rate

Topics: Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma; Prednisolone

Between June 1991 and January 1995 we performed 67 peripheral blood progenitor cell transplants (PBPCT). Ten patients (group 1) were mobilised with 7 gm/m2 of cyclophosphamide followed by daily G-CSF injections (5 micrograms/kg, subcutaneously). When the white cell count reached 1 x 10(9)/1 they were leukapheresed for 5 days. After stem cell infusion they received G-CSF (10 micrograms/kg/day) until the neutrophil count reached 1.5 x 10(9)/1. Fifty-six patients had PBPCs mobilised with 3 gm/m2 of cyclophosphamide followed by daily subcutaneous G-CSF (5 micrograms/kg) and PBPCs were harvested on 2 consecutive days, when the white cell count rose to 4 x 10(9)/1. After stem cell infusion this group did not receive G-CSF. In 47 of the 56 patients (group 2) adequate MNC (> or = 4 x 10(8)/kg) and/or CFU-GM (> or = 10 x 10(4)/kg) were obtained. Insufficient MNC and/or CFU-GM were obtained in 10 patients. They were therefore transplanted using a combination of bone marrow and peripheral blood progenitor cells (group 3). Overall 64 patients successfully engrafted. Median days to neutrophils > or = 0.5 x 10(9)/1 were 9 (range 8-13), 12 (range 8-25) and 11 (range 9-16) and to platelets > or = 50 x 10(9)/1 were 11 (range 9-23), 13 (range 9-90) and 16 (range 13-99) in groups 1, 2 and 3 respectively. Patients in group 1 had a faster neutrophil recovery than patients in group 2 (P = 0.0002). The three patients who failed to engraft all received a combination of autologous peripheral blood and bone marrow cells.

Topics: Adolescent; Adult; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carmustine; Cell Movement; Colony-Forming Units Assay; Cyclophosphamide; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Kidney Diseases; Leukapheresis; Leukocyte Count; Male; Melphalan; Middle Aged; Neoplasms; Podophyllotoxin; Retrospective Studies; Thiotepa; Transplantation Conditioning

Topics: Acute-Phase Reaction; Adult; Aged; Amyloid; Amyloidosis; B-Lymphocytes; Biopsy; Child; Contraindications; Female; Heart Transplantation; Humans; Immunoglobulins; Immunohistochemistry; Joints; Male; Melphalan; Middle Aged; Nervous System; Paraproteinemias; Prednisone; Prognosis; Randomized Controlled Trials as Topic; Renal Replacement Therapy; Skin; Staining and Labeling; Viscera

Topics: Amyloidosis; Colchicine; Dimethyl Sulfoxide; Humans; Melphalan

Amyloidosis is a disease involving the fibrillar deposition of proteins in a manner that uniformly leads to the presence of green birefringence on polarization microscopy after staining the involved tissues with Congo red. In the year summarized, a wide range of new information has accumulated about this disease. In this article, attention has been paid to several newly described proteins now known to precipitate into amyloid deposits, including the proteins transthyretin, apolipoprotein A-1, cystatin C, gelsolin, amyloid beta protein, beta 2-microglobulin, scrapie protein, and islet amyloid polypeptide. The number of these amyloid-related proteins has resulted in the need for a revised nomenclature and classification scheme. The results of a recent international symposium addressing this issue are summarized in table form. The varied clinical manifestations of amyloidosis are described according to organ system, with unusual or unique areas of involvement noted. Finally, the treatment of amyloidosis and its prognosis are addressed, and new areas of possible intervention suggested.

Topics: Amyloid; Amyloidosis; Colchicine; Humans; Melphalan; Prednisone; Prognosis

Topics: Amyloidosis; Colchicine; Dimethyl Sulfoxide; Female; Humans; Melphalan; Middle Aged; Prednisone

Topics: Alkylating Agents; Amyloidosis; Anemia; Anemia, Refractory; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Blood Transfusion; Bone and Bones; Bone Marrow Examination; Bone Marrow Transplantation; Bone Neoplasms; Calcium; Combined Modality Therapy; Diagnosis, Differential; Heavy Chain Disease; Humans; Immunoglobulin D; Immunotherapy; Interferons; Kidney Failure, Chronic; Leukemia; Melphalan; Mice; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Myeloma Proteins; Osteolysis; Osteosclerosis; Paraproteinemias; Plasma Cells; Plasmacytoma; Prednisone; Radionuclide Imaging; Waldenstrom Macroglobulinemia

Topics: Amyloidosis; Chlorambucil; Colchicine; Dimethyl Sulfoxide; Humans; Melphalan

The basic pathologic process in multiple myeloma is the neoplastic proliferation of a single clone of plasma cells. Although the events which trigger autonomous cell growth are not well understood, the secretion of an M component, a serum or urinary immunoglobulin molecule or a light chain fragment by the vast majority of myeloma cells has provided a biologic marker which has greatly facilitated the study of this disease Some of the more recent clinical concepts which have evolved from studies on the plasma cell and the immunoglobulin molecule are discussed.

Topics: Alkylating Agents; Amyloidosis; Bacterial Infections; Blood Viscosity; Bone Diseases; Clone Cells; Hemostasis; Humans; Hypercalcemia; Kidney Failure, Chronic; Melphalan; Multiple Myeloma; Paraproteins

Topics: Amyloid; Amyloidosis; Diagnosis, Differential; Immunoglobulins; Melphalan; Penicillamine; Prognosis

Topics: Amino Acid Sequence; Amyloid; Amyloidosis; Antigen-Antibody Complex; Aspartic Acid; Bence Jones Protein; Bone Neoplasms; Cyclophosphamide; Fluorescent Antibody Technique; Humans; Immunoglobulins; Melphalan; Molecular Weight; Multiple Myeloma; Myeloma Proteins; Peptides; Plasma Cells; Polysaccharides; Ultracentrifugation

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

Topics: Amyloidosis; Arrhythmias, Cardiac; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney Diseases; Melphalan; Transplantation, Autologous

In light of major advances in immunoglobulin light chain (AL) amyloidosis, we evaluated the trends in presentation, management, and outcome among 1551 newly diagnosed AL amyloidosis patients seen in our institution from 2000 to 2014. As compared with the 2 intervals 2000-2004 and 2005-2009, patients diagnosed in 2010-2014 were less likely to have >2 involved organs. Utilization of autologous stem cell transplant (ASCT) was similar across all periods, about one-third of patients, but there was an increase in the use of pre-ASCT bortezomib induction and of unattenuated melphalan conditioning in 2010-2014 compared with earlier periods. Non-ASCT first-line regimen changed with 65% of patients in 2010-2014 received bortezomib-based therapy, 79% of patients in 2005-2009 received melphalan-dexamethasone, and 64% of patients in 2000-2004 received melphalan-prednisone. The rate of better than very good partial response (VGPR) was higher in more recent periods (66% vs 58% vs 51%;

Topics: Aged; Amyloidosis; Autografts; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Humans; Immunoglobulin Light Chains; Induction Chemotherapy; Male; Melphalan; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning

We performed a phase 1 study to evaluate the safety and feasibility of bortezomib (BOR) with melphalan and dexamethasone (BMD) in patients with light chain amyloidosis (AL) without severe cardiac failure. Patients received BOR on a twice-weekly schedule (days 1, 4, 8, and 11 of 28-day treatment cycles) at planned doses of 1.0 (dose level 1) and 1.3 (dose level 2) mg/m(2) in combination with melphalan 8 mg/m(2) on days 1-4 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Dose-limiting toxicity (DLT) was evaluated at the end of cycle one, and treatment was continued for four cycles. Six patients were enrolled at dose level 1, and one showed DLT (grade 3: herpes zoster). Further 3 patients were enrolled at dose level 2, and none experienced DLT. Thus, the maximum tolerated dose was defined as BOR doses of 1.3 mg/m(2) for the twice-weekly schedule. A total of 32 cycles of BMD therapy were given, and the most common hematologic toxicity was thrombocytopenia (47%). Peripheral neuropathy was the most common non-hematologic toxicity (16%). We demonstrated that BMD is safe and tolerable for Japanese AL patients without severe cardiac damage.. UMIN000006604.

Topics: Adult; Aged; Amyloidosis; Bortezomib; Dexamethasone; Drug Administration Schedule; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Recurrence; Treatment Outcome

Cytogenetic aberrations detected by interphase fluorescence in situ hybridization (iFISH) of plasma cells are routinely evaluated as prognostic markers in multiple myeloma. This long-term follow-up study aimed to assess the prognosis of systemic light chain amyloidosis (AL) patients treated with high-dose melphalan (HDM) chemotherapy and autologous stem cell transplantation, depending on iFISH results. Therefore, we analyzed a consecutive cohort of 123 AL patients recruited from 2003 to 2014. HDM was safe, with only 1 of 123 patients dying as a result of treatment-related mortality, and effective, with a complete remission (CR) rate of 34%. Translocation t(11;14) as the most prevalent aberration (59%) led to an improved CR rate after high-dose therapy (41.2% vs 20.0%; P = .02), translating into a prolonged hematologic event-free survival (hemEFS; median, 46.1 vs 28.1 months; P = .05) and a trend for better overall survival (median, not reached vs 93.7 months; P = .07). In multivariate analysis, t(11;14) was confirmed as a favorable prognostic factor regarding hemEFS along with lower values for the difference between involved and uninvolved free light chains. Conversely, deletion 13q14, gain of 1q21, and hyperdiploidy had no significant prognostic impact. The high-risk cytogenetic aberrations t(4;14), t(14;16), and del(17p13) conferred an unfavorable prognosis, although statistical significance was reached only for univariate CR analysis in this small group of 9 patients. Thus, t(11;14) positivity in HDM-treated AL patients conferred superior CR rates and hemEFS. In view of the reduced response of t(11;14) to bortezomib, this highlights the impact of therapy on the prognostic role of cytogenetic aberrations.

Topics: Adult; Aged; Amyloidosis; Autografts; Chromosome Aberrations; Chromosomes, Human; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Remission Induction; Survival Rate

In a prospective multicenter phase II study, we evaluated the effect of three courses of vincristine, doxorubicin and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation on an intention-to-treat basis. Sixty-nine newly diagnosed patients with amyloid light chain amyloidosis were included between November 2000 and January 2006: 37 men and 32 women with a median age of 56 years, including 46% of patients with cardiac and 22% of patients with involvement of 3 or 4 organs. Initial results presented in 2008 showed a 4-year overall survival rate of 62% among all the patients, while the 4-year survival rate after transplantation was 78%. Here we report the long-term follow-up data after a median follow up of 115 months of the patients still alive. Median survival of all patients was 96 months from registration and for the transplanted patients ten years from the date of transplantation. Twelve (12%) patients died during induction therapy with vincristine, doxorubicin and dexamethasone, including 8 patients (12%) due to treatment-related mortality. Two patients died within one month following high-dose melphalan. We conclude that vincristine, doxorubicin and dexamethasone should not be applied as induction therapy for intensification in amyloid light chain amyloidosis. However, a 2-step approach consisting of a non-intensive less toxic induction therapy followed by high-dose melphalan and autologous stem cell transplantation may result in extended survival in newly diagnosed patients with amyloid light chain amyloidosis (clinicaltrials.gov identifier: 01207094).

Topics: Adult; Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Remission Induction; Transplantation, Autologous; Treatment Outcome; Vincristine

Cardiac involvement in light-chain amyloidosis (AL) predicts poor prognosis and is associated with higher TRM and morbidity during high-dose therapy and auto-SCT (HDT-ASCT). We studied the outcomes of 30 patients with cardiac amyloidosis undergoing HDT-ASCT at our center between January 1998 and March 2012. The median age of the patients was 53 years (range, 36-74) with a median follow-up of 35 months (range, 0.4-97 months). Twenty-seven patients (90%) had more than one organ involved besides the heart with 37% with cardiac stage ⩾3. Melphalan-based conditioning regimen (140-200 mg/m(2)) was used for HDT-ASCT. One-year TRM is 10%. Three-year OS and EFS from HDT-ASCT was 83% and 56.8%, respectively. Cumulative incidence of relapse at 3 years was 38.5%. Negative factors affecting survival included age >60 years, lack of novel induction therapy and BM plasmacytosis >10%. We conclude that HDT-ASCT is well tolerated in patients with high-risk cardiac amyloidosis and can lead to improved overall outcomes.

Topics: Adult; Aged; Amyloidosis; Autografts; Disease-Free Survival; Female; Follow-Up Studies; Heart Diseases; Humans; Male; Melphalan; Middle Aged; Myeloablative Agonists; Recurrence; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning

The depth of hematologic response has been shown to correlate with survival and organ responses for patients with light chain (AL) amyloidosis. We conducted a prospective trial of 2 cycles of induction with bortezomib and dexamethasone on a twice a week schedule followed by conditioning with bortezomib and high-dose melphalan (HDM) and autologous stem cell transplantation (SCT). The objectives were hematologic responses, tolerability, and survival. Thirty-five patients were enrolled from 2010 to 2013. Of these, 30 proceeded with SCT, whereas 5 did not because of clinical deterioration during induction (n = 3) or complications after stem cell collection (n = 2). Two patients developed features of an autologous graft-versus-host disease-like syndrome post-SCT, which responded to steroids; no other unusual complications were seen. Treatment-related mortality occurred in 8.5% (3/35). Hematologic responses were achieved by 100% of the 27 assessable patients (63% complete response, 37% very good partial response [VGPR]) who completed the planned treatment. By intention-to-treat, hematologic responses occurred in 77% of patients (49% complete response, 29% VGPR). With a median follow-up of 36 months, the median overall survival and progression-free survival were not reached. In conclusion, incorporating bortezomib into induction and conditioning yielded a high rate of hematologic responses after HDM/SCT in patients with AL amyloidosis.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents; Bortezomib; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Induction Chemotherapy; Male; Melphalan; Middle Aged; Prospective Studies; Survival Analysis; Transplantation Conditioning

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Stem Cell Transplantation

In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.

Topics: Aged; Amyloidosis; Biomarkers; Female; Follow-Up Studies; Heart Diseases; Hematopoietic Stem Cells; Humans; Immunoglobulin Light-chain Amyloidosis; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Proportional Hazards Models; Retrospective Studies; Stem Cell Transplantation; Time Factors; Treatment Outcome; Troponin I

Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low-dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met the criteria for Mayo Clinic cardiac stage III disease. Patients received up to nine cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28-day cycle); melphalan 0.18 mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, and 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. The overall survival rate at 1 year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front-line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high-risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. This trial was registered at www.clinicaltrials.gov (NCT00890552).

Topics: Aged; Aged, 80 and over; Amyloidosis; Cohort Studies; Dexamethasone; Drug Therapy, Combination; Female; Heart Diseases; Humans; Immunoglobulin Light Chains; Lenalidomide; Male; Melphalan; Middle Aged; Pilot Projects; Survival Rate; Thalidomide

We designed a trial using two sequential cycles of modified high-dose melphalan at 100 mg/m(2) and autologous SCT (mHDM/SCT) in AL amyloidosis (light-chain amyloidosis, AL), AL with myeloma (ALM) and host-based high-risk myeloma (hM) patients through SWOG-0115. The primary objective was to evaluate OS. From 2004 to 2010, 93 eligible patients were enrolled at 17 centers in the United States (59 with AL, 9 with ALM and 25 with hM). The median OS for patients with AL and ALM was 68 months and 47 months, respectively, and has not been reached for patients with hM. The median PFS for patients with AL and ALM was 38 months and 16 months, respectively, and has not been reached for patients with hM. The treatment-related mortality (TRM) was 12% (11/93) and was observed only in patients with AL after SCT. Grade 3 and higher non-hematologic adverse events were experienced by 81%, 67% and 57% of patients with AL, ALM and hM, respectively, during the first and second HDM/SCT. This experience demonstrates that with careful selection of patients and use of mHDM for SCT in patients with AL, ALM and hM, even in the setting of a multicenter study, OS can be improved with acceptable TRM and morbidity.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Thalidomide; Transplantation Conditioning; Transplantation, Autologous

To improve the efficacy of risk-adapted melphalan (MEL) in patients with amyloidosis (AL), we conducted a phase II trial using bortezomib and dexamethasone (BD) as consolidation. Forty untreated patients with renal (70%), cardiac (65%), liver/gastrointestinal (15%) or nervous system (13%) AL were assigned MEL 100, 140 or 200 mg/m(2) based on age, renal function and cardiac involvement. Hematological response was assessed at 3 months post stem cell transplant (SCT); patients with less than complete hematological response (CR) received BD consolidation. Four patients with advanced cardiac AL died within 100 days of SCT (10% treatment-related mortality). Survival at 12 and 24 months post treatment start was 88 and 82% overall and was 81 and 72% in patients with cardiac AL. At 3 months post SCT, 45% had ≥ partial response (PR) including 27% CR. Twenty-three patients received consolidation and in 86% response improved; all patients responded in one cycle. At 12 and 24 months, 79 and 60% had ≥ PR, 58 and 40% CR. Organ responses occurred in 55 and 70% at 12 and 24 months. Eight patients relapsed/progressed. One patient with serologic progression had organ impairment at time of progression. In newly diagnosed AL, BD following SCT rapidly and effectively improves responses resulting in high CR rates and maintained organ improvement.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Female; Humans; Male; Melphalan; Middle Aged; Pyrazines; Stem Cell Transplantation

We report results of a phase II trial of combination of melphalan, lenalidomide, and dexamethasone for the treatment of immunoglobulin light chain (AL) amyloidosis. The primary objectives were tolerability and hematologic response rate; secondary objectives were organ responses and survival. Treatment protocol consisted of melphalan 5 mg/m(2)/day for four days, lenalidomide 10 mg/day for 21 days and dexamethasone 20-40 mg once a week every 28 days for a total of 12 cycles. Sixteen subjects were enrolled of whom 14 completed at least 3 cycles and were evaluable for response. Grade 3/4 toxicities were experienced by 88% (n=14), the most common being myelosuppression (n=7). Dose reductions occurred in 85% (n=12 of 14) of subjects. Hematologic partial and complete responses were achieved by 43% (n=6 of 14) and 7% (n=1 of 14), respectively. The median overall survival has not been reached and median progression-free survival is 24 months. In conclusion, this combination is associated with significant myelosuppression leading to dose modifications and producing minor hematologic responses in AL amyloidosis. http://clinicaltrials.gov/ct2/show/NCT00679367.

Topics: Aged; Aged, 80 and over; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease Progression; Female; Humans; Immunoglobulin Light Chains; Lenalidomide; Male; Melphalan; Middle Aged; Thalidomide; Treatment Outcome

Topics: Adolescent; Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Female; Humans; Melphalan; Middle Aged

High-dose melphalan and auto-SCT (HDM/SCT) induces hematological complete responses (HCRs) in 40% of patients with immunoglobulin light chain (AL) amyloidosis. However, relapses occur in 8% of patients who initially achieve HCR. We conducted a study to explore the feasibility and efficacy of a second HDM/SCT in this setting. Eleven patients were enrolled. Five patients underwent repeat stem cell mobilization with G-CSF; the others had stem cells cryopreserved from the first mobilization. Six patients received 200 mg/m(2) HDM; five patients received modified HDM at 140 mg/m(2). Engraftment occurred at a median of 10 days for neutrophils and 12 days for platelets. There was no treatment-related mortality or death within the first year, but significant grade III/IV non-hematological toxicities occurred. In all, 4 of 11 patients (36%) achieved HCR at 1 year. Two of these patients are in continuous remission at 3 and 6 years; the other two relapsed at 2 and 3 years. Of the four patients who achieved partial hematological response at 1 year, three have relapsed at a median of 3 years. Three patients died of progressive disease at 1-2 years. In conclusion, one-third of patients with AL amyloidosis who relapse after HDM/SCT can achieve HCR with a second SCT.

Topics: Adult; Amyloidosis; Cohort Studies; Disease-Free Survival; Female; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Recurrence; Survival Analysis

Topics: Administration, Oral; Amyloidosis; Dexamethasone; Drug Therapy, Combination; Humans; Immunoglobulin Light Chains; Melphalan; Recurrence; Retrospective Studies

Topics: Aged; Amyloidosis; Antineoplastic Agents; Boronic Acids; Bortezomib; Female; Humans; Male; Melphalan; Middle Aged; Myeloablative Agonists; Pilot Projects; Pyrazines; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

New treatment options are required for primary systemic amyloid light chain (AL) amyloidosis. This phase 1/2 dose-escalation study aimed to determine the maximum tolerated dose (MTD) of lenalidomide in combination with melphalan and dexamethasone (M-dex), and assess the efficacy and tolerability of this therapy for patients with de novo AL amyloidosis. Twenty-six patients were enrolled across 4 cohorts: M-dex + lenalidomide 5, 10, 15, and 20 mg once daily on days 1 to 21 in a 28-day cycle. No dose limiting toxicity (DLT) was observed in cohorts 1, 2, and 3. 4. Seven patients in cohort 4, M-dex + lenalidomide 20 mg/day, experienced DLT. MTD was defined as 15 mg of lenalidomide. A complete hematologic response was achieved in 42% at the dose of 15 mg of lenalidomide per day. After a median follow-up of 19 months, estimated 2-year overall survival (OS) and event-free survival (EFS) were 80.8% and 53.8%, respectively. Hematologic and organ responses were both associated with superior EFS rates (P = .0001). A higher EFS was also observed in patients whose free light chains decreased by more than 50% during therapy (P = .019). Lenalidomide 15 mg/d + M-dex is a new effective combination therapy in patients with newly diagnosed AL amyloidosis. This study is registered at www.clinicaltrials.gov as NCT00621400.

Topics: Adult; Aged; Amyloidosis; Anti-Inflammatory Agents; Dexamethasone; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lenalidomide; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Thalidomide

To evaluate the efficiency of chemotherapy with standard doses of melfalan and dexamethazone versus autologous peripheral hemopoietic cell transplantation (auto-PHCT) in patients with AL amyloidosis and to reveal poor prognostic factors.. Of 36 patients diagnosed as having AL-amylodosis, 17 patients underwent auto-PHCT, 11 patients received chemotherapy only; 8 patients died prior to treatment.. In patients with AL-amyloidosis after chemotherapy and autotransplantation, 3-year overall survival was 28 and 64%, respectively. Low somatic ECOG status and cardiac lesion were independent poor prognostic factors of the disease. The number of involved organs failed to affect overall survival.. Auto-PHCT may be proposed as first-line therapy for patients with AL-amyloidosis who have a somatic ECOG score of 0 to 2 and not more than 3 organs involved. Young patients who have a satisfactory somatic status and no benefit from autotransplantation may undergo auto-PHCT. It is expedient to use average-dose melfalan and dexamethasone when treating patients who are ineligible for high-dose chemotherapy.

Topics: Adult; Aged; Amyloidosis; Dexamethasone; Disease-Free Survival; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous

Patients with primary (AL) amyloidosis and heart failure have a very poor prognosis and cannot tolerate aggressive therapy, such as autologous stem cell transplantation and high-dose dexamethasone-based regimens. We prospectively treated 22 patients with advanced cardiac amyloidosis combining oral melphalan, thalidomide, and reduced intensity dexamethasone (MTD). Six patients died due to cardiac amyloidosis before completing cycle 3. Early death was associated with reduced ejection fraction. Eight patients achieved a hematological response and four achieved a durable improvement of cardiac dysfunction. Treatment with MTD is feasible in patients with advanced cardiac AL amyloidosis and effective in subjects with preserved systolic function.

Topics: Aged; Amyloidosis; Dexamethasone; Drug Therapy, Combination; Female; Heart Diseases; Heart Failure; Humans; Male; Melphalan; Middle Aged; Stroke Volume; Survival Rate; Thalidomide; Treatment Outcome

Primary systemic amyloidosis (AL amyloidosis) continues to have a very poor prognosis. Most therapeutic strategies remain unsatisfactory. Conventional chemotherapy is known to offer at best only moderate efficacy. Several studies have yielded higher complete response rates after high-dose chemotherapy and autologous stem cell transplantation (ASCT) in addition to improving outcomes in a subgroup of patients. However, the superiority of an intensive approach in AL amyloidosis has not been confirmed in a randomised trial. The precise role of ASCT remains unclear. We report our experience in 16 patients diagnosed with AL amyloidosis and treated in a multidisciplinary approach with high-dose melphalan and ASCT. Median age was 59 (39-71) years. The kidneys were predominantly affected in 75% of cases; two or more organs were affected in 38%. Median time from diagnosis to transplantation was 2 (1-4) months. Three patients (19%) developed acute renal failure and required transient dialysis. Transplant-related mortality was 6% after 100 days. Haematological complete response (CR) was obtained in nine (56%) and organ response in six (38%) patients. Nine out of 12 patients (75%) with kidney involvement exhibited a sustained clinical benefit at 12 months. Half of all the patients (n = 8) were alive after a median follow-up of 33 months, including two in continuous CR. This suggests that high-dose chemotherapy and ASCT are still valid treatment options in AL amyloidosis and that a significant number of patients with renal involvement might benefit from this approach.

Topics: Adult; Aged; Amyloidosis; Female; Hematopoietic Stem Cell Transplantation; Humans; Kidney Diseases; Male; Melphalan; Middle Aged; Myeloablative Agonists; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome

The treatment of systemic light-chain (AL) amyloidosis with symptomatic cardiac involvement at diagnosis remains a challenge. We report the results of 40 consecutive newly diagnosed AL cardiac patients who were not candidates for stem cell transplant and therefore received monthly oral melphalan and dexamethasone. Median survival was 10.5 months and baseline predictors of survival included gender, troponin I and interventricular septal thickness. The most significant predictor of survival was response to therapy. The haematological response rate was 58% (23/40) with 13% (5/40) complete responses; most responses were noted in <3 cycles. Achievement of a rapid response to therapy extends survival.

Topics: Administration, Oral; Aged; Aged, 80 and over; Amyloidosis; Cardiomyopathies; Contraindications; Dexamethasone; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Prognosis; Sex Factors; Stem Cell Transplantation; Survival Analysis; Treatment Outcome

Clinical outcomes of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation (HDM/SCT) are tightly linked to the achievement of a hematologic complete response (HCR). We conducted a prospective trial to determine whether a second cycle of HDM/SCT could induce HCR in patients in whom the plasma cell dyscrasia persisted following initial treatment with HDM/SCT. Sixty-two patients were enrolled. Nine patients (15%) were removed from the protocol. Of the 53 patients continuing in this study, four died within 100 days of treatment (8%), and 27 (55%) achieved an HCR at 6 months after the first cycle of HDM/SCT. Of the 22 patients who did not achieve an HCR after initial treatment, 17 received a second HDM/SCT, 1 died within 100 days of treatment (6%), while 5 (31%) achieved an HCR. Thus, the HCR rate was 67% (32/48) for surviving patients on study, 60% (32/53) for all patients who received initial cycle of HDM/SCT, and 56% (35/62) by intention-to-treat. The median survival for all patients enrolled on the trial has not yet been reached. Thus, tandem cycles of HDM/SCT can increase the proportion of patients who achieve an HCR.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Patient Dropouts; Prospective Studies; Survival Rate; Transplantation, Autologous; Treatment Outcome

Long-term survival and outcome were determined for 80 patients with immunoglobulin light chain (AL) amyloidosis treated with high-dose melphalan and stem cell transplantation (HDM/SCT) more than 10 years ago. Seventeen (21%) patients died within the first year of treatment, of treatment-related complications (14%) or progressive disease (8%). Of the 63 surviving evaluable patients at one year, 32 (51%) achieved a complete hematologic response (CR). For all 80 patients, the median survival was 57 months (4.75 yrs). The median survival exceeds 10 years for patients achieving a CR after HDM/SCT, compared with 50 months for those not achieving a CR (P < .001). In conclusion, HDM/SCT leads to durable remissions and prolonged survival, particularly for those patients who achieve a hematologic CR.

Topics: Adult; Aged; Amyloidosis; Combined Modality Therapy; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Hypergammaglobulinemia; Immunoglobulin Light Chains; Kaplan-Meier Estimate; Melphalan; Middle Aged; Stem Cell Transplantation; Survivors; Time Factors; Treatment Outcome

High-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation has been reported to provide higher response rates and better overall survival than standard chemotherapy in immunoglobulin-light-chain (AL) amyloidosis, but these two strategies have not been compared in a randomized study.. We conducted a randomized trial comparing high-dose intravenous melphalan followed by autologous hematopoietic stem-cell rescue with standard-dose melphalan plus high-dose dexamethasone in patients with AL amyloidosis. Patients (age range, 18 to 70 years) with newly diagnosed AL amyloidosis were randomly assigned to receive intravenous high-dose melphalan plus autologous stem cells or oral melphalan plus oral high-dose dexamethasone.. Fifty patients were enrolled in each group. The results were analyzed on an intention-to-treat basis, with overall survival as the primary end point. After a median follow-up of 3 years, the estimated median overall survival was 22.2 months in the group assigned to receive high-dose melphalan and 56.9 months in the group assigned to receive melphalan plus high-dose dexamethasone (P=0.04). Among patients with high-risk disease, overall survival was similar in the two groups. Among patients with low-risk disease, there was a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive high-dose melphalan vs. 80% in the group assigned to receive melphalan plus high-dose dexamethasone; P=0.13).. The outcome of treatment of AL amyloidosis with high-dose melphalan plus autologous stem-cell rescue was not superior to the outcome with standard-dose melphalan plus dexamethasone. (ClinicalTrials.gov number, NCT00344526 [ClinicalTrials.gov].).

Topics: Aged; Amyloidosis; Combined Modality Therapy; Dexamethasone; Disease Progression; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Myeloablative Agonists

High-dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment-related mortality (TRM) has historically been high. We performed a phase II trial of risk-adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving < or =2 organ systems were assigned to MEL 100, 140, or 200 mg/m(2) with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post-SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4.4%. Thirty-one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention-to-treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow-up of 31 months, 2-year survival was 84% (95% confidence interval: 73%, 94%). Risk-adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients.

Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Adult; Aged; Amyloidosis; Combined Modality Therapy; Dexamethasone; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myeloablative Agonists; Proportional Hazards Models; Remission Induction; Risk Assessment; Survival Rate; Thalidomide; Transplantation, Autologous

Amyloid light-chain (AL) amyloidosis is a disorder of plasma cells in which depositions of immunoglobulin light-chain fragments cause progressive organ failure and death with a median survival of one year, but autologous stem-cell transplantation can induce high response rates, especially in isolated renal involvement.. Six patients aged between 43 and 59 years were diagnosed with AL-amyloidosis and had stem cells mobilized with either recombinant human granulocyte colony-stimulating factor (rhG-CSF) alone (n = 2) or cyclophosphamide (2-4 g/m(2)) and rhG-CSF (n = 4). All six patients had kidney involvement and nephrotic syndrome, four had cardiac involvement and two involvement of the vascular, nervous and gastrointestinal systems. Five of the patients received high-dose melphalan (200 mg/m(2)) and autologous blood stem-cell support.. One patient died as a result of sepsis after stem-cell mobilization. The other five patients received high-dose melphalan but experienced severe toxicity. One patient died as the result of gastrointestinal perforation on day 6, one presented with hyperfibrinolysis and spontaneous rupture of the spleen, and another experienced severe bleeding of the gastrointestine, tachyarrhythmia and hemolytic anemia. Four patients had acute renal failure: three required hemodialysis and one underwent renal transplant 21 months later. Restaging after a follow-up of 31-52 months revealed reversal of nephrotic syndrome in all three patients who regained adequate renal function. With respect to cardiac involvement (n = 2), one patient showed a decrease in NYHA class from II to I but baseline wall thickness remained stable.. Treatment of selected patients with AL-amyloidosis by high-dose melphalan and stem-cell support results in reversal of amyloid-related disease in a substantial proportion of patients and improved survival.

Topics: Adult; Amyloidosis; Chemotherapy, Adjuvant; Female; Graft Rejection; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Myeloablative Agonists; Transplantation, Autologous; Treatment Outcome

To determine the outcome of high-dose therapy with autologous hematopoietic stem cell transplantation (HSCT) in patients with primary systemic amyloidosis reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).. A total of 107 recipients of autologous HSCT for amyloidosis from 48 transplantation centers were reported to the CIBMTR between 1995 and 2001. Hematologic and organ responses were assessed at 100 days and 1 year. Transplantation-related mortality (TRM) was assessed at day 30 after HSCT. A multivariate analysis assessed factors that influenced overall survival.. Improvement at day 100 was seen in 1 or more amyloidosis-affected sites (bone marrow, kidney, liver, and/or heart) in 28 (36%) of 77 patients; the 1-year responses included complete response (16%), partial response (16%), stable disease (31%), and disease progression (10%). With a median follow-up of 30 months, the 1- and 3-year survival rates were 66% (95% confidence interval [CI], 56%-75%) and 56% (95% CI, 45%-66%), respectively. The day 30 TRM was 18% (95% CI, 11%-26%). In the multivariate analysis, only the year of transplantation (patients who most recently underwent transplantation) was associated with post-HSCT survival (P-.02).. In this multi-institutional CIBMTR study, the 3-year survival rate was comparable to single-center results, with patients who more recently underwent transplantation faring better. Of note, the TRM was higher than that reported by single centers, which may reflect differences in patient selection and/or experience in treating this challenging disease. We hope that a better understanding of the recently recognized prognostic factors and more stringent patient selection will result in lower TRM and improved survival.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; International Cooperation; Kidney; Liver; Male; Melphalan; Middle Aged; Myocardium; Retrospective Studies; Survival Rate; Transplantation, Autologous; Treatment Outcome

Recently, protocols using high-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation (HDM/SCT) have been developed for the treatment of patients with immunoglobulin light chain (AL) amyloidosis. Although peritransplantation mortality is greater than for other hematologic diseases, treatment leads to durable hematologic complete responses, improvements in organ function and quality of life, and extended survival in a substantial proportion of patients. To determine whether this treatment can be applied to older patients, we have analyzed HDM/SCT treatment outcomes for 65 patients (aged 65 years or older) with AL amyloidosis compared with outcomes for 280 younger patients. For patients over age 65 years who meet the same eligibility criteria as younger patients, toxicity, hematologic remission rate, and survival were not significantly different from those observed in younger patients, indicating that older patients should not be excluded a priori from consideration for HDM/SCT treatment.

Topics: Adult; Aged; Aging; Amyloidosis; Antineoplastic Agents, Alkylating; Disease-Free Survival; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Quality of Life; Recovery of Function; Remission Induction; Retrospective Studies; Survival Rate; Transplantation, Autologous

High-dose melphalan followed by stem cell transplantation (HDM-SCT) has become the treatment of choice for patients with immunoglobulin light chain amyloidosis (AL). Unfortunately, treatment mortality can be excessive in certain subpopulations. We have noted that patients who gained more than 2% body weight during mobilization had a poorer outcome following HDM-SCT. Excluding 2 patients for lack of weight record and denial of consent, 126 patients between July 1997 and June 2003 were retrospectively studied. Weight increased more than 2.0% during mobilization in 51.6% of the patients. Patients who accumulated more than 2.0% tended to have more proteinuria, more organs involved, lower serum albumin, more diuretic use, and dosage adjustment during mobilization. First-year mortality was significantly higher in those with more than 2% weight gain (33.9% versus 9.8%, P = .002). Multivariate analysis showed weight gain, glomerular filtration rate, and septal thickness to be independent predictors of first-year mortality. The increase in mortality was noted even after the excess weight was diuresed prior to conditioning. The impact on mortality dissipated after the first year. Weight gain during mobilization appears to be a new marker of adverse outcome following HDM-SCT. Better prognostication may improve the treatment mortality rate of these patients.

Topics: Adult; Aged; Amyloidosis; Biomarkers; Diuresis; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Mobilization; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Multivariate Analysis; Myeloablative Agonists; Prognosis; Retrospective Studies; Stem Cell Transplantation; Water-Electrolyte Imbalance; Weight Gain

A prospective randomized trial was conducted to study the timing of high-dose intravenous melphalan and autologous stem cell transplantation (HDM/SCT) in AL amyloidosis. In all, 100 newly diagnosed patients were randomized to receive HDM/SCT, either as initial therapy (Arm-1) or following two cycles of oral melphalan and prednisone (Arm-2). The objectives of the trial were to compare survival and hematologic and clinical responses. With a median follow-up of 45 months (range 24-70), the overall survival was not significantly different between the two treatment arms (P=0.39). The hematologic response and organ system improvements after treatment did not differ between the two groups. Fewer patients received HDM/SCT in Arm-2 because of disease progression during the oral chemotherapy phase of the study, rendering them ineligible for subsequent high-dose therapy. This affected patients with cardiac involvement particularly, and led to a trend for an early survival disadvantage in Arm-2. Hence, newly diagnosed patients with AL amyloidosis eligible for HDM/SCT did not benefit from initial treatment with oral melphalan and prednisone, and there was a survival disadvantage for patients with cardiac involvement if HDM/SCT was delayed by initial oral chemotherapy.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Female; Heart Diseases; Hematopoietic Stem Cell Transplantation; Humans; Kidney Diseases; Leukapheresis; Male; Melphalan; Middle Aged; Prednisone; Survival Analysis; Transplantation, Autologous; Treatment Outcome

AL amyloidosis is a fatal disease resulting from tissue deposition of amyloid fibrils derived from monoclonal immunoglobulin light chains. Treatment with oral chemotherapy is minimally effective.. To test survival and organ response in a large sample of patients treated with high-dose intravenous melphalan (100 to 200 mg/m2) and autologous blood stem-cell transplantation.. 8-year longitudinal analysis of clinical effectiveness.. University-affiliated specialty referral clinic.. 701 consecutive new patients with AL amyloidosis.. High-dose chemotherapy and autologous stem-cell transplantation for patients who met eligibility requirements based on organ involvement and clinical status.. Survival analysis of all patients evaluated and a detailed analysis of treatment outcome in the subgroup that received high-dose melphalan and stem-cell transplantation.. Among 701 patients with AL amyloidosis, 394 (56%) were eligible for high-dose melphalan and stem-cell transplantation; 82 did not proceed with treatment because of patient choice or disease progression. Median survival of the 312 patients who initiated treatment was 4.6 years. A complete hematologic response, defined as no evidence of an underlying plasma cell dyscrasia 1 year after treatment, was achieved in 40% of patients and was associated with prolonged survival. Statistically significant improvements occurred in end-organ disease and were greater in patients with a complete hematologic response. Mortality rate within 100 days of treatment with high-dose melphalan and stem-cell transplantation was 13%; patients with cardiomyopathy had the highest mortality rates.. Treatment of selected patients with AL amyloidosis by using high-dose melphalan and stem-cell transplantation resulted in hematologic remission, improved 5-year survival, and reversal of amyloid-related disease in a substantial proportion.

Topics: Aged; Amyloidosis; Female; Humans; Longitudinal Studies; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous

The most efficient therapeutic approach for immunoglobulin light chain amyloidosis (AL) is autologous stem cell transplantation (ASCT); however, the toxicity of ASCT limits its feasibility to a minority of patients. Patients ineligible for ASCT are usually treated with standard oral melphalan and prednisone, but the response rate to this regimen is unsatisfactory, and time to response is long. High-dose dexamethasone provides a rapid response time in patients with AL. We evaluated the combination of oral melphalan and high-dose dexamethasone (M-Dex) in 46 patients with AL ineligible for ASCT. Thirty-one (67%) achieved a hematologic response and 15 (33%) a complete remission. In 22 (48%) of the responsive patients functional improvement of the organs involved was observed. Five patients (11%) experienced severe adverse events, 3 required hospitalization, and no treatment-related deaths were observed. M-Dex represents a feasible and effective therapeutic option for patients with advanced AL who are ineligible for ASCT.

Topics: Adult; Aged; Amyloidosis; Contraindications; Dexamethasone; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Male; Melphalan; Middle Aged; Stem Cell Transplantation

Treatment of AL amyloidosis patients with high-dose melphalan chemotherapy followed by autologous peripheral blood stem cell transplantation (HDM/SCT) can produce hematologic complete responses (CRs) and improvement in organ function. To determine whether these responses are accompanied by improvement in quality of life (QOL), we employed the Medical Outcomes Study (MOS) 36-item Short Form General Health Survey (SF-36) questionnaire for 544 patients evaluated between 1994 and 2002. At baseline, the scores were significantly lower on all 8 SF-36 scales compared with age-matched population norms: the composite physical component summary (PCS) for the AL patients was 34.5 versus the population norm of 46.8, and the mental component summary (MCS) was 45.0 versus the norm of 51.5. All SF-36 scores improved at 1 year, with the MCS reaching the population norm. The PCS, though improved, was still lower than normal but was greater in the subgroup of patients who achieved a hematologic CR; the PCS normalized at 2 years in these patients. Thus, treatment of AL amyloidosis patients with HDM/SCT produces measurable and sustained improvements in quality of life, particularly in those patients who achieve hematologic CR.

Topics: Amyloidosis; Follow-Up Studies; Health Surveys; Humans; Melphalan; Middle Aged; Quality of Life; Stem Cell Transplantation; Surveys and Questionnaires; Survival Rate; Treatment Outcome

Stem cell transplantation was introduced as a new therapeutic modality for amyloidosis. The purpose of the current study was to determine the feasibility and toxicity of stem cell transplantation for amyloidosis in a cooperative group setting in which most participating institutions would have limited experience in managing the disorder. A total of 30 patients with biopsy-proven amyloidosis shown to be immunoglobulin light-chain type were enrolled on this trial. The protocol required mobilization of a minimum of 6 x 10(8) mononuclear cells/kg or 5 x 10(6) CD34(+) cells/kg ideal body weight. These targets had to be achieved within seven collections. Patients with advanced hepatic, renal, or cardiac failure were excluded. End points included objective response rate and overall survival. The secondary end point of the protocol was nonhematologic toxicity. Accrual to the study was faster than expected. The overall response rate (hematologic and organ) was 64%, with three treatment-related deaths. Another patient died before day 30 of sudden cardiac death not treatment related. The median follow-up of surviving patients is 30.3 months. Median survival has not been reached. Stem cell transplantation for selected patients with amyloidosis is feasible in a cooperative group setting. A multicenter phase 3 trial of high-dose therapy is indicated.

Topics: Adult; Aged; Amyloidosis; Antigens, CD34; Blood Component Removal; Cause of Death; Female; Hematopoietic Stem Cell Mobilization; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Remission Induction; Survival Rate

Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. With high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III-IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Doxorubicin; Drug Administration Schedule; Female; Hematopoietic Stem Cell Mobilization; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Prospective Studies; Regression Analysis; Remission Induction; Stem Cell Transplantation; Survival Rate; Transplantation, Autologous; Vincristine

Patients with AL amyloidosis were treated with VAD (vincristine, doxorubicin and dexamethasone) with or without high-dose melphalan followed by auto-PBSCT according to eligibility criteria based on disease severity, and prospectively investigated the therapeutic benefits and complications. Thirty-one patients were enrolled in this study. VAD and subsequent high-dose melphalan with auto-PBSCT were performed only in patients who met all of the eligibility criteria. Among patients ineligible for this treatment, VAD alone was performed in those with satisfactory general status. Eleven patients met the eligibility criteria, and of these, 7 were treated with VAD and subsequent high-dose melphalan with auto-PBSCT. Seven patients received VAD alone, and the remaining 17 were treated with the supportive therapy. Among the 14 patients treated with chemotherapy, 9 (5 of the 7 treated with VAD and high-dose melphalan, and 4 of the 7 treated with VAD alone) showed complete hematological response with apparent improvement of amyloidosis-related clinical symptoms. Serious complications of chemotherapy were cytomegalovirus infection and pneumocystis carinii pneumonia seen in 1 and 2 patients, respectively. These chemotherapies may be effective for reduction of M-protein and are also useful in improving of amyloidosis-induced organ dysfunction. In patients who cannot tolerate high-dose melphalan, VAD alone is a potent therapeutic option, although there are possible harmful effects on the heart and peripheral nerve.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents; Dexamethasone; Doxorubicin; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Vincristine

The development of end-stage renal disease (ESRD) is common among patients with amyloid light-chain AL amyloidosis-associated renal disease and survival of these patients is poor. High-dose intravenous melphalan and autologous stem cell transplantation induce remission of the plasma cell dyscrasia in a significant proportion of patients with AL amyloidosis. The efficacy and tolerability of such treatment for patients with AL amyloidosis-associated ESRD are unknown.. Between June 1994 and June 2000, 15 patients with AL amyloidosis-associated ESRD were treated with intravenous melphalan (70 to 200 mg/m2) and autologous peripheral blood stem cell transplantation. Clinical and laboratory data were prospectively collected prior to treatment, during the peritransplant period, and at 3 months, 12 months, and annually thereafter. Treatment outcomes and toxicities were compared with 180 non-ESRD patients treated during the study period.. Eight of 15 patients (53%) had a hematologic complete response following treatment. Two patients (13%) died during the peritransplant period. Transfusion requirements were greater and there was a trend toward increased severity of mucositis in the ESRD patients compared with the non-ESRD patients. Median survival for the ESRD patients with a hematologic complete response was 4.5 years. Five patients with hematologic complete response have either undergone or are awaiting renal transplantation.. High-dose intravenous melphalan with stem cell transplantation is an effective treatment in selected patients with AL amyloidosis-associated ESRD. Although the toxicity profile is greater in ESRD patients, the treatment offers the possibility of successful renal transplantation if hematologic remission is achieved. This treatment should be considered for patients with AL amyloidosis-associated ESRD.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Female; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Melphalan; Middle Aged; Prospective Studies; Remission Induction; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous

This study investigated the response rate and toxicity of blood cell transplantation as treatment for primary amyloidosis (AL). Twenty-three patients had stem cells collected between November 1995 and September 1998. Conditioning included melphalan and total body irradiation in 16 and melphalan alone in 4. Three patients did not undergo stem cell infusion because of poor performance status. Two died of progressive amyloid at 1 and 3 months. One patient is alive on hemodialysis. Fourteen males and six females (median age, 57 years) underwent transplantation. Renal, cardiac (by echocardiography), peripheral neuropathy or liver amyloidosis occurred in 14, 12, 3, and 1, respectively. Echocardiography demonstrated an interventricular septal thickness > or = 15 mm in six patients, five of whom died post transplantation. Three patients died of progressive amyloidosis at 7, 7, and 21 months. Thirteen patients are alive with a follow-up of 3 to 26 months. Twelve (60%) fulfilled the criteria of a hematologic or organ response. Severe gastrointestinal tract toxicity was seen in five (25%). We conclude that blood cell transplantation for amyloidosis had a much higher morbidity and mortality compared with transplantation for myeloma. The best results appear to occur in patients with nephrotic syndrome as the only manifestation of their disease.

Topics: Adult; Aged; Amyloidosis; Arrhythmias, Cardiac; Disease Progression; Female; Follow-Up Studies; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Liver; Male; Melphalan; Middle Aged; Myocardium; Nephrotic Syndrome; Peripheral Nervous System Diseases; Radiation Injuries; Renal Dialysis; Transplantation Conditioning; Treatment Outcome; Whole-Body Irradiation

AL amyloidosis patients ineligible for dose-intensive melphalan (200 mg/m2) were enrolled on a phase 11 trial to be treated with two cycles of intermediate-dose melphalan (IDM 100 mg/m2) and mobilized blood stem cells (BSC). For mobilization patients were randomized to either GM-CSF 250 microg/m2 for 3 d followed by G-CSF 10 microg/ kg for 3 d (GM+G), or G-CSF 10 microg/kg for 6 d (G-alone), with leukaphereses on days 5, 6 and 7. To minimize morbidity, we planned to support each cycle with 3 5 x 106 CD34+ cells/kg and had a collection target of 7 x 10(6) CD34+ cells/kg. Those who did not achieve the target were treated with one cycle of IDM. 30 patients, a median of 62 years old and 7 months from diagnosis, were enrolled. Both mobilization regimens were generally well tolerated, and similar in terms of CD34+ cells and CFU-GM collected, but only 6/28 patients achieved the collection target (GM+G four, G-alone two). Despite a 19% incidence of grade 4 toxicities, IDM therapy was well tolerated. At a median follow-up of 24 months (19-36) 57% of patients had survived, 17% with durable complete haematological responses and 40% with improved or stable amyloid organ involvement, including 3/9 patients with predominant cardiac amyloid who are alive 2-3 years after treatment. The 100 d mortality was 20%. In conclusion, no definitive differences were identified between the mobilization regimens and IDM was an active regimen in AL for selected patients.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Drug Combinations; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Leukapheresis; Male; Melphalan; Middle Aged; Survival Analysis

Primary systemic amyloidosis is an immunoglobulin deposition disorder in which insoluble light chains cause organ dysfunction and death. The established conventional therapy is treatment with melphalan and prednisone. We investigated whether treatment with multiple alkylating agents improved the response rate or survival time, compared with melphalan and prednisone therapy.. We treated 101 patients with biopsy-proven primary amyloidosis. The patients were randomly assigned to receive melphalan and prednisone (52 patients) or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (49 patients). Patients were stratified according to the presence of cardiac involvement, time from diagnosis to randomization, serum beta2-microglobulin level, and whether peripheral neuropathy was the major manifestation of the disease.. The median duration of survival after randomization was 29 months, with no differences in survival time between the two groups. There were 29 patients who fulfilled the response criteria: 15 in the vincristine, carmustine, melphalan, cyclophosphamide, and prednisone arm and 14 in the melphalan and prednisone arm.. Therapy with multiple alkylating agents did not result in a higher response rate or longer survival time, compared with standard melphalan and prednisone treatment in patients with primary systemic amyloidosis.

Topics: Adult; Aged; Aged, 80 and over; Alkylating Agents; Amyloidosis; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Prednisone; Prospective Studies; Survival Rate; Vincristine

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < . 01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

Topics: Adult; Amyloidosis; Antineoplastic Agents, Alkylating; Cohort Studies; Combined Modality Therapy; Erythrocyte Transfusion; Female; Hematopoietic Stem Cell Transplantation; Humans; Kidney; Life Tables; Liver; Male; Melphalan; Middle Aged; Myocardium; Nervous System; Paraproteins; Platelet Transfusion; Prognosis; Recurrence; Severity of Illness Index; Survival Analysis; Transplantation Conditioning; Treatment Outcome

Primary systemic amyloidosis is an uncommon disease characterized by the accumulation in vital organs of a fibrillar protein consisting of monoclonal light chains.. We treated 220 patients with biopsy-proved amyloidosis. The patients were randomly assigned to receive colchicine (72 patients), melphalan and prednisone (77), or melphalan, prednisone, and colchicine (71). They were stratified according to their chief clinical manifestations: renal disease (105 patients), cardiac involvement (46), peripheral neuropathy (19), or other (50).. The median duration of survival after randomization was 8.5 months in the colchicine group, 18 months in the group assigned to melphalan and prednisone, and 17 months in the group assigned to melphalan, prednisone, and colchicine (P<0.001). Among patients who had a reduction in serum or urine monoclonal protein at 12 months, the overall length of survival was 50 months, whereas among those without a reduction at 12 months, the overall length of survival was 36 months (P=0.03). Thirty-four patients (15 percent) survived for five years or longer.. Therapy with melphalan and prednisone results in objective responses and prolonged survival as compared with colchicine in patients with primary amyloidosis.

Topics: Aged; Amyloidosis; Antineoplastic Agents; Cardiomyopathies; Colchicine; Drug Therapy, Combination; Humans; Kidney Diseases; Melphalan; Middle Aged; Prednisone; Prospective Studies; Survival Analysis; Treatment Outcome

A clinical trial designed to test whether treatment with melphalan, prednisone, and colchicine (MPC) is superior to colchicine (C) alone was performed in patients with primary amyloidosis (AL), a nonmalignant plasma cell dyscrasia.. Patients were randomized to MPC or C with stratification according to sex, time from diagnosis to study entry (ie, less than 3 months or 3 to 12 months), and dominant organ system involvement (ie, cardiac, renal, neurologic, or others). Data were gathered monthly from patients, quarterly from physicians, and annually in the Clinical Research Center. One hundred consecutive patients with AL amyloidosis admitted between 1987 and 1992 who met eligibility requirements were treated and followed for a minimum of 18 months. Fifty patients (group A) received daily oral colchicine and 50 patients (group B) received cycles of oral melphalan and prednisone every 6 weeks for 1 year as well as colchicine.. The principal outcome measure was median survival, which was compared in the two treatment groups and in the subgroups. The overall survival of all patients from study entry was 8.4 months. Comparing group A (C) to group B (MPC), the survival was 6.7 months versus 12.2 months (P = 0.087). Both treatment groups had poor survival for patients in the cardiac subgroup, longest survival in the renal group, and significant differences favoring MPC treatment only in patients whose major system manifestations were neurologic (P = 0.037) or other (P = 0.007). Multivariate analysis showed a strongly significant treatment effect (P = 0.003) and improved survival associated with not having cardiac or gastrointestinal involvement.. MPC was advantageous for patients whose major manifestations of amyloid disease were other than cardiac or renal. Better survival regardless of treatment was noted in patients for whom a satisfactory supportive treatment such as transplant or dialysis exists for their organ failure.

Topics: Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Cause of Death; Colchicine; Drug Therapy, Combination; Female; Gout Suppressants; Humans; Male; Melphalan; Middle Aged; Prednisone; Survival Analysis; Treatment Outcome

Between June 1991 and January 1995 we performed 67 peripheral blood progenitor cell transplants (PBPCT). Ten patients (group 1) were mobilised with 7 gm/m2 of cyclophosphamide followed by daily G-CSF injections (5 micrograms/kg, subcutaneously). When the white cell count reached 1 x 10(9)/1 they were leukapheresed for 5 days. After stem cell infusion they received G-CSF (10 micrograms/kg/day) until the neutrophil count reached 1.5 x 10(9)/1. Fifty-six patients had PBPCs mobilised with 3 gm/m2 of cyclophosphamide followed by daily subcutaneous G-CSF (5 micrograms/kg) and PBPCs were harvested on 2 consecutive days, when the white cell count rose to 4 x 10(9)/1. After stem cell infusion this group did not receive G-CSF. In 47 of the 56 patients (group 2) adequate MNC (> or = 4 x 10(8)/kg) and/or CFU-GM (> or = 10 x 10(4)/kg) were obtained. Insufficient MNC and/or CFU-GM were obtained in 10 patients. They were therefore transplanted using a combination of bone marrow and peripheral blood progenitor cells (group 3). Overall 64 patients successfully engrafted. Median days to neutrophils > or = 0.5 x 10(9)/1 were 9 (range 8-13), 12 (range 8-25) and 11 (range 9-16) and to platelets > or = 50 x 10(9)/1 were 11 (range 9-23), 13 (range 9-90) and 16 (range 13-99) in groups 1, 2 and 3 respectively. Patients in group 1 had a faster neutrophil recovery than patients in group 2 (P = 0.0002). The three patients who failed to engraft all received a combination of autologous peripheral blood and bone marrow cells.

Topics: Adolescent; Adult; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carmustine; Cell Movement; Colony-Forming Units Assay; Cyclophosphamide; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Kidney Diseases; Leukapheresis; Leukocyte Count; Male; Melphalan; Middle Aged; Neoplasms; Podophyllotoxin; Retrospective Studies; Thiotepa; Transplantation Conditioning

The morbidity and lethality of AL amyloidosis is caused by the deposition of lg light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 to 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum lgs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor-mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 to 53 years were treated. Median performance status (SWOG) was 2 (1 to 3), and clinical presentations included nephrotic syndrome (n = 1), symptomatic cardiomyopathy (n = 1), gastrointestinal involvement with polyneuropathy (n = 2), and hepatomegaly (n = 1). With a median follow-up of 13 months (12 to 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In 3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment.

Topics: Adult; Amyloidosis; Cardiomyopathies; Feasibility Studies; Female; Follow-Up Studies; Gastrointestinal Diseases; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hepatomegaly; Humans; Karnofsky Performance Status; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Neutropenia; Peripheral Nervous System Diseases; Prednisone; Remission Induction; Treatment Outcome

Primary systemic amyloidosis (AL) is a rare disorder characterized by production of an aberrant monoclonal light chain. This insoluble light chain, or a fragment thereof, deposits in tissues as amyloid and results in disruption of organ function and, ultimately, death. Although melphalan and prednisone were reported to benefit subsets of patients with the disease, many patients showed no benefit; the median survival with the disease is approximately 2 years. There is a need to develop new agents for patients who fail to respond to a trial of cytotoxic chemotherapy. A study was undertaken of interferon alfa-2 in the treatment of 15 patients with AL because of its reported benefits in the induction and maintenance therapy for patients with multiple myeloma, a disease that has many characteristics in common with AL. None of the patients showed any objective regression of their disease; the median survival of the entire group was 26.3 months. This survival is not superior to that reported with other agents used for this disease. We conclude that interferon alpha-2 is not a valuable agent in the treatment of AL.

Topics: Adult; Aged; Amyloidosis; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Prednisone; Recombinant Proteins; Survival Rate

This is the first prospectively randomized study of the use of melphalan/prednisone and colchicine in the treatment of primary systemic amyloidosis. One hundred one patients were stratified according to their dominant clinical manifestation. Forty-nine patients initially received melphalan/prednisone and eight subsequently had colchicine added to their regimen. Fifty-two patients initially received colchicine and 35 subsequently required melphalan/prednisone because of progressive disease. There was no difference in survival when the two groups were analyzed in aggregate (melphalan/prednisone, 25.2 months versus colchicine, 18 months; p = 0.23). When the survival of patients receiving only one regimen was analyzed or when survival was analyzed from the time of entry into the study to the time of death or progression of disease, significant differences (p less than 0.001 and p less than 0.0001, respectively) were evident, favoring melphalan/prednisone. This study suggests that melphalan/prednisone is superior to colchicine in the treatment of primary amyloidosis, but to confirm this impression, a study without a crossover group is necessary.

Topics: Amyloidosis; Colchicine; Drug Therapy, Combination; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Prednisone; Prospective Studies; Random Allocation; Risk

Satisfactory treatment for primary amyloidosis does not exist. Because the amyloid fibrils consist of a portion of a monoclonal light chain, it appears reasonable to treat amyloidosis with alkylating agents that are effective against the plasma cells that synthesize monoclonal light chains. Fifty-five patients with primary systemic amyloidosis were randomized (double blind) to melphalan-prednisone or placebo. In comparison with the placebo group, patients given melphalan-prednisone were able to continue on treatment for a longer time and to receive larger doses before the code was broken. Among this group, the nephrotic syndrome disappeared in two patients and urinary excretion of protein was reduced by more than 50% in eight others. Of 13 patients who received melphalan-prednisone for more than 12 mo, 6 improved, 3 were stable, and 4 had progression of disease. Survival did not differ significantly between the groups.

Topics: Alkaline Phosphatase; Amyloidosis; Blood Coagulation; Clinical Trials as Topic; Creatinine; Double-Blind Method; Drug Therapy, Combination; Humans; Immunoelectrophoresis; Melphalan; Placebos; Prednisone; Proteinuria

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

Systemic light chains is the most common systemic amyloidosis. In patients with AL amyloidosis, the prognosis is influenced by the extent of organ damage, especially cardiac involvement. Autologous stem cell transplantation (ASCT) is a highly effective treatment for AL amyloidosis for selective patient METHODS: One hundred patients treated with ASCT for AL amyloidosis were reviewed in the Samsung Medical Center amyloidosis cohort. The cardiac, renal, and hematologic response was analyzed, and survival results compared based on organ involvement and hematologic response.. The most common involved organ was kidney (n = 62) followed by heart (n = 50). The organ response rate was 44.0% and 37.1% in the patients with cardiac and renal involvement, respectively. In hematologic response, overall response rate (ORR) was 79.0%, including 48.0% complete response (CR). Median overall survival (OS) in patients with and without hematologic CR were not reached and 64.2 months (95% CI, 19.5 to 109.0), respectively (P < .001). The survival rate was not significantly different between patients with or without cardiac or renal involvement. Treatment-related mortality (TRM) in 30 days and 100 days was 2.0% and 3.0%, respectively.. ASCT is an effective treatment option for eligible patients with AL amyloidosis. Achieving hematologic CR is essential for long-term survival.

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Republic of Korea; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

Amyloid light chain (AL) amyloidosis is a rare hematologic disease that may involve multiple organs. Amongst the organs, cardiac involvement causes the greatest concern as its treatment is challenging. Diastolic dysfunction rapidly progresses to decompensated heart failure, pulseless electrical activity, and atrial standstill due to electro-mechanical dissociation resulting in death. High-dose melphalan plus autologous stem cell transplantation (HDM-ASCT) is the most radical treatment but its risk is very high and thus only less than 20% of patients can receive this therapy under criteria that can suppress treatment-related mortality. In substantial proportion of patients, levels of M protein remain elevated, and organ response cannot be achieved. Moreover, relapse may occur, making prediction of treatment response and judgement of disease eradication very difficult. Herein we report a case of AL amyloidosis who was treated with HDM-ASCT, resulting in preserved cardiac function and resolution of proteinuria for more than 17 years after HDM-ASCT ensuing atrial fibrillation and complete atrioventricular block required management by catheter ablation and pacemaker implantation 10 years and 12 years after transplantation, respectively.

Topics: Amyloidosis; Atrial Fibrillation; Atrioventricular Block; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Neoplasm Recurrence, Local; Transplantation, Autologous

Topics: Amyloidosis; Benchmarking; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Stem Cell Transplantation; Transplantation, Autologous

AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA).

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Neoplasm Recurrence, Local; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

Objective High-dose melphalan and autologous stem cell transplantation (ASCT) therapy for AL amyloidosis are now associated with reduced mortality based on the application of strict criteria. However, there is no long-term evidence concerning the performance of induction therapy with newer agents, such as bortezomib or daratumumab. Concerns regarding long-term relapse despite treatment with ASCT exist, and missing the opportunity to perform ASCT might occur if induction proves to not be efficacious and cardiac amyloidosis progression deprives the patients of a chance to receive ASCT. We herein report good amyloid control by vincristine, doxorubicin, and dexamethasone (VAD) induction therapy and argue the importance of induction therapy before ASCT. Methods We compared patients who underwent VAD induction and ASCT (VAD+ASCT) with patients who underwent frontline ASCT in our hospital. Patients A total of 26 patients with histologically proven AL amyloidosis were included (18 in the VAD+ASCT group and 8 in the frontline ASCT). Results In the VAD+ASCT group, the 10-year overall survival and renal response rates were 82% and 43%, respectively. The renal response rate at two years in the VAD+ASCT group was significantly better than that in the frontline ASCT group. Although there was no significant difference in the survival rates between the two groups, the time to next treatment or death was significantly better in the VAD+ASCT group than in the the frontline ASCT group. Acute kidney injury was the most frequent reason for failure to receive two courses of VAD, and early mortality was mainly due to gastrointestinal complications. Conclusion Considering that only those who underwent 2 courses of VAD experienced a 10-year renal response, induction therapy was deemed to be directly related to the long-term control of AL amyloidosis.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Neoplasm Recurrence, Local; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous; Vincristine

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Longitudinal Studies; Melphalan; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

Immunoglobulin light chain (AL) amyloidosis is a rare disease. Treatment is challenging, justified in part by systemic compromise and limited scientific evidence.. Develop evidencebased recommendations that allow adequate treatment of patients with amyloidosis AL.. A list of PICO format questions focused on the effectiveness and safety of amyloidosis AL treatment was generated. PubMed, Cochrane and Epistemonikos were searched. The levels of evidence and grades of recommendation were based on the GRADE system.. 11 recommendations were generated. In selected patients with amyloidosis AL, autologous hematopoietic stem cell transplantation (ASCT) is recommended after induction with bortezomibbased regimens and conditioning with melphalan, since it could deepen the hematological and organ response, its durability and improve survival. In patients not eligible for ASCT, first-line treatment with bortezomib-based regimens is recommended, since it is likely to achieve a higher rate of hematological and organ response and improve survival. In patients with a contraindication or inaccessibility to bortezomib, treatment with alkylating agents and corticosteroids is recommended, since they are likely to achieve haematological and organ response and improve survival.. These treatment recommendations are based on the available evidence and the experience of the panel of experts, in a scenario of limited available resources, according to developing countries.. Introducción: La amiloidosis por cadenas livianas de inmunoglobulinas (AL) es una enfermedad poco frecuente. El tratamiento implica un desafío, justificado en parte por el compromiso sistémico y la evidencia científica escasa. Objetivos: Elaborar recomendaciones basadas en la evidencia que permitan realizar un adecuado tratamiento de pacientes con amiloidosis AL. Métodos: Se generó un listado de preguntas con formato PICO centradas en la efectividad y seguridad del tratamiento de la amiloidosis AL. Se realizó la búsqueda en PubMed, Cochrane y Epistemonikos. Los niveles de evidencia y los grados de recomendación se basaron en el sistema GRADE. Resultados: Se generaron 11 recomendaciones. En pacientes con amiloidosis AL seleccionados, se recomienda el trasplante autólogo de células progenitoras hematopoyéticas (TCPH) posterior a una inducción con esquemas basados en bortezomib y el acondicionamiento con melfalán, ya que podría profundizar la respuesta hematológica, de órgano, su durabilidad y mejorar la supervivencia. En pacientes no elegibles para TCPH, se recomienda el tratamiento de primera línea con esquemas basados en bortezomib, dado que es probable que logre mayor tasa de respuesta hematológica, de órgano y mejore la supervivencia. En pacientes con contraindicación o inaccesibilidad al bortezomib, se recomienda el tratamiento con agentes alquilantes y corticoides, dado que es probable que logren la respuesta hematológica, de órgano y mejoren la supervivencia. Discusión: Estas recomendaciones de tratamiento se basan en la evidencia disponible y la experiencia del panel de expertos, en un escenario de recursos disponibles limitados, acorde a los países en vías de desarrollo.

Topics: Amyloidosis; Bortezomib; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Transplantation, Autologous; Treatment Outcome

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m

Topics: Aged; Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Transplantation, Autologous

Cardiac light chain (AL) amyloidosis is a condition with a very poor prognosis. We report a retrospective analysis comparing the traditional melphalan and dexamethasone protocol with cyclophosphamide, bortezomib and dexamethasone in late-stage cardiac AL amyloidosis. The primary end points were overall survival and haematological response. Both regimens provided meaningful responses in this difficult to treat patient group.

Topics: Amyloidosis; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Retrospective Studies

Acute kidney injury (AKI) is a common complication after high-dose melphalan and autologous stem cell transplantation (HDM/SCT) in patients with light chain (AL) amyloidosis. However, its incidence, predictors and outcomes are not well known.. This observational study included 223 patients with AL amyloidosis who underwent HDM/SCT. AKI was defined as an increase in serum creatinine to ≥1.5 times the baseline occurring within the first 30 days of HDM/SCT.. The median age was 58 years (range: 30-77). Kidney and cardiac involvement were present in 86.1% and 56.8%, respectively. The median estimated glomerular filtration rate (eGFR) was 83.5 mL/min/1.73 m2 (range: 9-213) and proteinuria was 2899 mg/day (range: 0-19 966). AKI occurred in 29.1% of patients. Dialysis was initiated in 15 patients (6.7%) and of these 12 (80%) were able to discontinue dialysis. Most of the episodes of AKI occurred within the first 2 weeks; with a median follow-up of 4.5 years (range: 0.1-16.5), AKI was associated with increased overall mortality [hazard rato (HR) = 4.53, 95% confidence interval (CI) 2-10.23]. The 10-year overall survival was 87.1% without AKI, versus 56.9% with AKI. AKI was also associated with an increased risk for end-stage kidney disease (ESKD) (HR = 4.6, 95% CI 1.44-14.38). The risk of developing ESKD at 10 years was 18.9% with AKI, versus 8.1% without AKI. Several risk factors were found and using multivariate logistic regression, a prediction model was developed that included three readily available variables: eGFR <60 mL/min/1.73 m2, interventricular septal thickness in diastole >12 mm and albumin <3 g/dL. This model was able to predict AKI development with an area under the curve of 0.8.. AKI is common in the post-HDM/SCT period and it leads to increased risk for ESKD and death. Our prediction model is an easily deployable tool in clinical settings as part of the discussion with patients who are being prepared for HDM/SCT.

Topics: Acute Kidney Injury; Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney Failure, Chronic; Melphalan; Middle Aged; Renal Dialysis; Retrospective Studies; Risk Factors; Transplantation, Autologous

Systemic AL amyloidosis is a disease wherein amyloid proteins derived from monoclonal immunoglobulin light chains produced by abnormal plasma cells are deposited in the tissues through the whole body and cause organ failure. The treatment aims to minimize treatment-related toxicity and mortality to achieve a deeper and more persistent hematologic response as early as possible. Stem cell transplantation is preferred; however, only 20% of patients are eligible. Patients are selected as per strict transplant indication criteria. Transplant-ineligible patients receive chemotherapy with high efficacy, such as melphalan/dexamethasone, bortezomib/cyclophosphamide/dexamethasone, and daratumumab/bortezomib/cyclophosphamide/dexamethasone. The prognosis of advanced cardiac amyloidosis remains poor, and delays in diagnosis are fatal. Early diagnosis and early treatment are important to prevent and minimize organ damage.

Topics: Amyloidosis; Bortezomib; Dexamethasone; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Melphalan

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

The goal of therapy in AL amyloidosis is to inhibit further production of the amyloidogenic light chains, thereby allowing organ recovery and improving survival. We aimed to assess the impact of depth of hematologic response prior to ASCT on survival. We conducted a retrospective study of 128 newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic. The overall response rate to induction was 86% (CR 18%, VGPR 31% and PR 38%). With a median follow up of 52 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 34.1 months for patients achieving PR or less (P = 0.0009). The median OS was longer in patients with deeper responses (not reached for ≥VGPR vs. 128 months for PR or less (P = 0.02)). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR = 0.42; P = 0.036) and depth of response prior to transplant (RR 0.37; P = 0.0295). Hematologic response prior to transplant predicts improved post transplant outcomes in AL amyloidosis.

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

A 57-year-old man was admitted to hospital with diarrhea for 10 months and dizziness for 4 months. The patient had 1-2 liters watery stool per day, without pyogenic blood or abnormality in gastroenteroscopy examination. The level of hemoglobin and albumin was generally normal, and fasting test was positive. At the same time, he was accompanied with hyperalgesia of lower limbs and orthostatic hypotension. After the discussion of multiple disciplinary teams, the patient was diagnosed with amyloidosis by sural nerve biopsy, myocardial MRI, and the assays of urine immunoelectrophoresis and serum free light chain. Light chain amyloidosis was confirmed after excluded the diagnosis of familial amyloidosis. The patient was improved after courses of chemotherapy with melphalan and dexamethasone.. 患者男，57岁，因腹泻10个月，头晕4个月入院。患者每天1~2 L水样便，不含脓血，禁食试验阳性，胃肠镜检查无异常发现，血红蛋白及白蛋白大致正常；同时伴有双下肢感觉异常以及显著的直立性低血压症状。既往有多年的血糖异常及长期大量饮酒史。入院后经多科讨论，通过腓肠神经活检找到了淀粉样变的证据，并结合尿免疫固定电泳、血清游离轻链及心肌核磁检查，确诊为轻链型淀粉样变。予马法兰联合地塞米松化疗后病情缓解。.

Topics: Amyloidosis; Diarrhea; Humans; Hypotension, Orthostatic; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged

Topics: Amyloidosis; Bortezomib; Dexamethasone; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Melphalan; Standard of Care

Topics: Aged; Amyloidosis; Antineoplastic Agents; Bortezomib; Cyclophosphamide; Dexamethasone; Erythema; Female; Heart Failure; Humans; Melphalan; Monoclonal Gammopathy of Undetermined Significance

Cardiac deposition of misfolded light chains is the leading cause of morbidity and mortality in patients with immunoglobulin (AL) amyloidosis. Cardiac defibrillators can be used in the management of patients with advanced cardiac amyloidosis, but data concerning the use of these devices in patients undergoing treatment with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT) is limited. Herein we describe a single-institution experience of HDM/SCT in 15 patients with cardiac defibrillators. During the peri-transplant period, five of these patients (33%) had detectable cardiac arrhythmias and two patients (13%) had implantable cardiac defibrillator (ICD) discharges. Thirteen of the 14 evaluable patients (93%) achieved at least a partial hematologic response. Transplant-related mortality was 6.7% and median overall survival was 40.8 months, with multiple patients achieving an overall survival of >10 years. These data highlight the feasibility of HDM/SCT in patients with an ICD due to advanced cardiac AL amyloidosis, but highlight the need for additional research to appropriately determine which patients will benefit from this aggressive therapy.

Topics: Adult; Amyloidosis; Antineoplastic Agents, Alkylating; Defibrillators; Female; Heart; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation

Topics: Aged; Amyloidosis; Biomarkers; Female; Humans; Male; Melphalan; Middle Aged; Stem Cell Transplantation

Topics: Amyloidosis; Bortezomib; Female; Humans; Immunoglobulin Light Chains; Macroglossia; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prednisolone

Topics: Adult; Aged; Amyloidosis; Dexamethasone; Drug Combinations; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

Autologous stem cell transplantation (ASCT) is an important treatment modality in light chain (AL) amyloidosis. Use of reduced-dose melphalan conditioning is common, given the associated organ and functional decline. The impact of full-intensity melphalan conditioning (n=314) was compared to reduced-dose conditioning (n=143). Patients in the full-intensity group were younger, with better performance status, fewer involved organs, lower tumor burden and lower Mayo stage. Full-dose conditioning was associated with higher rate of very good partial response or better (79% vs 62%; P<0.001), complete response rate (53% vs 37%; P=0.003) and organ response rate (74% vs 59%; P=0.002) as compared to reduced-dose conditioning. PFS was superior in the full-intensity group compared to the reduced-dose group (4-year PFS 55% vs 31%; P<0.001) as well as a longer overall survival (OS) 4-year OS (86% vs 54%; P<0.001). In addition, the OS and PFS were significantly lower in the reduced-dose group compared to the full-intensity group in Mayo stage III/IV as well as stage I/II. A multivariate analysis confirmed an independent impact for conditioning dose on PFS/OS. This study calls for re-assessment of the use of reduced-dose conditioning in ASCT for AL amyloidosis.

Topics: Aged; Amyloidosis; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Remission Induction; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Topics: Aged; Amyloidosis; Female; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Male; Massachusetts; Melphalan; Middle Aged; Myeloablative Agonists; Psychometrics; Quality of Life; Retrospective Studies; Stem Cell Transplantation; Treatment Outcome

Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with

Topics: Amyloidosis; Bortezomib; Consolidation Chemotherapy; Disease-Free Survival; Follow-Up Studies; Humans; Immunoglobulin Light Chains; Melphalan; Middle Aged; Remission Induction; Retrospective Studies; Risk Adjustment; Stem Cell Transplantation; Survival Rate

Bortezomib-dexamethasone (BD) and high-dose melphalan (HDM) are effective for systemic light-chain (AL) amyloidosis, but have not been compared in detail. We retrospectively investigated patients treated with BD or HDM at our center between September 2001 and June 2016. Among 234 patients, 20 were treated with BD and 30 received HDM. With the exception of age, transplant eligibility, and previous history of other chemotherapy, there were no significant differences in most background parameters between the two groups. Median age was higher (63.2 vs. 55.8, P = 0.001), number of transplant-eligible patients was lower (60.0 vs. 96.7%, P = 0.002), and number of previously treated patients was higher (35.0 vs. 0.0%, P < 0.001) in the BD group. The BD group showed trends toward lower treatment-related mortality (5.0 vs. 10.0%, P = 0.641), greater hematological response (partial response or better) (90.0 vs. 73.3%, P = 0.279), higher complete response (60 vs. 50%, P = 0.487), and similar survival with the HDM group (neither reached, P = 0.705). In conclusion, BD was as effective and safe as HDM. Notably, BD achieved this outcome among patients with poorer clinical backgrounds compared with HDM.

Topics: Amyloidosis; Asian People; Bortezomib; Dexamethasone; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Middle Aged; Remission Induction; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Amyloidosis; Creatinine; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Kidney; Melphalan; Transplantation, Autologous

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Bortezomib; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Retrospective Studies; Transplantation, Autologous; Treatment Outcome

We report our retrospective analysis of 40 patients who received high-dose melphalan and autologous stem cell transplantation for systemic immunoglobulin light-chain (AL) amyloidosis. Between 2006 and 2013, 40 patients with AL amyloidosis were transplanted at our medical center. Their median age was 54 years (range 32-70 years): 18 were male. The dominant organs involved were the heart in 13 patients, and kidney in 22: and other organs were involved in five. The median melphalan dose administered was 129 (range 50-200) mg/m(2), and the median infused CD34(+) cells was 2.69 (range 1.17-11.26) × 10(6)/kg. Of the 40 patients, 30 are alive after a median follow-up of 42 (range 12-94) months, and the 4-year estimated overall survival rate was 74% (95% CI 56-86%). Four patients died ≤ 100 days post-ASCT (heart failure in three patients, bacteremia in one). The 4-year estimated survival of the patients with cardiac involvement was 54%, significantly lower than that of the other patients (91%). Hematological and organ responses were 52 and 50%, respectively. Careful patient selection and experienced management are important, especially for patients with cardiac involvement. It is also important to develop additional treatment for patients who do not achieve a hematological and/or organ response.

Topics: Adult; Aged; Amyloidosis; Cardiomyopathies; Cohort Studies; Female; Follow-Up Studies; Humans; Immunoglobulin Light Chains; Kidney Diseases; Male; Melphalan; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Transplantation, Autologous; Treatment Outcome

Hematologic response criteria in light chain (AL) amyloidosis were updated in 2012 to incorporate free light chain responses. These criteria have been validated in autologous hematopoietic cell transplantation in AL at 6 and 12 months after transplantation. Using a transplantation registry, we assessed day 100 responses in AL amyloidosis. We validate the prognostic significance of the new criteria at this time point. Further, we show that patients who do not achieve at least a very good partial response by this time point have equally worse outcomes, regardless of depth of response (partial versus no response). Thus, we conclude that the new criteria help identify the poor responders by day 100 after transplantation and that this subset of patients should be studied for early evaluation in consolidation trials.

Topics: Adult; Aged; Amyloidosis; Biomarkers; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Myeloablative Agonists; Prognosis; Registries; Risk Assessment; Survival Analysis; Transplantation, Autologous; Treatment Outcome

Amyloid light-chain (AL) amyloidosis is a disease caused by tissue deposition of light-chain proteins in vital organs that results in progressive organ damage. We analyzed the clinical characteristics of 123 AL amyloidosis patients and performed an overall survival (OS) analysis to identify critical baseline factors.. Patients (median age, 54 years) were diagnosed with organ involvement of kidney (98.4%), gastrointestinal (73%), cardiac (56%), liver (13%), or nervous system (10%), and multiorgan involvement was observed in 91% of patients. Treatment regimens of transplantation, bortezomib plus dexamethasone, melphalan plus dexamethasone, and prednisone-based regimens or no treatment resulted in 3-year OS rates of 72%, 60%, 55%, and 41%, respectively.. Median OS was 38 months and was affected by age (≥ 65 years), hypoalbuminemia, renal failure, heart involvement, and organ response time (within 3 months). Multivariate analysis indicated that these were independent prognostic factors on OS except for age.. The AL amyloidosis patients in this study presented somewhat different features and outcomes compared to others, with younger age and higher rates of organ involvement.

Topics: Adult; Aged; Aged, 80 and over; Amyloid; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Asian People; Bortezomib; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Prednisone; Retrospective Studies; Transplantation Conditioning; Treatment Outcome

To explore the feature of primary light chain amyloidosis patients treated with high-dose melphalan with auto peripheral blood stem cell transplantation (auto-PBSCT) and bortezomib plus dexamethasone (VD).. Thirty-eight patients diagnosed from September 2004 to September 2012 were analyzed retrospectively, including 15 cases received auto-PBSCT, 23 cases exposed with VD.. The median follow-up duration for the patients was 34 months (range, 1-112 months), including auto-PBSCT group of 38 months (range, 5-112 months) and VD group of 31 months (range, 1-108 months). The organ response rate in all the patients was 39.5% (15/38), and the organ response rate between these two groups has no significant difference [33.3% (5/15) vs 43.5% (10/23), P=0.532]. However, the median time of organ response was significant difference [6 (3-10) months vs 3 (1-6) months, respectively (P=0.032)]. The 3-year overall survival (OS) rates in the two groups were 72.0% and 66.9%, and their average survival were 84.7 months and 75.9 months, respectively (P=0.683). In the patients with auto-PBSCT, the occurrence of III-IV grade of bone marrow suppression (P<0.001), fever (P<0.001), nausea and infection (P=0.006) were obviously higher than those with VD, but there was no statistically significant difference in pulmonary infection (P=0.069) and bloodstream infection (P=0.059).. The preliminary results have presented that primary light chain amyloidosis patients treated with auto-PBSCT or VD had similar organ response rate and survival. However, more adverse events occurred in the group of auto-PBSCT.

Topics: Amyloidosis; Bortezomib; Dexamethasone; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Retrospective Studies

Autologous stem cell transplantation (SCT) is a common management strategy for select patients with immunoglobulin light-chain amyloidosis, but no trials have documented improved overall survival.. Eighty-nine patients with biopsy-proven immunoglobulin light-chain amyloidosis were allowed to select treatment with melphalan plus dexamethasone (n = 34) or SCT (n = 55); all patients were transplant eligible. Treatment preference resulted in imbalanced study arms. Patients who selected SCT were younger, more frequently had an Eastern Cooperative Oncology Group performance status score less than 2, had lower-stage amyloidosis, and had a lower incidence of cardiac amyloidosis.. Patients receiving melphalan plus dexamethasone had a 3-year progression-free survival rate of 29.1% and an overall survival rate of 58.8%. Patients undergoing SCT had a 3-year progression-free survival rate of 51.7% and an overall survival rate of 83.6%. An attempt to match patients between the 2 arms in terms of risk produced 24 matched triplet sets (2 SCT patients for each melphalan-dexamethasone patient); there was no difference in hematologic response, but there was better survival after autologous SCT. A propensity score-matched analysis of the cohorts (melphalan plus dexamethasone vs SCT) showed an overall mortality hazard ratio of 2.56 (P < .01).. Although the study had limitations, similar hematologic responses and improved survival were observed after SCT versus melphalan plus dexamethasone. Cancer 2016;122:2197-205. © 2016 American Cancer Society.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Combined Modality Therapy; Dexamethasone; Female; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Severity of Illness Index; Transplantation, Autologous; Treatment Outcome

Topics: Amyloid beta-Protein Precursor; Amyloidosis; Antineoplastic Agents, Alkylating; Cardiomyopathies; Fatal Outcome; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Penile Diseases; Penis; Prealbumin; Stem Cell Transplantation; Transplantation, Autologous; Ulcer

There is no consensus on whether patients with immunoglobulin light chain amyloidosis (AL) should receive induction therapy prior to an autologous stem cell transplant (ASCT). This study investigated the relationships between baseline bone marrow plasmacytosis (BMPC), cardiac staging, and pre-transplant induction in AL patients. All patients who received ASCT for AL within 12 months of diagnosis were included. Patient characteristics and outcomes were abstracted. Univariate and multivariate modeling was performed. Among 415 AL patients, 35% had induction prior to ASCT. Post-ASCT hematologic CR plus VGPR rates were significantly higher in those with baseline BMPC ≤ 10% compared to BMPC >10% (58% versus 40%, P = 0.0013). Significant risk factors for lack of attainment of CR included attenuated dose melphalan conditioning, baseline BMPC > 10%, no induction, and male gender. The 5-year OS for the entire group was 65%. On multivariate analysis, risk factors for inferior OS included no induction therapy, advanced AL amyloid staging, BMPC > 10%, attenuated conditioning melphalan dose, and male gender. Patients with Mayo 2012 stage I-II patients with BMPC ≤ 10%, who comprised 56% of the ASCT population fared exceedingly well regardless of whether or not they received induction therapy with a 5-year OS of 81 to 83%. Induction therapy pre-ASCT may improve outcomes among AL patients due to a rapid reduction of toxic light chains or alternatively by elimination of less fit patients by "testing" their ability to tolerate chemotherapy. Prospective studies will be required to sort out these and other questions. Am. J. Hematol. 91:984-988, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Protocols; Bone Marrow Examination; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myeloablative Agonists; Remission Induction; Retrospective Studies; Risk Factors; Sex Factors; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Treatment Outcome

A 57-year-old Japanese woman with a 5-year history of rheumatoid arthritis (RA) was admitted to our hospital for an evaluation of nephrotic range proteinuria (4.8 g/day). A renal biopsy led to the diagnosis of amyloidosis according to strong positivity for Congo red staining and the detection of microfibrillar structures on electron microscopy that were negative for AA and positive for kappa light chain. Combination therapy with high-dose melphalan and autologous stem cell transplantation was performed according to the regimen for AL amyloidosis. Her proteinuria and RA subsided, but relapsed after 3 years. This is the first report regarding kappa light chain amyloidosis in an RA patient.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Arthritis, Rheumatoid; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Proteinuria

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is an effective treatment modality for immunoglobulin light-chain (AL) amyloidosis; however, its application remains restricted to patients with good performance status and limited organ involvement. In recent years, the paradigm for AL amyloidosis has changed with the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). We hypothesized that use of novel agent induction regimens has improved outcomes for patients with AL amyloidosis undergoing HDM/SCT at our center.. All patients with AL amyloidosis, age ≥18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were included in this study. Any regimen administered within 6 months prior to HDM/SCT including an IMiD or a PI was considered a novel induction regimen. Use of induction regimen was evaluated in a Cox proportional hazard model for association with progression-free survival (PFS) and overall survival (OS).. Forty-five patients with AL amyloidosis underwent HDM/SCT. The median age was 57.2 years (range 39-74.4), 15 (33.3%) were women. The median number of organs involved was 2 (range 1-5), with 20 patients having only 1 (44.4%), 10 patients having 2 (22.2%), and 15 patients (33.3%) having ≥ 3 organs involved. Novel agent induction regimens were used prior to HDM/SCT in 21 patients (46.7%); these comprised PI in 13/21 (57.1%), IMiD alone in 6/21 (28.6%), PI and cyclophosphamide (CyBorD) in 3/21 (14.3%), and IMiD and PI in 3/21 (14.3%). Use of a novel agent induction regimen was associated with improved, but not OS. The 3-year PFS for patients who received a novel agent induction was 79%, while for those who did not was 53% (hazard ratio [HR] = 0.317, p = 0.048). The 3-year OS for patients who received novel agent induction regimens was 95%, while for those who did not was 71% (HR = 0.454, p = 0.247).. Our data suggest that use of a novel agent induction regimen including an IMiD or PI prior to HDM/SCT for patients with AL amyloidosis could improve outcomes, with improvement in PFS. Although these results are limited by sample size and lack of randomization, these results support possible further investigation of novel agent induction regimens in the context of a prospective clinical trial.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Cyclophosphamide; Disease-Free Survival; Drug Therapy, Combination; Female; Gene Expression; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Immunologic Factors; Induction Chemotherapy; Male; Melphalan; Middle Aged; Prognosis; Proteasome Inhibitors; Transplantation, Autologous

This article reports a case of primary localized conjunctival λ light-chain (AL) amyloidosis.. Case report.. A 73-year-old woman presented with a 1-year history of a painless growth in the conjunctiva of the left eye. A yellow-salmon pink diffuse mass of tissue was identified in the inferomedial bulbar conjunctiva and inferior fornix. An incisional biopsy was performed. The histopathological and immunohistochemical examinations revealed interstitial and vascular amyloid deposits of λ light chains. The diagnosis was amyloidosis of the conjunctiva. The systemic evaluation revealed normal findings and systemic amyloidosis was excluded. Nevertheless, due to an unexplained cardiac insufficiency and after consultation with the treating hematologist a treatment with three cycles of systemic chemotherapy with melphalan and prednisolone was initiated but 6 months later the conjunctival mass in the inferior fornix showed persistence and complete excision was performed. At 16, 24 and 44 months of follow-up no evidence of recurrence was seen on clinical examination. The magnetic resonance imaging (MRI) at 16 and 24 months of follow-up showed no associated cranial or orbital infiltration.. Conjunctival AL amyloidosis is a rare clinical entity. Because of the heterogeneity of amyloidosis in clinical presentation, pattern of amyloid-related organ toxicity, association with lymphoproliferative diseases and rate of disease progression, identification of amyloid deposits is essential and systemic involvement has to be excluded.

Topics: Aged; Amyloidosis; Anti-Inflammatory Agents; Conjunctival Diseases; Female; Humans; Melphalan; Prednisolone; Treatment Outcome

Despite successful treatment of the clonal plasma cell implicated in its pathogenesis, patients with AL amyloidosis (AL) experience significant morbidity related to underlying amyloid mediated organ dysfunction. While normalization of the serum free light chain measurements [normal ratio of involved and uninvolved free light chains (nFLCr)] is the goal of therapy and centerpiece of hematologic response criteria, achieving (or not achieving) meaningful organ response (OR) is clinically significant for its implications on long-term symptomatology as well as overall survival (OS), and remains the ultimate goal of treatment. Expectations for organ recovery following successful therapy leading to nFLCr in AL remain poorly described. We evaluated the timeframe and predictive factors for OR, and long-term outcome, in 313 AL patients who achieved nFLCr following therapy initiation. OR was seen in 80% of surviving AL patients within 1-year of nFLCr. Patients achieving early OR within 1 year of nFLCr had superior OS compared with those who despite obtaining nFLCr did not achieve early OR. We further evaluated factors predicting OR and OS among patients achieving nFLCr. Higher values of dFLC (involved-uninvolved) at diagnosis predict OR, and early OR predicts improved OS following successful hematologic therapy in AL.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Dexamethasone; Drug Monitoring; Female; Heart; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Kidney; Liver; Male; Melphalan; Middle Aged; Plasma Cells; Proteasome Inhibitors; Retrospective Studies; Survival Analysis; Transplantation, Autologous

Immunoglobulin light-chain (AL) amyloidosis is a systemic disorder that causes progressive organ dysfunction. The optimal treatment strategy requires accurate patient stratification with an emphasis on the extent of cardiac involvement. Reports on its prognosis are sparse and predominantly originate from highly selected centers. We aimed to evaluate patient characteristics and outcomes in a cohort treated at a single center.. This is a single-center retrospective study of 63 consecutive patients diagnosed with AL amyloidosis between January 2000 and December 2012. Patients were evaluated by treatment strategy and cardiac involvement.. The mean age at diagnosis was 61.4 years (±8.9), and 39 patients (62%) were male. Thirty-two (51%) patients presented with cardiac amyloid involvement (CA) and the remaining 31 (49%) had noncardiac amyloidosis (NCA). The median follow-up time was 12.7 months (0.3-90.8), and 38 (60%) patients died during follow-up. The median overall survival (OS) was 29 months (95% CI 12.1-57.2) and the OS was not significantly lower for patients with CA compared to NCA (log-rank = 0.21).. The prognosis in AL amyloidosis is grave, but the outcome with treatment in the current series was comparable to those in series from larger centers. CA did not significantly predict the OS.

Topics: Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Bone Marrow; Demography; Echocardiography; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myocardium; Retrospective Studies; Survival Rate; Transplantation, Autologous

To investigate the clinical characteristics and histopathological features of kidney disease in elderly patients.. We retrospectively analyzed the results of 4,185 consecutive renal biopsies, and 288 patients aged >60 years at the Second Hospital of Jilin University from January 1998 to December 2013 were finally included. All patients had been clinically and histologically diagnosed with kidney disease.. Nephrotic syndrome was the main clinical indication for biopsy. Twenty-four patients (8.33 %) experienced a minor complication related to their biopsy procedure. Among patients diagnosed as primary glomerulonephritis (GN), membranous nephropathy (MN) was the most frequent subclassification (24.7 %), followed by mesangioproliferative glomerulonephritis (MsPGN, 11.1 %) and IgA nephropathy (IgAN, 8.0 %). Amyloidosis (8.7 %) was the most common secondary GN, followed by antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune GN (5.2 %) and diabetic nephropathy (DN, 3.8 %). Based on renal biopsies results, 143/288 patients received immunosuppressive therapy and showed an overall remission rate (complete plus partial remissions) of 74.1 %. Among 71 MN patients, 29 patients received steroids plus cyclophosphamide and showed a remission rate of 79.3 %, while 42 patients received steroids and tacrolimus and showed a remission rate of 90.5 %. Among 25 patients with amyloidosis, 22 cases received melphalan plus dexamethasone and showed a remission rate of 40.9 %, while three patients received vincristine, adriamycin, and dexamethasone and showed a remission rate of 66.7 %.. Making an accurate pathologic diagnosis by renal biopsy is crucial for selecting the proper treatment for elderly patients with kidney disease.

Topics: Aged; Aged, 80 and over; Amyloidosis; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Antineoplastic Agents, Alkylating; Autoimmune Diseases; Biopsy; Cyclophosphamide; Dexamethasone; Diabetic Nephropathies; Female; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Amyloidosis; Antineoplastic Agents, Hormonal; Dexamethasone; Eyelid Diseases; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Prognosis

Topics: Amyloidosis; Antineoplastic Agents; Bortezomib; Female; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Male; Melphalan; Transplantation Conditioning

Hepatitis B virus (HBV) reactivation (so-called reverse seroconversion) is a rare but known complication of hematopoietic stem cell transplantation, immunosuppressive therapy, or high-dose chemotherapy plus rituximab. This event is linked to a treatment-related fall in titers of antibodies to hepatitis B surface antigen (HBsAb) below the protective threshold level.. A 77-year-old Korean man diagnosed with primary amyloidosis was started on melphalan/dexamethasone combination therapy. During treatment, laboratory indices of hepatic function suddenly deteriorated, and he developed acute hepatitis through reverse HBV seroconversion, becoming positive for hepatitis B surface antigen (HBsAg) and negative for HBsAb. HBV DNA was also detectable in serum to a profound extent. Normal liver function was gradually restored during the course of antiviral therapy (entecavir).. HBV reactivation may lead to fatal liver disease in a significant percentage of patients. As a result, physicians often screen for HBsAg and HBsAb prior to initiating chemotherapy, advising antiviral treatment in patients seropositive for HBsAg, even in the absence of hepatitis B e antigen. Here, a case of HBV reactivation is described, involving a patient given relatively low-dose chemotherapy (melphalan/dexamethasone) for primary amyloidosis.

Topics: Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Dexamethasone; Guanine; Hepatitis B; Hepatitis B Antibodies; Hepatitis B virus; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Virus Activation

The clinical presentation of AL amyloidosis is highly variable. In this series, we describe five cases of AL amyloidosis with vertebral compression fractures as initial presentation. All five patients had evidence of bone marrow replacement on magnetic resonance imaging and bone marrow biopsies demonstrating diffuse interstitial amyloid deposition. Hepatomegaly and elevated liver enzymes, consistent with liver involvement with amyloidosis, were also seen in each case. All five patients responded well to anti-plasma cell chemotherapy, with normalization of serum free light chain levels, reduction in alkaline phosphatase and improvement in pain and functional status. Although rare, AL amyloidosis should be considered in the differential diagnosis of selected patients with spontaneous vertebral compression fractures. Moreover, there seems to be an association of vertebral compression fractures with liver involvement in AL amyloidosis.

Topics: Alkaline Phosphatase; Amyloidosis; Antineoplastic Agents; Bone Marrow; Bortezomib; Dexamethasone; Diagnosis, Differential; Female; Fractures, Compression; gamma-Glutamyltransferase; Hematopoietic Stem Cell Transplantation; Hepatomegaly; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Liver; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Plasma Cells; Spinal Fractures

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Myeloablative Agonists

Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chain amyloidosis (AL), but it is associated with a high risk of early mortality (EM). In a multicenter randomized comparison against oral chemotherapy, autotransplantation was associated with 24% EM. We analyzed trends in outcomes after autologous hematopoietic cell transplantation for AL in North America.. Between 1995 and 2012, 1,536 patients with AL who underwent autotransplantation at 134 centers were identified in the Center for International Blood and Marrow Transplant Research database. EM and overall survival (OS) were analyzed in three time cohorts: 1995 to 2000 (n = 140), 2001 to 2006 (n = 596), and 2007 to 2012 (n = 800). Hematologic and renal responses and factors associated with EM, relapse and/or progression, progression-free survival and OS were analyzed in more recent subgroups from 2001 to 2006 (n = 197) and from 2007 to 2012 (n = 157).. Mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995 to 2000 to 5% and 11%, respectively, in 2001 to 2006, and to 3% and 5%, respectively, in 2007 to 2012. Correspondingly, 5-year OS improved from 55% in 1995 to 2000 to 61% in 2001 to 2006 and to 77% in 2007 to 2012. Hematologic response to transplantation improved in the latest cohort. Renal response rate was 32%. Centers performing more than four AL transplantations per year had superior survival outcomes. In the multivariable analysis, cardiac AL was associated with high EM and inferior progression-free survival and OS. Autotransplantation in 2007 to 2012 and use of higher dosages of melphalan were associated with a lowered relapse risk. A Karnofsky score less than 80 and creatinine levels 2 mg/m(2) or greater were associated with worsened OS.. Post-transplantation survival in AL has improved, with a dramatic reduction in early post-transplantation mortality and excellent 5-year survival. The risk-benefit ratio for autotransplantation has changed, and randomized comparison with nontransplantation approaches is again warranted.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Databases, Factual; Disease Progression; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Kaplan-Meier Estimate; Karnofsky Performance Status; Male; Melphalan; Middle Aged; Myeloablative Agonists; Retrospective Studies; Transplantation, Autologous; Treatment Outcome

Amyloid light-chain (AL) amyloidosis is a multi-organ disease due to deposition of misfolded monoclonal immunoglobulin light chains. IgM AL amyloidosis is a rare variant, about 6% of AL amyloidosis cases, and more data are needed for treatment guidance. In IgM AL amyloidosis, the clonal cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinical and laboratory features of 95 patients with IgM AL amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38-89) with 56% males. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinal tract (17%). Treatment responses were analyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. Overall hematologic response rates and very good partial or complete hematologic response rates, respectively, were: high-dose melphalan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose alkylating agents (Melphalan or cyclophosphamide) 63%;19%. Overall, 5-year survival rates were significantly higher in patients with a hematological response: 79.2 ± 8.5% versus 41 ± 14.9% in non-responders, which is more favorable than typically expected in AL amyloidosis.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Female; Humans; Immunoglobulin M; Male; Melphalan; Middle Aged; Retrospective Studies; Stem Cell Transplantation

The combination of oral melphalan and dexamethasone is considered standard therapy for patients with light-chain amyloidosis ineligible for autologous stem cell transplantation. However, previous trials reported different rates of response and survival, mainly because of the different proportions of high-risk patients. In the present study, including a total of 259 subjects, we treated 119 patients with full-dose melphalan and dexamethasone (dexamethasone 40 mg days 1-4), and 140 patients with advanced cardiac disease with an attenuated dexamethasone schedule (20 mg). Hematologic response rates were 76% in the full-dose group and 51% in the patients receiving the attenuated schedule; the corresponding complete response rates were 31% and 12%, respectively. The median survival was 7.4 years in the full-dose group and 20 months in the attenuated-dose group. Use of high-dose dexamethasone, amino-terminal pro-natriuretic peptide type-B >1800 ng/L, a difference between involved and uninvolved free light chains of >180 mg/L, troponin I >0.07 ng/mL, and response to therapy were independent prognostic determinants. In relapsed/refractory subjects bortezomib combinations granted high hematologic response rates (79% and 63%, respectively), proving the most effective rescue treatment after melphalan and dexamethasone. In summary, melphalan plus dexamethasone was highly effective with minimal toxicity, confirming its central role in the treatment of AL amyloidosis. Future randomized trials will clarify whether bortezomib is best used in frontline combination with melphalan and dexamethasone or as rescue treatment.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amyloidosis; Dexamethasone; Drug Therapy, Combination; Female; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Retreatment; Treatment Failure; Treatment Outcome

Chromosomal aberrations of plasma cells are well established pathogenetic and prognostic factors in multiple myeloma, but their prognostic implication in systemic light chain (AL) amyloidosis is unclear. Therefore, the aim of this study was to identify prognostic cytogenetic risk factors by interphase FISH in a series of 103 consecutive AL amyloidosis patients treated uniformly with melphalan/dexamethasone as first-line therapy. Detection of gain of 1q21 was predictive for a poor overall survival (OS) (median 12.5 versus 38.2 months, p = 0.002). Hematologic event free survival (hem EFS) for gain of 1q21 was 5.0 versus 8.5 months in median (p = 0.08) and haematologic remission rates (≥VGPR) after three cycles were 5% versus 25% (p = 0.06). Most important, in multivariate concordance analyses the adverse prognosis carried by gain of 1q21 was retained as an independent prognostic factor (OS: p = 0.003, average hazard ratio (AHR) = 3.64, hemEFS: p = 0.008, AHR = 2.35), along with the well established Mayo cardiac staging. Patients with t(11;14) had a longer median OS with 38.2 months versus 17.5 months, though no statistical significance was reached. Deletion 13q14 and hyperdiploidy turned out to be prognostically neutral. In conclusion, we have identified gain of 1q21 as an independent adverse prognostic factor in AL amyloidosis patients treated with standard chemotherapy.

Topics: Adult; Aged; Amyloidosis; Chromosome Duplication; Chromosomes, Human, Pair 1; Dexamethasone; Disease-Free Survival; Drug Therapy, Combination; Female; Humans; Immunoglobulin Light Chains; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models

High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) for light chain amyloidosis (AL) was performed in 31 patients at Oregon Health and Science University between 2005 and 2012. Fifteen patients had cardiac involvement.. Patients received melphalan 200 mg/m(2) or dose-adjusted HDM (100-140 mg/m(2)) depending on high risk features. Thirteen patients proceeded directly to ASCT after diagnosis, 12 patients received a bortezomib-containing regimen, and 6 received a variety of other induction regimens.. The day 100 treatment-related mortality was 9.6%. Overall hematologic (ORR) and organ response rates (OR) in the whole cohort after ASCT were 77% and 58%. ORR and OR in the bortezomib pretreated group were 92% and 75% vs. 69% and 54% in the group that received no pretreatment. The median time to maximum hematologic response after ASCT was reduced in the group that received bortezomib induction (3 vs. 14 months). Overall cardiac response rate was 60%; 100% in patients pretreated with bortezomib and 43% in those without induction treatment. With a median follow-up of 2.9 years, the 3-year progression-free and overall survival rates in the entire cohort were 66% and 73% and in those with cardiac involvement, 73% and 80%.. We observed that bortezomib-based induction is well tolerated in patients with and without cardiac involvement and suggest that this approach be studied in prospective multi-institutional trials.

Topics: Adult; Aged; Amyloidogenic Proteins; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cardiomyopathies; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Kaplan-Meier Estimate; Kidney Diseases; Lenalidomide; Male; Melphalan; Middle Aged; Myeloablative Agonists; Proteasome Inhibitors; Pyrazines; Remission Induction; Retrospective Studies; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

We report a 50-year-old female patient with diffuse and rapidly progressing splenic calcification. She had developed nephrotic syndrome and been diagnosed with renal amyloid light-chain amyloidosis in 2010. Although she had been given melphalan and dexamethasone therapy and high-dose melphalan followed by autologous blood stem-cell transplantation, her renal function worsened and hemodialysis was started in May 2011. Since November 2011, splenic calcification, probably associated with amyloidosis, had progressed, and diffuse calcification was observed throughout the splenic area in September 2012. During the same period, the patient was hospitalized for thrombocytopenia. Although splenic dysfunction due to calcification was suspected to be the cause of thrombocytopenia, the association between the two could not be established. The platelet count rose with an improvement in hepatic congestion due to reinforced fluid removal during dialysis.

Topics: Amyloidosis; Calcinosis; Dexamethasone; Disease Progression; Female; Humans; Melphalan; Middle Aged; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Renal Insufficiency; Splenic Diseases; Thrombocytopenia; Transplantation, Autologous

Nearly half of AL amyloidosis patients have cardiac involvement, an independent predictor of poor prognosis. High-dose melphalan and autologous stem-cell transplantation (HDM/SCT) can induce complete hematologic responses and prolong survival in AL amyloidosis. Granulocyte colony-stimulating factor (G-CSF)-induced mobilization of peripheral blood stem cell (PBSC) in AL amyloidosis patients is associated with volume overload, arrhythmias and capillary leak syndrome. Plerixafor has a different mechanism of action and has non-overlapping toxicities with G-CSF. We describe our experience in five patients with AL amyloidosis and cardiac involvement who received plerixafor with G-CSF for PBSC mobilization. Median age was 56 years; two patients had undergone heart transplantation within the year prior to HDM/SCT. Three patients received plerixafor after an initial trial of mobilization with G-CSF alone. No patient had any significant toxicities during mobilization and PBSC collection. The median total yield of PBSCs collected was 5.9 × 10(6) CD34+ cells/kg; the median number of leukapheresis days was 2. Neutrophil engraftment after HDM/SCT occurred at a median of nine days, platelet engraftment at a median of 13 days. Plerixafor was effective and well tolerated when used upfront or as rescue for PBSC mobilization in AL amyloidosis patients with cardiac involvement.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Benzylamines; Cyclams; Female; Graft Survival; Granulocyte Colony-Stimulating Factor; Heart Failure; Heart Transplantation; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Remission Induction; Transplantation, Autologous

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Hematopoietic Stem Cell Transplantation; Hospitalization; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Retrospective Studies; Transplantation Conditioning

Troponin-T (cTnT) and NT-proBNP provide prognostic information in light-chain amyloidosis (AL). Thus, these biomarkers are widely used in clinical routine for risk stratification. Recently, plasma level of osteopontin (OPN), a secreted phosphoglycoprotein expressed by a variety of cell types, has been reported as a risk predictor in various cardiovascular diseases.. OPN was determined retrospectively in 150 consecutive patients newly diagnosed with AL amyloidosis. All patients were evaluated according to a routine protocol including electrocardiography, echocardiography and laboratory testing.. Mean OPN was 591 ± 37 ng/mL. Cardiac involvement was established in 83 (55.3%). Median OPN plasma level were associated with number of organs involved, renal function, eligibility for high-dose melphalan chemotherapy and autologous stem cell transplantation, and severity of cardiac amyloidosis. Median follow-up was 19.2 months. 1-year all-cause-survival was 83.4%. The cut-offs discriminating 1-year all-cause-mortality for NT-proBNP, troponin T, and OPN were 2544 ng/L, 0.035 µg/L, and 426.8 ng/mL, respectively. Outcome was worse in patients with biomarkers above the individual ROC derived cut-off. A significant improvement of survival was observed in patients with cTNT >0.035 µg/L or NT-proBNP >2544 ng/L and OPN below ROC-derived cut-off of 426.8 ng/mL as compared to patients with OPN above 426.8 ng/L. No further discrimination was achieved by OPN in the cohorts of low troponin T or low NT-proBNP, respectively. Separate multivariate models identified OPN (cut-off 426.8 ng/mL) and troponin T (cut-off 0.035 µg/L) as independent predictors of all-cause-mortality.. These data demonstrated that OPN appears to be a valuable marker in the clinical routine for evaluation of patients with AL amyloidosis, especially if it is used in combination with cTNT and/or NT-proBNP.

Topics: Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Biomarkers; Cardiomyopathies; Female; Gene Expression; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Natriuretic Peptide, Brain; Osteopontin; Peptide Fragments; Prognosis; Retrospective Studies; ROC Curve; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Troponin T

Oral melphalan and dexamethasone (MDex) is a standard treatment for patients with AL amyloidosis who are not eligible for stem cell transplantation at many referral centers. However, following encouraging reports on the activity of bortezomib combined with alkylators and dexamethasone, these combinations are being moved to frontline therapy. We compared the outcome of 87 patients treated with bortezomib plus MDex (BMDex) with that of 87 controls treated with MDex. Patients and controls were matched for age, cardiac and renal function and free light chain burden. A higher rate of complete responses was observed with BMDex (42 vs 19%), but this did not result in a survival improvement in the overall population. However, a significant survival advantage for BMDex was observed in patients without severe (New York Heart Association class III or IV) heart failure and with N-terminal pro-natriuretic peptide type-B <8500 ng/l. Patients treated with full-dose dexamethasone had similar response rates and survival whether they received bortezomib or not. Intermediate-risk patients who are not fit enough to receive high-dose dexamethasone are likely to take the greatest advantage from the addition of bortezomib to MDex.

Topics: Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Case-Control Studies; Dexamethasone; Humans; Immunoglobulin Light Chains; Melphalan; Middle Aged; Pyrazines; Treatment Outcome

A 52-year-old woman with a high serum alkaline phosphatase (ALP) level underwent a liver biopsy, which showed diffuse heavy deposition of Aκ amyloid, and was diagnosed as having immunoglobulin light chain (AL) amyloidosis. Although she received high-dose melphalan with stem cell transplantation and achieved a hematologic complete response (CR), her ALP level began to increase one year after treatment. Further examinations revealed that she was still in a CR state with dominant bone-type ALP, and re-biopsied liver specimens demonstrated marked regression of amyliod deposition, providing important evidence that the turnover of hepatic amyloid proteins can actually occur more rapidly than previously thought.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Biopsy; Combined Modality Therapy; Diagnosis, Differential; Dose-Response Relationship, Drug; Female; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Liver; Melphalan; Middle Aged; Remission Induction; Stem Cell Transplantation; Tomography, X-Ray Computed; Transplantation, Autologous

Bortezomib combination chemotherapy appears to be active in light chain (AL) amyloidosis with high rates of hematologic and organ response. We report a retrospective evaluation of the clinical outcome of treatment with bortezomib, melphalan, and prednisolone (VMP) as first-line chemotherapy in patients with AL amyloidosis who were ineligible for autologous stem cell transplant. Among the 19 patients included in this study, 90% had two or more involved organs and most of the patients had advanced stage AL amyloidosis (84% with 2004 Mayo Stage III and 92% with 2012 Mayo Stage III or IV). Sixteen (84%) patients had a hematologic response, including seven (37%) with complete response, with time to response of 1-3 months. Cardiac and renal responses were observed in 44% and 33% of patients, respectively. Estimated 2-year survival is 39%, and 5 patients (26%) died during therapy. The common grade 3-4 adverse events were thrombocytopenia, diarrhea and pneumonia. A once-weekly bortezomib is more feasible than twice-weekly regimen. Our results suggest that triplet regimen of VMP appears to be an effective regimen in advanced AL amyloidosis ,but benefits in the patients with multi-organ dysfunction remain to be proven.

Topics: Aged; Amyloidosis; Boronic Acids; Bortezomib; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Prednisolone; Pyrazines; Retrospective Studies

High-dose melphalan with autologous stem cell transplantation (HDM/ASCT) is a promising treatment option for eligible patients with systemic immunoglobulin light chain (AL) amyloidosis. We present the results of ASCT following risk-adapted melphalan conditioning on the basis of criteria proposed by our group, including B-type natriuretic peptide (BNP). Ten patients with primary systemic AL amyloidosis treated at our institute were evaluated. A full dose of melphalan (200 mg/m(2)) was administered to patients who met all the following: performance status, 0 or 1; number of organs involved, 2 or less; serum creatinine, 1.5 mg/dL or less; EF 50 % or more and BNP 200 pg/mL or less; otherwise 140 mg/m(2). The hematologic complete response was achieved in four and organ response was seen in two patients. The median event-free survival (EFS) of all patients was 21.5 months, and median overall survival (OS) was 47.0 months. EFS and OS were significantly longer for patients who received 200 mg/m(2) of melphalan than for those who received lower dose (EFS: not reached vs. 13.9 months, P = 0.0217; OS: not reached vs. 13.8 months, P = 0.0186). No treatment-related mortality within 100 days from ASCT was observed. Evaluation of cardiac diastolic function may contribute to safer HDM/ASCT and improve outcome of AL amyloidosis.

Topics: Adult; Amyloidosis; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Natriuretic Peptide, Brain; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Systemic immunoglobulin light-chain amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem organ failure and death. Autologous hematopoietic stem-cell transplantation (ASCT) has been widely used to treat patients with AL. However, treatment-related mortality remains high and reported series are subject to selection bias.. To define the role of patient selection in stem cell transplantation, we evaluated 24 consecutive AL patients transplanted at our center.. Complete hematologic response was achieved in all 20 patients surviving >100 days posttransplantation. The 1-year overall survival (OS) rate after ASCT was 78.5%. The 5- and 10-year progression-free and OS rates were 57% and 47%, respectively. Treatment-related deaths owing to cardiovascular problems occurred in 16% of cases.. ASCT for AL amyloidosis can be safely performed in experienced transplantation centers, and increased risk is associated mainly with cardiovascular system involvement.

Topics: Adult; Aged; Amyloidosis; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Myeloablative Agonists; Patient Selection; Retrospective Studies; Survival Analysis; Transplantation, Autologous

A 62-year-old female patient was admitted to our hospital for evaluation of nephrotic syndrome. Monoclonal gammopathy (IgG λ type) and urinary Bence Jones proteins were detected in the serum and urine by the immunofixation method. The initial renal biopsy revealed amyloid deposition in mesangial area, glomerular capillary walls and arterioles by Congo-red staining, and amyloid fibers were detected by electron microscopy. On the bone marrow test, plasma cells accounted for 8.6%. Based on these findings, we diagnosed as AL amyloidosis associated with multiple myeloma. We treated her by high-dose intravenous injection therapy of melphalan combined with autologous peripheral blood stem cell transplantation. She achieved complete hematologic response 27 months later, however. Urine M-protein disappeared 2 months after treatment, and proteinuria slowly disappeared 17 months after treatment. On the other hand, amyloid fibers remained in renal biopsied tissues at 17 and 53 months after therapy. Electron microscopic examination also revealed the similar amyloid fibers in glomeruli. These findings suggest that, in this case, immunoglobulin light chains may cause directly and/or indirectly glomerular epithelial injury and nephrotic range proteinuria rather than via amyloid fiber formation.

Topics: Amyloidosis; Combined Modality Therapy; Female; Humans; Kidney Diseases; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous

A 74-year-old woman with refractory IgG-κ multiple myeloma developed massive melena caused by hemorrhagic submucosal tumors in the duodenum and middle jejunum. A biopsy revealed the tumor to be marked AL amyloid deposition. Treatment with bortezomib did not improve the melena or the underlying disease. The patient also developed multiple amyloidomas in the bilateral femoral heads, which caused a fracture in the left femoral head. Treatment with lenalidomide, as the final therapeutic option, resolved the intractable melena and improved both the intestinal lesions and myeloma. This case shows that successful treatment of multiple myeloma leads to marked improvement of accompanying AL amyloidosis.

Topics: Aged; Amyloid; Amyloidosis; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bone Diseases; Boronic Acids; Bortezomib; Carpal Tunnel Syndrome; Dexamethasone; Disease Progression; Doxorubicin; Duodenal Diseases; Female; Femur Head; Fractures, Spontaneous; Gastrointestinal Hemorrhage; Hip Fractures; Humans; Jejunal Diseases; Lenalidomide; Melphalan; Multiple Myeloma; Osteolysis; Prednisolone; Pyrazines; Thalidomide; Vincristine

Waldenström's macroglobulinemia (WM) is increasingly being associated with amyloidosis particularly of the amyloid light-chain variety. We report on one of the few cases of WM associated with serum amyloid A protein (AA) amyloidosis. Autologous stem cell transplant (ASCT) is now being increasingly used for the treatment of amyloidosis, but most studies are small case series. Traditionally AA amyloid is associated with connective tissue disorders and periodic fever syndromes and has been treated by addressing the underlying condition. We present the first case of serum amyloid A being treated with melphalan-based ASCT to deal with the underlying WM and thereby control the amyloid, thus demonstrating the viability of this novel approach for the treatment of this disorder.

Topics: Aged; Amyloidosis; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Myeloablative Agonists; Serum Amyloid A Protein; Transplantation, Autologous; Waldenstrom Macroglobulinemia

Symptomatic cardiac involvement is the most important prognostic factor in AL amyloidosis patients. Longterm survival is limited not only by cardiac involvement condition, but also by limited choice of treatment with unsatisfactory results. The aim of the present report is to assess the effect of achieved treatment response on survival of AL amyloidosis patients with symptomatic cardiac involvement under conventional treatment.. The monitored patient set consisted of 19 patients with systemic AL amyloidosis and symptomatic cardiac involvement, treated and monitored at the III. Clinic of Internal Medicine between 2004 and 2012. The male : female ratio was 17 : 2, and the age median was 64 (range 48 to 78 years). Thirteen patients died within the monitored period. Functional status was defined according to the NYHA classification, where five patients had class II involvement, 10 patients had class III involvement, and four patients had class IV involvement. Treatment response was assessed by the application of modified IMWG and ISA criteria; all patients were undergoing conventional treatment. Nine patients were treated by a combination of alkylating agents (alkeran, cyclophosphamide), six were treated by a combination treatment with thalidomide, and four were treated by a combination of bortezomib and dexamethasone. Data were analyzed with software SPSS v. 15 (SPSS, Inc., Chicago, USA). Log Rank Test was applied to survival evaluation.. The statistical analysis included only 13 patients who underwent at least three months of treatment, where six patients attained complete remission (CR), four patients attained partial remission (PR), and three patients attained only stabilization of disease (SD). Significant difference in patient survival was found to be correlated with attained hematological response, where the patients who attained CR had median survival of 39 months vs 10 months in patients who attained PR or SD (p = 0.005).. The results indicate that attainment of complete hematological remission is associated with significantly longer survival of AL amyloidosis patients with symptomatic cardiac involvement.

Topics: Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Female; Heart Neoplasms; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Pyrazines; Remission Induction; Thalidomide; Treatment Outcome

Topics: Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Boronic Acids; Bortezomib; Dexamethasone; Diagnostic Errors; Elastic Tissue; Fatal Outcome; Female; Humans; Melphalan; Multiple Myeloma; Predictive Value of Tests; Pseudoxanthoma Elasticum; Pyrazines; Skin; Treatment Outcome

Immunoglobulin light chain (AL) amyloidosis can be treated with high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Risk factors for infections may include hyposplenism, hypogammaglobulinemia, treatment-related neutropenia, melphalan-induced mucositis, and nosocomial exposures.. A review of 493 patients with AL amyloidosis undergoing treatment with HDM/SCT from August 1994 to August 2009 was performed. The objectives were to determine the rate and types of infections following HDM/SCT, to identify factors associated with microbiologically documented infections, and to assess the contribution of infections to all-cause treatment-related mortality (TRM; defined as deaths within 100 days of SCT).. Microbiologically documented infections after HDM/SCT occurred in 24% (n = 119) of patients. TRM was 10% (n = 48) overall, and 21% (n = 25) in patients who had a documented infection. Thus, the relative risk of TRM in a patient with a documented infection was 3.42 (95% confidence interval [CI] 2.02-5.79). Infections were caused by gram-positive bacteria in 51%, anaerobic bacteria in 16%, gram-negative bacteria in 13%, and fungi in 9% of cases. Serum creatinine >2 mg/dL was associated with increased risk of post-SCT infection (38% vs. 21%, P = 0.0007) with an odds ratio of 2.27 (95% CI 1.40-3.68). No significant association for infection was found for age, gender, cardiac involvement, prior steroid therapy, dose of melphalan, multiorgan involvement, days to neutrophil engraftment, or dose of CD34 +  cells infused.. Serum creatinine >2 mg/dL is a risk factor for infections in patients with AL amyloidosis undergoing HDM/SCT. The relative risk of TRM in a patient with a documented infection was increased >3-fold. A broad spectrum of infections, similar to that in other SCT patients, is seen in this population in the early post-SCT period.

Topics: Aged; Aged, 80 and over; Amyloidosis; Bacterial Infections; Combined Modality Therapy; Cross Infection; Dose-Response Relationship, Drug; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Mycoses; Myeloablative Agonists; Postoperative Complications; Risk Factors; Stem Cell Transplantation; Transplantation, Autologous

Amyloidosis is a systemic disease caused by abnormal deposition of amyloid material that is detected with Congo red staining and is difficult to diagnose. Involvement of the tracheobronchial tree is rare and is a challenge for pulmonologists because of the wide differential diagnosis of this disease. We present two cases where tracheobronchial affectation has been observed: in one of them as a primary disease, and in another as secondary affectation. The use of bronchoscopic techniques is essential for the diagnosis of tracheobronchial involvement. In the absence of an effective drug therapy, local management of this disease with endoscopic techniques for bronchial repermeabilization is able to provide clinical improvement and expand the treatment options and prognosis in this disease.

Topics: Airway Obstruction; Amyloidosis; Biopsy; Birefringence; Bone Marrow; Bronchial Diseases; Bronchial Neoplasms; Bronchoscopy; Coloring Agents; Combined Modality Therapy; Congo Red; Diagnosis, Differential; Female; Hemoptysis; Humans; Laser Therapy; Lung; Lung Neoplasms; Male; Melphalan; Middle Aged; Prednisone; Tracheal Diseases

The increasing number of effective agents allows rescue therapy of patients with light-chain (AL) amyloidosis refractory to ≥2 previous treatments. Lenalidomide is effective in this disease and its toxicity profile encourages its use in salvage regimens. All the patients with AL amyloidosis refractory to both melphalan and bortezomib referred to our center between July 2007 and July 2009 were treated with the combination of lenalidomide and dexamethasone. Twenty-four consecutive patients were enrolled. Seventy-nine percent were also refractory to thalidomide. Two patients died before evaluation of response, and 50% experienced severe adverse events. Survival was significantly shorter in subjects with troponin I >0.1 ng/mL and in patients diagnosed <18 months before treatment initiation. Hematologic response was observed in 41% of patients and prolonged survival (median 10 months vs. not reached, P = 0.005) independently from troponin I concentration and from pre-treatment disease duration. Salvage therapy beyond second line of treatment can improve survival in AL amyloidosis and lenalidomide plus dexamethasone is a valuable option in this setting.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Humans; Immunosuppressive Agents; Lenalidomide; Male; Melphalan; Middle Aged; Pyrazines; Recurrence; Salvage Therapy; Survival Rate; Thalidomide; Treatment Outcome

High-dose melphalan (HDM) plus stem cell transplantation is an effective treatment for light-chain amyloidosis (AL), but is associated with high treatment-related mortality in patients with cardiac involvement. We studied 187 patients with cardiac involvement with AL who underwent HDM between 1996 and 2008. The median age was 57 years and the median time from diagnosis to HDM was 3.6 months. Half of the patients received reduced-dose melphalan (100-160 mg/m(2)). The median overall survival (OS) was 66 months, 54 months from diagnosis and HDM, respectively, and 91 patients (49%) were alive at the last follow-up 52 months (median) from HDM. Thirty patients (16%) died within 100 days of transplantation; only low serum albumin predicted early deaths. Overall, hematologic response (HR) and cardiac responses were seen in 66% and 41% of patients, respectively. The median OS for patients with and without HR was not reached and 22 months, respectively (P < .01); and for those with any decrease and no decrease in N-terminal-pro-brain natriuretic peptide was not reached and 26 months, respectively (P < .01). In multivariate analysis of baseline factors, only reduced-dose melphalan predicted shorter OS. HDM is feasible in patients with cardiac amyloidosis, and achievement of HR and organ response is associated with improved survival.

Topics: Adult; Aged; Amyloidosis; Dose-Response Relationship, Drug; Feasibility Studies; Female; Follow-Up Studies; Heart Diseases; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Survival Analysis; Transplantation Conditioning

We present three long-term survivors treated with high-dose melphalan with autologous peripheral blood stem cell transplantation(auto PBSCT)for primary AL amyloidosis. Because melphalan toxicity is dose-related, patient age and the extent of organ involvement are very important factors for the success of high-dose melphalan treatment with PBSCT. The patients were therefore given high-dose melphalan using the risk-adapted approach to melphalan dosing. They received 3 courses of a vincristine, doxorubicin and dexamethasone(VAD)regimen, along with high-dose melphalan(100-200mg/m2)with auto PBSCT. There were no serious complications or transplantation-related mortalities. Patients survived for an average of 68 months(22-100 months)in partial response. A risk-adapted approach to melphalan dosing with PBSCT is an effective treatment in patients with primary AL amyloidosis.

Topics: Amyloidosis; Biopsy; Combined Modality Therapy; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation

Primary systemic immunoglobulin light chain amyloidosis (AL.) is an incurable clonal plasma cell disorder in which fragments of Ig light chain are deposited in tissues. High dose melphalan and hematopoietic cell transplantation (SCT) is a preferred technique, but only 20% of patients are eligible. Nontransplant candidates can be offered MelDex (melphalan-dexamethasone). Demonstrate comparable efficacy of treatment protocols including immunomodulatory drugs such as TCD (thalidomide, cyclophosphamide, dexamethasone), LMP (lenalidomide, melphalan, prednisone), or bortezomib in combination with dexamethasone. Results of treatment of patients with AL. based on immunomodulatory drugs are promising but require further multicenter clinical trial comparing the MelDex. The main obstacle to effective treatment of AL. still remains a late diagnosis of the disease.

Topics: Amyloidosis; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Drug Combinations; Drug Therapy, Combination; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Lenalidomide; Melphalan; Prednisone; Pyrazines; Thalidomide

To investigate the treatment of primary amyloidosis with high-dose melphalan and autologous hematopoietic stem cell transplantation to further examine the survival, hematologic response, and improvement of amyloid-related organ dysfunction.. Retrospective analysis of 20 patients with primary amyloidosis treated with autologous hematopoietic stem cell transplantation. The status of major organ function before transplantation, mobilization programs and conditioning regimen as possible risk factors for survival were also investigated.. Of 20 cases, 11 out of 15 evaluable cases achieved hematologic response, among them, 6 got complete remission (CR, 40%) and 5 partial remission (PR, 33%). The median onset time was 3.0 months (1.5 - 4.0 months) and 4 months (3 - 5 months), respectively after transplantation. The overall hematologic response was 73%. The 11 hematologic responders also had kidney responses. The median time to achieve kidney response was 3 months (2 - 6 months). The 3-year overall survival of the cohort of cases was 71.4%. The major causes of death were heart failure, renal dysfunction and gastrointestinal bleeding. G-CSF alone could obtain satisfactory mobilization results and most of patients well tolerated to the conditioning regimen of melphalan doses from 140 mg/m(2) to 200 mg/m(2).. Treatment of primary amyloidosis with high-dose melphalan followed by autologous peripheral blood stem cell transplantation produced high efficacy. The cardiovascular system involvement, renal dysfunction and the abnormality of coagulation function before transplantation may be the risk factors for survival.

Topics: Adult; Aged; Amyloidosis; Cardiovascular System; Female; Gastrointestinal Hemorrhage; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney; Male; Melphalan; Middle Aged; Retrospective Studies; Risk Factors; Survival Rate; Transplantation, Autologous; Treatment Outcome

Amyloid deposits are often found in the bone marrow in patients with Immunoglobulin light chain (AL) amyloidosis. We sought to determine whether this affects stem cell collection or engraftment after high-dose melphalan and autologous stem cell transplantation (HDM-SCT). We reviewed data on 361 patients with AL amyloidosis who had Congo red staining of pretreatment bone marrow biopsy specimens and underwent HDM-SCT between July 1994 and December 2011. We analyzed data on stem cell yield, days of stem cell collection, and days to neutrophil and platelet engraftment posttransplantation. Bone marrow amyloid deposits were found in 65% of patients (n = 233). There were no significant differences in median number of stem cells collected and days to neutrophil or platelet engraftment between patients with bone marrow amyloid deposits and those without these deposits. Thus, our data indicate that although amyloid involvement of the bone marrow is common, it does not negatively affect stem cell mobilization or neutrophil and platelet engraftment after HDM-SCT.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Bone Marrow; Combined Modality Therapy; Female; Hematopoietic Stem Cell Mobilization; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myeloablative Agonists; Plaque, Amyloid; Retrospective Studies; Stem Cell Transplantation

Long-term survival remains poor for patients with cardiac amyloidosis. High-dose melphalan (MEL) with stem cell transplantation (HDM/SCT) is an effective treatment for AL amyloidosis, but patients with cardiac involvement are ineligible because of high therapy-related mortality. Here we report detailed HDM/SCT outcomes of 9 patients with cardiac failure. Their median age was 56 years (range, 45∼66). After a median follow-up of 15 months (range 9∼32), three died of multiorgan failure within the early phase after HDM/SCT, and the other six including poor risk patients are alive at present. Their symptoms of cardiac decompensation have improved. Decreases in interventricular septum thickness were confirmed in 4 patients 6∼12 months after HDM/SCT by echocardiography. One-year overall survival rate was 67%, longer than previously reported rates. HDM/SCT may lead to improvements in quality of life and extended survival in cardiac amyloidosis patients. Meanwhile, the median dosage of MEL in our procedure was 103 mg/m(2) (range 68∼180), less than the recommended dose, and patients were maintained on miscellaneous therapies. Further studies are required to clarify an effective MEL dose and to refine selection criteria for patients undergoing HDM/SCT.

Topics: Aged; Amyloidosis; Cardiomyopathies; Female; Heart Failure; Heart Function Tests; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Transplantation, Autologous; Treatment Outcome

Topics: Amyloid; Amyloidosis; Biopsy; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Prednisolone; Skin

To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population.. We gathered for analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed.. There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation.. This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.

Topics: Aged; Amyloidosis; Biomarkers; Cohort Studies; Dexamethasone; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Survival Analysis

Topics: Adult; Aged; Amyloidosis; Cause of Death; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Melphalan; Middle Aged; Mortality; Myeloablative Agonists; Tertiary Care Centers; Time Factors

Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma cell dyscrasia. Delay in diagnosis is the major hurdle in improving the outcomes of AL patients. Almost all patients with systemic AL need cytotoxic therapy. Treatment can improve symptoms and quality of life, as well as extend survival. Supportive care is an integral part of the treatment plan. Severity of cardiac involvement is an important determinant of prognosis and influences the choice of therapy. Cardiac biomarkers and serum free light chain assay are important tools for assessing prognosis and monitoring treatment response. Myeloablative chemotherapy with melphalan and autologous stem cell rescue appears to offer survival benefit; however, it is an option for only a quarter of AL patients. Standard-dose combination chemotherapy with steroids and alkylating agents is a safe and effective treatment strategy that can result in improvement of organ function in many patients. Newer agents such as bortezomib and lenalidomide have shown promising activity and are being evaluated as part of combination regimens in clinical trials.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Boronic Acids; Bortezomib; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Lenalidomide; Melphalan; Myeloablative Agonists; Myocardium; Pyrazines; Steroids; Survival Analysis; Thalidomide; Transplantation, Autologous; Treatment Outcome

Although about 10 to 15% of patients with multiple myeloma (MM) develop AL amyloidosis, liver-restricted fatal amyloidosis is rare. We encountered such an MM patient. A 73-year-old female without a history of carpal tunnel syndrome was diagnosed with IgG-κ MM (Stage I by Durie & Salmon) in January, 2005. Because MM was exacerbated to Stage III in May, 2007, VAD (vincristine, adriamycin, dexamethasone) chemotherapy was performed with minor response, despite 3 courses of this regimen. Three courses of salvage chemotherapy (cyclophosphamide+melphalan; CM) were then performed with near partial response. In March, 2008, just before the 4th cycle of CM chemotherapy, she was slightly icteric with elevated biliary tract enzymes; therefore, treatment was switched to oral cyclophosphamide and prednisolone. At this time, she did not have macroglossia, skin eruption, gastrointestinal dysfunction, or bleeding. Echocardiography was also non-specific. One month later, she developed a marked bleeding tendency and leg edema. Laboratory tests showed a severe deterioration in liver function. In the middle of May, 2008, she progressed to hepatic coma and died of intracranial hemorrhage several days later. Autopsy showed that the liver was almost substituted by AL amyloid substance.

Topics: Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Fatal Outcome; Female; Hemorrhage; Humans; Immunoglobulin Light-chain Amyloidosis; Liver Failure; Melphalan; Multiple Myeloma; Vincristine

Cardiac dysfunction is a well-recognized complication of light chain amyloidosis (AL). Autologous stem cell transplant (auto-SCT) has emerged as a successful treatment modality for AL patients. In this study, we examined the effect of clonal immunoglobulin light chain genes (VL), which encodes the immunoglobulin light chain protein that ultimately forms amyloid, on cardiac function, in the context of auto-SCT and its impact on overall survival.. Longitudinal Doppler myocardial imaging parameters along with cardiac biomarkers were used to assess for cardiac function pre and post auto-SCT.. VL gene analysis revealed that Vl genes, in particular VlVI, were associated with worse cardiac function parameters than Vk genes. Clonal VL genes appeared to have an impact on left ventricular (LV) function post-transplant and also influenced mortality, with specific VL gene families associated with lower survival. Another key predictor of mortality in this report was change in tricuspid regurgitant flow velocity following auto-SCT. Correlations were also observed between systolic strain rate, systolic strain and VL genes associated with amyloid formation.. Clonal VL gene usage influences global cardiac function in AL, with patients having VlVI and VlII-III-associated amyloid more severely affected than those having Vk or VlI amyloid. Pulsed wave tissue Doppler imaging along with immunoglobulin gene analysis offers novel insights into prediction of mortality and cardiac dysfunction in AL after auto-SCT.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Biomarkers; Echocardiography, Doppler; Female; Genes, Immunoglobulin; Humans; Immunoglobulin Light Chains; Immunoglobulin Variable Region; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Proportional Hazards Models; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity; Statistics, Nonparametric; Transplantation, Autologous; Treatment Outcome; Ventricular Dysfunction, Left

Current response criteria for light-chain amyloidosis (AL) relegate FLC response to a subsidiary status relative to serum M-protein response. Given that light chains form the substrate for amyloid fibril formation, we hypothesized that changes in FLC might better predict outcome compared to changes in intact immunoglobulin levels. Two patient cohorts were studied, 347 patients who underwent an autologous stem-cell transplant (SCT) and 96 patients treated with melphalan/dexamethasone. We identified the lowest value following therapy for intact serum M-protein and the difference between involved and uninvolved FLC (FLC-diff). We first examined the relative contribution of M-protein and FLC-diff on the overall survival (OS), and found that FLC reduction, rather than M-protein reduction, significantly impacted OS. The median OS was not reached among those with a 50% decrease in FLC-diff compared to 20 months for the remainder. On regression analysis, a 90% reduction in FLC-diff following SCT best predicted being alive at 3 or 5 years. The median OS among those with a 90% decrease was not reached compared to 37.4 months for the rest P < 0.001. The current study supports the notion that FLC response is a more useful measure of hematological response than M-protein response. It also highlights the importance of achieving at least a 90% reduction in the FLC-diff to improve the outcome of patients with light-chain AL.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Antibodies, Monoclonal; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Immunoglobulins; Male; Melphalan; Middle Aged; Myeloma Proteins; Predictive Value of Tests; Prognosis; Survival Analysis; Treatment Outcome

We report four cases of de novo amyloidosis occurring after 16, 18, 28 and 31 years following kidney transplantation. These patients presented with proteinuria and progressive allograft dysfunction. Kidney biopsy showed AL amyloidosis in all compartments of the allograft kidney. Serum immunofixation studies revealed monoclonal lambda light chains in all four cases. Bone marrow examination showed 10% plasma cells in one case, 5-10% in two cases and less than 5% in one case. Two patients died unexpectedly within 3 months and 1 year of the diagnosis of allograft AL amyloidosis. Of the remaining two, one underwent autologous stem cell transplant that resulted in complete hematologic remission. However, the patient relapsed within 2 years and also developed progressive kidney allograft failure. The patient received a second autologous stem cell transplant with complete hematologic response, followed by a second kidney transplant, which showed no evidence of amyloid at 1-year posttransplant. The remaining case was treated with prednisone and bortezomib, which has stabilized kidney function in the short term. In conclusion, this study shows that AL amyloidosis is an uncommon but important cause of late onset proteinuria in the kidney allograft that results in kidney allograft failure.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Female; Hematopoietic Stem Cell Transplantation; Humans; Kidney Transplantation; Male; Melphalan; Middle Aged; Prednisone; Proteinuria; Pyrazines; Remission Induction; Treatment Outcome

High-dose melphalan and autologous stem cell transplantation (HDM) is an effective treatment for systemic amyloid light chain (AL) amyloidosis but the eligibility criteria exclude many patients with this disorder. The aim of this study was to determine appropriate treatment strategies for systemic AL amyloidosis according to each patient's clinical condition in Japan.. Historical cohort study. Fifty-three patients with systemic AL amyloidosis (those with malignancies were excluded) were treated in our hospital with HDM (15 patients), melphalan + prednisolone (MP) (17 patients), vincristine + adriamycin + dexamethasone (VAD) (11 patients), or supportive treatment (no chemotherapy, 10 patients). We compared the survival rates among these treatment groups.. Mean survival was significantly longer in the HDM group than in the other three groups (P < 0.01, log-rank test). This trend remained the same when patients were divided into those with and without cardiac amyloid involvement. Furthermore, in patients with heart involvement, survival in the VAD therapy group was significantly inferior to that in the MP therapy group (P < 0.01 by log-rank test). Significant factors related to the survival rate included the presence or absence of heart involvement and treatment modality.. HDM should be considered the treatment of choice in eligible patients with systemic AL amyloidosis even in the presence of cardiac amyloidosis. If HDM is not eligible, indications for VAD therapy should be carefully evaluated in patients with cardiac amyloidosis.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Combined Modality Therapy; Dexamethasone; Doxorubicin; Female; Heart Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Liver Diseases; Male; Melphalan; Middle Aged; Prognosis; Survival Rate; Vincristine

An atypical case of late-onset lattice corneal dystrophy is described in a 61-year-old man without a family history of eye disease. Mutational analysis of the TGFBI gene excluded any pathogenic sequence variants. However, 2 years later, renal impairment and nephrotic syndrome were diagnosed, resulting in a diagnosis of systemic heavy-chain amyloidosis.. Slit-lamp examination, corneal photography, and in vivo confocal microscopy were performed. General systemic evaluation included blood and urine assessment, bone marrow and renal biopsies, and cardiologic evaluation. A DNA sample underwent initial mutational analysis of TGFBI and, subsequently, gelsolin. The renal biopsy sample was subject to direct protein sequencing by mass spectrometry.. A bilateral, atypical, fine, midperipheral lattice corneal dystrophy with minor central subepithelial scarring was clinically characterized. Subsequently, abnormal renal functions with proteinuria, IgG lambda paraproteinemia, extensive deposition of amyloid in renal glomeruli, and increased plasma cells in bone marrow were identified. No pathogenic sequence mutations were identified in TGFBI or the gelsolin genes. Direct protein sequencing by mass spectrometry showed amyloid to be heavy-chain deposition rather than the more usual light-chain deposition.. Atypical midperipheral lattice corneal dystrophy presenting with adult onset and negative family history should arouse suspicion for an association with paraproteinemias or amyloidosis. Exclusion of TGFBI mutations should alert the clinician to the possibility of potentially life-threatening conditions, with referral for careful systemic evaluation.

Topics: Amyloid; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Corneal Dystrophies, Hereditary; Dexamethasone; DNA Mutational Analysis; Extracellular Matrix Proteins; Gelsolin; Glucocorticoids; Humans; Immunoglobulin Heavy Chains; Male; Mass Spectrometry; Melphalan; Microscopy, Confocal; Middle Aged; Mutation; Nephrotic Syndrome; Paraproteinemias; Pyrazines; Sequence Analysis, Protein; Transforming Growth Factor beta

Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Antineoplastic Agents, Alkylating; Disease-Free Survival; Female; Hematologic Tests; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myeloablative Agonists; Transplantation, Autologous; Treatment Outcome

Topics: Adrenergic beta-Antagonists; Amyloidosis; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Boronic Acids; Bortezomib; Calcium Channel Blockers; Dexamethasone; Diuretics; Drug Therapy, Combination; Female; Heart Failure; Humans; Lenalidomide; Melphalan; Middle Aged; Myocardium; Prealbumin; Pyrazines; Severity of Illness Index; Stem Cell Transplantation; Thalidomide; Treatment Outcome

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Male; Melphalan; Myeloablative Agonists

Topics: Aged; Amyloidosis; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunoglobulin kappa-Chains; Macroglossia; Magnetic Resonance Imaging; Melphalan; Prednisolone; Risk Assessment; Severity of Illness Index; Thalidomide; Treatment Outcome

The prognosis in amyloid light chain (AL)-amyloidosis and multiorgan involvement is poor, with a high-treatment-related mortality after high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Some patients, however, might benefit from the therapy. We report a case of cardiac AL-amyloidosis with multiorgan involvement where the progressive cardiomyopathy was halted after successful treatment with HDM/SCT in 2001. The patient is in an excellent cardiac condition with a good quality of life, receiving treatment with angiotensinogen receptor blockers and a flexible diuretics regimen at follow-up after 10 years.

Topics: Amyloidosis; Female; Follow-Up Studies; Gastrointestinal Diseases; Heart Diseases; Humans; Immunoglobulin Light Chains; Liver Diseases; Melphalan; Middle Aged; Myeloablative Agonists; Myocardium; Stem Cell Transplantation

Aggressive treatment with high-dose i.v. melphalan followed by auto-SCT (HDM/SCT) is effective in inducing hematological and clinical remissions, and in extending survival in AL amyloidosis. Tandem cycles of HDM/SCT have been shown to increase hematologic complete response rates in patients with AL amyloidosis. Between April 1994 and July 2008, 57 patients with AL amyloidosis at the Boston University Medical Center were treated with a second cycle of HDM/SCT after failing to achieve a complete response after a first transplantation. A total of 11 of 57 patients (19%) treated with tandem transplantation developed high fever 12-24 h after melphalan administration. The average peak temperature was 39.1 degrees C. Other clinical features include hypotension, acute renal failure and skin rash. No infectious etiology was identified. One of the patients had serum available for measurement of cytokines before, during and after the febrile reaction. The concentration of several pro-inflammatory cytokines, including IL-6 and TNFalpha, increased significantly, showing a clear physiological response correlating with the clinical findings. We conclude that an unusual cytokine-mediated febrile reaction can occur in patients with AL amyloidosis exposed to a second cycle of high-dose melphalan, which we have termed a 'melphalan recall' reaction.

Topics: Adult; Amyloidosis; Antineoplastic Agents, Alkylating; Cytokines; Female; Fever; Humans; Male; Melphalan; Middle Aged; Paraproteinemias; Stem Cell Transplantation; Transplantation Conditioning

High-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation (HDM/SCT) has been shown to result in a durable hematologic response and prolonged overall survival in systemic amyloid light-chain (AL) amyloidosis as well as multiple myeloma. However, little is known about the myeloma associated with AL amyloidosis (MM/AL). In this retrospective study, we evaluated 87 patients with MM/AL from 1994 to 2007. Sixteen of these patients underwent HDM/SCT at Boston University Medical Center. Three patients (19%) died from treatment-related mortality. The overall median survival for all 87 patients was 22 months by Kaplan-Meier estimates. However, this was improved to 54.5 months for those who received HDM/SCT compared to 21 months for those who did not receive HDM/SCT. A hematologic complete response was achieved by 25% (4/16) of patients at 6 months after HDM/SCT. Hematologic relapses occurred in 60% of patients at a median of 1 year after HDM/SCT. In conclusion, HDM/SCT can prolong overall survival in patients with MM/AL who are eligible to receive it.

Topics: Adult; Aged; Aged, 80 and over; Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Dose-Response Relationship, Drug; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Protein Subunits; Retrospective Studies; Stem Cell Transplantation; Survival Analysis; Time Factors; Treatment Outcome

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Biomarkers; Dexamethasone; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Monitoring, Physiologic; POEMS Syndrome; Vascular Endothelial Growth Factor A

Treatment with oral melphalan and dexamethasone (M-Dex) was reported to be effective and feasible in patients with systemic light chain amyloidosis (AL) not eligible for high-dose melphalan. We report on 61 patients with advanced AL who were treated with intravenous M-Dex as first-line therapy. Estimated median overall survival (OS) was 17.5 months. Seventeen patients (28%) died within 3 months, mostly of disease-related complications. In addition, nonhematologic toxicity of Common Terminology Criteria grade 3 or 4 was observed in 20 patients, whereas hematologic toxicity was low. Twenty-seven patients (44%) had hematologic response, including complete in 7 patients (11%) and partial remission in 20 patients (33%). Organ response was observed in 15 patients (25%). The amount of the involved free light chains in serum and Karnofsky Index at diagnosis significantly influenced OS. Plasma levels of the cardiac biomarkers before start of treatment and their increase after the third M-Dex cycle also were strong negative predictors of OS. These parameters might help to identify patients who will not benefit from M-Dex chemotherapy.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Heart Diseases; Humans; Immunoglobulin Light Chains; Injections, Intravenous; Lymphoproliferative Disorders; Male; Melphalan; Middle Aged; Prognosis; Retrospective Studies; Severity of Illness Index; Survival Analysis

Topics: Amyloid; Amyloidosis; Antifibrinolytic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Blood Coagulation; Blood Coagulation Factors; Dexamethasone; Disseminated Intravascular Coagulation; Female; Humans; Immunoglobulin kappa-Chains; International Normalized Ratio; Melphalan; Middle Aged; Nephrotic Syndrome; Partial Thromboplastin Time; Vitamin K

Patients with light chain (AL) amyloidosis who present with severe heart failure due to cardiac involvement rarely survive more than 6 months. Survival after cardiac transplantation is markedly reduced due to the progression of amyloidosis. Autologous stem-cell transplantation (ASCT) has become a common therapy for AL amyloidosis, but there is an exceedingly high treatment-related mortality in patients with heart failure.. We developed a treatment strategy of cardiac transplant followed by ASCT. Twenty-six patients were evaluated, and of 18 eligible patients, nine patients underwent cardiac transplantation. Eight of these patients subsequently received an ASCT.. Six of seven evaluable patients achieved a complete hematologic remission, and one achieved a partial remission. At a median follow-up of 56 months from cardiac transplant, five of seven patients are alive without recurrent amyloidosis. Their survival is comparable with 17,389 patients who received heart transplants for nonamyloid heart disease: 64% in nonamyloid vs. 60% in amyloid patients at 7 years (P=0.83). Seven of eight transplanted patients have had no evidence of amyloid in their cardiac allograft.. This demonstrates that cardiac transplantation followed by ASCT is feasible in selected patients with AL amyloidosis and heart failure, and that such a strategy may lead to improved overall survival.

Topics: Adult; Aged; Alanine; Amyloidosis; Aspartate Aminotransferases; Cardiotonic Agents; Female; Heart Failure; Heart Transplantation; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Stroke Volume; Transplantation, Autologous

We evaluated the capability of soluble cardiac biomarkers to predict tolerability and outcomes of IMiD-containing treatments among 106 patients treated on clinical trials. Baseline elevations in troponin T (TnT) and N-terminal brain naturietic protein (NT-proBNP) predicted for an inability to tolerate IMiD-based regimens. The best predictors for early attrition during cycle 1 were TnT ≥ 0.07 μg/L and NT-proBNP ≥ 11,939 ng/L. NT-proBNP-response underperformed TnT-response as a predictor for overall survival (OS), but both predicted for early protocol attrition. Despite hematologic response, IMiD-treated patients were at higher risk for NT-proBNP rises and early drug discontinuation than a control population but not for early death. These observations prompt two questions: (1) does IMiD-based therapy lead to increased fluid retention and/or cardiac toxicity and (2) is an NT-proBNP-driven cardiac response system valid in IMiD-treated amyloidosis patients? Recognition of potential drug-induced cardiac toxicity is important so that increased cardiac surveillance and drug dose-adjustment or discontinuation may be implemented.

Topics: Amyloid; Amyloidosis; Biomarkers; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Drug Therapy, Combination; Heart Failure; Humans; Immunoglobulin Light Chains; Immunologic Factors; Lenalidomide; Melphalan; Natriuretic Peptide, Brain; Patient Dropouts; Peptide Fragments; Stem Cell Transplantation; Thalidomide; Troponin T

Cancer is the consequence of sequential acquisition of mutations within somatic cells. Mutations alter the relative reproductive fitness of cells, enabling the population to evolve in time as a consequence of selection. Cancer therapy itself can select for or against specific subclones. Given the large population of tumor cells, subclones inevitably emerge and their fate will depend on the evolutionary dynamics that define the interactions between such clones. Using a combination of in vitro studies and mathematical modeling, we describe the dynamic behavior of two cell lines isolated from the same patient at different time points of disease progression and show how the two clones relate to one another. We provide evidence that the two clones coexisted at the time of initial presentation. The dominant clone presented with biopsy proven cardiac AL amyloidosis. Initial therapy selected for the second clone that expanded leading to a change in the diagnosis to multiple myeloma. The evolutionary dynamics relating the two cell lines are discussed and a hypothesis is generated in regard to the mechanism of one of the phenotypic characteristics that is shared by these two cell lines.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Dexamethasone; Disease Progression; Evolution, Molecular; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-6; Melphalan; Multiple Myeloma; Mutation

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Immunoglobulin Light-chain Amyloidosis; Medical Oncology; Melphalan; Patient Care; Treatment Outcome

Aggressive treatment of amyloid light chain (AL) amyloidosis with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT because of amyloid-associated organ dysfunction.. We report on 70 patients with AL amyloidosis treated with oral cyclic melphalan and dexamethasone.. Of 48 evaluable patients who survived and returned for follow-up assessment, 6 patients (13%) achieved a complete hematologic response and 12 patients (25%) a partial hematologic response. Responses were non-inferior for patients receiving weekly "low-dose" dexamethasone compared with those receiving 4 day pulses. Median survival for the 70 patients has not yet been reached with a median follow-up of 17 months. Nineteen patients (27%) received additional treatment leading to improvement in survival.. Melphalan/dexamethasone can lead to hematologic responses and improvement in survival, particularly for those who can receive additional treatment for AL amyloidosis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Dexamethasone; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Male; Melphalan; Middle Aged; Retrospective Studies; Survival Analysis; Treatment Outcome

Simultaneous cardiac and renal involvement is associated with a particularly poor prognosis in patients with AL amyloidosis (AL-A). We report the first case of a successful long-term outcome of combined heart and kidney transplantation not followed by autologous stem cell transplantation in a patient with systemic AL-A. The recipient was a 46-year-old man with end-stage renal failure associated with serious cardiac involvement in the context of AL-A. Before transplantation, two courses of oral melphalan plus prednisone induced partial hematologic remission, as shown by the decrease in circulating free light chain with no improvement of renal or heart function. The patient underwent combined heart and kidney transplantation as a rescue treatment. During the follow-up period (36 months), plasma cell dyscrasia remains in complete remission, with normal free lambda light chain levels and no recurrence of amyloid deposition on heart and kidney grafts. This case report demonstrates that combined heart and kidney transplantation not systematically associated with stem cell transplantation may be considered an additional therapeutic option in AL-A patients with severe organ dysfunction and partial hematologic remission.

Topics: Amyloidosis; Heart Transplantation; Humans; Kidney Transplantation; Male; Melphalan; Middle Aged; Prednisone; Transplantation Conditioning; Treatment Outcome

Among the many clinical manifestations of light-chain (AL) amyloidosis, musculoskeletal involvement is rarely reported. We describe the case of a 72-year-old woman who was referred to our rheumatology department for fixed flexion contractures of the fingers that developed concomitantly with a decline in general health. Macroglossia and recent-onset dyspnea were noted. Investigations, which included a tongue biopsy, established the diagnosis of kappa light-chain amyloidosis with soft tissue, bone, and cardiac deposits. Melphalan and dexamethasone therapy was successful in stabilizing the clinical and laboratory abnormalities within 6 months. This case is remarkable in that the musculoskeletal manifestations were at the forefront of the clinical picture and led to the diagnosis.

Topics: Aged; Amyloidosis; Contracture; Dexamethasone; Female; Finger Joint; Humans; Immunoglobulin kappa-Chains; Melphalan; Treatment Outcome

High-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation has been shown to result in durable hematologic response and prolonged overall survival in systemic AL amyloidosis. In this retrospective study, we evaluated clinical and hematologic responses in 69 patients with predominant liver involvement who were treated with high-dose intravenous melphalan and autologous stem cell transplantation from 1998 to 2006. Nine patients (13%) died from treatment-related mortality, similar to patients without hepatic involvement. The overall survival was 81% at one year and 61% at five years, by Kaplan-Meier estimates. A hematologic complete response was achieved by 53% (31/58) of patients at one year. A hepatic response occurred in 57% (33/58) at one year after high-dose intravenous melphalan and autologous stem cell transplantation and 63% (19/30) at two years after high-dose intravenous melphalan and autologous stem cell transplantation. In conclusion, hepatic disease improves in almost 2/3 patients treated with high-dose intravenous melphalan and autologous stem cell transplantation who have a complete or partial hematologic response to treatment.

Topics: Adult; Aged; Amyloidosis; Female; Humans; Liver; Liver Diseases; Male; Melphalan; Middle Aged; Myeloablative Agonists; Retrospective Studies; Stem Cell Transplantation; Treatment Outcome

We report a 58-year-old Japanese man with primary systemic AL amyloidosis who achieved disappearance of proteinuria including Bence-Jones protein (lambda-type) after two courses of VAD therapy (vincristine, doxorubicin, and dexamethasone) and subsequent high-dose melphalan, followed by autologous peripheral blood stem cell transplantation. Because this patient did not have any apparent amyloidosis-related heart or liver damage and met all of the eligibility criteria for this therapy, this treatment was performed. Both proteinuria and M-protein disappeared completely, and he is doing well clinically at 19 months after treatment. However, amyloid deposits were still found in the kidneys, including the glomeruli and tubulointerstitium, when renal biopsy was done at 8 months after treatment. In the future, we may reach a time when clinical remission corresponds to histological remission.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Kidney; Male; Melphalan; Middle Aged; Vincristine

A male patient with primary AL amyloidosis who had been suffering from systemic lymphadenopathy with IgMkappa-type M-proteinemia received two courses of VAD and high-dose melphalan with in vivo elimination of CD20(+) cells using rituximab followed by autologous peripheral blood stem cell transplantation. Four years after complete hematological remission he showed marked reduction in size of the amyloid-laden lymph nodes. Deposits of AL amyloid may regress from the tissue if the chemotherapy succeeds in persistent inhibition of the production of amyloidogenic immunoglobulin light chains.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Humans; Immunoglobulin M; Lymph Nodes; Lymphatic Diseases; Male; Melphalan; Middle Aged; Radiography

Topics: Amyloid; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Drug Therapy, Combination; Humans; Melphalan; Prednisone; Prognosis; Stem Cell Transplantation; Treatment Outcome

Unlike systemic amyloidosis, the diagnosis of brain amyloidoma without systemic manifestations is clinically challenging. Despite the availability of advanced brain imaging technology, such conditions are difficult to ascertain without brain biopsy or autopsy. We report the case of a 64-year-old woman who presented with frontal lobe syndrome with abnormal linear enhancement on brain magnetic resonance imaging. Results from a stereotactic biopsy revealed lambda-positive protein deposition in the brain parenchyma. During the course of illness, the patient had an acute cerebral hemorrhage, which manifested with hemiparesis, dysarthria, and pathologic crying. Review of the literature revealed 15 cases of primary brain amyloidoma. Patients had similar protein deposits but in different regions of the brain and therefore presented with various neurologic symptoms.

Topics: Amyloidosis; Anticonvulsants; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cerebral Hemorrhage; Dexamethasone; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Melphalan; Middle Aged; Thalidomide; Valproic Acid

The described report deals with the case of a patient with diagnosis of ischemic-hypertensive cardiomyiopathy based on the history of angina and inducible myocardial ischemia with normal coronary arteries. However, after cardiac magnetic resonance, the typical amyloidotic pattern is found and the final diagnosis of multiple myeloma is made at osteomedullary biopsy.

Topics: Amyloidosis; Angina Pectoris; Antineoplastic Agents, Alkylating; Biopsy; Bone Marrow Examination; Cardiomyopathies; Combined Modality Therapy; Diagnostic Errors; Dyspnea; Electrocardiography; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Multiple Myeloma; Myocardial Ischemia; Peripheral Blood Stem Cell Transplantation

The prognosis of advanced cardiac light-chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis.. Nineteen patients with cardiac amyloidosis but no obvious involvement of other organs were scheduled for heart transplantation. Four to 6 months later, high-dose melphalan chemotherapy and autologous stem cell transplantation (HDM-ASCT) was planned in patients not in complete remission. Seven of nineteen patients died while waiting for heart transplantation. The remaining 12 patients (complete remission, n = 4) underwent surgery. Chemotherapy in patients not in complete remission consisted of HDM-ASCT (n = 5/12; subsequent complete remission, n = 2; partial remission, n = 3) or melphalan-prednisolone (partial remission, n = 1). Two of twelve patients were ineligible for any chemotherapy. Three of twelve patients died [423.5 (105-2131) days] from progressive disease, relapse, or sepsis. The 1- and 3-year survival rates were 83 and 83%, respectively, similar to those of patients undergoing heart transplantation for standard indications. Corresponding survival rates stratified by haematological response were 100 and 100% for complete remission (partial remission, 100 and 100%; progressive disease, 0 and 0%).. Heart transplantation in advanced cardiac amyloidosis is a promising approach to interrupting the vicious circle of ineligibility for potential curative chemotherapeutic treatment and extremely poor prognosis of cardiac amyloidosis without chemotherapy. Highly urgent heart transplantation combined with subsequent HDM-ASCT appears to offer a successful treatment option to improve the poor outcome of cardiac amyloidosis. However, it should be restricted to highly selected patients in specialized centres.

Topics: Amyloidosis; Cohort Studies; Combined Modality Therapy; Disease-Free Survival; Female; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Male; Melphalan; Probability; Prognosis; Retrospective Studies; Risk Assessment; Severity of Illness Index; Survival Rate; Transplantation, Autologous; Treatment Outcome; Waiting Lists

A male patient with primary AL amyloidosis who had been suffering from systemic lymphadenopathy with IgMkappa-type M-proteinemia received two courses of VAD and high-dose melphalan with in vivo elimination of CD20(+) cells using rituximab followed by autologous peripheral blood stem cell transplantation. Four years after complete hematological remission he showed marked reduction in size of the amyloid-laden lymph nodes. Deposits of AL amyloid may regress from the tissue if the chemotherapy succeeds in persistent inhibition of the production of an amyloidogenic immunoglobulin light chain.

Topics: Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Humans; Lymphatic Diseases; Male; Melphalan; Middle Aged

A 60-year-old woman was admitted with acute heart failure and was diagnosed as having primary systemic AL amyloidosis with cardiac involvement by endomyocardial biopsy. Electrophoresis revealed an IgG-lambda monoclonal component and amyloidosis was evident in the gastric and rectal mucosa. Her cardiac function at diagnosis was poor, including an ejection fraction of 59% and IVS of 19 mm, and serum cardiac troponin T (cTnT) was elevated (0.12 ng/ml). She was treated with melphalan-dexamethasone (Mel-Dex) therapy once a month. After more than a year, cardiac function and performance status were maintained, with decreasing levels of cTnT, indicating that Mel-Dex represents a feasible and effective therapeutic option for patients with AL amyloidosis with cardiac dysfunction.

Topics: Acute Disease; Amyloidosis; Biomarkers; Dexamethasone; Female; Heart Failure; Humans; Melphalan; Middle Aged; Treatment Outcome; Troponin T

A 55-year-old woman with primary Immunoglobulin light chain (AL) systemic amyloidosis died due to spontaneous rupture of her liver following treatment with high-dose melphalan and autologous stem cell transplant (HDM/SCT). She was first diagnosed after developing nephrotic-range proteinuria. Spontaneous rupture of her liver occurred 10 days after treatment with HDM/SCT and was complicated by septic shock. She was not eligible for surgical intervention and died shortly after. Amyloid fibrils were extracted from the autopsied liver sample (05-135L) and the biochemical nature of the fibrils was analyzed using electrophoretic and immunohistochemical techniques. Our testing showed that the fibrils were composed of immunoglobulin lambda light chains that were not glycosylated. While the liver is often involved in AL amyloidosis, this is the first documented case of a spontaneous hepatic rupture in a patient during treatment with HDM/SCT. A literature review of spontaneous liver rupture in patients with amyloidosis is presented.

Topics: Amyloid; Amyloidosis; Electrophoresis, Polyacrylamide Gel; Fatal Outcome; Female; Humans; Immunohistochemistry; Liver Diseases; Melphalan; Middle Aged; Rupture, Spontaneous; Stem Cell Transplantation; Transplantation Conditioning

AL-amyloidosis is a serious disease with a short median survival without treatment. Treatment with high-dose melphalan with autologous stem cell support (HMAS) has a potential to increase survival, but is associated with toxicity and mortality. In this paper we report the Norwegian results retrospectively.. We used questionnaires and had personal contact with a local physician from each hospital with HMAS experience. Diagnosis and treatment were evaluated according to the guidelines at the time of treatment, and the results were compared to internationally published reports.. Stem cell harvesting was attempted in 18 patients from 1997 to 2006. 15 of these received HMAS treatment. Treatment-related mortality was 20%, and 5 of 11 (45%) had an organ response. Median survival was not reached within the 55-month median observation time. The course of the disease was more complicated when known risk factors for HMAS treatment were present, such as reduced kidney function, advanced heart involvement, reduced performance status, and multiorgan disease. Three of 18 patients were not diagnosed according to relevant guidelines. In seven of 12 patients the response to treatment was not evaluated adequately with respect to haematology.. AL-amyloidosis is a difficult diagnosis and the condition is probably under-diagnosed in Norway. The results of HMAS treatment in Norway are comparable with those in published reports from centres abroad. The follow-up of patients should be improved.

Topics: Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Humans; Melphalan; Middle Aged; Practice Patterns, Physicians'; Retrospective Studies; Stem Cell Transplantation; Surveys and Questionnaires; Survival Rate; Transplantation, Autologous

Survival of patients with plasma cell disorders has increased. However, the expanding use of melphalan in patients with longer survival suggests that myelodysplasia may become increasingly important. The objective of this study was to determine the risk of myelodysplasia after treatment with melphalan for patients with amyloidosis. We reviewed the long-term follow-up data (more than 12 years) from 101 patients with immunoglobulin light-chain amyloidosis. We identified 10 patients with myelodysplasia or acute nonlymphocytic leukemia that directly caused death for 8 and transfusion dependency for 2. Two of the 10 patients did not have development of myelodysplasia until 144 months after first exposure to alkylating agents. The actuarial risk of myelodysplasia development at ten years was 18%. As the survival of patients with plasma cell disorders improves, myelodysplasia may be a more common cause of morbidity and mortality for this group.

Topics: Adult; Aged; Amyloidosis; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Risk Factors; Time Factors

Immunoglobulinic (AL) amyloidosis is a complication of plasma cell dyscrasia, characterized by widespread deposition of amyloid fibrils derived from monoclonal light chains. Cardiac amyloid is the main prognostic factor, with a median survival of six months. Cardiac transplantation in AL amyloidosis is associated with high mortality, due to disease recurrence in the allograft and systemic progression. Suppression of light chain (LC) production with chemotherapy by melphalan plus dexamethasone (MD) or high dose melphalan followed by autologous stem cell transplantation (HDM/ASCT) improves survival. However, both the indications and results of chemotherapy in patients transplanted for cardiac AL amyloidosis remain unclear.. To assess the outcome of cardiac transplantation and haematological therapy in patients with cardiac AL amyloidosis.. Eight French patients, who underwent heart transplantation for cardiac AL amyloidosis between 2001 and 2006 were studied retrospectively.. Before transplantation, six patients received MD (n=5) or HDM/ASCT (n=1). Haematological remission was obtained in three patients treated with MD. In the three remaining patients, postoperative HDM/ASCT (n=2) or allogeneic bone marrow transplantation (n=1) resulted in haematological remission in one patient. In 2 patients not treated before transplantation, post-operative treatment with MD resulted in complete hematological remission in one. After a median follow-up of 26 months from cardiac transplantation, six patients were alive and four had sustained haematological remission, as indicated by normal serum free LC levels.. Appropriate haematological therapy, including MD, may result in a survival benefit in AL amyloidosis patients with advanced heart failure requiring transplantation.

Topics: Adult; Amyloidosis; Cardiomyopathies; Combined Modality Therapy; Dexamethasone; Female; France; Heart Transplantation; Hematopoietic Stem Cell Mobilization; Humans; Male; Melphalan; Middle Aged; Myeloablative Agonists; Recurrence; Retrospective Studies; Stem Cell Transplantation; Time Factors; Transplantation, Autologous; Treatment Outcome

We report the case of a 51-year old man with symptoms of heart failure due to severe cardiac amyloidosis, in whom treatment with melphalan and dexamethasone yielded significant improvement in clinical status and both systolic and diastolic left ventricular (LV) function over a 12-week follow-up. The improvement in LV performance was detected by Tissue Doppler (TD) and strain analysis, despite no changes in standard indices such as ejection fraction and Doppler pattern of mitral inflow. Color TD-derived myocardial velocity and deformation indices also revealed a reduction in intra-ventricular early diastolic asynchrony after therapy. In addition, an improvement in intra-ventricular systolic synchrony was detected by strain rate and strain, but not by color TD velocity imaging. These findings suggest that treatment with melphalan and dexamethasone may improve symptoms of heart failure and LV performance in subjects with cardiac amyloidosis, and that TD and particularly strain imaging could represent useful techniques to monitor the effect of therapy on LV function in the follow-up of these patients.

Topics: Amyloidosis; Dexamethasone; Drug Therapy, Combination; Echocardiography, Doppler; Heart Diseases; Humans; Male; Melphalan; Middle Aged; Ventricular Function, Left

In high doses with stem-cell transplantation, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-) amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival, while no response (a less than 50% reduction) is not. Gene-expression studies and a stringently supervised analysis identified calreticulin as having significantly higher expression in the pretreatment plasma cells of patients with systemic AL-amyloidosis who then had a complete response to high-dose melphalan. Calreticulin is a pleiotropic calcium-binding protein found in the endoplasmic reticulum and the nucleus whose overexpression is associated with increased sensitivity to apoptotic stimuli. Real-time PCR and immunohistochemical staining also showed that expression of calreticulin was higher in the plasma cells of those with a complete response. Furthermore, wild-type murine embryonic fibroblasts were significantly more sensitive to melphalan than calreticulin knock-out murine embryonic fibroblasts. These data have important implications for understanding the activity of melphalan in plasma-cell diseases and support further investigation of calreticulin and its modulation in patients with systemic AL-amyloidosis receiving high-dose melphalan.

Topics: Amyloidosis; Animals; Apoptosis; Calreticulin; Cell Line; Embryo, Mammalian; Endoplasmic Reticulum; Female; Fibroblasts; Gene Expression Regulation; Humans; Immunoglobulin Light Chains; Immunohistochemistry; Male; Melphalan; Mice; Mice, Knockout; Myeloablative Agonists; Plasma Cells; Reverse Transcriptase Polymerase Chain Reaction; Stem Cell Transplantation; Transplantation, Autologous

Topics: Amyloidosis; Combined Modality Therapy; Female; Humans; Kidney Diseases; Melphalan; Middle Aged; Stem Cell Transplantation

Amyloidosis is a rare systemic disorder of protein metabolism with progressive extra-cellular deposition of insoluble fibrillary protein, disorganization of tissue architecture, and subsequent organ dysfunction. Primary amyloidosis is the most common form of this disorder, however, it can develop secondary to plasma cell dyscrasias such as multiple myeloma (MM); 10-15% of MM patients may develop amyloidosis of vital organs. Amyloidosis is usually associated with bleeding, but less commonly with thrombosis. We present a 52-year-old Saudi female with amyloidosis secondary to multiple myeloma. She presented with both venous and extensive arterial thrombosis. Although relatively rare, plasma cell dyscrasias such as amyloidosis and multiple myeloma could present with thrombotic rather than hemorrhagic complications.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Aortography; Arterial Occlusive Diseases; Biopsy; Female; Humans; Kidney; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Treatment Outcome; Venous Thrombosis

Cardiac amyloidosis (CA) is associated with a poor prognosis and a survival rate of less than 30% 2 years after clinical manifestation. Considered as a semi-malignant disease, CA is often a contraindication for HTx; however, depending on the type of CA, there are excellent treatment regimes that can be combined with HTx. In AL-amyloidosis, chemotherapy and stem cell transplantation are necessary and in TTR-amyloidosis, where the liver is the source of the pathologic protein, liver transplantation is recommended after HTx.. More than 60 patients with AL-amyloidosis and more than 25 patients with ATTR-amyloidosis have been investigated at our centre. Eighteen patients showed signs of end-stage heart failure. Four patients died within 1 month after listing for HTx. Seven patients with AL (mean age 41.8 years) and five patients with ATTR-amyloidosis (mean age 42.6 years) were successfully transplanted with an actual survival rate of 91.6%. One patient died 8 months after HTx due to infection. Five AL patients received chemotherapy and SCT and one ATTR patient was liver transplanted. Three AL patients showed complete remission of amyloidosis.. Cardiac amyloidosis is a potentially curative disease after HTx when combined with either chemotherapy and SCT or LiverTx depending on the type of the amyloidosis. Due to the natural course of the disease, urgent HTx after cardiac manifestation is mandatory. With this approach, excellent survival rates and even remission of the underlying disease is possible.

Topics: Adult; Amyloidosis; Cardiomyopathies; Decision Trees; Disease Progression; Female; Heart Failure; Heart Transplantation; Humans; Liver Transplantation; Male; Melphalan; Middle Aged; Myeloablative Agonists; Severity of Illness Index; Stem Cell Transplantation; Survival Analysis

Topics: Amyloidosis; Dexamethasone; Drug Therapy, Combination; Humans; Immunoglobulin Light Chains; Melphalan; Myeloablative Agonists; Risk

Topics: Amyloidosis; Dexamethasone; Drug Therapy, Combination; Humans; Immunoglobulin Light Chains; Melphalan; Myeloablative Agonists; Research Design

Topics: Amyloidosis; Biomarkers; Dexamethasone; Drug Therapy, Combination; Humans; Immunoglobulin Light Chains; Melphalan; Myeloablative Agonists; Rare Diseases

Topics: Amyloidosis; Combined Modality Therapy; Dexamethasone; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Melphalan; Myeloablative Agonists

Recurrence in the allograft and progression in other organs increase mortality after cardiac transplantation in AL amyloidosis. Survival may be improved after suppression of monoclonal light chain (LC) production following high dose melphalan and autologous stem cell transplantation (HDM/ASCT). However, because of high treatment related mortality, this tandem approach is restricted to few patients without significant extra-cardiac involvement. A diagnosis of systemic AL amyloidosis was established in a 45-year old patient with congestive heart failure related to restrictive cardiomyopathy, nephrotic syndrome, peripheral neuropathy, postural hypotension, macroglossia, and lambda LC monoclonal gammopathy. After melphalan and dexamethasone (M-Dex) therapy, which resulted in 80% reduction of serum free lambda LC, he underwent orthotopic cardiac transplantation. Two years later, he remains in a sustained hematologic remission, with no evidence of allograft or extra-cardiac amyloid accumulation. M-Dex should be considered as an alternative therapy in AL amyloid heart transplant recipients ineligible for HDM/ASCT.

Topics: Amyloidosis; Dexamethasone; Drug Therapy, Combination; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Paraproteinemias; Peripheral Nervous System Diseases; Secondary Prevention

Acquired loss of functional von Willebrand factor (VWF) has been termed the acquired von Willebrand syndrome (AVWS). AVWS is a rare adult-onset bleeding diathesis that is clinically similar to congenital von Willebrand disease (VWD), and occurs with a variety of autoimmune, lymphoproliferative, or myeloproliferative disorders. We have identified four patients with AVWS in association with immunoglobulin light chain (AL) amyloidosis. These patients, lacking any pre-existing or family history of abnormal bleeding, developed cutaneous, mucosal, or gastrointestinal bleeding in the course of their disease without deficiency of clotting factor X or other factors; the activated partial thromboplastin time (aPTT) was prolonged in three out of the four cases. Despite normal VWF antigen levels, VWF ristocetin cofactor activity (VWF:RCo) was low. Electrophoresis patterns of high molecular weight (HMW) VWF multimers were abnormal in two of the four cases. Two of the patients were treated with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) and achieved hematologic remission. In these two patients, the bleeding diathesis improved and the coagulation parameters normalized, confirming a causal relationship between the plasma cell dyscrasia and the AVWS. AVWS should be considered in AL amyloidosis patients with hemorrhagic diatheses and normal clotting factor levels.

Topics: Adult; Amyloidosis; Antigens; Blood Protein Electrophoresis; Electrophoresis, Agar Gel; Hemorrhage; Humans; Immunoglobulin Light Chains; Male; Melphalan; Molecular Weight; Partial Thromboplastin Time; Peripheral Blood Stem Cell Transplantation; Remission Induction; Ristocetin; Transplantation, Autologous; von Willebrand Diseases; von Willebrand Factor

Refractory pleural effusions present a challenging management problem and are associated with a poor prognosis in patients with primary systemic amyloidosis (AL). We report a series of four patients with AL who presented with bilateral pleural effusions that were refractory to diuretic therapy. After treatment with bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, three of the four patients had improvement in their pleural effusions, peripheral edema, and functional status. Additional studies are needed to further define the role of bevacizumab in the management of this group of patients.

Topics: Amyloidosis; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Captopril; Chest Tubes; Combined Modality Therapy; Dexamethasone; Diuretics; Drug Resistance; Edema; Fatal Outcome; Furosemide; Humans; Hypoalbuminemia; Male; Melphalan; Metolazone; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Pleural Effusion; Prednisolone; Serum Albumin; Spironolactone; Thalidomide; Thoracostomy; Transplantation, Autologous; Vascular Endothelial Growth Factor A

Topics: Abdomen; Aged; Amyloidosis; Anti-Inflammatory Agents; Biopsy; Glucocorticoids; Hepatomegaly; Humans; Liver; Liver Diseases; Male; Melphalan; Myeloablative Agonists; Prednisone; Prognosis; Radiography, Abdominal; Radiography, Thoracic; Tomography, X-Ray Computed; Ultrasonography

Primary amyloidosis is a plasma cell dyscrasia characterised by excess production of abnormal immunoglobulin light chains with their subsequent accumulation in kidneys, heart, liver as well as gastrointestinal tract and bone marrow 1-21, 2. These tissue deposits take the form of a fibrillar protein which damages the involved organ in proportion to the extent of the infiltration and roughly parallels the duration of the disease. Most cases have evidence of the underlying lymphoplasmacytoid neoplasm recognisable in two ways. Firstly, the monoclone appears in the serum [2]. Secondly is a morphologically and immunohistochemically distinctive cellular infiltrate in the bone marrow [3] that has a specific microscopic and ultrastructural pattern 4-54, 5. Interestingly occasional patients, who survive long enough, may progress to multiple myeloma [6] but the correlation is variable [7].

Topics: Adult; Aged; Amyloidosis; Antibodies, Monoclonal; Bone Marrow; Bone Marrow Transplantation; Colchicine; Diagnosis, Differential; Disease Management; Female; Humans; Immunotherapy; Lymphoproliferative Disorders; Male; Melphalan; Methylprednisolone; Middle Aged; Plasma Cells; Prednisone; Radioimmunotherapy; South Africa; Survival Rate

Topics: Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Dexamethasone; Follow-Up Studies; Humans; Immunoglobulin Light Chains; Melphalan; Stem Cell Transplantation; Survival Analysis; Survivors; Time Factors

Multicentric Castleman disease is a systemic lymphoproliferative disease with incomplete understood etiology. The various renal complications of this disease may include minimal change disease, mesangial proliferative glomerulonephritis, membranous glomerulonephritis and nephrotic syndrome, caused by secondary amyloidosis. In several reported cases of localized Castleman disease associated with renal amyloidosis and nephrotic syndrome, resection of organs involved by lymphoid proliferation resulted in complete remission. However, therapy of multicentric Castleman disease with renal amyloidosis is not well-established. We treated a case of a 39-year-old woman with multicentric Castleman disease complicated by nephrotic syndrome caused by secondary AA amyloidosis. The patient underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), achieving complete remission. Autologous stem cell transplantation may be an attractive choice in therapy for refractory multicentric Castleman disease.

Topics: Adult; Amyloidosis; Castleman Disease; Female; Humans; Kidney Failure, Chronic; Melphalan; Myeloablative Agonists; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation

AL amyloidosis is a disease in which immunoglobulin L chain is deposited in multiple organs, and the prognosis of cardiac amyloidosis is extremely poor. Although several treatments based on that for multiple myeloma, have been performed, there is no clear evidence that cardiac function is improved. We report a case of AL cardiac amyloidosis with moderate cardiac dysfunction for which we performed autologous peripheral blood stem cell transplantation (auto-PBSCT) in combination with high-dose melphalan therapy. This treatment resulted in significant improvement in cardiac function and good prognosis for about 3.5 years after the diagnosis. Therefore, auto-PBSCT is a possible option as up-front therapy for AL cardiac amyloidosis.

Topics: Amyloidosis; Cardiomyopathies; Combined Modality Therapy; Female; Heart; Humans; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Prognosis

A 63-year-old man, known to have Bechterev's disease was admitted because of weight gain and nocturnal sweating. He also had signs of heart failure with progressive exertional dyspnoea. Many months previously numerous bleedings had occurred in the skin, predominantly the face (periorbital and perioral), the inguinal region and the penis.. Extensive diagnostic test failed to find any evidence of tumor. The Rumpel-Leede tourniquet test was positive, while platelet functions was normal, suggesting vascular disease. The skin biopsy showed many perivascular amyloid deposits (AL). Immunochemical differentiation also demonstrated the same amyloid in rectal and hepatic biopsies. But there was AA amyloid in a hepatic artery. Immunophoresis indicated a biclonal gammopahty of unknown significance.. These findings indicated the diagnosis of primary AL amyloidosis associated with a gammopathy of unknown significance and a secondary AA amyloidosis in the presence of chronic Bechterev s disease. The clinical picture also showed cardiac complications, predominantly heart failure and numerous previous myocardial infarctions without S-T elevations. Echocardiography, which revealed marked thickening of the left ventricle with a restrictive filling pattern, suggested cardiac co-morbidity. The patient underwent chemotherapy with melphalan and prednisone but had a sudden cardiac death.. In a case of bleeding of unknown cause systemic amyloidosis should be considered in the differential diagnosis. A tendency towards bleeding, as in this patient, may be the first sign of amyloidosis, which ist often diagnosed quite late in the course of the disease.

Topics: Amyloidosis; Death, Sudden, Cardiac; Diagnosis, Differential; Fatal Outcome; Glucocorticoids; Heart Failure; Hemorrhagic Disorders; Humans; Male; Melphalan; Middle Aged; Myocardial Infarction; Paraproteinemias; Prednisone; Spondylitis, Ankylosing

No established treatments for systemic AL amyloidosis have been determined, and only four reports have described allogeneic stem cell transplantation for this disease. We report the case of a patient with orthostatic hypotension, diarrhea, nephrotic syndrome, and cardiac amyloidosis due to systemic AL amyloidosis. Reduced intensity allogeneic stem cell transplantation (RIST) was performed using a conditioning regimen comprising fludarabine 125 mg/m2 and melphalan 90 mg/m2. Hematologically complete remission and symptomatic improvement were obtained without severe transplantation-related complications. RIST may thus offer a useful treatment strategy for systemic AL amyloidosis complicated by cardiac amyloidosis.

Topics: Adult; Amyloidosis; Diarrhea; Drug Therapy, Combination; Heart Diseases; Humans; Hypotension; Japan; Kidney Diseases; Male; Melphalan; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Remission Induction; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which amyloidogenic monoclonal light chains deposit in various tissues resulting in organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. Several phase II studies report haematological and clinical remission in up to 50% of patients after high-dose melphalan and autologous stem cell transplantation. We analysed retrospectively the long-term outcome of 19 patients treated in this way between August/1996 and December/2001. We observed a relatively high treatment-related mortality of 26%, but 12 patients (63%) were high-risk candidates. Eight patients (42%) surviving longer than 100 days achieved haematological remission and long-term survival, whereas 6 (32%) obtained no clear benefit from high-dose therapy. However, 62% of patients survived beyond 2 years and the median survival from transplant was 48 months (range 0-104 months).

Topics: Adult; Amyloidosis; Female; Humans; Male; Melphalan; Middle Aged; Myeloablative Agonists; Remission Induction; Stem Cell Transplantation; Stem Cells; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

AL amyloidosis, a systemic disorder characterized by widespread deposition of amyloid fibrils derived from monoclonal Ig light chains in organs and soft tissues, is typically caused by an underlying plasma cell dyscrasia. However, this disease can also be associated rarely with a B-cell lymphoproliferative disorder. In this report, we describe the presentation and clinical course of 16 patients with this association. Although amyloid-related organ involvement in these patients was typical of AL amyloidosis, the patients in this series were on average older and more likely to be female than patients with disease associated with a plasma cell dyscrasia. They were also more likely to have multisystem involvement. Treatment decisions were based primarily on the dominent hematopathologic features of the associated lymphoproliferative disorder. However, high-dose melphalan and stem cell transplantation was the primary therapy in 5 patients, and each of these patients had prolonged survival, ranging from 36 to 102 months.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Antineoplastic Agents, Alkylating; B-Lymphocytes; Bone Marrow Cells; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Paraproteinemias; Peripheral Blood Stem Cell Transplantation; Radiotherapy; Treatment Outcome

Amyloidosis is often difficult to diagnose and cardiac involvement worsens the prognosis.. We report the case of a 72-year old man consulting for cardiac failure with pleural effusion. A restrictive cardiomyopathy was discovered by echocardiography, and amyloidosis was then suspected. First histological localization was pleural. Cardiac involvement was confirmed. The diagnosis was supported by digestive and cutaneous localizations. It was an AL amyloidosis. Treatment with melphalan and dexamethasone allowed stabilization during more than six months.. This is an original case report, because of the first clinical signs (cardiac failure), the histological proof (pleural histology). Echocardiography is particularly helpful in internal medicine.

Topics: Aged; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Cardiomyopathy, Restrictive; Dexamethasone; Drug Therapy, Combination; Echocardiography; Humans; Male; Melphalan; Pleural Effusion; Treatment Outcome

Topics: Aged; Amyloidosis; Bone Marrow Cells; Clinical Trials as Topic; Humans; Immunoglobulin Light Chains; Immunoglobulin M; Melphalan; Middle Aged; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

Diagnostics of primary (AL) amyloidosis is difficult enough; treatment of this disease in not less difficult or more adequate. Because of similarity of the pathogenesis of AL-amyloidosis and that of multiple myeloma, similar therapeutic regimens, directed towards depression of plasma cell dyscrasia, are used in both cases: administration of melphalan in various doses together with prednisolone, administration of vincristine, adriablastine and dexamethasone, as well as high-dose chemotherapy with melphalan and autologic stem cell transplantation. This therapeutic approach makes it possible to reach clinico-laboratory remission and prolong the life of patients with AL-amyloidosis. The article contains a case description of a patient with AL-amyloidosis, who underwent a successful high-dose melphalan therapy with subsequent autologic stem cell transplantation.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Diagnosis, Differential; Drug Therapy, Combination; Humans; Immunoglobulin G; Male; Melphalan; Middle Aged; Prednisolone

At age of 57 years, a man experienced an episode of rhabdomyolysis. On that occasion muscle biopsy was not performed, however monoclonal gammopathy of undetermined significance (MGUS) was diagnosed. Further he developed a moderate proximal muscle weakness with CK level persistently elevated (1000-1200U/l). When he came to our observation, at age 67, a muscle biopsy revealed an amyloid myopathy and multiple myeloma was at the same time disclosed. Terminal complement complex C5b9 (membrane attack complex) deposits were found in the vessel walls and muscle fibers surface depicted by amyloid. Our case suggests to keep in mind the possibility that amyloid myopathy may begin as an isolate episode of rhabdomyolysis. The detection of complement complex C5b9 suggests that complement cascade is implicated in the muscular damage of amyloid myopathy.

Topics: Aged; Amyloidosis; Betamethasone; Biopsy; Blood Vessels; Complement Membrane Attack Complex; Complement System Proteins; Creatine Kinase; Glucocorticoids; Humans; Male; Melphalan; Muscle Weakness; Muscle, Skeletal; Muscular Diseases; Myeloablative Agonists; Rhabdomyolysis; Treatment Outcome

Topics: Adult; Amyloidosis; Heart Transplantation; Humans; Male; Melphalan; Myeloablative Agonists; Stem Cell Transplantation; Transplantation, Autologous

Cardiac involvement occurs in up to 50% of patients with primary or A amyloidosis (ALA) and is associated with very poor prognosis. B-type natriuretic peptide (BNP) has been proposed as a guide for treatment of heart failure patients and as an index of myocardial dysfunction in patients with ALA. Data about BNP dosage for cardiovascular monitoring of patients with ALA on renal replacement therapy are lacking.. A 64 year old Caucasian man was admitted because of nephrotic syndrome in July 2003. Renal diagnosis was ALA. Melphalan and prednisolone were given but renal function worsened and in April 2004 standard bicarbonate hemodialysis was started. In March 2004 thalidomide was added to his therapy. During the follow-up ejection fraction was stable and was 65% on the contrary E/A ratio gradually increased and overtook 1. BNP plasma levels were increased and the values recorded during the follow-up were: 2505 pg/mL in October 2003 (normal reference values<100), 1827 in April 2004, 4006 in June 2004, 5000 in September 2004, 3750 in January 2005 and 1920 in April 2005. In September 2005 BNP was 3380 pg/mL. The patient was still alive after a follow-up longer than two years.. In ALA patients a powerful prognostic role of BNP has been reported whose expression is increased in ventricular myocytes of patients with cardiac involvement. BNP level monitoring does not appear to be superior to standard echocardiography in evaluating cardiovascular status of uremic patients with ALA.

Topics: Amyloidosis; Anti-Inflammatory Agents; Bicarbonates; Buffers; Cardiac Output, Low; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Melphalan; Middle Aged; Natriuretic Peptide, Brain; Nephrotic Syndrome; Prednisolone; Renal Dialysis; Thalidomide; Treatment Outcome

A 67-year-old woman was admitted to our hospital because of breathlessness. Systemic amyloidosis had been diagnosed 5 years previously. Her chest X-ray film showed multiple nodules in both lung fields. Chest computed tomography (CT) revealed some of the nodules had calcifications. Bronchoscopy demonstrated amyloid deposits in the bronchial walls. The serum titer of anti-SS-A antibody was high. Results of both the Schirmer Test and the Rose-Bengal Test were positive. The final diagnosis was systemic amyloidosis with Sjögren's syndrome. She was treated by chemotherapy using high dose melphalan with autologous peripheral blood stem cell transplantation (PBSCT). It was obvious that her chest X-ray film findings and bronchoscopic findings had improved 9 months after high dose chemotherapy with PBSCT. The disappearance of M protein and improvement of thirst, a symptom of Sjögren's syndrome, were also observed.

Topics: Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Drug Administration Schedule; Female; Humans; Melphalan; Peripheral Blood Stem Cell Transplantation; Sjogren's Syndrome; Solitary Pulmonary Nodule; Transplantation, Autologous; Vincristine

The treatment of AL amyloidosis was not successful until the advent of myeloablative chemotherapy consisting of high-dose intravenous melphalan followed by autologous peripheral blood stem cell transplantation. This new treatment has achieved better survival rates and, remarkably, it has obtained complete remission. Among patients with renal involvement, achievement of a complete hematological response was associated with a 50% reduction in proteinuria and stable creatinine clearance in more than 2/3 of patients. Despite of these excellent results, this new therapy is associated with significant toxicity, including the development of acute renal failure due to white blood cell lysis syndrome. We report a 59 year-old female with a nephrotic syndrome due to primary amyloidosis successfully treated autologous stem cell transplantation who developed acute renal failure caused by white blood cell lysis syndrome. The patient required treatment with granulocytic colony stimulating factor and intermittent hemofiltration and was discharged 23 days after melphalan administration with a satisfactory renal function and white blood cell count. After one year of follow up, she maintains a good glomerular filtration rate, a proteinuria of less than, 1 g/day and normal hematological values.

Topics: Acute Kidney Injury; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Melphalan; Middle Aged; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous; Tumor Lysis Syndrome

High-dose melphalan with autologous peripheral blood stem cell transplantation (ASCT) is an effective treatment for systemic primary amyloidosis. This procedure is, however, associated with substantial toxicity and mortality, particularly if the heart is involved. Refined selection of patients suitable for transplantation and personalized adaptation of the doses of melphalan might improve the outcome.. Twenty-two consecutive patients were selected for age, number of organ systems involved, heart and kidney function, and treated with risk-adapted melphalan conditioning. This was first-line therapy in 81% of cases.. Fifty-five percent of the patients had amyloid involvement of two organ systems, with renal involvement predominant in half. Approximately 70% received full-dose melphalan. Toxicity was manageable and three transplant-related deaths (14%) occurred only in the early phase of the study. The median overall survival was 68 months. The intent-to-treat hematologic response rate was 55% at +12 months (complete, 36%; partial, 19%), which was accompanied by organ responses in 75%. Survival was positively influenced by: (i) hematologic response at +3 months (complete+partial responses 55%, median not reached, more than 108 months; no response, median 17 months) (p=0.001); (ii) amyloid involvement of a single organ system (p=0.016). Prolonged follow-up demonstrated that remissions are durable, but relapses may occur as 4 of 12 responsive patients (33%) relapsed, three from complete response, between +30 to +38 months.. The present risk-adapted approach produced acceptable toxicity and peri-transplant mortality with prolonged survival in responsive patients. Additional therapy should be considered if no hematologic response is observed at +3 months after ASCT.

Topics: Adult; Aged; Amyloidosis; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Risk Factors; Survival Analysis; Time; Transplantation Conditioning; Transplantation, Autologous

Treatment of patients with AL amyloidosis with high-dose melphalan and autologous peripheral blood stem cells (PBSC) produces hematologic remissions in approximately 40% of evaluable patients, accompanied by improvements in organ disease and quality of life. These patients, who frequently have amyloid deposits in bone marrow blood vessels and interstitium and impaired function of kidneys, liver, spleen, and heart, represent an unusual population for stem cell transplantation, with unique problems. To identify factors influencing engraftment rates after chemotherapy and autologous granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC reinfusion, we studied a group of 225 patients. The median time to neutrophil engraftment was 10 days (range, 8-17 days). In a multivariate analysis, the factors positively affecting the rate of neutrophil engraftment were CD34+ stem cell dose, female gender, and minimal prior alkylator therapy. The median time to platelet engraftment was 13 days (range, 7-52 days). Factors positively affecting platelet engraftment, in addition to CD34+ cell dose, included preserved renal function and the absence of neutropenic fever. The conditioning dose of intravenous melphalan was not found to be an independent predictive factor for hematopoietic recovery. Thus, in this patient population, organ function and host and hematopoietic factors influence engraftment after PBSC rescue.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Antigens, CD34; Antineoplastic Agents, Alkylating; Blood Platelets; Female; Fever; Graft Survival; Humans; Kinetics; Male; Melphalan; Middle Aged; Neutrophils; Peripheral Blood Stem Cell Transplantation; Predictive Value of Tests; Proportional Hazards Models; Retrospective Studies; Sex Factors; Transplantation, Autologous

Patients with primary systemic amyloidosis (AL) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality.. Consecutive AL patients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-dose melphalan was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum creatinine level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy.. Of the 80 patients studied, ARI developed in 18.8% of the patients after high-dose melphalan. Univariate analysis identified age, hypoalbuminemia, heavy proteinuria, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03).. The timing of renal injury strongly suggests melphalan as the causative agent. Ongoing tubular injury may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients.

Topics: Acute Kidney Injury; Adult; Aged; Amyloidosis; Drug Administration Schedule; Female; Humans; Male; Melphalan; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Survival Rate

Topics: Adult; Aged; Aged, 80 and over; Amyloid; Amyloidosis; Animals; Antineoplastic Agents, Alkylating; Child; Clinical Trials as Topic; Cohort Studies; Diagnosis, Differential; Disease Models, Animal; Etanercept; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Melphalan; Mice; Receptors, Tumor Necrosis Factor; Serum Amyloid A Protein; Stem Cell Transplantation; Transplantation, Autologous

We here report a case of a 50-year-old man who showed histologically evident resolution of primary amyloidosis by melphalan and prednisolone. The patient was admitted to our hospital for further evaluation of nephrotic syndrome and remarkable hepatomegaly with refractory ascites, on September 11, 1998. Laboratory tests at presentation showed nephrotic syndrome with slight renal impairment and elevation of the enzymes of the biliary system. Monoclonal light chains were not detected in the serum or urine by immunoelectrophoresis. A renal biopsy revealed global deposition of amyloid in all glomeruli, interstitium and blood vessels. Immunofluorescence staining was positive for kappa light chains. Liver biopsy specimens showed extensive deposition of amyloid along sinusoid walls. Bone marrow aspiration contained 7% plasma cells but no clusters or abnormal cells. Based on these findings, systemic AL- (amyloid light chain) amyloidosis was diagnosed, and the treatment with combinations of melphalan and prednisolone was started from October 1998 at intervals of 4-6 weeks. Renal impairment progressed, resulting in the initiation of maintenance hemodialysis in February 1999. Reinfusion of ascitic fluid into the hemodialysis circuit had been performed from March 1999 for refractory ascites, and ascites disappeared in July 1999. Furthermore, urinary output increased after 14 courses of chemotherapy. Renal function gradually ameliorated with a concomitant reduction in the enzymes of biliary system, and finally hemodialysis was discontinued in April 2001. Sixteen courses of chemotherapy were administered by April 2001. Proteinuria was negative in August 2001. A second renal biopsy was performed on November 20, 2001, which showed markedly decreased amyloid deposition and a proliferation of mesangial cells and increase in matrix in various degrees. We report a case of a patient with primary amyloidosis who was successfully treated by melphalan and prednisolone, resulting in marked resolution of renal amyloidosis.

Topics: Alkylating Agents; Amyloidosis; Drug Therapy, Combination; Glucocorticoids; Humans; Kidney Diseases; Male; Melphalan; Middle Aged; Prednisolone; Treatment Outcome

Immunoglobulin-related free light chains (FLCs) in serum have recently become quantitatively detectable using the nephelometric assay in plasma cell disorders, including multiple myeloma and AL amyloidosis. To investigate whether FLCs are useful as a diagnostic and therapeutic marker in Japanese patients with primary systemic AL amyloidosis, we determined these values in serum before and after chemotherapy.. The serum FLC analysis was carried out in 25 patients with primary systemic AL amyloidosis (mean age, 60.1+/-8.4 years). All of the patients were shown to have either ALkappa- or ALlambda-immunoreactive amyloid deposits on biopsied tissues. Thirteen patients were treated with VAD (vincristine, doxorubicin and dexamethasone) alone (n=6) or VAD and subsequent high-dose melphalan followed by autologous stem cell support (n=7), and serum FLCs were serially determined before and after the chemotherapy.. Before chemotherapy the amyloidogenic FLC was elevated in serum with or without abnormal e/e ratios in 24 patients, including 5 with undetectable M-protein in both serum and urine on immunofixation. After chemotherapy the amyloidogenic FLC in serum was significantly decreased irrespective of high-dose melphalan (p<0.05), and all the patients with normalized kappa/lambda ratios showed a good prognosis.. With respect to sensitivity and quantification serum FLCs will be a key marker for diagnosis and therapeutic effects in primary systemic AL amyloidosis. The prognosis of patients with this disease may be improved if the kappa/lambda ratio in serum can be normalized by intensive chemotherapy.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopsy; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Immunoassay; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Immunoglobulin Light Chains; Incidence; Infusions, Intravenous; Intestinal Mucosa; Japan; Kidney; Male; Melphalan; Middle Aged; Myeloma Proteins; Nephelometry and Turbidimetry; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Treatment Outcome; Vincristine

A patient with primary systemic AL amyloidosis achieved partial hematological response after 2 courses of VAD (vincristine, doxorubicin and dexamethasone) and subsequent high-dose melphalan followed by autologous peripheral blood stem cell transplantation despite involvement of multiple organs, including the heart. In this patient natriuretic peptides and free light chains in serum were useful as markers of cardiac involvement and therapeutic effects, respectively. When amyloidosis-related dysfunction is seen in multiple organs, this intensive chemotherapy might be a possible therapeutic option, although several modifications in the regimen and careful management are necessary.

Topics: Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Biopsy, Needle; Bone Marrow; Echocardiography; Follow-Up Studies; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Myocardium; Natriuretic Peptides; Peripheral Blood Stem Cell Transplantation; Submandibular Gland; Time Factors; Tongue; Transplantation, Autologous

Topics: Amyloidosis; Humans; Kidney Failure, Chronic; Kidney Transplantation; Melphalan; Stem Cell Transplantation; Transplantation, Autologous

Serum free light-chain (FLC) concentrations were measured by a sensitive nephelometric immunoassay in 66 patients with AL amyloidosis before and after treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT). At 1 year after HDM/SCT, 27 patients (41%) achieved a complete hematologic response (CR), that is, disappearance of the monoclonal gammopathy previously evident by immunofixation electrophoresis (IFE) in serum and urine and of plasma cell clonality in the bone marrow. Abnormally elevated FLC levels became normal in 27 patients (41%), and decreased by >90% in 37 (56%). Average improvements in FLC were 94% for patients who achieved a CR and 72% for those who did not (P=0.0001). However, a reduction in FLC of >90% was associated with a similar high likelihood of clinical improvement and prolonged survival, whether or not patients achieved a CR. While CR, as defined by standard criteria, is a more stringent indicator of hematologic response than are decreases in abnormally elevated FLC levels per se, these measures of hematologic response are complementary, and decreases in FLC are more readily detected early after treatment than are the changes in IFE and marrow studies required to determine CR.

Topics: Adult; Aged; Amyloid; Amyloidosis; Bone Marrow; Culture Media, Serum-Free; Disease-Free Survival; Female; Humans; Immunoassay; Immunoelectrophoresis; Immunohistochemistry; Male; Melphalan; Middle Aged; Paraproteinemias; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Time Factors; Transplantation, Autologous; Treatment Outcome

We describe a case of a systemic amyloidosis of kappa-AL type, presenting at CT as focal lung parenchymal nodules or areas of consolidation with or without a halo,showing different sizes and morphologic kinetics at follow-up. Lesions accompanied by a halo revealed faster progression and earlier response to chemotherapy with almost complete resolution after high dose therapy with a cytostatic alkylating agent(Melphalan) and autologous peripheral stem cell transplantation than their counterparts without a halo. Amyloid deposition was histologically confirmed, and severe inflammatory activity was found in and at the margins of the amyloidomas, the latter correlating in CT with the halo sign. In our case, this sign had a high prediction for growth kinetics and response to therapy of pulmonary amyloid.

Topics: Amyloid; Amyloidosis; Disease Progression; Follow-Up Studies; Forecasting; Humans; Immunoglobulin kappa-Chains; Lung Diseases; Male; Melphalan; Middle Aged; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Remission Induction; Tomography, X-Ray Computed; Treatment Outcome

Systemic amyloid light chain amyloidosis is a protein conformation disorder caused by a clonal plasma cell dyscrasia. Symptoms result from fibrillar extracellular deposits in kidney, heart, liver, gut, peripheral nervous system and other tissues. The deposits disrupt organ function and ultimately lead to death. The prognosis of systemic amyloid light chain (AL) amyloidosis is poor; less than 5% of all patients survive 10 years or longer. Using conventional chemotherapy, the median survival could be prolonged by 4 months. Treatment with high-dose melphalm (HDM) and autologous stem cell transplantation (ASCT) of selected patients has been shown to arrest and even to reverse the disease course. This procedure however remains controversial because treatment related mortality (TRM) in AL amyloidosis is substantially higher (15-40%) than in multiple myeloma (<5%). Here we review recent results of ASCT, eligibility criteria for HDM and report our own treatment results in 41 patients.

Topics: Adult; Aged; Amyloidosis; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous

Since the prognosis of localized amyloidosis remains unclear, we conducted a survey to define the characteristics and the course of this disease. The charts of 35 patients with either laryngeal (14 patients), tracheobronchial (10 patients), colonic (1 patient), or lower urinary tract amyloidosis (10 patients) were analyzed. The average age at diagnosis was 52.7+/-12 years (range 33-73 years). The amyloid protein type was specified to be amyloid light chain (AL) in 15 cases. All patients had undergone additional biopsies (accessory salivary glands, rectal, fat pad and bone marrow aspirates) to rule out a systemic disease. Symptomatic treatments included endoscopic excision and laser therapy. Colchicine and chemotherapy with prednisone and melphalan were prescribed with limited success. During a mean follow-up period of 6.1+/-5.3 years no patient developed a systemic form of amyloidosis. Six deaths were reported, one related to the disease because of a fatal airway hemorrhage. We suggest that immunolabeling studies should be more routinely performed. There was no risk of developing a systemic disease from local amyloid deposits in our survey. However, local evolution can be life-threatening. Such patients should be referred to specialist centers for further evaluation. Management requires close follow-up to exclude recurrence and to determine the appropriate symptomatic treatment.

Topics: Adult; Aged; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Case-Control Studies; Colchicine; Colon; Data Collection; Endoscopy; Female; Follow-Up Studies; Gout Suppressants; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Phototherapy; Prednisone; Prognosis; Respiratory System

Topics: Aged; Amyloidosis; Female; Humans; Longitudinal Studies; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous

Systemic amyloidosis with hepatic involvement is a rare disorder, which is characterized by the deposits of amyloid fibrils in the liver. The prognosis is poor and the median survival is 13 months. Bleeding problems resulting from coagulopathy frequently complicates systemic amyloidosis. We present two patients with a severe factor X deficiency and hepatomegaly as the presenting abnormalities of systemic amyloidosis. One of the patients was treated with high dose melphalan chemotherapy and autologous stem cell reinfusion, resulting in a normalization of the liver enzyme tests and the factor X level. The diagnosis and treatment of systemic amyloidosis with hepatic involvement and the management of the multifactorial coagulopathy in these cases is discussed.

Topics: Alkaline Phosphatase; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Blood Coagulation Tests; Dexamethasone; Doxorubicin; Factor X; Factor X Deficiency; gamma-Glutamyltransferase; Hepatomegaly; Humans; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

Topics: Amyloid; Amyloidosis; Calcinosis; Female; Humans; Intestinal Diseases; Intestinal Mucosa; Intestine, Large; Melphalan; Middle Aged; Prednisolone; Protein Denaturation; Treatment Outcome

Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity.

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Paraproteinemias; Proteinuria; Remission Induction; Salvage Therapy; Transplantation, Homologous; Treatment Failure

Topics: Amyloidosis; Antineoplastic Agents; Dexamethasone; Diagnosis, Differential; Glucocorticoids; Humans; Melphalan; Prednisolone; Stem Cell Transplantation

This report concerns a patient with IgM AL amyloidosis due to a B cell lymphoproliferative disorder who was successfully treated with VAD and subsequent high-dose melphalan followed by autologous stem cell support. After this chemotherapeutic regimen, the patient showed complete hematological remission and improvement in nephrotic syndrome. These findings suggest that high-dose melphalan may also be effective for lymphoplasmacytoid cells producing monoclonal IgM which are phenotypically distinct from plasma cells. Myeloablative therapies, such as high-dose melphalan, should definitely be considered as a treatment option for AL amyloidosis, irrespective of the type of precursor immunoglobulin.

Topics: Amyloidosis; B-Lymphocytes; Humans; Immunoglobulin M; Lymphoproliferative Disorders; Male; Melphalan; Middle Aged; Plasma Cells; Stem Cell Transplantation; Transplantation, Autologous

A 65-year-old male patient presented with right upper-quadrant abdominal pain. Ultrasonography revealed hypoechoic lesion in the perihepatic and intraparenchymal area. Computed tomography (CT) showed hypodense lesion in the same localization. A fine needle biopsy specimen of the perihepatic lesion was hemorrhagic. On abdominal CT, the liver showed enhancement, but the spleen did not enhance. The spleen could not be detected by scintigraphic imaging using Tc99m sulfur dioxide. A diagnosis of primary amyloidosis was made by renal biopsy. Melphalan 10 mg/day for 4 days/month was started. The clinical and radiological follow up demonstrated a resorption of the hematoma. The patient is still alive at the eighth month of therapy.

Topics: Abdominal Pain; Aged; Amyloidosis; Biopsy, Needle; Diagnosis, Differential; Follow-Up Studies; Hematoma; Humans; Immunohistochemistry; Liver Diseases; Male; Melphalan; Radionuclide Imaging; Risk Assessment; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography, Doppler

High-dose chemotherapy and autologous stem cell transplantation are used increasingly to treat patients with light-chain-related amyloidosis (AL). Treatment-related mortality is approximately 15%. To enable more patients to undergo stem cell transplantation, a risk-adapted strategy has been developed to treat with lower chemotherapy doses those patients who are at excessive risk. It is unclear whether reducing the chemotherapy dose in patients at excessive risk of treatment toxicity reduces the overall response. We retrospectively reviewed 171 AL patients who underwent conditioning chemotherapy with stem cell transplantation. The patients comprised two groups: those receiving standard high-dose melphalan and those receiving intermediate-dose melphalan. Responses were categorized as hematologic response, which used criteria for myeloma response. The two groups showed statistically significant differences; the overall response rates were 75% in the high-dose group and 53% in the intermediate-dose group although treatment-related mortality was the same in both groups. Reducing the melphalan dose appeared to render more AL patients eligible for stem cell transplantation but sacrificed an element of response. Methods are needed to reduce treatment-related toxicity so that more patients can receive full-dose conditioning chemotherapy.

Topics: Adult; Aged; Amyloidosis; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Retrospective Studies; Risk Adjustment; Survival Analysis; Transplantation Conditioning; Treatment Outcome

Topics: Aged; Amyloidosis; Drug Therapy, Combination; Factor X Deficiency; Female; Humans; Melphalan; Paraproteinemias; Prednisone; Treatment Outcome

We report here a case of a 35-year-old male who presented with multi-system disease, which on evaluation was found to be due to primary systemic amyloidosis. We present the myriad manifestations of this uncommon disease entity.

Topics: Adult; Amyloidosis; Diagnosis, Differential; Humans; Male; Melphalan; Prednisolone; Prognosis

Amyloidosis is a systemic disease characterized by generalized deposition of beta-organized proteic fibrillar material with green birefringence under polarized light, in different tissues and organs, the most frequent kidney, liver and heart, with important clinical repercussion. Primary or AL amyloidosis is the most common subtype of amyloidosis (1), confirmed by biopsy-proved amyloid deposition in abdominal fat pad, rectum, kidney or liver, if necessary, in which fragments of monoclonal light chains are deposited. Cases with factor X (Stuart factor) of coagulation deficiency associated are described, due to adsorption of this factor to amyloid fibrills. Normally, evolution is fatal, with only few months of survival. We report a case of primary amyloidosis with nephrotic syndrome, severe factor X deficiency (without bleeding complications), possible heart affection and short-term good response to chemotherapic treatment.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Drug Therapy, Combination; Factor X Deficiency; Glucocorticoids; Humans; Immunoglobulin lambda-Chains; Kidney; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Prednisone; Treatment Outcome

A 63-year-old patient had experienced bilateral spontaneous periorbital hemorrhage for one year. After hospitalization because of recurring hemoptysis, biopsies of skin and colon revealed systemic ALlambda amyloidosis. In addition, the heart and lungs appeared to be involved. Monoclonal gammopathy was excluded by a normal plasma cell count and a polyclonal expression pattern in a bone marrow sample and by radiographic examination. The patient was treated with a relatively non-aggressive regimen of melphalan and prednisolone monthly with careful hematologic monitoring. This approach led to a significant improvement in relevant parameters. Recent advances in diagnosis, monitoring and therapy have made it easier to manage patients with amyloidosis with their poor prognosis.

Topics: Amyloidosis; Drug Combinations; Eye Hemorrhage; Facial Dermatoses; Humans; Male; Melphalan; Middle Aged; Prednisolone; Treatment Outcome; Vascular Diseases

Primary AL amyloidosis involves vital organs from the early phase of illness, resulting in a poor prognosis. We report a patient with nephrotic syndrome due to this type of amyloidosis, who was successfully treated with two courses of VAD (vincristine, doxorubicin and dexamethasone) and subsequent high-dose melphalan (140 mg/m2) with autologous stem cell support. Following the serial chemotherapy his proteinuria improved, and M protein became undetectable in both serum and urine. To avoid the progression of primary AL amyloidosis, intensive chemotherapy should be actively used when the general status and vital organ functions are well preserved.

Topics: Amyloid; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Transplantation, Autologous

Primary (AL) and secondary (AA) amyloidosis are systemic diseases characterized by a process of amyloid deposition in many organs with unsatisfactory survival of patients. Apart from surgical intervention in those patients with bronchiectasias or osteomyelitis, the possibilities of influencing the development of AA amyloidosis are limited. The milestone therapy in patients with rheumatic diseases includes early treatment with DMARDs (disease-modifying antirheumatic drugs). A new promising therapeutic alternative is represented by anti-tumour necrosis factor-alpha (TNF-alpha) drugs such as infliximab and etanercept. The last class of agents used in the treatment of AA interferes with fibril formation: iododoxorubicin and low molecular weight sulfates (fibrilex). In the group of patients with AL, in addition to the standard combination of melphalan and prednisone, other therapeutic approaches such as ASCT (autologous stem cell transplantation) and new drugs with different mechanisms of action have been added recently. For the future, we can expect the development of immunotherapy (both active vaccination and passive immunization). In our department, we have treated 17 patients with AL and 14 patients with AA amyloidosis since 1995. We used various treatment regimens in both groups of patients. The treatment stabilized the disease or achieved partial remission in only 36% of patients with AA amyloidosis despite the use of intensive therapeutic modalities, while in the AL group a response was achieved in 82% of patients. ASCT improves patients survival in AL amyloidosis, but strict selection criteria are necessary (less than two affected organs and no signs of myocardial dysfunction).

Topics: Adult; Aged; Amyloid; Amyloidosis; Cohort Studies; Combined Modality Therapy; Dexamethasone; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Prednisone; Retrospective Studies; Risk Assessment; Severity of Illness Index; Stem Cell Transplantation; Survival Analysis; Treatment Outcome

Topics: Aged; Amyloidosis; Fatal Outcome; Glucocorticoids; Heart Diseases; Humans; Male; Melphalan; Prednisolone

We describe here an extremely rare case of primary amyloidosis which presented moderate pleural effusion and high fever. A 71-year-old man was admitted to our hospital because of exertional dyspnea, fatigue and fever. A chest X-ray showed right-sided moderate pleural effusion. A thoracocentesis revealed an exudative pleural effusion. Cytology and cultures of the effusion were negative. External drainage failed to control the effusion. To determine the etiology of the effusion and fever, bronchoscopy was performed. Biopsies of the tracheal wall showed amyloid deposition. The pleural effusion might have been due to the inflammation and the disturbed lymphatic drainage caused by the amyloid deposition. Treatment with melphalan (6 mg) and prednisolone (35 mg) for 4 days every 6 weeks decreased the fever and alleviated his symptoms.

Topics: Aged; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Bronchoscopy; Dyspnea; Exudates and Transudates; Fever; Humans; Lung Diseases; Male; Melphalan; Pleural Effusion; Prednisolone; Treatment Outcome

Topics: Acute Kidney Injury; Amyloidosis; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Kidney Function Tests; Melphalan; Middle Aged; Nephrotic Syndrome; Recovery of Function; Risk Assessment; Severity of Illness Index; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown.. In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow.. In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy.. Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.

Topics: Amyloid; Amyloidosis; Antineoplastic Agents, Alkylating; Female; Hematopoietic Stem Cell Transplantation; Humans; Kidney Diseases; Male; Melphalan; Middle Aged; Paraproteinemias; Remission Induction; Transplantation, Autologous

We present a 26-year-old man with edema, ascites and bloody diarrhea that later proved to be due to gastrointestinal and renal amyloidosis. Interestingly, he was also diagnosed as having ankylosing spondylitis,-possibly after a delay of 12 years. The obscure diagnosis and challenging treatment of secondary amyloidosis are further discussed.

Topics: Adult; Amyloidosis; Biopsy, Needle; Colchicine; Colonoscopy; Disease Progression; Drug Therapy, Combination; Fatal Outcome; Gastrointestinal Diseases; Humans; Immunohistochemistry; Male; Melphalan; Risk Assessment; Spondylitis, Ankylosing

To investigate whether monoclonal plasma cells in the bone marrow are useful as a therapeutic marker in AL amyloidosis, serial flow cytometry was performed in five patients with this disorder before and after chemotherapy. Four patients were treated with 2 or 3 courses of VAD (vincristine, doxorubicin and dexamethazone) and subsequently with high-dose melphalan followed by auto-PBSCT. The remaining one patient was treated with two courses of VAD alone. Before treatment all patients exhibited a CD19- CD56+ subpopulation, which indicated monoclonal plasma cells, in varying degrees. After treatment all patients showed a decrease in monoclonal plasma cells in accordance with the disappearance of M-protein in serum and/or urine. In two patients treated with VAD followed by auto-PBSCT, polyclonal (CD19+ CD56-) and total plasma cells gradually increased in the follow-up study, while monoclonal plasma cells stayed at less than 0.3% nine months after treatment. No apparent correlation was found between altered maturation of plasma cells and disappearance of M-protein. With respect to easy detection of monoclonal plasma cells producing amyloidogenic M-protein, flow cytometry of bone marrow aspirates is useful and reliable in the follow-up of patients with AL amyloidosis and in the evaluation of the effects of chemotherapy.

Topics: Aged; Amyloidosis; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Combined Modality Therapy; Dexamethasone; Doxorubicin; Female; Flow Cytometry; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; Male; Melphalan; Middle Aged; Myeloma Proteins; Plasma Cells; Vincristine

Topics: Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Drug Therapy, Combination; Fatal Outcome; Humans; Male; Melphalan; Multiple Myeloma; Muscle, Skeletal; Muscular Diseases; Prednisolone

Topics: Amyloid; Amyloidosis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Gastroscopy; Humans; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Stomach Diseases; Treatment Outcome; Vincristine

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Fatal Outcome; Female; Humans; Immunoglobulin A; Immunoglobulin Heavy Chains; Immunoglobulin kappa-Chains; Melphalan; Middle Aged; Paraproteinemias; Prednisone

High dose melphalan (HDM) followed by reinfusion of autologous blood stem cells (ASCT) has been applied in AL amyloidosis. Vincristine, doxorubicin, and dexamethasone (VAD) rapidly decrease light chain production in multiple myeloma. In a Phase I/II study of VAD followed by HDM and ASCT in AL amyloidosis, toxicity, feasibility, and response to this regimen were evaluated. Over a 5-year period 38 patients with AL amyloidosis were seen of which 12 out of 18 eligible patients participated in the study. VAD induced a distinct clonal response in 50% (6/12) of the patients, but without clinical improvement. In 11 patients HDM and ASCT was applied. Six months after ASCT 78% (7/9) of the surviving patients showed partial clonal response and none responded completely. Clinical condition evidently improved in 67% (6/9) of survivors, whereby clonal response, clinical response, performance score, and SAP scintigraphs were concordant. Therefore a complete clonal response is not a prerequisite for clinical improvement. With median follow-up after ASCT of 25 months, 75% of the study group patients were alive. Mortality was strongly depending on the number of organs involved Patients treated with HDM and ASCT had better survival than those not eligible (P < 0.0005).

Topics: Adult; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Etoposide; Female; Humans; Male; Melphalan; Middle Aged; Radionuclide Imaging; Stem Cell Transplantation

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Humans; Melphalan; Stem Cell Transplantation

Median survival of patients with AL amyloidosis with clinically significant cardiac involvement is 5 months when treated with cyclic melphalan and prednisone. We investigated a regimen of continuous oral melphalan as a single agent for patients with cardiac amyloidosis who were unable to tolerate prednisone or more aggressive chemotherapy. Thirty patients with amyloid cardiomyopathy were treated with continuous oral melphalan. Seven of 13 patients, evaluable after 3-4 months of treatment, achieved a partial haematological response and three achieved a complete haematological response; six patients have survived for > 1 year. This regimen appeared to be effective in inducing haematological responses in patients who received total doses of melphalan > 300 mg.

Topics: Aged; Aged, 80 and over; Amyloidosis; Antineoplastic Agents, Alkylating; Drug Administration Schedule; Female; Heart Diseases; Humans; Male; Melphalan; Middle Aged; Survival Analysis

Acquired deficiency of factor X occurs in patients with systemic amyloid light-chain (AL) amyloidosis, presumably due to adsorption of factor X to amyloid fibrils. Of 368 consecutive patients with systemic AL amyloidosis evaluated at Boston Medical Center, 32 patients (8.7%) had factor X levels below 50% of normal. Eighteen of these patients (56%) had bleeding complications, which were more frequent and severe in the 12 patients below 25% of normal; 2 episodes were fatal. Ten factor X-deficient patients received high-dose melphalan chemotherapy followed by autologous stem cell transplantation. Of 7 patients alive 1 year after treatment, 4 had a complete hematologic response, and all 4 experienced improvement in their factor X levels. One of 2 additional patients with partial hematologic responses had improvement in factor X. Thus, aggressive treatment of the underlying plasma cell dyscrasia in AL amyloidosis can lead to the amelioration of amyloid-related factor X deficiency.

Topics: Amyloid; Amyloidosis; Antineoplastic Agents; Blood Coagulation Tests; Factor X Deficiency; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hemorrhage; Incidence; Melphalan; Transplantation, Autologous; Treatment Outcome

Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation induces remission of the plasma cell dyscrasia in a substantial proportion of patients with AL amyloidosis. The impact of this treatment on associated renal disease is not known.. To determine the effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on AL amyloidosis-associated renal disease.. Prospective cohort study.. Academic medical center.. 65 patients with AL amyloidosis and urinary protein excretion greater than 1 g/24 h who received dose-intensive intravenous melphalan and autologous blood stem-cell transplantation between 1 July 1994 and 30 June 1998.. 24-hour urinary protein excretion, serum cholesterol level, serum albumin level, creatinine clearance, urine and serum immunoelectrophoresis, and bone marrow biopsy. Renal response was defined as a greater than 50% reduction in urinary protein excretion in the absence of a 25% or greater reduction in creatinine clearance. Complete hematologic response was defined as absence of detectable monoclonal protein in serum and urine and a bone marrow specimen containing less than 5% plasma cells without clonal dominance of kappa or lambda isotype.. Among the 50 patients who survived for at least 12 months, proteinuria, hypoalbuminemia, and hypercholesterolemia improved during follow-up; 36% met criteria for a renal response. Median 24-hour urinary protein excretion decreased from a baseline value of 9.6 g/24 h to 1.6 g/24 h at 12 months among patients with complete hematologic response, and 71% met criteria for a renal response. Twenty-hour urinary protein excretion did not decrease during follow-up among patients with persistent plasma cell disease, and only 11% had a renal response at 12 months (P < 0.001 for hematologic responders vs. nonresponders).. Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation improves the nephrotic syndrome in patients with AL amyloidosis-associated renal disease. The benefit is largely limited to patients achieving eradication of the underlying plasma cell dyscrasia.

Topics: Adult; Aged; Amyloidosis; Cholesterol; Combined Modality Therapy; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Hypercholesterolemia; Infusions, Intravenous; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Proteinuria; Transplantation, Autologous; Treatment Outcome

A 47 years old woman was admitted with severe congestive heart failure. Cardiac echography showed increased intra-ventricular septum thickness, and there was a serum Ig G lambda monoclonal component. Cardiac biopsies confirmed diffuse amyloidosis of Al type. To avoid cardiac toxicity of chemotherapy, the patient received first a heart transplantation (HT), followed six months later by melphalan 200 mg/m(2) and autologous peripheral blood stem cell support (PBSCT). This case suggests that such strategy is feasible with a favorable outcome, and HT may be an appropriate procedure for some patients with Al amyloidosis who meet the criteria for PBSCT.

Topics: Amyloidosis; Fatal Outcome; Female; Heart Failure; Heart Transplantation; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Transplantation, Autologous

Topics: Amyloidosis; Anti-Inflammatory Agents; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Prednisone; Treatment Outcome

Lymphadenopathy associated with hemorrhage as a presenting feature of primary (AL) amyloidosis has not previously been described. We report two such cases one of whom had an acquired factor X and IX deficiency. The clinical presentations were characterized by sudden spontaneous enlargement of lymph nodes followed by partial regression. In both cases significant delay in diagnosis, and hence treatment, occurred due to the mode of presentation. One patient died with rapidly progressive disease but the other has had an excellent response to therapy with high-dose melphalan (HDM, 200 mg/m2) and peripheral blood stem cell rescue. AL amyloid should be considered in all patients presenting with hemorrhagic lymphadenopathy.

Topics: Adult; Amyloid; Amyloidosis; Diagnosis, Differential; Factor X Deficiency; Fatal Outcome; Hematopoietic Stem Cell Transplantation; Hemophilia B; Hemorrhage; Humans; Liver; Lymphatic Diseases; Male; Melphalan; Microscopy, Polarization; Middle Aged

Topics: Aged; Amyloidosis; Anti-Inflammatory Agents; Humans; Male; Melphalan; Prednisolone; Sjogren's Syndrome

Topics: Amyloidosis; Drug Therapy, Combination; Glucocorticoids; Humans; Immunoglobulin Light Chains; Melphalan; Prednisolone

Amyloidosis may be primary or myeloma-associated. Skeletal lesions and the percentage of bone marrow plasma cells (<10% in primary, >20% in myeloma) account for the major differences between the two varieties. In the literature there are rare cases of primary amyloidosis presenting without myeloma and followed by development of myelomatous manifestations. Usually, the primary disease (i.e. the myeloma) is advanced, when amyloidosis is diagnosed. We describe a patient who had presented with a severe and progressive systemic amyloidosis and was diagnosed later to have a mild light chain myeloma. Aggressive treatment with melphalan, prednisone and colchicine resulted in a temporary partial remission, followed by a rapid downhill course, and the patient's death. The point of relatively mild myeloma following a rapidly progressive course of advanced amyloidosis is emphasized. Awareness of the possibility of such a combination may lead to early diagnosis, a more aggressive or novel therapeutic approach and, possibly, to a better prognosis.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Colchicine; Disease Progression; Fatal Outcome; Female; Heart Failure; Humans; Melphalan; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Prednisone

Primary systemic amyloidosis (AL) is a plasma cell dyscrasia characterized by the extracellular deposition of immunoglobulins light chains in different organs and systems. Median survival with current standard treatment is less than 2 years. Intensive chemotherapy followed by hematopoietic stem cell rescue has been used in AL for the last five years. The reported results are encouraging, with a high response rate (65%). Nonetheless, this procedure is associated to an important toxicity, with high transplant related mortality (about 25%). In patients with advanced AL (more than two involved organs) and/or complicated cardiac disease, the mortality is particularly high. In the current report we describe the outcome of the first five patients who received high dose therapy for AL at our institution.. This treatment was administered to patients up to the age of 70 years, who met the standard eligibility criteria for an autologous bone marrow transplantation. Intensive treatment consisted of melphalan 200 mg/m2 in all patients but one who received 140 mg/m2.. Two patients died during the first month after the transplant (arrhythmia: 1, multiorganic failure: 1). Both patients had a poor performance status and advanced disease, with more than two organs involved. The response in the remaining three was of stabilization of the nephrotic syndrome in one and objective response in all the involved organs in the remaining two.. High dose therapy (HDT) with stem cell rescue in AL produces a high response rate. Nevertheless, this treatment approach is associated to a high toxicity.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Postoperative Complications; Time Factors

Despite significant efficacy of melphalan and prednisone in the therapy of systemic AL(light chain amyloid)amyloidosis the prognosis of the disease is poor. In patients with severe renal manifestation the reported results of low-dose melphalan therapy are inconclusive with respect to relief of clinical symptoms and overall prognosis.. We report our results of therapy in a group of 22 patients (8 women, 14 men, mean age 60 years) with renal involvement as the main manifestation of systemic AL-amyloidosis without overt myeloma.. Ten patients were treated with low doses of melphalan and prednisone. No significant clinical improvement was observed in any case: the patients died an average of 12 months after diagnosis of the disease. Three patients were treated with high doses of melphalan followed by autologous stem cell transplantation. One patient died due to septicaemia after high-dose chemotherapy. Two of the patients experienced significant remission and live virtually free of clinical symptoms 12 and 18 months after therapy. Nine patients were treated only symptomatically: four of them were alive an average of 30 months after diagnosis of systemic AL-amyloidosis.. Only high-dose melphalan therapy offered a realistic chance of amelioration of clinical symptoms in our group of patients, although therapy-associated risks seem to be high. In patients with severe renal amyloidosis, who are not considered for high-dose therapy, particularly careful consideration of potential benefits and possible risks of conventional melphalan therapy is necessary, because the results of this approach are in doubt.

Topics: Adult; Aged; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Drug Therapy, Combination; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Kidney Diseases; Male; Melphalan; Middle Aged; Prednisone; Risk Factors; Time Factors; Transplantation, Autologous

Topics: Amyloidosis; Antigens, CD34; Antineoplastic Agents, Alkylating; Blood Transfusion, Autologous; Cardiomyopathies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Shock, Cardiogenic; Stem Cells

Topics: Aged; Amyloidosis; Arm; Dexamethasone; Dilatation, Pathologic; Female; Femoral Artery; Glucocorticoids; Humans; Iliac Artery; Melphalan; Popliteal Artery; Ultrasonography, Doppler; Varicose Veins

Amyloidosis should be considered in any patient older than 40 years who has nephrotic syndrome, congestive heart failure (not on an ischemic basis), idiopathic peripheral neuropathy, or unexplained hepatomegaly. When a patient has one of these problems, immunoelectrophoresis and immunofixation of the serum and urine should be done for the detection of a monoclonal light chain. If a monoclonal light chain is found, a diagnosis usually can be established by amyloid stains performed on a bone marrow biopsy specimen or a subcutaneous fat aspirate. The presence or absence of cardiac involvement with amyloid is the most important prognostic factor. Treatment can range from observation to oral chemotherapy to hematopoietic stem cell transplantation. A practical understanding of the mechanisms underlying this disease can lead to prompt diagnosis and early therapeutic intervention.

Topics: Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Diagnosis, Differential; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Prednisone; Prognosis; Vincristine

In a patient with nephrotic syndrome, renal biopsy revealed AL amyloid deposits. Monoclonal lambda light chains were identified in serum and urine. A low percentage of monoclonal plasma cells was detected in the bone marrow. The patient received four cycles of VAD and subsequent high-dose chemotherapy (HDCT) with melphalan (200 mg/m2) followed by autologous peripheral blood stem cell transplantation. Proteinuria rapidly diminished during chemotherapy. Three months after HDCT, the patient has no edema, and no signs of plasma cell dyscrasia are currently detectable. Using VAD before starting HDCT may improve the condition of patients with amyloidosis and reduce transplantation-related morbidity and mortality.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Recurrence; Transplantation, Autologous; Vincristine

We report a case of a 39-year-old man with lambda-light-chain multiple myeloma, nephrotic syndrome due to lambda-light-chain deposition disease in kidneys and amyloidosis in other tissues. The patient was treated with melphalan and prednisone for 1 year. After that, he was administered interferon-alpha2b (IFN-alpha2b; 3 MU, 3 times a week) as maintenance therapy for 2 years. At present, 5 years and 6 months after the initial diagnosis, the patient receives IFN-alpha2b (3 MU, twice a week) and remains in complete haematological remission.

Topics: Adult; Amyloidosis; Antineoplastic Agents; Humans; Immunoglobulin Light Chains; Interferon-alpha; Male; Melphalan; Multiple Myeloma; Nephrotic Syndrome; Prednisone; Remission Induction; Survivors

AL amyloidosis was diagnosed in a 56-year-old woman with spontaneous purpura, macroglossia and hepatomegaly, a serum IgGk monoclonal gammopathy and a 25% plasma cell bone marrow infiltration. She was started on high-dose treatment consisting of four monthly cycles of VID chemotherapy, then underwent a stem cell collection after priming with cyclophosphamide + G-CSF. Myeloablative therapy was with melphalan and busulfan. Hematologic recovery was fast and uncomplicated. At follow-up 22 months from ASCT, the patient shows a complete remission of the clonal plasma cell disorder, normalization of liver size and alkaline phosphatase level and a significant improvement in the signs of vascular and soft tissue amyloid infiltration.

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cyclophosphamide; Dexamethasone; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hepatomegaly; Humans; Idarubicin; Macroglossia; Melphalan; Middle Aged; Purpura; Transplantation, Autologous; Treatment Outcome; Vincristine

Topics: Adult; Amyloidosis; Colchicine; Cortisone; Drug Therapy, Combination; Female; Humans; Melphalan

Despite significant effects of melphalan and prednisone in the therapy of systemic AL-amyloidosis, overall prognosis is poor and remission of clinical symptoms cannot generally be expected. The course of the disease and results of therapy are possibly influenced by the degree and distribution of organ manifestation at the time of diagnosis. We report a group of patients with renal involvement as the main manifestation of disease.. Fifteen patients with systemic Al-amyloidosis without symptomatic myeloma (4 women, 11 men, median age 61 [34 to 71] years) have been attended to at our department and were treated throughout the course of the disease.. Since primary symptoms were frequently unspecific, the maximum time to diagnosis came to 28 months. Renal involvement was primarily evident at the time of diagnosis when all patients manifested proteinuria or renal insufficiency. Ten patients were treated with a melphalan and prednisone containing chemotherapeutic protocol. A significant clinical improvement was observed in no case. One patient in an advanced stage of disease died after the administration of a high-dose regimen of melphalan with blood stem-cell support subsequent to sepsis.. We do not see an absolute indication for chemotherapy. The unfavorable prognosis--14 patients died an average of 13 months after diagnosis--requires a particularly careful consideration of potential benefits and possible risks accompanying cytostatic therapy.

Topics: Adult; Aged; Amyloidosis; Edema; Female; Humans; Kidney Failure, Chronic; Male; Melphalan; Middle Aged; Paresthesia; Prednisone; Prognosis; Proteinuria; Survival Rate

High-dose melphalan (HDM) with peripheral blood stem cell transplant (PBSCT) is a common treatment for patients with multiple myeloma (MM) and more recently also with AL amyloidosis (ALA). We report two female patients with severe renal failure who underwent treatment with HDM for MM (patient 1) and ALA (patient 2). Both patients developed severe encephalopathy with generalised tonic-clonic seizures and a Glasgow Coma Scale (GCS) of 3/15. Causes for coma such as infections, metabolic disturbances, cerebral ischaemia or haemorrhage were excluded. Patient 1 died on day 25 post transplant while comatose. Patient 2 recovered from her comatose state 18 days after transplantation. To our knowledge this is the first report on a possible role of high-dose melphalan in the development of encephalopathy.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Coma; Combined Modality Therapy; Epilepsy, Tonic-Clonic; Fatal Outcome; Female; Glasgow Coma Scale; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Treatment Outcome

Tumour lysis syndrome (TLS) in plasma cell dyscrasias is extremely rare. TLS has been described in eight cases of multiple myeloma undergoing high-dose therapy with autologous stem cell transplant (ASCT). Recently, clinical trials of intensive chemotherapy followed by autologous or allogeneic stem cell support has been shown to offer potential benefit in AL (amyloid light-chain) amyloidosis. TLS in primary AL amyloidosis in this setting has not been previously reported. We report a case of TLS in a patient with AL amyloidosis which developed after high-dose melphalan chemotherapy supported by ASCT.

Topics: Acute Disease; Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Fatal Outcome; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Tumor Lysis Syndrome

Here we report an unusual case of primary systemic amyloidosis. The cutaneous lesions were polymorphic and included involvement of both external auditory canals. The visceral involvement was covert. Mapping of amyloid deposits was performed using scintigraphy with technetium-99m (V) dimercaptosuccinic acid ([99mTc (V)] DMSA). Therapy with melphalan, prednisone and colchicine resulted in considerable improvement.

Topics: Aged; Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Colchicine; Female; Gout Suppressants; Humans; Melphalan; Prednisone; Radionuclide Imaging; Skin Diseases; Technetium Tc 99m Dimercaptosuccinic Acid

Primary systemic amyloidosis (AL) and multiple myeloma both are clonal plasma cell proliferative disorders. Although 10-15% of patients with myeloma have coexisting primary amyloidosis, it is unusual for patients with primary amyloidosis to progress to myeloma at a later date. The authors describe a case series of six patients in whom such progression occurred.. A computerized search was done of the medical records of all patients seen at the Mayo Clinic between January 1, 1960 and December 31, 1994 with a diagnosis of AL. Of 1596 patients with AL, 6 patients (age range, 60-74 years; median age, 68 years) with biopsy-proven AL were reviewed in whom delayed (at least 6 months after the diagnosis of AL) progression to multiple myeloma occurred.. At the time of the diagnosis of AL, none of the six patients had evidence of multiple myeloma. The dominant manifestation of AL was peripheral neuropathy in three patients and cutaneous AL, renal AL, and amyloid arthropathy in one patient each. The diagnosis of multiple myeloma was made 10-81 months after the diagnosis of AL, based on the demonstration of multiple osteolytic lesions (4 patients) or marked bone marrow infiltration (> or = 50%) by plasma cells (5 patients). Two patients had received chemotherapy (melphalan and prednisone) for AL. Five patients received chemotherapy (four patients) or high dose methylprednisolone (one patient) after the diagnosis of multiple myeloma. Five patients died, and the median actuarial survival after the diagnosis of multiple myeloma was 20 months. Multiple myeloma was the cause of death in four patients; one patient died of systemic amyloidosis. In 2 patients death occurred within 3 months.. AL occasionally progresses to overt multiple myeloma. These cases usually occur in patients without significant cardiac or hepatic AL who live long enough to develop multiple myeloma.

Topics: Aged; Amyloidosis; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Retrospective Studies; Survival Rate

We reviewed clinical presentation, investigations, therapy, prognosis and outcome of 232 patients with primary (AL) cardiac amyloidosis. There were 142 men and 90 women. Median age at presentation was 59 years (range 29-85). AL heart disease was unusual both in patients under the age of 40 (3.0%) and in non-Caucasians (6.5%). Fatigue and weakness were the commonest presenting symptoms. Hallmark features of periorbital ecchymoses and macroglossia were present in 12.5% and 27.2%, respectively. AL cardiac amyloidosis was unusual in isolation (3.9%), and most frequently patients had features of multiorgan dysfunction; heavy proteinuria and features of malabsorption predominating in this respect. Heart involvement represents the worst prognostic indicator, with a median survival from diagnosis of 1.08 years, falling to 0.75 years with the onset of heart failure. Current therapeutic procedures appear to prolong survival, with left ventricular wall thickness, mass and ejection fraction on echocardiography and late potentials on signal averaged electrocardiography of use in prognostic stratification. Cardiac involvement from AL amyloidosis is rapidly fatal. It should be suspected in all patients with heart failure who have wall thickening on echo, normal chamber sizes, low EKG voltages and evidence suggesting a multisystem disease.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Cardiomyopathies; Colchicine; Drug Therapy, Combination; Ecchymosis; Echocardiography; Electrocardiography, Ambulatory; Fatigue; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunoglobulin Light Chains; Macroglossia; Male; Melphalan; Middle Aged; Prednisolone; Prognosis

We retrospectively investigated the feasibility and the toxicity of autologous stem cell transplantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high-dose melphalan (HDM) alone (n = 18) or in combination with 12 Gy total body irradiation (n = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow-up of 14 months, the OS and the EFS rates at 4 years were 57.1% (+/-10.8) and 29.9% (+/-14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance < 30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4-year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra-haematological toxicity, ASCT should not be considered in other cases.

Topics: Adult; Amyloidosis; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Prognosis; Retrospective Studies; Transplantation, Autologous; Whole-Body Irradiation

We describe a euthyroid patient who presented with a goiter that continued to enlarge despite levothyroxine administration. Three fine-needle aspirations for cytology were nondiagnostic. An open biopsy was complicated by bleeding from the surgical site. Primary systemic amyloidosis was diagnosed on the basis of the goiter histology, bone marrow aspirate, and urine immunoelectrophoresis. The patient received melphalan and steroid treatment and survived for an additional 16 months. This period was complicated by congestive heart failure, generalized seizures, and upper gastrointestinal bleeding. Our case illustrates the difficulties in making the diagnosis and in treatment of primary systemic amyloidosis.

Topics: Adult; Amyloidosis; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Diagnosis, Differential; Goiter; Humans; Male; Melphalan; Prednisolone; Thyroid Gland; Thyroxine; Tomography, X-Ray Computed; Ultrasonography

A 56 year-old woman was admitted due to exertional dyspnoea. Her chest x-ray and CT scanning showed widespread diffuse infiltrative changes in both lungs, associated with a pronounced decrease in diffusion capacity. Transbronchial biopsies showed primary (AL) amyloidosis. Systemic AL-amyloidosis was excluded and diagnosis of localised diffuse parenchymal pulmonary amyloidosis was established. Treatment with prednisolone and melphalan for one year has stabilised the condition. Lung transplantation will be considered in case of deterioration.

Topics: Amyloidosis; Anti-Inflammatory Agents; Female; Humans; Lung; Lung Diseases; Melphalan; Middle Aged; Prednisolone; Tomography, X-Ray Computed

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Female; Heart Failure; Humans; Melphalan; Middle Aged

Patients with AL amyloidosis and congestive heart failure have a very poor prognosis. To date, the recovery of these patients has not been described in detail.. To determine the frequency and characteristics regression of disease in patients with congestive heart failure due to AL amyloidosis.. Review of patients with systemic AL amyloidosis.. An international referral center for amyloidosis in the United States.. 140 patients with congestive heart failure due to Al amyloidosis who were seen between 1983 and 1994.. Functional status, Doppler echocardiography, and objective measurements of disease activity.. 3 of 140 patients (2.1%) had marked resolution of congestive heart failure and evidence for remission of disease activity. All 3 had been treated with melphalan.. Melphalan appears to have had a favorable effect in 3 patients with AL amyloidosis and heart failure. The abolition of light chains that was seen in these 3 patients suggests that light-chain toxicity may play a role in the genesis of heart failure in patients with AL amyloidosis.

Topics: Amyloidosis; Colchicine; Drug Therapy, Combination; Echocardiography, Doppler; Female; Heart Failure; Humans; Male; Melphalan; Middle Aged; Remission Induction

Topics: Adult; Amyloidosis; Bone Diseases; Colchicine; Diagnosis, Differential; Drug Therapy, Combination; Female; Femoral Neck Fractures; Fractures, Spontaneous; Humans; Male; Melphalan; Middle Aged; Prednisolone

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunoglobulin kappa-Chains; Intestinal Diseases; Male; Melphalan; Middle Aged; Plasmacytoma; Prednisolone; Remission Induction; Stomach Diseases

Topics: Amyloidosis; Combined Modality Therapy; Humans; Immunohistochemistry; Male; Melphalan; Middle Aged; Plasmapheresis

Topics: Acute Disease; Amyloidosis; Cardiomyopathies; Cholangitis; Cholestasis; Female; Humans; Liver Diseases; Melphalan; Middle Aged

Renal failure frequently complicates both multiple myeloma and systemic amyloidosis. Renal replacement therapy (RRT) may be poorly tolerated and its role in such patients is not clearly defined. Of fifty patients (26 males and 24 females) referred to a single centre because of renal failure associated with multiple myeloma or systemic amyloidosis 37 progressed to end-stage renal failure and 30 of these patients received RRT. Nine patients have been treated by CAPD, 13 by haemodialysis, and 8 patients have required both forms of dialysis. Overall one year and two year survival rates were 66% and 57% respectively. The median duration on RRT was 7.5 months (range 1-96 months) with a 51% one year, and a 46% two year survival rate. Of 7 patients with amyloidosis who underwent renal transplantation, 3 died within 6 months of transplantation. Undiagnosed cardiac involvement contributed to this early mortality. We conclude that renal replacement therapy is appropriate for some patients with multiple myeloma and systemic amyloidosis who develop endstage renal failure. Careful assessment and selection of patients is necessary prior to renal transplantation.

Topics: Adolescent; Adult; Aged; Amyloidosis; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Melphalan; Middle Aged; Multiple Myeloma; Peritoneal Dialysis, Continuous Ambulatory; Prednisolone; Renal Dialysis; Retrospective Studies; Survival Rate

A 42-year-old Japanese male was admitted to our hospital because of congestive heart failure (CHF). A diagnosis of primary amyloidosis was made on the basis of a heavy deposition of amyloid in the gastric submucosal tissue in addition to the hematological and immunological findings. Intermittent chemotherapy in combination with daily oral dimethylsulfoxide (DMSO) resulted in a dramatic decrease of plasma cells in the marrow as well as a gradual improvement of CHF. With this therapy, the cardiac ejection fraction was markedly improved. This case indicates that the long-standing administration of DMSO combined with cytoreductive chemotherapy is therefore effective in treating some cases with primary amyloidosis.

Topics: Adult; Amyloidosis; Dimethyl Sulfoxide; Drug Therapy, Combination; Heart Failure; Hepatomegaly; Humans; Male; Melphalan; Prednisone

Topics: Adult; Aged; Amyloidosis; Colchicine; Humans; Kidney; Kidney Function Tests; Male; Melphalan; Nephrotic Syndrome; Prednisone; Proteinuria

Patients (153) with biopsy-proven primary systemic amyloidosis (AL) were evaluated for their response rate to alkylating agent-based chemotherapy. Twenty-seven of the patients (18%) responded. The serum creatinine concentration had an adverse effect on response rate (P = .05). In patients with nephrotic syndrome, a normal serum creatinine value, and no echocardiographic evidence of cardiac amyloidosis, the response rate was 39% (12 of 31). Five of 34 patients with amyloid cardiomyopathy responded. Two of these five are alive 10 years after diagnosis. None of the 18 patients with amyloid peripheral neuropathy showed regression of their disease. The median time to achieve response was 11.7 months. The median survival of the 27 patients was 89.4 months and 21 of 27 survived 5 years (78%). Eight patients remain alive with a minimum follow-up of 90 months. Seven died of acute leukemia or dysmyelopoietic syndrome, a presumed complication of melphalan therapy. In the group of 126 patients who showed no response to alkylating agent-based therapy, the median survival was 14.7 months and 9 (7%) survived over 5 years. All 126 patients have died. Alkylating agent-based chemotherapy for AL is beneficial in a subset of patients and a trial of chemotherapy is strongly recommended. Those patients who do respond demonstrate survival benefit.

Topics: Amyloidosis; Discriminant Analysis; Humans; Melphalan; Multivariate Analysis; Nephrotic Syndrome; Prednisone; Survival Analysis; Time Factors

Six patients are presented in whom a diagnosis of amyloidosis of immunoglobulin origin was established by light and electron microscopy of biopsy samples. Treatment with a regimen of intermittent doses of melphalan and prednisone resulted in a survival of 48-82 months in four of the patients while two patients died within three months of diagnosis, too soon for the therapy to have been effective. When compared with published series which suggest that the median survival of this condition is approximately 14 months, our results suggest that this treatment prolongs life successfully. These patients also enjoyed a greatly improved quality of life while receiving treatment.

Topics: Aged; Amyloidosis; Drug Therapy, Combination; Humans; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Prednisone; Survival Analysis

We followed up 153 patients with biopsy-proven primary systemic amyloidosis to determine their risk for acute nonlymphocytic leukemia or a dysmyelopoietic syndrome. In 10 patients cytogenetic abnormalities developed consistent with alkylator-induced damage to hematopoietic cells. In this group, the total melphalan dose ranged from 476 to 2450 mg (median, 1764 mg) administered over 21 to 92 months (median, 38 months). Eight of the 10 patients died as a direct result of pancytopenia, 1 died of progressive renal amyloid, and 1 remains alive with persistent complex cytogenetic abnormalities. Four patients had acute nonlymphocytic leukemia; 5 had a dysmyelopoietic syndrome; and 1 had a nondiagnostic bone marrow examination. Although only 6.5% of the entire group had leukemia or a dysmyelopoietic syndrome, the actuarial risk in patients surviving 3.5 years was 21%. Median survival from onset of dysmyelopoietic syndrome or acute leukemia was 8.1 months.

Topics: Aged; Amyloidosis; Chromosome Aberrations; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Risk Factors; Survival Rate; Time Factors

Topics: Amyloid; Amyloidosis; Colchicine; Diagnosis, Differential; Hepatomegaly; Humans; Melphalan; Serum Amyloid A Protein; Serum Amyloid P-Component

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Factor VII Deficiency; Factor X Deficiency; Humans; Hypoprothrombinemias; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Shock, Hemorrhagic; Vincristine

Topics: Amyloidosis; Bone Diseases, Metabolic; Bone Marrow; Colchicine; Drug Therapy, Combination; Female; Humans; Liver Diseases; Melphalan; Middle Aged; Prednisone; Remission Induction

Topics: Aged; Amyloidosis; Factor X Deficiency; Humans; Hypoprothrombinemias; Liver; Male; Melphalan; Prednisone

Topics: Amyloidosis; Drug Therapy, Combination; Factor X Deficiency; Humans; Hypoprothrombinemias; Melphalan; Prednisone

A 57 year old female presented with an amyloid myopathy in association with lambda light chain myeloma. Treatment with melphalan and prednisolone resulted in remission of both myeloma and myopathy.

Topics: Amyloidosis; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone

Seven patients with immunoglobulin type (AL) amyloidosis were treated with combination chemotherapy, including melphalan, prednisone, and colchicine. Two patients died within 5 months of the beginning of therapy. Both had amyloid cardiomyopathy. Five patients were alive 17-60 months after the start of therapy, and none had shown progression of disease. The most significant findings were the resolution of the nephrotic syndrome in 2 patients, and improvement of liver function, as demonstrated by excretion of indocyanine green, in 2 patients. These results are encouraging and support the need for further studies of this regimen of combination chemotherapy for patients with AL amyloidosis.

Topics: Aged; Amyloid; Amyloidosis; Colchicine; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Prednisone; Prognosis

Topics: Amyloidosis; Dimethyl Sulfoxide; Humans; Lung Diseases; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Pulmonary Alveoli

We report the first case of biopsy-proven primary hepatic amyloidosis in which histologic regression was demonstrated after therapy with melphalan and prednisone. On the basis of the cumulative reported experience regarding the treatment of this rare plasma cell dyscrasia, we recommend a trial of cytotoxic therapy for patients with primary hepatic amyloidosis.

Topics: Adult; Amyloidosis; Female; Humans; Liver Diseases; Male; Melphalan; Middle Aged; Prednisone

A 45-year-old man with primary amyloidosis was initially seen with nephrotic syndrome. Factor X was found to be 5% and antithrombin III (AT III) 45% of normal plasma values. During an 11-month period, despite severe factor X deficiency, the patient did not have any bleeding complications. He developed progressive renal failure and AT III levels increased to normal, at which time he developed severe bleeding complications. These findings suggest a protective role of AT III deficiency against bleeding in a patient with severe factor X deficiency.

Topics: Amyloidosis; Antithrombin III Deficiency; Biopsy; Blood Coagulation Tests; Colchicine; Factor X Deficiency; Gastrointestinal Hemorrhage; Humans; Hypoprothrombinemias; Kidney; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Prednisone; Splenectomy

A patient with multiple myeloma is described who developed severe intrahepatic cholestasis secondary to hepatic deposition of amyloid. This is the first reported case of this complication's developing in a patient with multiple myeloma.

Topics: Amyloidosis; Cholestasis; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone

A 37-year-old woman with amyloidosis derived from light chain immunoglobulin had hepatosplenomegaly, elevated serum alkaline phosphatase values, and progressively destructive bony lesions. A 44-month intermittent course of chemotherapy with melphalan and prednisone resulted in regression, confirming the occasional efficacy of cytotoxic chemotherapy in this disease.

Topics: Adult; Amyloidosis; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Liver Diseases; Melphalan; Prednisone; Splenic Diseases

We describe two patients with primary systemic amyloidosis (AL) and the nephrotic syndrome. The administration of melphalan and prednisone was associated with resolution of the nephrotic syndrome. The serum albumin level returned to normal, proteinuria decreased to near normal, edema resolved, and the monoclonal protein in the serum and urine disappeared. In both patients, renal function remained stable and hepatomegaly disappeared. In both, however, amyloid deposition was greater in follow-up renal tissue than in the initial specimen. The effect of systemic therapy in AL must be assessed with histologic observations as well as clinical indexes.

Topics: Adult; Amyloid; Amyloidosis; Female; Humans; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Prednisone

The Authors describe a case of systemic amyloidosis with hepatic renal, intestinal and presumably cardiac involvement in the course of multiple myeloma (light K chain type). Notwithstanding the presumptions of the pathogenesis of amyloidosis and the capacity of colchicine to inhibit amyloid synthesis in rats treated with casein, the form in question derived little benefit from the association of colchicine (0.5 mg t.i.d.) and Melphalan (cycles of 4 days every 6 weeks - 0.25 mg/Kg/die).

Topics: Amyloidosis; Colchicine; Female; Humans; Immunoglobulin kappa-Chains; Kidney; Liver; Melphalan; Middle Aged; Multiple Myeloma; Rectum

The appearance of amyloidosis during the course of multiple myeloma is a well known fact and has an overall incidence of 6 to 15%. However, the total transformation of a plasmocytoma into a voluminous amyloid tumor is a very rare event. A female patient was diagnosed of lambda light chain disease after developing a conspicuous rib plasmocytoma over the same region where a pathological fracture had appeared three years before. She was treated with discontinuous courses of melphalan and methyl-prednisolone, and developed a reversible nephrotic syndrome and a pathological fracture of the right clavicle. At necropsy there was generalized amyloidosis and complete substitution of the rib plasmocytoma by amyloid substance, with another important accumulation of amyloid in the region of the clavicular fracture. The present concepts on amyloidogenesis in multiple myeloma are reviewed, and the peculiarities of the present case together with the possible role of initiating factors and the effects of therapy are discussed. The case herein reported appears to represent a human model of focal amyloidogenesis in myeloma.

Topics: Aged; Amyloidosis; Clavicle; Female; Fractures, Spontaneous; Humans; Melphalan; Methylprednisolone; Nephrotic Syndrome; Plasmacytoma; Ribs

Topics: Amyloidosis; Attitude to Death; Depression; Drug Therapy, Combination; Humans; Male; Melphalan; Middle Aged; Prednisone

The variety of cutaneous lesions in primary systemic or multiple myeloma-associated amyloidosis is impressive and includes purpura, waxy papules, tumors, plaques, alopecia, and, rarely, bullae. We report a patient in whom the diagnoses of amyloidosis and multiple myeloma were established after he presented with bullae and extensive infiltrated, purpuric plaques. Immunoelectrophoresis of the blister fluid revealed an IgA kappa monoclonal protein similar to that found in the patient's serum and urine.

Topics: Aged; Amyloidosis; Humans; Immunoglobulin A; Male; Melphalan; Multiple Myeloma; Prednisone; Skin Diseases, Vesiculobullous

Topics: Alkylating Agents; Amyloidosis; Cyclophosphamide; Humans; Immunoglobulin A; Immunoglobulin D; Immunoglobulin G; Immunoglobulin kappa-Chains; Immunoglobulin Light Chains; Immunoglobulin M; Male; Melphalan; Middle Aged; Prednisone

Two patients with progressive primary amyloidosis, monoclonal serum and urinary proteins, multiple organ involvement, and nephrotic syndrome were treated with melphalan and prednisone for one year. In one patient, splenomegaly and nephrotic syndrome rapidly responded to therapy but massive hepatomegaly responded slowly, requiring 15 months' time for normalization of size. Results of liver function tests, although improved, remained abnormal, and amyloid deposits remained in the marrow. A second patient also demonstrated dramatic diminution in proteinuria and improvement in liver function abnormalities, but macroglossia persisted. These observations suggest that amyloid organ involvement may be reversible with differences in organ responsiveness to chemotherapy. An empirical trial of chemotherapy may be indicated in some patients with progressive primary amyloidosis, and therapy may need to be continued for a prolonged period of time before seeing an effect.

Topics: Amyloidosis; Colchicine; Drug Therapy, Combination; Female; Hepatomegaly; Humans; Melphalan; Middle Aged; Nephrotic Syndrome; Prednisone; Splenomegaly

Topics: Amyloidosis; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Oxymetholone; Paraproteinemias; Penicillamine; Prednisone

Topics: Amyloidosis; Drug Therapy, Combination; Fluoxymesterone; Humans; Melphalan; Penicillamine; Prednisone

A patient with primary amyloidosis is described with extensive vital organ involvement including infiltration of the liver, kidney and myocardium. Treatment with intermittent melphalan and prednisone resulted in improved hepatic and renal function, a reduction in liver size and arrested amyloid deposition in the myocardium. These observations suggest that chemotherapy can halt tissue amyloid deposition, and improve the prognosis of primary amyloidosis.

Topics: Adult; Amyloidosis; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Melphalan; Prednisone

Topics: Amyloidosis; Drug Therapy, Combination; Female; Fluoxymesterone; Follow-Up Studies; Humans; Melphalan; Penicillamine; Prednisone

Topics: Amyloidosis; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone

Topics: Amyloidosis; Drug Therapy, Combination; Humans; Immunoglobulin D; Immunoglobulin Light Chains; Male; Melphalan; Multiple Myeloma; Nails; Prednisone; Remission, Spontaneous; Sebaceous Glands; Skin Diseases

Topics: Adult; Amyloidosis; Antigens; Cadaver; Colchicine; Female; Humans; Immune Complex Diseases; Immunoglobulin Light Chains; Kidney; Kidney Diseases; Kidney Transplantation; Male; Melphalan; Middle Aged; Postoperative Complications; Remission, Spontaneous; Renal Dialysis; Transplantation, Homologous

Topics: Amyloidosis; Female; Humans; Melphalan; Middle Aged; Paraproteinemias; Peripheral Nervous System Diseases; Prednisone

A case of primary amyloidosis is described in association with Bence-Jones myeloma and increased fibrinolytic activity. Epsilon aminocaproic acid reversed the fibrinolytic activity and clinical improvement was maintained with melphalan and prednisolone.

Topics: Aminocaproates; Amyloidosis; Female; Fibrinolysis; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Purpura

Described here is a 59 year old man with dermatomyositis and hypogammaglobulinemia. His muscle power improved after corticosteroid therapy, but extensive amyloidosis and repeated infections appeared. Bone marrow morphology suggested multiple myeloma, but treatment with cytotoxic drugs had no beneficial effect on the amyloidosis. Because of rapid progression of the amyloidosis and further infections, cytotoxic drug therapy was stopped, corticosteroid dosage was decreased, and supplementary immunoglobulin therapy was instituted. The infections occurred less frequently and the amyloidosis appeared to regress. This case suggests that immunosuppressive therapy may exacerbate amyloidosis. The literature is reviewed, and the possible role of humoral immunodeficiency in the pathogenesis of amyloidosis is discussed. It is suggested that supplementary immunoglobulin may be beneficial in amyloidosis.

Topics: Agammaglobulinemia; Amyloidosis; Bence Jones Protein; Dermatomyositis; gamma-Globulins; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Procarbazine; Sepsis; Skin Tests

This group of proliferative diseases of the plasma cell line, in which manifestations of abnormal immunoglobulin production are associated with variable degrees of depressed antibody synthesis, pose fascinating problems crossing many clinical and research disciplines. The present state of diagnosis and clinical management is assessed.

Topics: Alkylating Agents; Amyloidosis; Antibodies, Anti-Idiotypic; Bence Jones Protein; Blood Cell Count; Blood Proteins; Bone Marrow; Bone Marrow Cells; Cyclophosphamide; Drug Therapy, Combination; Heavy Chain Disease; Humans; Immunoelectrophoresis; Immunoglobulins; Kidney Diseases; Melphalan; Multiple Myeloma; Prednisone; Proteinuria

A patient with primary amyloidosis with evidence for a plasma cell dyscrasia but no abnormal immunoglobulin components had nephrotic syndrome with severe renal impairment. Kidney and bone marrow had extensive amyloid infiltration. She was treated with penicillamine, malphalan, prednisone, and fluoxymesterone; through 6 months renal function gradually improved; urine protein excretion dropped dramatically, serum albumin rose; liver size decreased; the bone marrow returned towards normal. During the next 4 1/2 years melphalan, prednisone, and fluoxymesterone treatment was continued with further improvement in renal function to normal levels. The morphologic characteristics and cellular relations of amyloid fibrils in the bone marrow were studied before, during, and after successful chemotherapy; the findings are evidence for a dual role for the reticuloendothelial cell in the formation and destruction of primary amyloidosis. This patient's response suggests that a multi-agent chemotherapy approach should be further studied.

Topics: Adult; Amyloidosis; Biopsy; Bone Marrow; Bone Marrow Cells; Female; Fluoxymesterone; Humans; Kidney Glomerulus; Melphalan; Microscopy, Electron; Nephrotic Syndrome; Penicillamine; Phagocytosis; Prednisone; Remission, Spontaneous

Topics: Adult; Amyloidosis; Arthritis; Chronic Disease; Female; Humans; Melphalan

Topics: Amyloidosis; Cyclophosphamide; Humans; Kidney Diseases; Male; Melphalan; Middle Aged

Topics: Alopecia; Amyloidosis; Blood Proteins; Drug Therapy, Combination; Eye Manifestations; Humans; Immunoglobulin D; Immunoglobulin Fragments; Keratosis; Male; Melphalan; Middle Aged; Mucinosis, Follicular; Mucous Membrane; Multiple Myeloma; Nails; Plasmacytoma; Prednisolone; Proteinuria; Scalp; Skin; Syndrome; Trichophyton

Topics: Aged; Amyloidosis; Biopsy; Bone Neoplasms; Cell Nucleus; Cyclophosphamide; Electromyography; Female; Humans; Hypesthesia; Melphalan; Microscopy, Electron; Multiple Myeloma; Muscles; Muscular Atrophy; Musculocutaneous Nerve; Myelin Sheath; Neural Conduction; Reflex, Abnormal

Topics: Aged; Amyloidosis; Cardiomyopathies; Ecchymosis; Electrocardiography; Female; Humans; Immunoglobulin G; Melphalan; Multiple Myeloma; Muscles; Myofibrils; Polyneuropathies

Topics: Amyloidosis; Blood Cell Count; Blood Platelets; Blood Transfusion; Bone Marrow Examination; Cephalothin; Cytarabine; Erythrocytes; Gentamicins; Hemoglobins; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Proteinuria; Thioguanine

Topics: Adult; Amino Acid Sequence; Amyloid; Amyloidosis; Arthritis, Rheumatoid; Bence Jones Protein; Child; Female; Humans; Immunoglobulins; Melphalan; Microscopy, Electron; Multiple Myeloma; Staining and Labeling; Thyroid Neoplasms; X-Ray Diffraction

Topics: Adult; Amyloidosis; Antibody Formation; Antigen-Antibody Complex; Azathioprine; Chloramphenicol; Cysteine; Heart Diseases; Humans; Intestinal Obstruction; Malabsorption Syndromes; Male; Melphalan; Penicillamine; Prednisone; Time Factors; Vascular Diseases

Topics: Adult; Aged; Amyloid; Amyloidosis; Bence Jones Protein; Biopsy; Blood Protein Disorders; Electrophoresis; Female; Humans; Kidney Diseases; Male; Melphalan; Middle Aged; Proteinuria; Time Factors

Topics: Amyloidosis; Autopsy; Bone and Bones; Carbon Dioxide; Coronary Vessels; Female; Humans; Lung; Lung Diseases; Melphalan; Middle Aged; Multiple Myeloma; Myocardium; Oxygen; Pulmonary Ventilation; Respiration; Spirometry; Vital Capacity

Topics: Aged; Amyloidosis; Bone Marrow; Bone Marrow Examination; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Time Factors

Topics: Adult; Aged; Amyloidosis; Anemia; Bence Jones Protein; Cyclophosphamide; Female; gamma-Globulins; Humans; Hypercalcemia; Immunochemistry; Immunoglobulin M; Male; Melphalan; Middle Aged; Multiple Myeloma; Uremia

Topics: Adrenal Cortex Hormones; Adult; Amyloidosis; Autoimmune Diseases; Bence Jones Protein; Cold Temperature; Cryoglobulins; Humans; Hyperlipidemias; Immunoglobulin M; Male; Melphalan; Mucous Membrane; Multiple Myeloma; Mycosis Fungoides; Osteoporosis; Plasma Cells; Plasmacytoma; Purpura, Hyperglobulinemic; Pyoderma; Skin Manifestations; Skin Ulcer; Tongue; Xanthomatosis

Topics: Adult; Aged; Amyloidosis; Electrocardiography; Female; Heart Diseases; Humans; Male; Melphalan; Middle Aged

Topics: Amyloidosis; Animals; Cortisone; Diet; Electrophoresis; gamma-Globulins; Mechlorethamine; Melphalan; Mice; Microscopy, Electron; Multiple Myeloma; Neoplasm Transplantation; Neoplasms, Experimental; Plasmacytoma

Topics: Amyloidosis; Anniversaries and Special Events; Blood Protein Disorders; Cryoglobulins; Drug Therapy; Hemorrhagic Disorders; Humans; Melphalan; Multiple Myeloma