melphalan and Cardiomyopathies

Chemotherapy for amyloid light chain (AL) amyloidosis has evolved over the years. Although high-dose melphalan and stem cell transplantation remain the standard of care for eligible patients, a vast majority of the patients at the time of presentation are not eligible for this approach and require low-intensity but highly effective induction therapy, usually based on bortezomib. Immunomodulatory agents are not well tolerated, particularly by patients with AL amyloidosis cardiomyopathy, and are reserved for second-line or later therapy. Because there currently is no Food Drug and Administration-approved therapy, participation in well-designed clinical trials of high scientific merit should be considered.

Topics: Allografts; Bortezomib; Cardiomyopathies; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Severity of Illness Index; Stem Cell Transplantation

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

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

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

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

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

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

The prognosis of cardiac light-chain (AL) amyloidosis is considered to be very poor. We studied the treatment efficacy and outcomes by retrospectively analyzing the clinical results of 45 patients with cardiac AL amyloidosis treated at our hospital between September 2008 and March 2016. The group of patients analyzed included 29 males and 16 females with a median age of 68 years. Their baseline median NT-proBNP, cTnT, and dFLC were 3167 pg/ml, 0.080 ng/ml, and 286.17 mg/l, respectively. Twenty-eight patients were in Cardiac Stage (CS) III and 17 patients were in Revised Prognostic Stage (RPS) IV. At the median follow-up of 10 months, the median overall survival (OS) was 16 months and 3-year OS was 35.9%. The patients in CS III showed significantly poorer survival rate than those in CS I or II (3-year OS: 12.2% vs. 65.8%, p = 0.0115) and the patients in RPS IV showed significantly poorer survival rate than those in RPS I, II, or III (3-year OS: 11.0% vs. 53.3%, p = 0.000914). Regardless of the therapeutic approaches, patients who achieved hematological CR or cardiac organ response demonstrated significantly improved prognosis. Therefore, achievement of hematological and organ responses is important in the treatment of cardiac AL amyloidosis.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bortezomib; Cardiomyopathies; Cyclophosphamide; Dexamethasone; Drug Therapy, Combination; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Japan; Male; Melphalan; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peripheral Blood Stem Cell Transplantation; Prognosis; Retrospective Studies; Retroviridae Proteins, Oncogenic; Severity of Illness Index

To determine whether echocardiographic longitudinal systolic strain (LS) parameters identify short-term improvement following chemotherapy for light-chain (AL) cardiac amyloidosis (CA). Among patients with CA, standard echocardiographic measures are commonly unchanged at 1 year following successful chemotherapy, despite observed reductions in cardiac biomarkers.. We retrospectively identified 61 patients with AL-CA treated with high-dose melphalan or bortezomib-based regimens. Patients were classified by hematologic response at 1 year into two groups: complete response (CR; n = 18, or 30%) or non-CR (non-CR; n = 43, or 70%), and followed for 20 months. Serum free light chains (FLC), B-type natriuretic peptide (BNP), troponin I (TnI), and echocardiography including LS, were acquired at baseline and 1 year. Seven patients died (11.5%), all in the non-CR group (P < 0.01). At 1 year, while reductions were observed in BNP (44% CR, 18% non-CR) and FLC (94% CR, 73% non-CR), both P < 0.05 from baseline, there were no differences in wall thickness, EF, or diastolic function in either group. LS improved only in the CR group with notable improvement in apical to basal strain ratio (P < 0.05). Strain improvement and BNP reduction were correlated (R = 0.6, P < 0.01). Baseline global LS < -10.2% was associated with survival and proved superior to BNP and TnI. The addition of global LS to biomarkers identified the patients at highest risk of mortality.. These data suggest that LS is a sensitive measure of pre-treatment cardiac functional impairment in AL-CA, can predict survival over and above that of cardiac biomarkers, and detect early cardiac functional improvement following chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bortezomib; Boston; Cardiomyopathies; Cohort Studies; Echocardiography, Doppler, Color; Female; Follow-Up Studies; Heart Function Tests; Hospitals, University; Humans; Immunoglobulin Light-chain Amyloidosis; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Prognosis; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left

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

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

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

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

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

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

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

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

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

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

We conducted a pilot study in 20 patients with high-risk or recurrent/refractory non-Hodgkin's lymphoma (NHL) using high-dose sequential chemotherapy (HDSC) and autologous hematopoietic cell transplantation (AHCT). After cytoreduction with standard salvage therapy, HDSC/AHCT was administered in 4 phases at 2- to 4-week intervals. Phase 1 consisted of cyclophosphamide 7 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg per day and leukapheresis upon recovery from white blood cell nadir. The hematopoietic cell product was enriched by Percoll gradient separation and purged with a B-cell or T-cell monoclonal antibody panel and complement. Phase 2 consisted of methotrexate 8 g/m2 with leucovorin rescue and vincristine 1.4 mg/m2. Phase 3 was etoposide 2 g/m2 with G-CSF 5 microg/kg per day. In phase 4, the preparative regimen of mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 was administered followed by AHCT. The NHL histologies were diffuse large cell, follicular/diffuse mixed, small noncleaved cell, T-cell-rich B-cell, lymphoblastic, and peripheral T cell. The remission status was first partial remission (PR1; n = 1) or beyond first complete remission (post-CR1; n = 19). Of the 20 patients enrolled, 11 proceeded through all 4 phases. Nine were removed from the study after the first or second phase because of progressive disease (n = 5), poor hematopoietic cell mobilization (n = 1), excessive toxicity (n = 2), and chronic active hepatitis C (n = 1). Treatment-related toxicities in the remaining 11 transplant recipients were cardiomyopathy, hemorrhagic cystitis, persistent cytopenias, acute renal failure, abnormal liver function test results, and infectious complications. There were no treatment-related deaths. Eight of the 11 transplant recipients were alive, 6 without disease, at a median follow-up of 2.7 years. The estimated median 2-year event-free survival was 55%, and overall survival was 70%. We conclude that HDSC/AHCT in refractory/recurrent NHL is associated with considerable acute and chronic toxicities. Given the toxicity profile, efficacy data were not sufficiently promising to warrant further study.

Topics: Acute Kidney Injury; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Purging; Cardiomyopathies; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cyclophosphamide; Cystitis; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infections; Leucovorin; Life Tables; Lymphoma, Non-Hodgkin; Male; Melphalan; Methotrexate; Middle Aged; Mitoxantrone; Pilot Projects; Salvage Therapy; Survival Analysis; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

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

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

We have studied 60 pediatric patients with different neoplastic diseases, treated with anthracyclines. We have followed them clinically and echocardiographically to detect the cardiotoxicity due to anthracyclines and the enhanced factors promptly. We have detected a more important incidence of cardiomyopathy in patients with non-Hodgkin's lymphoma, osteosarcoma and neuroblastoma despite cumulative doses under 550 mg/m2 of anthracyclines. The 2 first groups were treated with high doses of cyclophosphamide and methotrexate, and neuroblastomas with melphalan. The anthracyclines cardiotoxicity is evaluated around 5% in patients treated with doses under 550 mg/m2, and is increased in case of previous or simultaneous aggressive therapy. Continued echocardiography enables a premature detection of cardiotoxicity in these high risk patients.

Topics: Antibiotics, Antineoplastic; Cardiomyopathies; Child; Cyclophosphamide; Doxorubicin; Drug Synergism; Echocardiography; Heart; Humans; Melphalan; Methotrexate; Neoplasms

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

Topics: Adolescent; Adult; Aged; Anemia; Cardiomyopathies; Chemotherapy, Cancer, Regional Perfusion; Child; Cyclophosphamide; Electrocardiography; Humans; Leg; Leukopenia; Melphalan; Middle Aged; Neoplasms; Tachycardia; Thiotepa; Vascular Diseases