melphalan and Factor-X-Deficiency

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

A 55-year-old man was admitted to our institute to undergo evaluation for proteinuria (5.4 g/day) with lambda-type Bence-Jones protein (BJP). Primary amyloid light chain (AL) amyloidosis and acquired factor X deficiency were diagnosed. High-dose melphalan combined with autologous stem cell transplantation was performed. After three years, the patient's proteinuria normalized, he was negative for urinary BJP, and his factor X activity improved to 105%. Serial renal biopsy showed no progression of amyloid deposition at a biopsy after 5 years, but showed a slight increase in the amyloid deposition after 11 years. This therapy can improve the prognosis of AL amyloidosis; however, there are limitations to the strategy.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bence Jones Protein; Biopsy; Combined Modality Therapy; Doxorubicin; Etoposide; Factor X Deficiency; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Remission Induction; 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: Aged; Amyloidosis; Drug Therapy, Combination; Factor X Deficiency; Female; Humans; Melphalan; Paraproteinemias; Prednisone; Treatment Outcome

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

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

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

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