Caryn A. Libbey

High-Dose Melphalan and Autologous Stem-Cell Transplantation in Patients with AL Amyloidosis: An 8-Year Study

Context AL amyloidosis responds poorly to oral chemotherapy and rarely leads to elimination of plasma cell dyscrasia. Amyloid cardiomyopathy is a particularly fatal complication of the disease. Contribution Analysis of consecutive patients with AL amyloidosis from 6 separate trials over 8 years shows that high-dose intravenous melphalan therapy combined with autologous stem-cell transplantation greatly improves duration of survival and ameliorates organ dysfunction. Implications Intravenous melphalan therapy combined with stem-cell transplantation represents a clinically significant improvement in treating AL amyloidosis and shows promise in reversing amyloid cardiomyopathy. The Editors The most common form of systemic amyloidosis in the United States is AL (or primary) amyloidosis. In this disease, amyloid fibrils are derived from monoclonal immunoglobulin light chains that are produced by an underlying clonal plasma cell dyscrasia. Although the burden of plasma cells is generally low, accumulation of amyloid deposits in vital organs leads to progressive disability and death. The median survival of untreated patients after diagnosis is 12 months and less than 5 months for those with cardiomyopathy (1-5). AL amyloidosis is reported to occur in 5 to 12 persons per million per year in the United States; however, death records and autopsy results suggest that the incidence may be higher (6, 7). Treatment with oral melphalan results in a modest increase in median survival but rarely eliminates the plasma cell dyscrasia and is not effective for rapidly progressive disease (8-10). Alternative chemotherapy regimens have not improved survival further (11-15). Promising treatment outcomes observed with high-dose intravenous melphalan and autologous stem-cell transplantation in multiple myeloma (16-19) provided a rationale for testing the hypothesis that this treatment would improve survival for patients with AL amyloidosis. Favorable responses to high-dose melphalan and stem-cell transplantation in patients with AL amyloidosis have been reported in case reports and in small series; however, treatment-related mortality was high in multicenter trials (20-28). Our initial experience with treatment in AL amyloidosis indicated that selected patients can tolerate treatment and that hematologic responses and reversal of amyloid-related organ dysfunction can be achieved (29-32). Since 1994, we have evaluated 701 patients with AL amyloidosis, 312 of whom initiated high-dose melphalan treatment and stem-cell transplantation. This longitudinal study examines survival, hematologic response, and improvement of amyloid-related organ disease in patients who were treated with high-dose melphalan and stem-cell transplantation. We contrast these data with features and survival of a simultaneous cohort of patients who were not eligible for treatment. Methods Patients Between July 1994 and June 2002, 701 consecutive patients with AL amyloidosis were evaluated and clinical data were collected with the approval of the Institutional Review Board of Boston University Medical Center. All patients had biopsy-proven amyloid disease and a documented plasma cell dyscrasia, which was diagnosed by the presence of clonal plasma cells in the bone marrow or a monoclonal gammopathy detected by immunofixation electrophoresis of serum or urine proteins (Figure 1). To exclude another type of systemic amyloidosis and a monoclonal gammopathy of unknown significance, all patients with findings compatible with familial or secondary (AA) amyloidosis were tested by DNA analysis for gene mutations in transthyretin, apolipoprotein A1, fibrinogen, and lysozyme known to be associated with amyloidosis and by immunohistochemistry of the biopsy tissue for AA amyloid fibril deposits (33). Patients with multiple myeloma (bone marrow plasmacytosis 30% or lytic bone lesions) were excluded. In patients older than 70 years of age with cardiomyopathy only, a diagnosis of senile cardiac amyloidosis (caused by wild-type transthyretin) was excluded by immunohistochemical examination of a tissue biopsy specimen using antiserum to transthyretin. All patients were evaluated for degree of organ involvement by physical examination, standardized blood tests, electrocardiography, echocardiography, chest radiography, pulmonary function tests, and a 24-hour urine collection. All patients were evaluated by a hematologist and cardiologist and, when appropriate, by nephrology, pulmonology, gastroenterology, and neurology specialists. Figure 1. Algorithm for patient selection and treatment with high-dose melphalan and stem-cell transplantation. High-Dose Melphalan and Stem-Cell Transplantation Eligibility and Protocols Patients were enrolled in several sequential institutional review boardapproved protocols during the 8-year study period. Eligibility criteria for all protocols required biopsy-proven amyloid disease; evidence of a plasma cell dyscrasia; at least 1 major organ affected by amyloid disease; and minimum measures of cardiac, pulmonary, and performance status (Figure 1). Functional measures included cardiac ejection fraction 0.4 or greater, absence of symptomatic pleural effusions, absence of heart failure or arrhythmia resistant to medical management, oxygen saturation of 95% or greater on room air, lung diffusing capacity of 50% or more of predicted, supine systolic blood pressure of 90 mm Hg or greater, and Southwest Oncology Group performance status score of 2 or less unless limited by neuropathy (on a scale of 0 to 4, reflecting percentage of the day [0%, 25%, 50%, 75%, or 100%] spent in bed or in a chair). Minor variations in eligibility requirements for age, renal function, amount of previous chemotherapy, and time from diagnosis while on some protocols are noted in the following discussion; the number of patients affected is also given. The first protocol (July 1994 to December 1995) enrolled 13 patients 60 years of age or younger with serum creatinine values of 176.8 mol/L (2.0 mg/dL) or less; these patients were treated with melphalan, 200 mg/m2 (29). Subsequent protocols had no restriction for impaired renal function. A second protocol (April 1995 to October 1996) enrolled 28 patients 70 years of age or younger and used a lower dose of melphalan, 100 mg/m2 (31). Two protocols (January 1996 to June 1998) evaluated the use of CD34+-selected stem cells in 16 patients (34). The fifth protocol (October 1996 to September 2000) randomly assigned 100 previously untreated patients to treatment with high-dose melphalan and stem-cell transplantation immediately or after 2 cycles of oral melphalan and prednisone. There was no age limit for this protocol; however, melphalan, 140 mg/m2, was given to patients who were older than 65 years of age or had a cardiac ejection fraction between 0.40 and 0.44. The sixth protocol (November 2000 to the present) has enrolled 29 patients 65 years of age or younger. On this protocol, enough stem cells are collected initially to give a second cycle of chemotherapy within the first year if a complete response has not been achieved after an initial course of melphalan at a dose of 200 mg/m2. Other patients who met eligibility criteria (August 1996 to the present) but were excluded from an active protocol because of previous treatment or time from diagnosis were treated by using the established dosing guidelines. Patients who did not meet eligibility for treatment with high-dose melphalan and stem-cell transplantation were grouped according to reasons for ineligibility and were analyzed for survival. Organ system involvement was defined by physical examination; postural blood pressure determinations; standardized serologic laboratory measurements of kidney, liver, and endocrine function; coagulation studies, including factor X levels; electrocardiography; echocardiography; chest radiography; pulmonary function tests with walking oximetry; and a 24-hour urine collection for protein excretion. Cardiac involvement was defined by septal or posterior wall thickening of 13 mm or greater on echocardiography or a clinical syndrome of congestive heart failure or cardiac arrhythmia in the absence of preexisting cardiac disease. Renal involvement was diagnosed by proteinuria of 500 mg/24 h or greater or an elevated serum creatinine concentration in the absence of other causes of renal disease. Gastrointestinal involvement was diagnosed by involuntary loss of 10% of body weight, unexplained diarrhea, hepatomegaly of 4 cm or more below the right costal margin on physical examination, or alkaline phosphatase level 2 or more times the upper limit of normal values. Peripheral neuropathy was diagnosed by symptoms and physical examination or nerve conduction studies, and autonomic neuropathy was defined by orthostatic hypotensiona decrease in systolic blood pressure of 20 mm Hg or greater with upright posture in euvolemic patients. Soft tissue involvement was diagnosed by clinical evidence of macroglossia, soft tissue or subcutaneous deposits, amyloid arthropathy, lymphadenopathy, or nail dystrophy. Coagulation factor X level was considered deficient if it was 50% or less of normal. Stem-Cell Collection and High-Dose Chemotherapy Peripheral blood stem cells were collected by leukapheresis after mobilization using granulocyte colony-stimulating factor. A minimum yield of 2.0 106 CD34+cells/kg of body weight was required to support high-dose chemotherapy. The patients age and cardiac status and the number of stem cells collected determined the melphalan dose (Figure 1). A dose of 200 mg/m2 was administered to patients who were 65 years of age or younger and who had a cardiac ejection fraction of 0.45 or greater and a stem-cell collection of at least 2.5 106 CD34+cells/kg. A dose of 140 mg/m2 was administered to patients who were older than 65 years of age, who had a cardiac ejection fraction of 0.4 to 0.44, or who had a stem-cell collection of 2.0 to 2.5 106 CD34+cells/k

Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only

PURPOSE 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 AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Survival of patients with primary (AL) amyloidosis: Colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973)☆

Primary amyloidosis has a variable course, but is generally associated with a short life expectancy. To date, no specific therapy has been available. Fifty-three patients with AL amyloidosis seen between 1976 and 1983 were treated with colchicine, and their clinical course and survival were compared with that in 29 other patients seen between 1961 and 1973. Of the variables measured, the treatment, the patients sex, and the time interval from diagnosis to referral of treatment were significantly associated with length of survival. Median survival for the colchicine-treated patients was 17 months, compared with six months for the non-colchicine-treated patients. A surprising finding was the longer life span in female patients (median eight months versus four and a half months in the non-colchicine-treated group, and 25.5 months versus 10 month in the colchicine-treated group). The study suggests that colchicine has improved the life expectancy in AL amyloidosis. Although it is not a specific therapy, it may be a reasonable form of adjunctive treatment in this complex disorder.

Lowered Prealbumin Levels in Patients with Familial Amyloid Polyneuropathy (FAP) and Their Non-Affected But At Risk Relatives

Amyloid fibrils in familial amyloid polyneuropathy, the familial (AF) form of systemic amyloidosis, are composed of the monomeric unit (14,000 MW) of prealbumin molecules. By radioimmunoassay, the serum level of prealbumin was measured in 25 patients from 12 different kinships with this dominantly inherited form of amyloidosis and 56 unaffected, but at risk, relatives from two of the kinships. Results were compared to prealbumin levels in normal individuals and patients with primary (AL) and secondary (AA) forms of systemic amyloidosis. Significantly lowered prealbumin levels were found in the AF patients (149.2 ug/ ml) and their at risk relatives (169.0 ug/ml) when compared to normal individuals (232.9 ug/ml), AL patients (221.9 ug/ml) and AA patients (211.7 ug/ml). No abnormality was found in levels of retinol binding protein (RBP), which is carried by prealbumin, in the serum of either the AF patients or their relatives. The depressed prealbumin levels may indicate a structural variant molecular form, an extra hepatic synthesis or an abnormality in catabolism of this protein that is present prior to the clinical or histopathologic onset of the AF disease.

Familial amyloid polyneuropathy. Demonstration of prealbumin in a kinship of german/english ancestry with onset in the seventh decade

A family with autosomal dominant transmitted familial amyloid polyneuropathy residing in Texas is described. Clinically, the prominent sensory and severe autonomic nervous system involvement resembles the Andrade (Portuguese) type I familial amyloid polyneuropathy but is unique in that the age of onset is in the seventh decade in all family members affected to date. Using an immunoperoxidase technique, prealbumin was demonstrated in the amyloid deposits. This finding suggests that this family shares biochemical as well as clinical characteristics consistent with similar kinships with type I familial amyloid polyneuropathy of diverse geographic origin.

High-dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and 1-year survival at a single institution

Treatment with high-dose melphalan chemotherapy supported by hematopoietic rescue with autologous stem cells produces high rates of hematologic responses and improvement in survival and organ function for patients with AL amyloidosis. Ongoing clinical trials explore pre-transplant induction regimens, post-transplant consolidation or maintenance approaches, and compare transplant to non-transplant regimens. To put these studies into context, we reviewed our recent experience with transplant for AL amyloidosis in the Amyloid Treatment and Research Program at Boston Medical Center and Boston University School of Medicine. Over the past 10 years, there was a steady reduction in rates of treatment-related mortality and improvement in 1-year survival, now approximately 5% and 90%, respectively, based upon an intention-to-treat analysis. Median overall survival of patients treated with this approach at our center exceeds 7.5 years. Introduction: Treatment of AL amyloidosis patients with high-dose intravenous melphalan chemotherapy and autologous hematopoietic stem cell support (HDM/SCT) produces a high rate of hematologic complete responses and improvement in organ function. Nephrotic syndrome can resolve [1], myocardial wall thickness can decline (MeierEwert et al., this volume), and quality of life improves [2]. Good outcomes are dependent upon the safe application of the therapy. Our first large patient series, published in 2004, reported a 100 day treatment-related mortality (TRM) of 14% [3]. Since then, we have refined patient selection and transplantation techniques and seen a concomitant decline in the rate of serious complications. Methods: Data on patients evaluated and treated in the Amyloid Treatment and Research Program at Boston University School of Medicine and Boston Medical Center were collected under protocols approved by the Boston University Medical Campus IRB after informed consent was signed. Data on patients enrolled into protocols using HDM/SCT from January 2000–December 2009 were reviewed retrospectively. Survival of all patients was determined through the end of December 2010, providing at least 1 year of follow-up on 100% of patients. Kaplan-Meier survival and confidence intervals for median overall and event-free survival were determined. Results and discussion: In the 10-year-period from January 2000 through December 2009, 323 patients began treatment on institutional or cooperative group protocols using HDM/SCT. The age range of enrolled patients was 28–80 years (median 57). The overall TRM was 8.4%, and the 1-year survival (1 YS) was 86.1% by intention-to-treat analysis. In the more recent 5-year-period from January 2005 through December 2009, 158 patients were treated; the age range was 28–77 years (median 57), the TRM was 5.1%, and the 1YS was 89.2%. Annual trends are plotted in Figure 1. The overall survival and progression free survival of all 323 patients are plotted in Figure 2. We attribute these improvements to two factors: firstly, rigorous selection of appropriate patients; and secondly, experienced multidisciplinary management during the peri-transplant period. Appropriate patient selection requires a comprehensive multidisciplinary clinical evaluation. The key evaluation components are summarized below. Chronological age is not a critical factor [4]. Patients who are potential candidates for HDM/SCT are assessed by sub-specialists highly familiar with the clinical manifestations of amyloidosis and with the complications of HDM/SCT. Cardiopulmonary function: Many studies have demonstrated that outcomes for patients with AL amyloidosis are driven by cardiac disease, defined by clinical parameters, echocardiographic parameters, and biomarkers for cardiac function. We use all of these to judge cardiac risk, including careful review of symptoms, physical examination for signs of heart Figure 1. Trends in TRM (lower line) and 1YS (upper line) each year in the 10-year-period from 2000 through the end of 2009, for a total of 323 patients. 127

Late Onset Hereditary Amyloidosis in a Family From Texas

A new kinship of German-English ancestry with familial amyloid polyneuropathy (FAP) is described. Four siblings of a large Texan family have been studied with what appears to be an autosomal dominant transmission. The onset is very similar to the Andrade (Portuguese) type I FAP in that autonomic dysfunction and sensory findings precede motor involvement. This particular family however is unique in that the age of onset is the seventh decade in all members affected to date. Renal involvement appears to be less prominent and has occurred several years after onset of polyneuropathy symptoms. In contrast to other types of familial amyloid, scalloped pupils have not been seen. The clinical symptoms of cardiac and gastrointestinal involvement became manifest more slowly (10 or more years after first neuropathic symptoms) in this elderly onset Texan family. The pattern of disease, however, was similar to that of typical FAP type I. Immunohistochemical staining techniques have shown that the amyloid is prealbumin. These data indicate characteristics of FAP may be a broader continuum of disease processes rather than a single definite entity.

The Life Span of Patients with Primary (AL) Amyloidosis and the Effect of Colchicine Treatment

There is no specific treatment for any variety of amyloidosis [1]. Primary (AL) amyloidosis, now the more commonly seen form of the disorder, usually has a poor prognosis and short life expectancy [2]. Colchicine, which effectively prevents acute fibril attacks in patients with familial Mediterranean fever (FMF), a condition that predisposes to amyloidosis, has been shown to block amyloid production in the mouse model [3,4]. In addition, reports indicate that patients with FMF receiving colchicine no longer develop amyloidosis and suggest improvement in some amyloidotic patients with this form of AA amyloid [5, 6].