Laura M. Dember

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

Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.

CONTEXT The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. OBJECTIVE To determine whether clopidogrel reduces early failure of hemodialysis fistulas. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. INTERVENTION Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. MAIN OUTCOME MEASURES The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. RESULTS Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). CONCLUSION Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.

Amyloidosis-Associated Kidney Disease

The amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing progressive organ dysfunction. The kidney is one of the most frequent sites of amyloid deposition in AL, AA, and several of the hereditary amyloidoses. Amyloid fibril formation begins with the misfolding of an amyloidogenic precursor protein. The misfolded variants self-aggregate in a highly ordered manner, generating protofilaments that interact to form fibrils. The fibrils have a characteristic appearance by electron microscopy and generate birefringence under polarized light when stained with Congo red dye. Advances in elucidating the mechanisms of amyloid fibril formation, tissue deposition, and tissue injury have led to new and more aggressive treatment approaches for these disorders. This article reviews the pathogenesis, diagnosis, clinical manifestations, and treatment of the amyloidoses, focusing heavily on the renal aspects of each of these areas.

Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency

BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.

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.

Individual RNA Recognition Motifs of TIA-1 and TIAR Have Different RNA Binding Specificities

TIA-1 and TIAR are two closely related RNA recognition motif (RRM) proteins which possess three RRM-type RNA binding domains (RRMs 1, 2, and 3). Although both proteins have been implicated as effectors of apoptotic cell death, the specific functions of TIA-1 and TIAR are not known. We have performed in vitro selection/amplification from pools of random RNA sequences to identify RNAs to which TIA-1 and TIAR bind with high affinity. Both proteins selected RNAs containing one or several short stretches of uridylate residues suggesting that the two proteins have similar RNA binding specificities. Replacement of the uridylate stretch with an equal number of cytidine residues eliminates the protein-RNA interaction. Mutational analysis indicates that, for both TIA-1 and TIAR, it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs. Although RRM 2 is both necessary and sufficient for this interaction, the affinity for the selected RNA (as determined by filter binding assays) does increase when the second domain of TIAR is expressed together with the first and third domains (K = 2 × 10M) rather than alone (K = 5 × 10M). Although RRM 3 (of either TIA-1 or TIAR) does not interact with the uridylate-rich sequences selected by the full-length proteins, it is a bona fide RNA binding domain capable of affinity-precipitating a population of cellular RNAs ranging in size from 0.5 to 5 kilobases. In contrast, RRM 1 does not affinity-precipitate cellular RNA. The inability of RRM 1 to interact with RNA may be due to the presence of negatively charged amino acids within the RNP 1 octamer.

An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis

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. Bone Marrow Transplantation (2001) 28, 637–642.

Thrombosis in End-Stage Renal Disease

ABSTRACT Although renal failure has classically been associated with a bleeding tendency, thrombotic events are common among patients with end‐stage renal disease (ESRD). A variety of thrombosis‐favoring hematologic alterations have been demonstrated in these patients. In addition, “nontraditional” risk factors for thrombosis, such as hyperhomocysteinemia, endothelial dysfunction, inflammation, and malnutrition, are present in a significant proportion of chronic dialysis patients. Hemodialysis (HD) vascular access thrombosis, ischemic heart disease, and renal allograft thrombosis are well‐recognized complications in these patients. Deep venous thrombosis and pulmonary embolism are viewed as rare in chronic dialysis patients, but recent studies suggest that this perception should be reconsidered. Several ESRD treatment factors such as recombinant erythropoietin (EPO) administration, dialyzer bioincompatibilty, and calcineurin inhibitor administration may have prothrombotic effects. In this article we review the pathogenesis and clinical manifestations of thrombosis in ESRD and evaluate the evidence that chronic renal failure or its management predisposes to thrombotic events.

Effect of Dose-Intensive Intravenous Melphalan and Autologous Blood Stem-Cell Transplantation on AL Amyloidosis–Associated Renal Disease

Primary (AL) amyloidosis is a plasma cell dyscrasia in which clonal plasma cells in the bone marrow produce a monoclonal immunoglobulin protein (M protein). The M protein light chains or light-chain fragments form insoluble fibrils with -pleated sheet configurations, rendering them avid for Congo red dye. The deposition of amyloid fibrils into the extracellular matrix of a variety of tissues results in severe organ dysfunction and poor patient survival. The kidney is one of the most common sites of amyloid deposition in AL amyloidosis, with clinically evident renal disease occurring in 48% to 82% of patients (1-5). Renal disease associated with AL amyloidosis is usually characterized by the nephrotic syndrome, often with massive proteinuria and refractory peripheral edema (6). The natural history of renal disease associated with AL amyloidosis is persistence of the nephrotic syndrome and progressive decrease in glomerular filtration rate (5, 7). In one series, one third of patients presenting with renal involvement began long-term dialysis therapy at a median of 13.8 months after diagnosis (2). Randomized, controlled trials have shown that cyclic oral melphalan and prednisone can prolong the life of patients with AL amyloidosis (1, 4). However, response to this treatment is limited: Serum or urine monoclonal protein levels decrease in only 20% of patients, and the median survival is only 16 to 18 months. Since 1994, we have been using dose-intensive intravenous melphalan with autologous blood stem-cell support to treat selected patients with AL amyloidosis. The goal of this treatment is to eliminate the clonally expanded plasma cells that produce the amyloidogenic light chains, thereby preventing further amyloid deposition into vital organs. In previous studies of this treatment approach, we found that complete remission of the plasma cell dyscrasia occurred in more than 50% of patients who received 200 mg/m2 of intravenous melphalan and in more than 40% of patients who received 100 to 140 mg/m2 of intravenous melphalan followed by autologous stem-cell transplantation (8-10). The objective of the present study was to investigate the effect of this treatment on AL amyloidosisassociated renal disease. Methods Patients In our analysis, we included patients with AL amyloidosis and renal involvement who were treated with dose-intensive intravenous melphalan and autologous blood stem-cell transplantation at Boston University (Boston, Massachusetts) between 1 July 1994 and 30 June 1998. We excluded patients who were dialysis dependent before treatment. Persons who underwent stem-cell mobilization and collection but did not receive intravenous melphalan because of inability to tolerate the former or death before melphalan administration were included in the analysis of treated patients. The diagnosis of AL amyloidosis required both tissue demonstration of amyloid by Congo red staining and evidence of monoclonal immunoglobulin protein in serum, urine, bone marrow, or tissue amyloid deposits. Patients were considered to have renal involvement if urinary protein excretion exceeded 1 g/24 h. The hematologic outcomes of the first 23 of these patients have been reported elsewhere (9, 10), and a brief description of the renal outcome was provided for 13 of the patients (9). To be eligible for intravenous melphalan with autologous blood stem-cell transplantation, patients needed to be at least 18 years of age, have a Southwest Oncology Group performance status score of 0 to 3, have a left ventricular ejection fraction greater than 0.4, and have supine systolic blood pressure greater than 85 mm Hg. Approximately 40% of patients with AL amyloidosis evaluated at our center during the study period met these eligibility criteria and elected to undergo stem-cell transplantation. The institutional review board of Boston University Medical Center approved the study. Treatment Blood stem cells were mobilized and collected as described elsewhere (9, 10). We used granulocyte colony-stimulating factor (Filgrastim, Amgen, Thousand Oaks, California), 10 to 16 g/kg of body weight, as the sole mobilizing agent in 59 patients and in combination with granulocyte-macrophage colony-stimulating factor (Sargramostim, Immunex, Seattle, Washington), 250 g/m2, in 6 patients (10). Seven patients received CD34-selected stem cells (Isolex 300, Baxter Biotech, Irving, California). All other patients received unselected stem cells. Melphalan was administered intravenously during 2 consecutive days at a total dose of 100 to 200 mg/m2. Stem cells were infused 24 to 72 hours after completion of melphalan administration. The dose of melphalan given before autologous stem-cell transplantation was determined on the basis of patient age and clinical status. Eligibility criteria for the highest dose of melphalan (200 mg/m2) included age younger than 61 years, left ventricular ejection fraction of at least 0.45, pulmonary diffusion capacity at least 50% of the predicted value, serum creatinine concentration less than 177 mol/L (2.0 mg/dL), and Southwest Oncology Group performance status score of 0 to 2 (9). Patients who did not meet these criteria were treated with a modified dose (100 mg/m2 or 140 mg/m2, or two cycles of 100 mg/m2 given 4 to 6 months apart). Evaluation and Outcome Measures Patients were evaluated before treatment, at 3 and 12 months after treatment, and annually thereafter. At each evaluation, 24-hour urinary protein excretion and creatinine excretion were measured and the status of the plasma cell clone was determined by bone marrow biopsy and both serum and urine immunofixation electrophoresis. Complete hematologic response was defined as absence of detectable monoclonal protein by serum and urine immunofixation and a bone marrow biopsy specimen containing less than 5% plasma cells without clonal dominance of or isotype. Patients with a partial hematologic response (for example, those who showed loss of serum monoclonal protein but persistence of urine monoclonal protein or bone marrow clonality) or no hematologic response were categorized as having persistent plasma cell disease. A renal response was defined as a greater than 50% reduction in 24-hour urinary protein excretion in the absence of a 25% or greater reduction in creatinine clearance. Statistical Analysis Comparisons were performed by using the Wilcoxon test for continuous variables and the Fisher exact test for categorical variables. All analyses used a two-tailed significance value of 0.05 and were performed by using SAS for Windows (SAS Institute, Inc., Cary, North Carolina). Confidence intervals for medians were calculated nonparametrically by using the method of Hahn and Meeker (11). Confidence intervals provided for proportions are exact 95% intervals based on the binomial distribution. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Patients Seventy-two patients with AL amyloidosisassociated renal disease were treated with intravenous melphalan and autologous peripheral blood stem-cell transplantation during the 4-year study period. Seven of these patients were dialysis dependent before treatment and were therefore excluded. The median age of the remaining 65 patients was 57 years; in 88%, the monoclonal immunoglobulin light-chain isotype was (Table 1). Multiorgan involvement was common, and 40% of patients had symptomatic cardiac disease. In most patients, amyloidosis had been diagnosed less than 12 months before intravenous melphalan treatment. Approximately one third of patients had previously been treated with oral melphalan. Table 1. Baseline Clinical Characteristics of Patients with Renal Amyloidosis The dose of intravenous melphalan preceding autologous stem-cell transplantation was 200 mg/m2 in 39 patients (60%) and 100 or 140 mg/m2 in 26 patients (40%). Fifty patients (77%) survived at least 12 months after treatment and were included in the analysis of renal response to treatment. The patients who survived at least 12 months were younger, had fewer organ systems involved, received a higher intravenous melphalan dose, and had higher serum cholesterol concentration at baseline than the 15 patients who died within 12 months (Table 1). Of the 50 patients who survived at least 12 months, 40 (80%) had nephrotic-range proteinuria (>3 g/d) at baseline and 13 (26%) had a baseline serum creatinine concentration of at least 133 mol/L (1.5 mg/dL). Treatment Toxicity In 15 patients (23%), the serum creatinine concentration doubled or increased by at least 88 mol/L (1 mg/dL) during the peritransplantation period (defined as 100 days after administration of intravenous melphalan or during stem-cell mobilization or collection). Two of these patients required temporary dialysis. The creatinine concentration returned to its baseline value within 1 to 5 weeks in all but 3 patients; of these 3, 1 died of multiorgan failure 19 days after stem-cell reinfusion, 1 had stabilization of creatinine concentration during the peritransplantation period but subsequently had progressive renal insufficiency requiring initiation of long-term dialysis 13 months after treatment, and 1 had gradual improvement in renal function over the 12 months after treatment. Other treatment-related toxicities included mucositis (53%), peripheral edema (23%), bacteremia (19%), pulmonary edema (18%), elevation in liver enzyme or bilirubin levels (13%), gastrointestinal bleeding (10%), and nongastrointestinal bleeding (10%). None of the patients had sustained dependence on blood product transfusions. Six patients (9%) died during the peritransplantation period. Five of these deaths occurred in patients with symptomatic cardiac disease, and all six occurred in patients who had three or more organ systems affected by amyloid. Hematologic Response Twenty-three of the 65 patients (35%) had

High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial

Summary: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.