Rodney H. Falk

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

Diagnosis and Management of the Cardiac Amyloidoses

Cardiac amyloidosis is a manifestation of one of several systemic diseases known as the amyloidoses.1,2 This uncommon disease is probably underdiagnosed, and even when a diagnosis of amyloidosis of the heart is made, the fact that there are several types of amyloid, each with its unique features and treatment, is often unrecognized. This can lead to errors in management and in the information conveyed to the patient. The purpose of this review is to familiarize the reader with the clinical features of amyloidosis and to address the approach to the patient with this disease, focusing on the various types of amyloidosis, their prognosis and treatment. The common feature of this group of diseases is the extracellular deposition of a proteinaceous material that, when stained with Congo red, demonstrates apple-green birefringence under polarized light and that has a distinct color when stained with sulfated Alcian blue (Figure 1). Viewed with electron microscopy, the amyloid deposits are seen to be composed of a β-sheet fibrillar material (Figure 2). These nonbranching fibrils have a diameter3 of 7.5 to 10 nm and are the result of protein misfolding.4,5 Cardiac involvement in amyloidosis may be the predominant feature or may be found on investigation of a patient presenting with another major organ involvement. The presence of cardiac amyloidosis and its relative predominance varies with the type of amyloidosis. Thus, senile systemic amyloidosis and some forms of transthyretin amyloidosis invariably affect the heart, whereas cardiac involvement ranges from absent to severe in amyloidosis derived from a light-chain precursor (AL amyloidosis). Secondary amyloidosis almost never affects the heart in any clinically significant manner.6 The specific composition of the fibrils differs in the different types of amyloid7 and are outlined in the Table. Both on the basis of common usage and for …

Longitudinal Myocardial Function Assessed by Tissue Velocity, Strain, and Strain Rate Tissue Doppler Echocardiography in Patients With AL (Primary) Cardiac Amyloidosis

Background—AL amyloidosis with heart failure is associated with decreased longitudinal myocardial contraction measured by pulsed tissue Doppler imaging. We sought to clarify whether new modalities of myocardial strain Doppler (change in length per unit length) or strain rate (the temporal derivative of strain) were more sensitive than tissue Doppler and could detect early regional myocardial dysfunction before the onset of congestive heart failure (CHF) in patients with AL (primary) amyloidosis. Methods and Results—Ninety-seven biopsy-proven patients with AL amyloidosis were divided into 3 groups. Group 1 patients had no cardiac involvement (n=36), group 2 had heart involvement but no CHF (n=32), and group 3 had heart involvement and CHF (n=29). All patients underwent tissue velocity (TV) imaging, strain, and strain rate imaging (SR) at the basal, mid, and apical ventricle in 2 apical views. With the use of TV, differences in systolic function were only apparent between group 3 (basal mean value, 3.0±1.1 cm/s) and groups 1 and 2 (5.0±1.3 and 4.6±1.2 cm/s, respectively). In contrast, basal peak systolic SR (l/s) showed significant differences among all 3 groups (−2.0±0.4, −1.55±0.6, and −0.76±0.3 for groups 1 to 3, respectively. P <0.01). Basal strain also demonstrated statistically significant differences among the groups (−19±4%, −15±4.5%, and −8.0±5%;P <0.01). Conclusions—Cardiac amyloidosis is characterized by an early impairment in systolic function at a time when fractional shortening remains normal. This abnormality precedes the onset of CHF and can be detected by strain and SR but is not apparent by TV imaging.

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.

Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter

OBJECTIVES This study sought to determine the safety and efficacy of a single bolus of intravenous dofetilide, a pure class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. BACKGROUND Dofetilide is a highly selective blocker of the rapid component of the delayed rectifier current causing action potential prolongation. These effects, and preliminary clinical data, suggest that it may be effective in the treatment of atrial fibrillation and flutter. METHODS Ninety-one patients with sustained atrial fibrillation (75 patients) or flutter (16 patients) were entered into a double-blind, randomized multicenter study of one of two doses of dofetilide (4 or 8 micrograms/kg body weight) or placebo. RESULTS Dofetilide effectively terminated the arrhythmia in 31% of patients receiving 8 micrograms/kg, a statistically significant difference from those receiving 4 micrograms/kg (conversion rate 12.5%, p < 0.05) or placebo (no conversion, p < 0.01). Patients with atrial flutter had a greater response to dofetilide (54% conversion rate) than those with atrial fibrillation (14.5% conversion rate, p < 0.001). CONCLUSIONS Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm. However, its efficacy is greater in flutter--a response that contrasts with the poorer response seen with class I agents. This finding potentially represents an important advance in the pharmacologic termination of atrial flutter.

Amyloid Heart Disease

The systemic amyloidoses are an uncommon group of disorders characterized by the extracellular deposition of amyloid in one or more organs. Cardiac deposition, leading to an infiltrative/restrictive cardiomyopathy, is a common feature of amyloidosis. It may be the presenting feature of the disease or may be discovered while investigating a patient presenting with non-cardiac amyloidosis. In this article we review the features of cardiac amyloidosis and its varied manifestations. The need for a high index of suspicion and the critical importance of precise biochemical typing of the amyloid deposits is stressed in light of recent advances in therapy which can, when appropriately used, significantly improve prognosis.

Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis

Background— Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. Methods and Results— Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0–100). Conclusions— Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.

Progression of ventricular wall thickening after liver transplantation for familial amyloidosis.

BACKGROUND Familial amyloidosis (FAP) is characterized by the progression of neurologic and cardiac impairment ultimately leading to death within 7 to 15 years after the onset of the disease. Liver transplantation represents the only definitive therapy for this disease and has been performed since 1990. METHODS To determine the effect of liver transplantation on disease progression, electrocardiography and Doppler echocardiography were performed and blindly analyzed on 11 patients with FAP who were followed 0.8 to 8.6 years before liver transplantation and 0.8 to 4.1 years after liver transplantation. RESULTS; After liver transplantation, five patients showed progression of left ventricular wall thickening with increased left ventricular mass, and three of these five showed a reduction in electrocardiographic voltage despite abolition of the mutant protein from the serum. Of the five patients showing progressive wall thickening, four had the transthyretin variant Glu 42 Gly and one patient had the Ala 36 Pro variant; none of the remaining six patients, all of whom possessed the Val 30 Met variant, showed echocardiographic changes. Although 9 of the 11 patients have shown symptomatic improvement in neurologic symptoms, 1 patient has developed heart failure and a second patient has suffered a sudden cardiac death. CONCLUSIONS After liver transplantation, patients with FAP should have regular clinical evaluations including electrocardiographic and echocardiographic examinations to look for continued deterioration in heart structure or function.

Proarrhythmia in Patients Treated for Atrial Fibrillation or Flutter

OBJECTIVE To review data on the type, mechanism, and prevalence of the proarrhythmic effect of drugs used to treat atrial fibrillation or flutter. DATA SOURCES English-language literature from the early 1960s to the present was identified by manual search of the literature; relevant articles were reviewed. Pertinent earlier studies were identified from references in the articles reviewed and were included when relevant. STUDY SELECTION All studies, controlled and uncontrolled, as well as individual case reports that contained data convincingly linking atrial antiarrhythmic therapy to a proarrhythmic side effect were included. DATA EXTRACTION Key data were extracted from each article in studies in which a causal relationship between the use of a drug and a proarrhythmic response appeared likely. DATA SYNTHESIS Antiarrhythmic therapy aimed at stabilizing the atrium may have adverse effects on the ventricle including torsade de pointes and, less commonly, sustained ventricular tachycardia. Different antiarrhythmic agents appear to have differing potentials for this proarrhythmic response, which is most common with class 1A agents. Other proarrhythmic responses to atrial antiarrhythmic agents include the acceleration of the ventricular response either by enhancing atrioventricular nodal or bypass tract conduction or by converting atrial fibrillation to flutter with 1:1 conduction. Calcium-channel blocking agents and, less commonly, digoxin may perpetuate the duration of paroxysmal atrial fibrillation, and virtually all agents can cause sinus node dysfunction or atrioventricular block. CONCLUSIONS Although drug therapy for atrial fibrillation or flutter is generally well tolerated, the potential exists for uncommon but serious proarrhythmic effects. Knowledge of the risk factors and symptoms of these adverse reactions will help to further reduce this risk.

Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis

Thirty-one patients with documented cardiac amyloidosis were compared to 39 control subjects with left ventricular hypertrophy to determine specific 2-dimensional echocardiographic features of amyloid. In 16 patients, increased myocardial echogenicity was present when a single short-axis view was examined, and had a sensitivity of 63% and a specificity of 74% for the diagnosis of amyloidosis. When complete echocardiograms were reviewed (15 patients), an improved sensitivity of 87% and specificity of 81% based on increased echogenicity was seen. Increased atrial septal thickness was present in 60% of amyloid patients and no controls. The combination of increased myocardial echogenicity and increased atrial thickness was 60% sensitive and 100% specific for the diagnosis of amyloidosis. The ratio of electrocardiographic voltage (S in V1 + R in V5 or V6) to left ventricular cross-sectional area also was examined. A ratio of less than 1.5 was 82% sensitive and 83% specific for amyloid (excluding the 2 patients with left bundle branch block), but added little to the diagnosis as determined from the 2-dimensional echocardiogram.