John L. Berk

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

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.

Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999.

Tracheobronchial amyloidosis (TBA), an idiopathic disorder characterized by deposition of fibrillar proteins in the tracheobronchial tree, occurred in 10 patients referred to the Amyloid Program at Boston University over the past 15 years. Fewer than 100 cases of TBA have been described; only 1 series encompassed more than 3 patients. We analyzed our experience with biopsy-proven TBA to define better its natural history. Follow-up averaged approximately 8 years and was obtained in all cases, making this outcome reporting the largest and most complete to date. Three of these patients were prospectively studied for up to 24 months to examine the utility of bronchoscopy, computerized tomography (CT) imaging, and pulmonary function tests (PFTs) in monitoring disease progression. No patient with TBA developed signs or symptoms of systemic amyloidosis during the period reviewed. Conversely, tracheobronchial disease was not diagnosed in 685 patients with primary systemic (AL) amyloidosis during the 15-year study period at Boston University. Bronchoscopy proved most useful in establishing the diagnosis by biopsy. Narrowing of major airways limited its inspection of the tracheobronchial tree, however. In contrast, CT imaging provided quantitative assessment of airway narrowing and mural thickening--2 major consequences of amyloid infiltration. These CT features, in the presence of mural calcifications sparing the posterior tracheal membrane, have been reported in few disorders other than TBA. The ability of CT to map airway involvement and identify extraluminal manifestations of TBA made it the study of choice for establishing disease extent. Three patterns of disease were evident by CT imaging and bronchoscopic examination: proximal, mid, and distal airways involvement. Those with severe proximal disease had significantly decreased air flows, air trapping, and fixed upper airway obstruction on PFTs. Patients with distal disease had normal airflows. PFTs could not clearly distinguish proximal from severe mid airways disease. Thirty percent of patients died within 7-12 years after diagnosis, all having proximal or severe mid airways disease. Repeated rigid bronchoscopic debridement and laser treatments did not prevent progressive airways narrowing in patients dying from TBA. Most patients with mid airways involvement, and all distal airway cases, had either stagnant disease or slowly increasing amyloid deposits when followed for up to 14 years. In a small subset of patients followed prospectively, serial PFTs were most sensitive to disease progression. CT-derived measures of airway lumen diameter and wall thickness did not change significantly despite marked improvements in airflow after rigid bronchoscopy. Our experience suggests that serial PFTs and CT imaging together offer the best assessment of airway involvement and disease progression in patients with TBA. In the future, radiation therapy may provide more definitive treatment of TBA than debulking procedure have to date.

Long-Term Results of Conformal Radiotherapy for Progressive Airway Amyloidosis

PURPOSEnTo evaluate the efficacy of conformal external beam radiotherapy (RT) for local control of progressive airway amyloidosis.nnnMETHODS AND MATERIALSnWe conducted a retrospective review of patients with biopsy-proven progressive airway amyloidosis treated with conformal RT between 2000 and 2006 at Boston Medical Center. The patients were evaluated for performance status and pulmonary function, with computed tomography and endoscopy after RT compared with the pretreatment studies. Local control was defined as the lack of progression of airway wall thickening on computed tomography imaging and stable endobronchial deposits by endoscopy.nnnRESULTSnA total of 10 symptomatic airway amyloidosis patients (3 laryngeal and 7 tracheobronchial) received RT to a median total dose of 20 Gy in 10 fractions within 2 weeks. At a median follow-up of 6.7 years (range, 1.5-10.3), 8 of the 10 patients had local control. The remaining 2 patients underwent repeat RT 6 and 8.4 months after initial RT, 1 for persistent bronchial obstruction and 1 for progression of subglottic amyloid disease with subsequent disease control. The Eastern Cooperative Oncology Group performance status improved at a median of 18 months after RT compared with the baseline values, from a median score of 2 to a median of 1 (p = .035). Airflow (forced expiratory volume in 1 second) measurements increased compared with the baseline values at each follow-up evaluation, reaching a 10.7% increase (p = .087) at the last testing (median duration, 64.8 months). Acute toxicity was limited to Grade 1-2 esophagitis, occurring in 40% of patients. No late toxicity was observed.nnnCONCLUSIONSnRT prevented progressive amyloid deposition in 8 of 10 patients, resulting in a marginally increased forced expiratory volume in 1 second, and improved functional capacity, without late morbidity.

Pleural effusions in systemic amyloidosis.

Purpose of review Large, recurrent pleural effusions in systemic amyloidoses are rare but clinically challenging events predominantly affecting patients with primary systemic amyloidosis. Examining the mechanisms by which these effusions form and persist offers perspective on the pathophysiology and basis for therapeutic interventions. Recent findings Between 1977 and 2003, the literature consisted of approximately 21-25 case reports on pleural effusions in systemic amyloidosis. In 2003, Boston University published a retrospective single-center analysis of 35 primary systemic amyloidosis patients with large, refractory pleural effusions. To define the role of cardiomyopathy in large, refractory pleural effusions, the Boston University Amyloid Program compared demographics, pleural fluid chemistries, echocardiographic indices, and renal function measures of the pleural effusion group with data from 120 primary systemic amyloidosis cardiomyopathy patients with no pleural effusions. Neither cardiomyopathy nor nephrotic syndrome explained pleural effusions in primary systemic amyloidosis patients. The large number of exudative effusions supported primary disruption of the pleural surface and its function by amyloid. Disease mechanisms, natural history, and management options are discussed here. Summary Large pleural effusions in systemic amyloidosis occur most often in primary systemic amyloidosis, predominantly resulting from direct infiltration of the parietal pleural surface. Left atrial hypertension from primary systemic amyloidosis cardiomyopathy contributes to but is not sufficient to form and sustain these effusions. Untreated patients have a median survival of 1.6 months. Secondary, familial, and senile systemic amyloidosis do not infiltrate the pleural surfaces or induce pleural effusions in a clinically significant fashion.

Cardiac Amyloidosis: Evolving Approach to Diagnosis and Management

Opinion statementThe systemic amyloidoses are a group of heterogeneous disorders characterized by extracellular deposition of misfolded fibrillar protein that results in organ dysfunction. Involvement of the heart (cardiac amyloidosis) is manifest by increased cardiac wall thickness and impairment of myocardial diastolic and systolic properties, changes that result in heart failure, dysrhythmia, and death. Amyloidosis is classified by precursor protein, with light-chain (AL) and transthyretin (TTR) disease being most common in the United States. TTR amyloid can result from misfolding of variant TTR, a genetically inherited disease, or wild-type TTR, an acquired form of disease (termed senile systemic amyloidosis). In recent years, advances in the diagnosis and treatment of cardiac amyloidosis include identification and validation of disease biomarkers, new imaging techniques, and consensus treatment guidelines. Elevations of B-type natriuretic peptide and cardiac troponins can identify cardiac amyloidosis with a high degree of precision and confer important prognostic information. Non-invasive cardiac imaging techniques, such as cardiac magnetic resonance imaging and echocardiography with strain quantification, afford the ability to diagnose cardiac amyloidosis most often without the need for a confirmatory heart biopsy. Treatment of heart failure resulting from cardiac amyloidosis differs in many respects from most other etiologies of cardiomyopathy. The mainstay of treatment involves volume control with diuretics, low dose β-adrenergic antagonists or amiodarone for dysrhythmia, and warfarin to prevent thromboembolism. Although widely held to have a dismal prognosis, modern treatments such as high-dose melphalan with stem cell transplantation (HDM/SCT) for AL disease achieve a complete hematologic response in nearly half of eligible patients and yield long-term survival. For patients with advanced AL cardiac amyloidosis, cardiac transplantation followed by HDM/SCT is also an option that has proven highly effective. For familial amyloid derived from variant TTR, liver transplantation is the one validated treatment; however, small molecule therapeutic agents now in clinical trials appear capable of slowing or halting TTR amyloid deposition.

Oral Cyclic Melphalan and Dexamethasone for Patients With AL Amyloidosis

PURPOSEnAggressive treatment of amyloid light chain (AL) amyloidosis with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT because of amyloid-associated organ dysfunction.nnnPATIENTS AND METHODSnWe report on 70 patients with AL amyloidosis treated with oral cyclic melphalan and dexamethasone.nnnRESULTSnOf 48 evaluable patients who survived and returned for follow-up assessment, 6 patients (13%) achieved a complete hematologic response and 12 patients (25%) a partial hematologic response. Responses were non-inferior for patients receiving weekly low-dose dexamethasone compared with those receiving 4 day pulses. Median survival for the 70 patients has not yet been reached with a median follow-up of 17 months. Nineteen patients (27%) received additional treatment leading to improvement in survival.nnnCONCLUSIONnMelphalan/dexamethasone can lead to hematologic responses and improvement in survival, particularly for those who can receive additional treatment for AL amyloidosis.

The diflunisal trial: Update on study drug tolerance and disease progression

Abstract: Familial amyloidotic polyneuropathy (FAP) is a lethal genetic disorder that affects the peripheral and autonomic nervous systems, heart, gastro-intestinal (GI) tract, and soft tissues. Di ...

Macroglossia – not always AL amyloidosis

AL amyloidosis and transthyretin (ATTR) amyloidosis are the most frequent forms of systemic amyloidosis diagnosed in the United States. Macroglossia is considered to be a pathognomonic feature of AL amyloidosis. We report on two cases of systemic amyloidosis with macroglossia that defied routine clinical diagnosis, in which the deposits were typed as ATTR in one case and AL in the other using immunoelectron microscopy. These cases highlight: (1) the difficulty of typing amyloidosis on clinical criteria alone; (2) the utility of immunoelectron microscopy and (3) that macroglossia, while occurring much more frequently in AL, can also accompany ATTR amyloidosis.

Diaphragm paralysis in primary systemic amyloidosis.

A patient with primary (AL) systemic amyloidosis developed mononeuropathy multiplex complicated by diaphragmatic failure. High dose melphalan and autologous stem cell transplantation did not ameliorate neuropathy or diaphragm dysfunction. Nocturnal non-invasive ventilation lowered arterial carbon dioxide levels and improved daytime dyspnea. This is the first case associating AL amyloid-induced neuropathy with diaphragm dysfunction.