Autologous Attack on Amyloidosis

Abstract

Amyloidosis results from the extracellular deposition of fibrillar amyloid protein. Amyloid is defined by the tinctorial properties of binding of Congo red dye and green birefringence under polarized light. The symptoms of the disorder, including fatigue, edema, and weight loss, are vague and are generally not helpful in the formulation of an appropriate differential diagnosis. Amyloidosis must be considered in the differential diagnosis of monoclonal gammopathies and in any patient presenting with nephrotic range-proteinuria, unexplained cardiomyopathy, unexplained hepatomegaly, or peripheral and autonomic neuropathy. Suspicion of amyloidosis should lead to immunofixation of the serum and urine as well as an immunoglobulin-free light chain assay. One of these 3 tests will be abnormal in 99% of patients with immunoglobulin light chain amyloidosis.1Katzmann JA Dispenzieri A Abraham RS Kyle RA Performance of free light chain assays in clinical practice [abstract].Blood. 2004; 104 (Abstract 757.): 216aGoogle Scholar The diagnostic verification of amyloidosis requires a biopsy. Although patients with amyloid nephrotic syndrome, cardiomyopathy, hepatomegaly, or neuropathy will have the diagnosis established by renal, cardiac, liver, or nerve biopsy, respectively, most patients do not need to have this invasive, potentially risky procedure. The diagnosis can be established by doing Congo red stains on a bone marrow biopsy specimen, which will detect amyloid deposits in 50 to 60% of patients.2Gertz MA Lacy MQ Dispenzieri A Hayman SR Amyloidosis: diagnosis and management.Clin Lymphoma Myeloma. 2005; 6: 208-219Abstract Full Text PDF PubMed Scopus (64) Google Scholar The subcutaneous fat aspirate is a convenient, noninvasive technique that demonstrates amyloid deposits in 70% to 80% of patients.2Gertz MA Lacy MQ Dispenzieri A Hayman SR Amyloidosis: diagnosis and management.Clin Lymphoma Myeloma. 2005; 6: 208-219Abstract Full Text PDF PubMed Scopus (64) Google Scholar Biopsy of the minor salivary glands, gingiva, rectum, and skin can reveal deposits at little risk to the patient. Immunohistochemical staining of tissues with commercially available antisera helps confirm the nature of the amyloid as AL. The ultimate prognosis of amyloidosis is determined in large part by the extent and functional impairment that results from cardiac amyloid infiltration. Assessment of cardiac function with 2-dimensional echocardiography and use of cardiac biomarkers, troponin and brain natriuretic peptide, can help assess the severity of cardiac involvement and the ultimate prognosis for a patient. The treatment of immunoglobulin light chain amyloidosis (AL) remains inadequate. Often, the diagnosis is made late in the course of the disease. When advanced organ dysfunction is present, particularly of the heart, effective suppression of light chain synthesis will not result in recovery of impaired organ function, and the natural history of the disease cannot be altered. Even when diagnosed early, amyloidosis remains a therapeutic challenge. Initially, therapy for amyloidosis was based on the use of colchicine because of the drug's efficacy in preventing the secondary amyloidosis of familial Mediterranean fever. Since then, however, all therapies have paralleled those used for multiple myeloma. This is reasonable since both amyloidosis and multiple myeloma result from a clonal proliferation of plasma cells.3Gertz MA Greipp PR Kyle RA Classification of amyloidosis by the detection of clonal excess of plasma cells in the bone marrow.J Lab Clin Med. 1991; 118: 33-39PubMed Google Scholar In most patients with amyloidosis, the clonal plasma cells are nonproliferative, and overt multiple myeloma does not coexist. Multiple myeloma produces symptoms as a result of tumor mass, impairment of erythropoiesis, and bone destruction, etc. Symptoms of amyloidosis are rarely related to tumor mass and are a consequence of either the deposition of insoluble light chains or heavy chains as β-pleated sheets into the tissue or the production of toxic soluble intermediates that directly interfere with organ function.4Khurana R Gillespie JR Talapatra A et al.Partially folded intermediates as critical precursors of light chain amyloid fibrils and amorphous aggregates.Biochemistry. 2001; 40: 3525-3535Crossref PubMed Scopus (290) Google Scholar Thirty years ago, the combination of melphalan and prednisone in oral formulations was introduced for the treatment of amyloidosis. Prospective randomized studies demonstrated survival benefit.5Kyle RA Gertz MA Greipp PR et al.A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine.N Engl J Med. 1997; 336: 1202-1207Crossref PubMed Scopus (627) Google Scholar Unfortunately, measurable response rates in that era were only in the 15% range, and the median survival of treated patients was only 17 months, although nearly 5% can survive 10 years.6Kyle RA Gertz MA Greipp PR et al.Long-term survival (10 years or more) in 30 patients with primary amyloidosis.Blood. 1999; 93: 1062-1066PubMed Google Scholar The Southwest Oncology Group demonstrated the activity of dexamethasone in the treatment of amyloidosis and reported a hematologic response rate of 24% and an organ response rate of 45%.7Dhodapkar MV Hussein MA Rasmussen E et al.Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628.Blood. 2004 Dec 1; 104 (Epub 2004 Aug 12.): 3520-3526Crossref PubMed Scopus (91) Google Scholar Dexamethasone has subsequently been incorporated into melphalan-containing regimens with hematologic response rates of 67% and organ response rates of 48%.8Palladini G Perfetti V Obici L et al.Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation.Blood. 2004 Apr 15; 103 (Epub 2003 Dec 18.): 2936-2938Crossref PubMed Scopus (341) Google Scholar In multiple myeloma, autologous stem cell transplantation has been shown to produce survival benefits in carefully performed phase 3 studies. Therefore, it was logical to apply this technique to patients with amyloidosis (another plasma cell disorder). However, the management of amyloidosis with high-dose chemotherapy is distinct from that of multiple myeloma. Patients with multiple myeloma have abnormal bone marrow but generally have good organ function, and mortality rates at Mayo Clinic are between 1% and 2%.9Gertz MA Lacy MQ Dispenzieri A Hayman SR Kumar SK High-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with multiple myeloma.Expert Rev Anticancer Ther. 2006; 6: 343-360Crossref PubMed Scopus (18) Google Scholar Amyloidosis, however, is characterized by bone marrow that is only minimally involved with tumor, but organ dysfunction can be widespread, leading to a wide range of posttransplantation complications, including dialysis-dependent renal, cardiac, and hepatic failure.10Leung N Leung TR Cha SS Dispenzieri A Lacy MQ Gertz MA Excessive fluid accumulation during stem cell mobilization: a novel prognostic factor of first-year survival after stem cell transplantation in AL amyloidosis patients.Blood. 2005 Nov 15; 106 (Epub 2005 Jul 21.): 3353-3357Crossref PubMed Scopus (35) Google Scholar At Mayo Clinic, the overall day-100 mortality rate associated with transplantation since the start of our program is 12%, but in calendar year 2005, it was decreased to 8%, presumably a result of increasing experience with autologous stem cell transplantation and appropriately modifying conditioning chemotherapy dosage.11Gertz MA Lacy MQ Dispenzieri A et al.Risk-adjusted manipulation of melphalan dose before stem cell transplantation in patients with amyloidosis is associated with a lower response rate.Bone Marrow Transplant. 2004; 34: 1025-1031Crossref PubMed Scopus (104) Google Scholar Vesole and colleagues in this issue of Mayo Clinic Proceedings12Vesole DH Pérez WS Akasheh M Boudreau C Reece DE Bredeson CN Plasma Cell Disorders Working Committee of the Center for International Blood and Marrow Transplant Research High-dose therapy and autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis: a center for international blood and marrow transplant research study.Mayo Clin Proc. 2006; 81: 880-888Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar present data from the International Blood and Marrow Transplant Registry on 107 patients who underwent autologous hematopoietic stem cell transplantation to treat amyloidosis. One advantage of this study is that it provides a perspective on transplantation outcomes not attainable from single-center reports. At the same time, because 48 transplant centers contributed patients, each center contributed very few patients. As such, most patients in the report received their care at centers with limited experience. Issues regarding patient selection by inexperienced centers might account for the 30-day treatment-related mortality of 18%. The 30-day mortality rate for autologous hematopoietic stem cell transplantation in the Mayo program is 7.4%.13Gertz MA Lacy MQ Dispenzieri A Hayman SR Amyloidosis.Best Pract Res Clin Haematol. 2005; 18: 709-727Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Vesole et al report high response rates, with only 10% of patients experiencing disease progression after transplantation. The survival data, however, must be viewed carefully since the median projected survival is 47 months, but the median follow-up is only 30 months. Of note, there were 304 patients in the registry but sufficient data in only 107, and the loss of two thirds of the population may lead to unanticipated reporting bias. The role of transplantation experience in improving outcomes is seen as the only predictor of survival in this study because performing transplantation within the past 5 years was associated with decreased early mortality. Therefore, it remains unclear whether transplantations for amyloidosis should be performed only in specialized centers with extensive experience or can be done at centers with transplantation experience in nonamyloid disease. An Eastern Cooperative Oncology Group study suggested no difference in mortality in patients with amyloidosis between centers.14Gertz MA Blood E Vesole DH Abonour R Lazarus HM Greipp PR A multicenter phase 2 trial of stem cell transplantation for immunoglobulin light-chain amyloidosis (E4A97): an Eastern Cooperative Oncology Group Study.Bone Marrow Transplant. 2004; 34: 149-154Crossref PubMed Scopus (43) Google Scholar Stem cell transplantation has not been proved to be superior therapy for amyloidosis. Patients eligible for autologous transplantation represent a highly selected group by virtue of younger age, a lower proportion with advanced cardiac involvement, and fewer numbers of organs involved. This selection of the “cream of the crop” has been demonstrated in analyzing the outcomes of patients eligible for transplantation but did not undergo transplantation.15Dispenzieri A Lacy MQ Kyle RA et al.Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.J Clin Oncol. 2001; 19: 3350-3356PubMed Google Scholar These patients had a much better outcome than other patients who would not have been suitable for transplantation. One case-matched control series has suggested an improved outcome for amyloidosis,16Dispenzieri A Kyle RA Lacy MQ et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004 May 15; 103 (Epub 2004 Jan 22.): 3960-3963Crossref PubMed Scopus (217) Google Scholar but a recently reported phase 3 trial involving 100 patients with amyloidosis was unable to demonstrate survival benefit of transplantation.17Jaccard A Moreau P Leblond V et al.Autologous stem cell transplantation (ASCT) versus oral melphalan and high-dose dexamethasone in patients with AL (primary) amyloidosis: results of the French Multicentric Randomized Trial (MAG and IFM Intergroup) [abstract].Blood. 2005; 106 (Abstract 421.): 127aGoogle Scholar However, in that study, transplant-related mortality at day 100 was 24%, and at the end of the study, only 29 patients undergoing transplantation were evaluable for response.16Dispenzieri A Kyle RA Lacy MQ et al.Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.Blood. 2004 May 15; 103 (Epub 2004 Jan 22.): 3960-3963Crossref PubMed Scopus (217) Google Scholar A determination of the ultimate value of stem cell transplantation will depend on a phase 3 study with a larger number of patients. Until that time, the best treatment for amyloidosis remains uncertain. There have been reports that the natural history of amyloidosis varies among centers,18Palladini G Kyle RA Larson DR Therneau TM Merlini G Gertz MA Multicentre versus single centre approach to rare diseases: the model of systemic light chain amyloidosis.Amyloid. 2005; 12: 120-126Crossref PubMed Scopus (40) Google Scholar and the number of patients referred for consideration of autologous transplantation cannot be known from a registry study. At Mayo Clinic, no more than a quarter of patients referred ultimately undergo stem cell transplantation. Nonetheless, the report by Vesole et al represents the largest number of patients reported from multiple centers and is a realistic appraisal of the feasibility and risks associated with autologous transplantation for amyloidosis. Outside of a study, it is difficult to routinely recommend stem cell transplantation as clearly superior based on the current body of knowledge, and patients should be enrolled in scientifically conducted clinical trials. Current protocols using novel agents in the treatment of multiple myeloma, such as lenalidomide and bortezomib, are under way. Whether these agents will ultimately affect the decision to administer myeloablative chemotherapy to patients with AL remains unknown. High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation for Patients With Primary Systemic Amyloidosis: A Center for International Blood and Marrow Transplant Research StudyMayo Clinic ProceedingsVol. 81Issue 7PreviewTo determine the outcome of high-dose therapy with autologous hematopoietic stem cell transplantation (HSCT) in patients with primary systemic amyloidosis reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Full-Text PDF