Managing cardiac amyloidosis: Auto or allotransplant?
Authors: Ambuga Badari, Karen Brown, Pamela Paplham, Maggie Syta, Michelle Burgess, Karen Arnold, Joann Liu, George Chen, Hong Liu, Maureen Ross, Theresa Hahn, Philip McCarthy
Journal: American Journal of Hematology (2011)

Patients with cardiac amyloidosis are difficult to manage and have high mortality. There is no standard treatment for primary cardiac amyloidosis that is considered curative. We present two cases of cardiac amyloidosis: one treated with reduced intensity allogeneic hematopoietic cell transplant (alloHCT) and the other with autologous (auto)HCT and a summary of alloHCT in the management of primary amyloidosis. A 45-year-old African-American male presented with dyspnea and was found to have congestive heart failure (CHF). A two-dimensional echocardiogram (2D ECHO) demonstrated interventricular septal and left ventricular thickening, and he underwent a cardiac biopsy demonstrating extensive interstial and endocardial kappa light chain amyloid light chain (AL) amyloidosis. Workup demonstrated serum and urine kappa light chains and 10% plasma cells on bone marrow biopsy. Treatment with lenalidomide and dexamethasone was stopped at 3 weeks because of intolerance. At 3 months after presentation, he underwent peripheral blood stem cell (PBSC) collection followed by autoHCT with melphalan at a dose of 120 mg/m2 and attained a partial response (Table I). He had multiple marrow biopsies, routine labs, and repeat 2D ECHO. His disease progressed at 11 months and became progressively pancytopenic in the postautologous transplant period. A 2D ECHO at 1year postautotransplant showed significant improvement in diastolic dysfunction. At evaluation for a second autoHCT, he was found to have myelodysplastic syndrome (MDS). Multiple marrow biopsies in this period were negative for amyloid.There was minimal dysplasia on his marrow aspirates. There were 1.5% bone marrow blasts and a cellularity of 15%, 11 months postautologous transplant. However, fluorescence in-situ hybridization (FISH) revealed del 12p13 in 51/200 interphase nuclei, consistent with secondary MDS. There was an abnormal chromosome 12 with deletions of portions of both the short and the long arms in 10 of 21 metaphases on conventional cytogenetic analysis with a constitutional pericentric inversion of chromosome 9 in all the cells examined. The peripheral blood counts at the time of diagnosis were: hemoglobin 10.5 g/dL, platelet count 79,000/μ L, and a white blood cell count (WBC) of 4,400/μL with an ANC of 1.8. His serum kappa:lambda ratio decreased from 16.88 before autotransplant to 3.18 at the time of MDS diagnosis. The duration between his autotransplant and MDS diagnosis was 11 months. He underwent an human leukocyte antigen (HLA)-matched sibling alloHCT with fludarabine 160 mg/m2, Melphalan 50 mg/m2, and 400 cGy of total body irradiation for conditioning. He required a cardiac pacemaker because of heart block within the first 100 days post-alloHCT. His CHF symptoms improved, with improvement in diastolic function by 2D ECHO (Table I). Brain natriuretic peptide (BNP) levels were not obtained serially. He developed mild chronic graft-versus-host disease (GvHD) of the skin, treated with topical steroids. A bone marrow biopsy at 1 year post-alloHCT was without plasmacytosis, and he had full lymphoid and myeloid engraftment. He is 21 months post-alloHCT without CHF. A 53-year-old white male with history of diabetes mellitus presented with dyspnea and was found to have CHF and atrial flutter. Workup revealed nephrotic range proteinuria and abdominal fat, renal, and bone marrow biopsies showed lambda amyloidosis, the latter with <5% plasma cells. 2D ECHO revealed normal systolic function with enlarged atria and borderline septal thickening (Table II). The patient was started on bortezomib, tolerating only one cycle because of orthostatic hypotension. He underwent PBSC mobilization followed by high dose chemotherapy with melphalan 120 mg/m2 and autoHCT. His post-transplant course was complicated by severe CHF requiring a prolonged intensive care unit (ICU) stay. Day 100 workup demonstrated decreased 24-hr proteinuria but continued amyloid deposition in the bone marrow. On day + 138, patient was admitted for CHF exacerbation, and alloHCT was offered to the patient because of worsening CHF and proteinuria. However, alloHCT was not authorized by his insurance company, and the patient was risk averse, not wishing to appeal the insurance denial. The patient was being considered for a second autoHCT, but developed refractory CHF and died. Renal and cardiac involvement occur in more than 50% of amyloid light chain (AL) amyloidosis patients with cardiac involvement, the most important factor affecting outcome [1]. The median survival is ∼ 6 months in untreated or nonresponsive patients [2]. The optimal management of cardiac AL amyloidosis is controversial. Unlike multiple myeloma, where hematologic response and tumor burden reduction are primary endpoints, cessation and reversal of end organ dysfunction are outcome goals for AL amyloidosis patients. Patients with renal disease will respond to autoHCT with low treatment-related mortality (TRM). However, patients with cardiac amyloid have higher TRM rates because of poor tolerance of the high dose chemotherapy [3]. In a study involving 434 patients with AL amyloidosis undergoing autoHCT, the day 100 mortality was 10.1%, often because of multiorgan failure [4]. A case report from Japan [5] documented improved cardiac function, normalization of serum BNP, and symptom-free survival of over 3 years in a 63-year-old woman after autoHCT. Good organ response and improved survival have been reported in a small number of cardiac AL amyloid patients who underwent cardiac transplant followed by chemotherapy including autoPBSCT [6]. However, cardiac transplantation is limited by organ availability. In addition, amyloid protein deposition in the transplanted heart followed by disease progression post-autoHCT is a major concern. AlloHCT, often with a reduced intensity regimen, can be considered as a reasonable approach in cardiac AL amyloidosis patients. In a report from the european group for blood and marrow transplantation (EBMT), organ responses were observed in 9 of 15 patients undergoing alloHCT for AL amyloidosis [7]. However, the TRM was up to 40% because of the poor performance status of the patients, especially because of cardiac involvement. Among the eight patients who received reduced intensity alloHCT, only two patients (25%) died of TRM. The remaining patients achieved complete response (CR) (2), had progressive disease (1), or died of disease progression (2). Achievement of CR is an important predictor of long-term survival after alloHCT, and the presence of chronic GvHD favored CR [7]. Thus, alloHCT for AL amyloidosis with cardiac involvement, while promising, faces several barriers, including identification of appropriate patients before a decline in performance status, utilization of reduced intensity conditioning regimens and education of insurance company groups regarding the curative potential of alloHCT in an otherwise rare, incurable disease. Further study of reduced intensity alloHCT in young primary amyloidosis patients with good performance status is needed.