High-Dose Melphalan for AL Amyloidosis: The Importance of Case Selection to Improve Clinical Outcomes
Authors: Jimenez-Zepeda Victor H , Franke Norman , Delgado Diego , Winter Andrew , Stewart Keith , Mikhael Joseph R. , Reece Donna E. , Trudel Suzanne , Chen Christine , Kukreti Vishal 
Published: October 2019

Abstract
Abstract 2403
Immunoglobulin light chain amyloidosis (AL) is a monoclonal plasma cell disorder characterized by the accumulation of monoclonal light chain fragments that have undergone a conformational transformation and deposit as amyloid fibrils in different tissues. High-dose melphalan (HDM) with autologous hematopoietic stem-cell transplant (ASCT) is increasingly used to treat patients (pts) with AL Amyloidosis. However, transplant-related mortality (TRM) is high, ranging between 13% to 43%. The survival benefit of HDM has been attributed to a patient-selection bias. Recently, a randomized clinical trial by Jaccard A et al, showed longer survival in the group assigned to receive melphalan plus dexamethasone (Mel/Dex) than in the group assigned to receive HDM. The present is a retrospective study aiming to define which pts with AL are most likely to benefit from HDM. Patients and Methods We retrospectively reviewed the medical records of all the pts included in the Princess Margaret Hospital Amyloidosis Database who underwent ASCT from January 2004 to March 2010 to determine: a) TRM, b) Hematological response (HR) and Organ response (OR) and c) Overall survival (OS). We included transplanted pts who had received no more than two previous courses of any chemotherapy regimen who did not have concurrent myeloma, and who had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 2 or better. As part of the ASCT the stem cells were obtained from the peripheral blood with granulocyte colony-stimulating factor (G-CSF) alone (5 μ g/kg subcutaneously, twice daily). Pts then received HDM, 200 mg/m2 given intravenously on day 0, and stem cells were infused on day 1. The HDM was reduced to 140 mg/m2 for pts 65 years of age or older and for those with an important decrease of the ejection fraction, a calculated creatinine clearance of less than 30 ml per minute, or severe liver disease. HR and OR was assessed using 2004 Amyloidosis Consensus Response Criteria (Gertz, M et al, 2004). For statistical evaluation, HR was defined as observing complete or partial remission (CR or PR); stable disease (SD) or progression was considered as no HR. All statistical tests were 2-sided X2 t test and P values less than .05 were considered to be statistically significant. Results Seventy seven pts were evaluated with a median age of 56 years (33-74). Clinical characteristics are seen in Table 1. Only 18/77 pts (23%) received induction therapy: Dexamethasone alone n=9, Cyclophosphamide and Prednisone n=2, Mel/Dex n=4, VAD n=2 and Melphalan and Prednisone n=1. TRM observed was 12% mainly due to congestive heart failure and sepsis. Complete HR was achieved in 38 cases (49%) and OR was seen in 59%. Among the most common complications to ASCT, febrile neutropenia was reported in 67%, transient renal impairment in 10% and congestive heart failure in 3%. Median OS was significantly lower for patients with B-type natriuretic peptide (BNP) >300 pg/ml (17.7 vs 64.46 months) (p0.0004), Troponin I >0.07 ng/ml (19.25 vs 97.4 months) (p0.00001) and those who achieved a complete HR (115 vs 88 months) (p0.0345). Multivariate Cox regression analysis showed that BNP>300 pg/ml and Troponin I >0.07 ng/ml (normal <0.07) were the most important factors to predict OS for patients with AL who underwent ASCT (p0.0002 and 0.04 respectively). Conclusions Based on this study of 77 patients, clinical selection is the most important factor to better improve outcomes for HDM in AL. Patients with BNP>300 pg/ml and/or abnormal levels of Troponin I (>0.07) should not be considered eligible for transplants due to a high degree of mortality. Our series showed a CR rate of 49% which is higher than 33% reported by Palladini et al with Mel/Dex. Stringent case selection may be the most important factor in decreasing mortality rate associated to ASCT leading to better outcomes.
Table 1. Clinical Characteristics of patients with AL Amyloidosis undergoing ASCT (at initial diagnosis) Clinical Characteristics N Median Range % Age (years) 77 57 33–74 Hemoglobin (g/L) 77 138 104–182 Creatinine (μ mol/L) 77 129 37–700 **BNP (pg/ml) 44 180 10–1670 ***BMPC (%)– 77 7 1–30 24 Hr Proteinuria (g/d) 77 5.5 0–24.9 Intraventricular Septal Distance (mm) 77 13 9–23 Kappa/lambda ratio 53 4.4 0.001–71.2 Kidney Involvement 71 Heart Involvement 52 Liver involvement 23 GI involvement 10 3 or more organs involved by AL 16 ** B-Type Natriuretic Peptide *** BMPC: Bone marrow plasma cells

Disclosures:
Stewart: Millennium: Consultancy; Celgene: Honoraria. Reece: Celgene: Honoraria, Research Funding. Chen: Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti: Celgene: Honoraria.