High-Dose Melphalan and Stem Cell Transplantation for Patients with AL Amyloidosis and Cardiac Involvement
Authors: Girnius Saulius , Seldin David C , Quillen Karen , Andrea Nancy T , Sloan John Mark , Berk John L , Ruberg Frederick L , Meier-Ewert Hans , Sanchorawala Vaishali 
Published: October 2019

Abstract
Abstract 2043
Treatment of AL amyloidosis (AL) with high dose melphalan and autologous stem cell transplant (HDM/SCT) results in a high rate of durable complete hematologic responses associated with clinical responses and improvement in survival. However, patients with cardiac involvement are at increased risk of treatment-related mortality (TRM). Recently, cardiac biomarkers, B-type natriuretic peptide (BNP) and troponins, have been used to predict survival for AL amyloidosis patients, including those undergoing treatment with HDM/SCT. Here we report on treatment-related mortality (TRM), overall survival, and time to next treatment (progression) and hematologic responses in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarker stage, treated with HDM/SCT. Eligibility for HDM/SCT was based upon strict functional and clinical criteria rather than upon staging based upon biomarkers, and required a Zubrod performance status <2, NYHA heart failure class < III, left ventricular ejection fraction (LVEF) >40%, and adequate cardiopulmonary reserve at a stair climb. Cardiopulmonary exercise testing was also used for some patients. Cardiac involvement was determined by electrocardiographic and echocardiographic abnormalities, as defined by Consensus Opinion of the 10th Symposium on Amyloid and Amyloidosis. A cardiac risk assessment or “cardiac staging” system incorporating biomarkers was used, with patients assigned to stage I (normal biomarkers, BNP < 100 pg/mL and troponin I < 0.1 ng/mL), II (one elevated biomarker) or III (both biomarkers elevated). Between 1/2008 and 10/2010, 35 patients with AL amyloidosis and cardiac involvement were treated with HDM/SCT. The median age was 58 years (range, 41–72). There were 17 males (49%) and 29 (83%) with lambda clonal plasma cell dyscrasia. All but one patient had multi-organ involvement and 80% (n=28) had renal involvement. Eleven percent (n=4) patients had cardiac biomarker stage I disease, 31% (n=11) had stage II disease, and 57% (n=20) had stage III disease. The median troponin I level was 0.121 ng/mL (range, 0.006 – 0.523), and the median BNP was 224 pg/mL (range, 18–923). The median interventricular septal thickness was 13 mm (range, 9–18) and the median LVEF was 60% (range, 40–70). Peripheral blood stem cells were mobilized using G-CSF alone at 10–16 m/kg/day for 3–4 days. The total dose of melphalan, administered over two consecutive days, depending on age, severity of cardiac disease and performance status. Forty % (n=14) received 200 mg/m2 HDM and 60% (n=21) received 140 mg/m2 HDM. TRM, defined as deaths within 100 days of SCT, occurred in 3 patients (9%), all cardiac stage III (3/20, 15% of the stage III patients); patients with cardiac stage I or II did not have any TRM. This compares to a TRM of 3% (n=1/30) in patients without cardiac involvement who were treated with HDM/SCT during the same time period (Fisher's exact test, p=0.6177). There were two additional deaths during the first year after HDM/SCT, one with cardiac stage II disease and one with stage III disease. Three-year overall survival for combined Stage I and II disease was 93%, for Stage III it was 76%, and for the cohort without cardiac involvement it was 96% (p=0.08). Three-year progression free survival for combined Stage I and II disease was 69%, for Stage III it was 45%, and without cardiac involvement it was 69% (p=0.0424). Median overall survival and progression free survivals have not been reached, with a median follow-up for 21 months. By intention-to-treat analysis, 23% (n=8) of patients achieved a hematologic complete response (CR) and 46% (n=16) a partial response (PR) at 1 year following HDM/SCT. Thirty % (n=11) required additional treatment by one year following HDM/SCT. While the cardiac biomarker stage III group clearly encompasses patients at high risk of early mortality from disease and complications of treatment, for patients that meet functional criteria for HDM/SCT, this therapeutic modality may offer the potential for effective treatment for selected stage III patients.

Disclosures:
No relevant conflicts of interest to declare.