Abstract
Abstract
Risk-adapted dosing of melphalan (MEL) has been proposed as a means of reducing treatment-related mortality (TRM) in patients with AL undergoing SCT but recent retrospective studies show poorer response rates in patients receiving < 200mg/m2 of MEL (Ann Intern Med2004;140; BMT2004;34). We have prospectively studied a combined approach using risk-adapted MEL followed by adjuvant D ± T with the goals of achieving low TRM and optimal hematologic and organ response rates. To be eligible, patients with systemic AL with ≤ 2 organ systems involved and no advanced cardiac disease had to be untreated and diagnosed within 12 months of enrollment. Patients received MEL200, 140, or 100 mg/m2 with autologous SCT based on age, renal function, and cardiac involvement (Blood2002;99). Those not achieving a hematologic complete response (CR) at 3 months post-SCT were treated with 9 months of D (20mg/m2, 1–3 pulses monthly) + T (50–200mg nightly), or only D if they had prior DVT or neuropathy. Forty-five patients (51% men) enrolled, a median of 57 years old (range 34–73) and 2 months from diagnosis. Dominant organ involvement was renal in 58% (n=26), cardiac in 24% (n=11), and liver/GI or peripheral nervous system in 18% (n=8). A third (n=15) had 2 organ systems involved. Twenty-one percent (8/38) had elevated serum troponin I levels (>0.06ng/ml) and 53% (19/36) had elevated serum brain natriuretic peptide levels (>100pg/ml) at baseline. Dose-assignments were MEL200 (n=15), MEL140 (n=24) and MEL100 (n=6). TRM was 4.4% (2/45), with 6 patients out of hospital and well < 100 days post-SCT. At 3 months post-SCT, 63% of patients had hematologic responses (8 CR, 15 PR). Persistent clonal plasma cell disease was found in 29 patients; 1 refused and 2 were too ill for D+T, 17 received D+T and 9 D. Ten completed 9 months of adjuvant therapy, with 13 discontinuing and 3 still on therapy. Reasons for discontinuation were progressive disease (n=4), DVT/PE (n=2), RSV pneumonia (n=2), femoral avascular necrosis (n=1), anxiety (n=1) and intolerance (n=3). Thirty-five percent (9/26) on adjuvant therapy had improvements in hematologic response at 12 mos post-SCT, including 4 PR to CR (2 D+T, 2 D) and 5 stable disease (SD) to PR (3 D+T, 2 D). The hematologic response rate at 12 months was 79% (22/28; 9 CR, 13 PR) with no significant difference based on dose of MEL. Forty-six percent (13/28) had organ responses at 12 months, while 32% had stable and 21% worsened organ function. Only patients who achieved a hematologic response at 12 months had organ responses (59% (13/22) of PR/CR patients vs. 0% (0/6) with stable or progressive disease, p=0.01). With a median follow-up of 18 months (range 1–33), overall survival is 76% and median survival is not yet reached. In summary, risk-adapted MEL has a low TRM and adjuvant D±T can improve hematologic response in a third of patients with persistent clonal plasma cell disease post-SCT, albeit with moderate toxicity. Further study of such combined approaches in AL SCT patients is warranted.