Abstract
Autologous stem cell transplant (SCT) with high-dose melphalan is a standard therapy for selected patients with AL. Treatment-related mortality (TRM), however, remains 10% to 15%. Risk-adapted melphalan (MEL) aims to reduce TRM (Blood2002;99). Over the past 6 years we have used risk-adapted MEL at 200, 140 and 100 mg/m2. Dosing was based on age (MEL200 if ≤ 60, MEL140 if 61 to 71, MEL100 if > 71) for patients with no cardiac involvement, involvement of 1 or 2 major organ systems (of kidneys, liver/GI tract and peripheral nervous system) and creatinine clearance (CrCl) ≥ 51ml/min. Similarly, with cardiac involvement and/or CrCl < 51, MEL140 was used for those < 61 and MEL100 for those 61 to 71. Patients < 41 were treated with MEL200 as a rule. Patients with advanced involvement of the heart or ≥3 organ systems, or with cardiac involvement and age ≥ 71, were not SCT candidates. We followed TRM, defined as death during G-CSF mobilization or within 100 days of SCT, and also asked if survival at 3 months post-SCT was affected by achievement of complete hematologic response (CR) or by clonal Ig VL germline gene use. Of the 303 amyloid patients seen in that period, 94 were mobilized with G-CSF for SCT, 50M/44W with a median age of 57 (range, 32–73) at a median of 3 months from diagnosis (1–43). None had prior SCT and 71% (n=67) were untreated for plasma cell disease, including 45 who entered a clinical study employing adjuvant oral therapy after SCT. Fifty percent had dominant renal amyloid, 28% (n=27) cardiac, and 71% (n=67) single organ involvement. Clonal lambda disease was present in 83% (n=78) and serum free light-chain abnormalities in 95% (57/60). Patients were assigned to MEL200 (n=35), MEL140 (n=42) or MEL100 (n=17). There were 8 early deaths, 4 related to treatment (RTT), 1 in mobilization and 3 in SCT, and 4 related to progression of disease before SCT. All were associated with cardiac amyloid. Seven of the 8 were in the MEL100 group (RTT=3) and 1 was MEL140 (RTT=1). Overall TRM was 4.3% (4/94) with 3 in the MEL100 group. With a median follow-up of 22 months (1–77), survival is 81% and median survival has not been reached. From mobilization, non-cardiac patients had significantly better survival [88% (59/67) vs 63% (17/27), p<0.01] but from 3 months post-SCT they survived no better than those with cardiac amyloid (p=0.29). Median survival for the MEL100 group is 47 months (vs MEL 200, p=0.02) while median survivals for the others are not yet reached. At 3 months post-SCT, CR neither differed by dose [MEL200 34% (11/32), MEL140 29% (11/38), MEL100 50% (5/10)] nor significantly affected survival [CR 93% (25/27) versus non-CR 88% (45/53), p=0.22]. Clonal Ig VL germline donors were identified in 81 cases [common: 6a=23, 2a2=15, 3r=9, DPK1=5] but did not affect survival. In sum, risk-adapted dosing of melphalan has a low TRM. Patients with cardiac involvement are at risk of early death but by 3 months post-SCT their survival is not significantly different than non-cardiac patients. These results highlight the need for new approaches to improve survival of AL cardiac patients during SCT with risk-adapted melphalan.
Treatment-related mortality in children with cancer: Prevalence and risk factors
