Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation: Final Report of a Phase I-II Study

Abstract 1948

Reduced intensity conditioning has limited short term toxicity of allogeneic transplantation but disease recurrence represents a major challenge. Clofarabine is a novel nucleoside analog with activity in leukemia and lymphoma. In order to optimize its synergy with alkylating agents, we conducted a phase I-II study of transplant conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Post-transplant GVHD prophylaxis consisted of tacrolimus until day 100 for matched sibling and day 180 for matched unrelated donor recipients. Ten pts were accrued to the phase I portion which utilized an accelerated titration design. No DLT was observed and clofarabine 40 mg/m2 x5, melphalan 140 mg/m2x1 and alemtuzumab 20 mgx5 was adopted for the phase II study which accrued 72 patients. Median age was 54 years (21–73) and 40 patients had unrelated donors. There were 44 AML or MDS, 27 NHL, 9 other hematologic malignancies. The largest subgroup of 35 patients had ASBMT high risk, active disease. Seven had failed previous autologous transplant. Five had failed previous allogeneic transplant. All evaluable patients engrafted promptly. Engraftment was durable, though stable mixed chimerism was frequently observed as is common with alemtuzumab based conditioning. The cumulative incidence of treatment related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. OS was 80% (95% CI 71–89) at 100 days and 59% (95% CI 47–71) at 1 year. PFS was 45% (95% CI 33–67) at 1 year far exceeding the phase II primary endpoint of PFS of 32% or more.

Transient liver function abnormalities were common and occasionally reached CTC level 3 or 4, but they were always rapidly reversible. No cases of SOS/VOD were observed. Seven cases of grade 3 hand foot syndrome were observed, 6 of which were at the 40 mg/m² level. Renal failure was the main toxicity in the phase II study and occurred in 5 of 24 patients treated with clofarabine 40 mg/m² x5. 27 subsequent pts received clofarabine 30 mg/m² x5, but grade 3–4 renal toxicity was again observed in 7 patients. Infusion time was lengthened to three hours, but 4 cases of grade 3–4 renal toxicity were observed in the last cohort of 23 patients. Overall grade 3–5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Sepsis was associated in only two of these cases. In the majority of cases the onset of decline in GFR occurred within days of the start of conditioning. There was a significant correlation between age and the occurrence of renal toxicity (r=0.26,p=0.018) and between baseline GFR and occurrence of renal toxicity. Increasing age and lower baseline GFR were themselves highly correlated.

Clofarabine melphalan alemtuzumab conditioning yields promising response and duration of response. Hepatic toxicity has limited impact and skin toxicity is manageable, but renal toxicity poses a considerable risk particularly in older patients. Ongoing pharmacokinetic analysis, will help to better characterize this toxicity and to design future studies that mitigate renal toxicity.