A randomized study of two dose levels of intravenous (IV) clofarabine (CLO) in the treatment of patients (pts) with higher-risk myelodysplastic syndrome (MDS).

Abstract

6504 Background: CLO is a second-generation deoxyadenosine nucleoside analog with activity in pts with AML. Early reports also suggested activity in MDS. Methods: We designed an adaptively randomized phase II study of IV CLO at 15 vs 30 mg/m2/Dx5 every 4–6 wks. Maximum duration of therapy was 12 cycles. Pts were eligible with MDS and 5% blasts or IPSS int-2 and high-risk, CMML, and RAEB-t by FAB. Growth factor support was permitted. Results: 58 pts (1 RA,15 RAEB-1,26 RAEB-2,9 CMML,7 RAEB-t) were treated. 43 pts (74%) had high- or int-2 risk disease. Median age was 68 yrs. More than 40% of pts were >70 yrs. 15 pts (26%) had history of prior malignancy and 35 (60%) failed prior hypomethylator (10 azacitidine, 17 decitabine, 8 both). Cytogenetics were intermediate in 12 (30%) and poor in 22 (38%). 37 pts received CLO 15 mg/m2 and 21 30 mg/m2. Responses of the 58 evaluable pts are summarized in the Table. Among 35 pts who failed prior hypomethylator, responses were CR in 5 (14%) and HI in 1 (3%). The median number of cycles to response was 1 (1–3). Of 17 pts who received further consolidation cycles, the median number was 1 (1–8). 11 pts (19%) died on study, most commonly related to infections. Common AEs were nausea, vomiting, skin rash, hyperbilirubinemia, and transaminase elevations. Toxicities grade 3 were rare. Acute renal failure occurred in 6 pts (2 [15 mg/m2], 4 [30 mg/m2]) in the context of myelosuppresssion-associated infectious complications. Myelosuppression and hospitalizations for neutropenic fever were common, but prolonged myelosuppression (> 42 days) was rare in responding pts. Infections occurred in 26 (45%) pts and were more frequent in pts receiving CLO at 30 mg/m2. Conclusions: IV CLO achieves a RR of 36% in pts with higher-risk MDS. IV CLO 15 mg/m2 appears as active and less toxic than CLO 30 mg/m2. Future studies should expand exploration of lower doses and combinations with hypomethylating agents. Response Overall N=58 CLO 15 mg/m2 N=37 CLO 30 mg/m2 N=21 Overall (%) 21 (36) 15 (41) 6 (29) CR 15 (26) 10 (27) 5 (24) HI 6 (10) 5 (14) 1 (5) Resistant (%) 26 (45) 17 (46) 9 (43) Death (%) 4-week 7 (12) 4 (11) 3 (15) 8-week 11 (19) 5 (14) 6 (29) 1-year OS (%) 37 37 38 1-year PFS (%) 39 50 25 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Novartis, Wyeth