Clofarabine (CLO) is an adenosine nucleoside analog with activity in adult acute myeloid leukemia (AML). Its activity in MDS is less well defined. To evaluate the activity and safety of CLO in MDS we designed two phase II studies with iv CLO and po CLO, respectively. Pts were eligible if they had MDS with ≥ 5% blasts, fell into IPSS intermediate-2 and high-risk groups, or had CMML. No prior intensive chemotherapy or high-dose cytarabine was allowed. Hematopoietic growth factor support was permitted. In the iv study pts were adaptively randomized to receive CLO 15 or 30 mg/m2 iv daily x 5 every 4–6 weeks. The second study used a starting dose of CLO 40 mg/m2 orally daily x 5 every 4–6 weeks (assuming oral bioavailability about 50%), which was then decreased to 30 mg/m2 orally daily x 5. Thirty pts (18 RAEB, 6 RAEB-T, 6 CMML) have been treated. Assignment by IPSS for RAEB and RAEB-T pts: 10 high-risk, 10 intermediate-2, and 4 intermediate-1. Fifteen pts received iv CLO and 15 po CLO. Median age was 68 yrs (range 57–86). Median number of prior therapies was 1 (0–4). Twenty (67%) pts received prior decitabine or azacitidine. Karyotype was abnormal in 24 (80%) pts, including 10 pts with −5/−7 abnormalities. Responses were determined according to International Working Group criteria (IWG). Twenty-seven pts were evaluable for response (2 pts too early, one refused further treatment on day 4 of first course). Eleven (41%) pts responded [7 (26%) CR, 2 (7%) HI, 2 (7%) clinical benefit (CB)] (see table).

Response (%)
RouteDose (mg/m2)NCRHICB
po 40 1 (17) 
 30 1(17) 2 (33) 1 (17) 
iv 30 2 (33) 
 15 4 (44) 
Response (%)
RouteDose (mg/m2)NCRHICB
po 40 1 (17) 
 30 1(17) 2 (33) 1 (17) 
iv 30 2 (33) 
 15 4 (44) 

Response by IPSS: 67% intermediate-1, 44% intermediate-2, 40% high. Twenty-seven pts are evaluable for toxicities. Grade ≥ 3 toxicities occurred in 8 of 13 pts on iv CLO (rash, hyperbilirubinemia, elevated transaminases, elevations of creatinine, acute renal failure) and 4 of 14 pts with po CLO (rash, hyperbilirubinemia, elevated transaminases). Myelosuppression resulting in febrile episodes and hospitalizations with both iv and po CLO was ubiquitous, but prolonged myelosuppression (> 42 days) was rare. In summary, CLO has activity in pts with higher-risk MDS. The optimal dose and schedule for po and iv CLO have not been defined yet. Lower doses of CLO are associated with responses. Correlative PK studies may help to provide further support for optimal dose and route of administration of CLO in pts with MDS.

Author notes

Disclosure:Consultancy: Genzyme. Research Funding: Genzyme. Membership Information: Advisory Committee Genzyme. Off Label Use: Clofarabine in MDS.

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