Oral (po) and Intravenous (iv) Clofarabine for Patients (pts) with Myelodysplastic Syndrome (MDS)

Clofarabine (CLO) is a second generation deoxyadenosine nucleoside analog with activity in pts with acute myeloid leukemia (AML). Early reports also suggested activity in MDS, but the role of CLO in MDS has not been defined. To evaluate the activity and safety of CLO in MDS we designed two phase II studies of IV CLO and PO CLO, respectively. Pts were eligible with MDS and ≥5% blasts or IPSS intermediate-2 and high-risk, CMML, and RAEB-t by FAB. Hematopoietic growth factor support prior to and during the study was permitted. In the IV study pts were adaptively randomized (based on response) to receive CLO 15 or 30 mg/m² IV over 1 hr. daily × 5 every 4–6 weeks. For the PO study, the starting dose of CLO was 40 mg/m² orally daily × 5 every 4–6 weeks (oral bioavailability assumed ~ 50%, based on preclinical data), which was decreased to 30 mg/m² orally daily × 5 after 6 pts had been treated on the higher dose. Sixty-one pts (6 RA/RARS/RCMD, 17 RAEB-1, 16 RAEB-2, 11 CMML, 11 RAEB-t) were treated. Forty-two pts (69%) had high- or intermediate-2 risk disease by IPSS. Thirty-six pts received IV CLO and 25 PO CLO. Median age was 67 yrs (range 25–89) (IV) and 70 yrs (54–86) (PO). Overall, > 80% of pts were older than 60 yrs. Approximately 1/3 of pts had secondary MDS: 13 (36%) (IV) and 8 (32%) (PO), respectively. Seventeen (47%) (IV) and 10 (40%) (PO) of pts had unfavorable cytogenetics (by IPSS definition). Thirty-nine (64%) pts failed prior hypomethylator therapy with either decitabine or azacitidine (22 [61%] pts on IV and 17 [68%] pts on PO CLO). Responses of 60 evaluable pts (one pt refused continuation of therapy on D4 of first course) are summarized in the Table:

Six pts (10%) died on study (all IV CLO; most commonly related to infectious complications). All pts were evaluable for toxicities. Common AEs were nausea, vomiting, skin rash, hyperbilirubinemia and transaminase elevations. Toxicities ≥ grade 3 were rare. Acute renal failure occurred in 7 pts (2 IV [15 mg/m²], 3 IV [30 mg/m²], 2 PO). Myelosuppression and hospitalizations for neutropenic fever were common, but prolonged myelosuppression (> 42 days) was rare. In conclusion, CLO has activity in pts with higher-risk MDS. Optimal dose and schedule for PO and IV CLO remain to be defined. Lower doses of CLO are also associated with responses. Additional dose finding trials are underway to define the MTD and DLT of IV and PO CLO in high-risk MDS.