A Phase I Trial of Low-Dose Protracted Oral Clofarabine for the Treatment of Myelodysplastic Syndromes Patients Who Have Failed Frontline Therapy

Clofarabine is a nucleoside analog approved in an intravenous form on a daily × 5 schedule to treat relapsed/refractory pediatric acute lymphoblastic leukemia. It is also active in adult acute myeloid and lymphoblastic leukemia. Clofarabine, given orally at a dose of 20 – 40 mg/m² daily for 5 consecutive days, was shown to achieve a response rate of 43% in patients with high-risk MDS (Faderl S et al. J Clin Oncol 28:2755-60,2010). In that study the toxicity profile (mainly pancytopenia) was better with lower doses, while response rates did not differ. Animal models suggest that protracted administration of clofarabine is more efficacious and less toxic. The optimal dose and schedule of oral clofarabine for the treatment of patients with MDS is unknown. The goal of this study was to establish the safety and maximum tolerated dose (MTD) of clofarabine administered orally at a low daily dose over a protracted period for the treatment of MDS.

Adult patients (ECOG performance status of 0–2) with MDS and a prognostic score of INT-1 or higher according to the International Prognostic Scoring System were eligible. INT-1 patients had to be transfusion-dependent. Patients had to have failed first line therapy consisting of either a hypomethylating agent, or lenalidomide in the case of patients with the 5q- abnormality. The starting dose and schedule of oral clofarabine was 5mg (fixed dose) daily for 10 consecutive days of a 28 day cycle. This dose and schedule were modified as outlined below. Bone marrow biopsies were done after 3, 6 and 12 cycles of treatment. Patients could receive up to 12 cycles.

A total of 7 patients (4 women and 3 men) were enrolled. The median age was 72 years (56-81). Two patients had 5q- MDS and had failed or developed disease progression after prior lenalidomide treatment. Two patients had CMML-1 and CMML-2. One patient had MDS/MPD. Two patients had RA and MDS-U. The non 5q- patients had all received treatment with either decitabine or azacitidine. Patient 1 had RA with del(5)(q13q33) and complex cytogenetics. She became transfusion independent on lenalidomide therapy but relapsed 8 months after stopping therapy due to lenalidomide toxicity. She then received 5mg of oral clofarabine daily for 10 days and developed grade IV pancytopenia. Her bone marrow at day 18 revealed complete aplasia. Her blood counts recovered by day 47 and ultimately normalized. She remained transfusion-independent off therapy for 2 months. Patient 2 had CMML-1 with grade 3 thrombocytopenia. He failed azacitidine therapy and was treated on study with oral clofarabine at a dose of 5mg daily for 10 consecutive days. He developed grade 4 thrombocytopenia which recovered to transfusion-independence 4 months after start of therapy. The protocol was then modified to start patients on 1mg orally of clofarabine daily for 10 consecutive days. Patient 3 had RA with trisomy 8. She was transfusion dependent and had failed decitabine, lenalidomide and immunosuppressive therapy. She received 2 cycles of oral clofarabine at 1mg daily for 10 days. She developed grade 4 thrombocytopenia after cycle 2. Her platelet count recovered to baseline on day 26. She continues to be transfusion-dependent. The protocol was modified again to reduce the number of treatment days to 7 if patients developed more than a 25% drop in baseline blood counts after 10 days of clofarabine at 1mg daily. All patients who were treated with 1mg oral clofarabine daily for 10 days had a greater than 25% drop from baseline blood counts with cycle 1 and received only 7 days of therapy for subsequent cycles. On the 7 day treatment cycle we did not observe any significant toxicity. One patient with a mixed MPD/MDS who was transfusion-dependent after failing 4 cycles of decitabine therapy remained transfusion-independent for 12 months while on monthly clofarabine. One patient with CMML-2 who had failed decitabine therapy remains on therapy after 7 cycles of treatment and is transfusion-independent. After 6 cycles of therapy her bone marrow blasts had dropped from a baseline of 18% to 8%.

Low dose oral clofarabine shows promise for the treatment of high-risk MDS. However, this patient population seems to be particularly sensitive to protracted treatment schedules of clofarabine. A dose of oral clofarabine of 1mg daily for 7 days on a 28 day cycle is safe in this patient population and shows promising efficacy. This dose is adopted for an ongoing Phase II study.

Shami:Genzyme: Honoraria, Research Funding.