Based on the observations of changes in DNA methylation status of various tumor suppressor genes, epigenetic targeting of myelodysplastic syndrome (MDS) with DNA hypomethylating agents are currently used for these patients. However, only up to 40% of the patients respond to these treatments. Therapeutic options for non-responders or responders whose disease progresses while on therapy are very limited. Based on our recent findings that low concentration clofarabine induced DNA hypomethylation, we carried out a Phase II study of elderly MDS patients who had failed 5-azacytidine (5-aza) therapy to determine the efficacy and toxicities of low dose intravenous clofarabine (ClinicalTrials.gov Identifier NCT00700011). Patients in Cohort 1 received intravenous clofarabine at 10 mg/m2/day and patients in Cohort 2 5 mg/m2/day for 5 days, each infusion given over 2 hours and each cycle repeated every 4 to 8 weeks, depending on the rate of bone marrow recovery. Eight patients were planned for each of the treatment dose. The patients were treated until disease progression or intolerable toxicities. The International Working Group response criteria were used.
The study was closed after 10 patients were treated. Of the 10 patients (6 males and 4 females) treated, ei8 received 10 mg/m2/day (Cohort 1) of clofarabine and 2 patients 5 mg/m2/day (Cohort 2). The median age was 73 years (range 65–78). Five patients had only received 5-aza prior to being treated with clofarabine while the other 5 patients had also received other therapy (lenolidomide and decitabine).
Three patients received 1 cycle, 4 patients received 2 cycles, 1 patient received 3 cycles and 2 patients received 4 cycles of clofarabine. The following responses were observed in the 9 evaluable patients: 1 CR (11%), 1 PR (11%), 2 HI (22%), 3 SD and 2 PD. The overall response rate was 44% in this group of elderly patients. All responses were observed in patients who received clofarabine 10 mg/m2/day. Response rate of 67% (4/6) was observed in patients with low risk MDS (IPSS < 1). In contrast, all 3 evaluable patients with high risk/Int.-2 MDS showed disease progression. The median time to response was 6 weeks (range 4–6 weeks) and 1 cycle of clofarabine. The patient who achieved a CR remained in CR for 14 months. The 2 patients who achieved HI both restored the erythroid-responsiveness to recombinant erythropoietin and became transfusion-independent, both for 10 months (1 patient received only 1 cycle and the other patient 2 cycles of clofarabine). As of July 31, 2010, diseases in all four responders have relapsed/progressed. The median duration of response was 10 months (range 5–14).
Despite using low doses of clofarabine, severe and prolonged pancytopenia was observed in all 10 patients. All 10 patients needed considerable blood and platelet transfusions. Eight of these ten patients also needed hospitalization for neutropenic fever. Of the 22 cycles of clofarabine administered, there were a total of 13 hospital admissions with 100 hospital days. A total of 169 units of irradiated packed red blood cells (median 10 units/cycle; range 1.5–14 units/cycle) and 211 units of irradiated single donor platelets (median 10 units/cycle; range 2–30.5 units/cycle) were used. One patient died, within 2 weeks of completing cycle 1 of clofarabine, from intracranial bleed despite intensive support of severe thrombocytopenia with aggressive platelet transfusion. This patient was already thrombocytopenic prior to starting clofarabine and had a history of severe thrombocytopenic gastrointestinal bleed prior to starting on clofarabine. Nonhematologic toxicities occurred very infrequently and were mainly Grade 2 or lower. In all cases, clofarabine was discontinued due to either disease progression (2 patients) or toxicities (8 patients). With a median follow-up of 7.5 months (range 0.5–22), the overall survival for the whole group was 50%.
In conclusion, elderly MDS patients, especially those with low risk disease, who have failed 5-aza may respond to low dose clofarabine. However, even at the low doses used in this study, bone marrow toxicity was significant. It remains to be determined whether the dose of clofarabine can be reduced further to minimize toxicities without compromising efficacy in this group of patients. Future studies should investigate the role of low dose clofarabine in low risk MDS patients.
Study supported by Genzyme Corporation, Cambridge, MA, USA
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.