Phase I trial of low-dose oral Clofarabine in myelodysplastic syndromes patients who have failed frontline therapy

• Low-dose oral Clofarabine was studied in patients with relapsed/refractory MDS.
• Oral Clofarabine at 5 mg daily for 10/28 days led to Grade IV pancytopenia.
• Oral Clofarabine at 1 mg daily for 7/28 days was well tolerated.
• Clofarabine at 1 mg/day for 7/28 days led to durable responses in 2/7 patients.
• MDS patients are sensitive to the myelotoxicity of protracted oral Clofarabine.

We investigated protracted low-dose oral Clofarabine for the treatment of myelodysplastic syndromes (MDS). Adults with an International Prognostic Scoring System (IPSS) score of INT-1 or higher who had failed first line therapy were eligible. INT-1 patients had to be transfusion-dependent. We started with oral Clofarabine at 5 mg (fixed dose) daily for 10 consecutive days on a 28-day cycle. Toxicity prompted a modification to 1 mg PO daily for 10 days and then 1 mg PO daily for 7 days. Patients received treatment indefinitely until loss of response or unacceptable toxicity. Nine patients (5 women) were enrolled and evaluable (median age 65 years; range 55–81). A 10-day regimen of oral Clofarabine at 5 mg/day induced Grade IV pancytopenia. A dose of 1 mg/day for 7/28 days was very well tolerated without significant toxicity. Three patients had responses (2 with responses lasting up to 21 and 51 cycles) defined as stable disease in spite of no significant change on bone marrow evaluation. Low-dose oral Clofarabine (1 mg daily for 7/28 days) proved both effective and safe for patients with MDS who had failed prior therapy. This patient population is particularly sensitive to more protracted Clofarabine treatment schedules.