Abstract LB-178: Phase I trial of low-dose oral clofarabine in myelodysplastic syndromes patients who have failed frontline therapy.
Authors: Rudrapatna Venkatesh K. , Morley Kimberly , Kushner James P. , Pierson Andrew S. , Shull Christian T. , Shami Paul J. 
Published: August 2014

Abstract
Introduction: The nucleoside analogue clofarabine, given orally at 20 - 40 mg/m2 daily for 5 consecutive days, achieved a response rate of 43% in patients with high-risk MDS (J Clin Oncol 28:2755-60,2010). Toxicity was better at lower doses, with similar responses. Animal models suggest that protracted administration of clofarabine is more efficacious and less toxic. The goal of this study was to establish the safety of protracted low dose oral clofarabine for the treatment of MDS.
Methods: Adults with MDS and an IPSS score of INT-1 or higher who had failed first line therapy (a hypomethylating agent or lenalidomide in cases with the 5q-) were eligible. INT-1 patients had to be transfusion-dependent. The starting dose and schedule of oral clofarabine was 5mg (fixed dose) daily for 10 consecutive days of a 28-day cycle. This was modified as outlined below. Patients received treatment indefinitely until loss of response or unacceptable toxicity.
Results: Ten patients (5 women and 5 men) were enrolled and evaluable (median age 66.5 years; range 56-81). Because of grade IV cytopenias in the first 2 patients, the treatment was modified to 1mg/day for 10 consecutive days and then 1mg/day for 7 consecutive days out of 28 days. On the latter dose and schedule there was no significant toxicity.
There were 4 responses. Patient 1 (78 year old woman with a del(5)(q13q33) and complex cytogenetics) became transfusion-dependent 8 months after stopping lenalidomide due to toxicity. With 5mg of oral clofarabine daily for 10 days she developed grade IV pancytopenia. Her blood counts recovered by day 47. She remained transfusion-independent off therapy for 2 months. Patient 4 (72 year old man with a mixed MPD/MDS) was red blood cell transfusion-dependent after 4 cycles of decitabine therapy. He received 1 cycle of clofarabine at 1mg/day for 10 days that was reduced to 1mg/day for 7 days for subsequent cycles. He did not have a marrow response but remained transfusion-independent for 12 months while on clofarabine. The following 2 patients with responses received 7mg of clofarabine/day for 7 out of 28 days. Patient 7 (74 year old woman) had CMML-2 and failed decitabine therapy. She remains on therapy after 33 cycles of clofarabine treatment and is transfusion-independent with normal blood counts. Her bone marrow blasts have dropped from a baseline of 18% to 8-11%. Patient 10 (68 year old woman) had a del(5)(q13q33) and was red blood cell transfusion-dependent. After losing her response to lenalidomide, she received a total of 21 cycles of clofarabine during which she remained transfusion-independent even though there was no improvement in her bone marrow findings.
Conclusion: Low dose oral clofarabine shows promise for the treatment of high-risk MDS. This patient population is particularly sensitive to protracted treatment schedules. A dose of oral clofarabine of 1mg daily for 7/28 days is safe and shows promising efficacy.
Citation Format: Venkatesh K. Rudrapatna, Kimberly Morley, James P. Kushner, Andrew S. Pierson, Christian T. Shull, Paul J. Shami. Phase I trial of low-dose oral clofarabine in myelodysplastic syndromes patients who have failed frontline therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-178. doi:10.1158/1538-7445.AM2013-LB-178
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.