Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndromes (MDS) Who Have Relapsed or Are Refractory to Hypomethylating Agent (HMA) Therapy

Background: Treatment with HMAs such as azacitidine and decitabine has changed the overall outcome of patients with MDS. Failure to respond to or relapse from HMA treatment is associated with poor prognosis without further approved therapy. Clofarabine is a second-generation nucleoside analog with single-agent activity in MDS.

Aim: This is a phase II trial to evaluate the safety and activity of the combination of clofarabine and low-dose cytarabine in the treatment of patients with high-risk MDS who failed prior HMA therapy.

Materials and Methods: Eligible patients were adults older than 18 years with MDS who had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine and an ECOG performance status of ≤ 2 at the time of study entry. Responses were defined according to IWG 2006 criteria. Induction therapy consisted of clofarabine 15 mg/m² IV daily for 5 days (days 1-5) and cytarabine 20 mg SC twice daily for 7 days (days 1-7). Responding patients proceeded with consolidation therapy with clofarabine 15 mg/m² IV daily for 3 days (days 1-3) and cytarabine 20 mg SC twice daily for 5 days (days 1-5) every 4 weeks for a maximum of 12 cycles. Overall survival (OS) was defined as the time between the date of the first dose of clofarabine and the date of death from any cause. Univariate (UVA) and multivariate analysis (MVA) related to response and survival were performed with Cox regression analysis.

Results: Between January 2012 and December 2013, 56 patients were enrolled. Fifty-two patients were evaluable for response (4 patients had not been on-study long enough to evaluate). The median follow-up is 15.3 months (range, 1.2-27.7+), and the median age at enrollment was 71 years (31-83). Ten patients (19%) had prior chemotherapy and 12 (23%) had prior radiation therapy. Median bone marrow blast percentage was 15% (6-30%). Three patients (6%) had CMML-1, 4 (8%) had CMML-2, 7 (14%) had RAEB-1, 19 (37%) had RAEB-2, and 19 (37%) had RAEB-T. Eight (15%) patients had intermediate-1 risk, 23 (44%) had intermediate-2 risk, and 21 (40%) had poor risk by IPSS. By IPSS cytogenetic risk, 25 patients (48%) had low-risk cytogenetics, 15 (29%) had intermediate-risk, and 12 (23%) had high-risk. Mutational analysis detected 2 (4%) FLT3-ITD, 0 FLT3-D835, 7 (13%) RAS, 2 (4%) NPM1, and 2 (4%) JAK2 mutations. Thirty-nine patients (75%) received prior azacitidine therapy and 15 (29%) received prior decitabine therapy.

The overall response rate (ORR) was 48% (9 [17%] achieved complete remission [CR], 3 [6%] complete remission with incomplete platelet recovery [CRp], 7 [13%] marrow CR, and 6 [12%] had stable disease with hematological improvement), and median duration of response was 12.0 months (range, 2.0-26.7+). Five patients (10%) went on to receive allogeneic stem cell transplantation. Of the 25 patients with low-risk cytogenetics, 16 (64%) achieved OIR, 5 (20%) CR, 3 (12%) CRp, 6 (24%) mCR, and 2 (8%) HI. Of the 15 patients with intermediate-risk cytogenetics, 5 (33%) had OIR, 4 (27%) CR, and 1 (4%) mCR. Of 12 patients with high-risk cytogenetics, 2 (17%) had OIR, 1 (8%), CR, and 1 (8%) HI.

Median OS was 6.8 months (range, 0.4-27.7+). The median OS in patients with response and those without response was >12.4 months (range, 3.5-27.7+) and 3.4 months (range, 0.4-16.1), respectively. Most toxicities were of grade ≤ 2 and included elevated liver enzymes in 41% of patients, elevated bilirubin in 38%, rash in 28%, nausea in 31%, headache in 24%, and febrile neutropenia in 28%. Grade ≥ 3 toxicities included elevated liver enzymes (3%) and elevated bilirubin (3%). 21 (40%) patients had clofarabine dose reduction after a median of 2 courses (range, 1-8). UVA and MVA for survival identified performance status ≥2 (p=0.002; HR, 4.860; 95%CI, 1.784-13.244), stable disease or progressive disease after clofarabine (p<0.001; HR, 8.372; 95%CI, 3.233-21.677), thrombocytopenia <30 (/10⁹L) (p=0.001; HR, 3.659; 95%CI 1.682-7.958), and complex cytogenetics (UVA, p<0.001; MVA, p= 0.110, HR, 2.329; 95%CI 0.826-6.564) as prognostic factors for poorer OS.

Conclusion: The combination of clofarabine and low-dose cytarabine has an ORR of 48% in patients with MDS who failed prior therapy with HMA. The study continues to accrue, and updated results with longer follow up will be presented at the meeting.