Clofarabine, Etoposide and Mitoxantrone In the Therapy of Relapsed and Refractory Acute Myelogenous Leukemia

Abstract 4353

Currrent therapy for acute myelogenous leukemia depends on the activity of cytosine arabinoside (ara-C). The development of regimens without this agent would potentially provide non-crossresistant treatment options for these disorders. Clofarabine, a novel agent showing significant single agent activity in AML, provides a platform for potentially effective treatment independent of ara-C. We treated 10 patients ages 30–67 (median 51) with relapsed or refractory AML with a phase I dose finding protocol employing a three drug combination based on clofarabine. The objectives were to define a maximally tolerated and recommended phase 2 dose and identify early phase 2 activity. Seven patients (70%) were refractory to 1 or 2 treatment regimens immediately prior to enrollment, the other 3 pts (30%) were relapsed following a remission. All patients had relapsed following or were refractory to standard 7+3 chemotherapy and 7/10 had received intermediate or high dose cytarabine within <52 weeks of enrollment. Patients received clofarabine 20mg/m² (Dose level 1 – DL1 – 4 patients treated) or 25mg/m² (DL2 – 6 patients) days 2–6, etoposide 100mg/m² days 1–5, and mitoxantrone 8mg/m² days 1–3. Treatment emergent non-hematological toxicities included mucositis (4 patients, ≤ grade 2) and diarrhea (2 patients, ≤ grade 3). Two out of 6 patients (33%) at DL2 failed to recover absolute neutrophils (ANC) to 500/mcL by Day 42, and this was judged a potentially treatment related toxicity given lack of residual leukemia in day 14 marrows. Seven of 9 (78%) day 14 marrows were markedly hypocellular or aplastic, and two showed residual leukemia. Four out of 10 patients (40%) showed complete remission (CR – 2 patients) or remission with incomplete hematopoietic recovery (CRi – 2 patients). Three patients survive in remission 34, 98, and 236 days from enrollment.

We conclude that the clofarabine, etoposide and mitoxantrone combination has acceptable toxicity and is an active regimen for significantly pretreated acute myelogenous leukemia. The total response rate compares favorably with other AML salvage regimens. As there has been delayed myeloid recovery at higher doses, we are pursuing DL1. The activity of this regimen is potentially non-crossresistant with ara-C, therefore larger studies are justified. Currently, patients are enrolling in an expanded cohort at the recommend phase 2 dose.