Phase I-II Study of Fludarabine, Cytarabine and Oxaliplatin In Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

The prognosis of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) is dismal. We designed a Phase I-II combination therapy of fludarabine, cytarabine and oxaliplatin (FAO) for patients with relapsed/refractory AML or high-risk MDS, hypothesizing that a mechanistic interaction of these agents combined would increase the leukemic cell death.

FAO consisted of fludarabine 30mg/m² IV (Days 2–6); cytarabine 500mg/m² IV continuous infusion (Days 2–6); and escalating doses of oxaliplatin (20, 25, 30 or 35mg/m²/day IV) (Days 1–4) (phase I). Patients received antibacterial, antiviral, antinausea and tumor lysis prophylaxis. Treatment was given every 28 days. Dose limited toxicity (DLT) was defined as any ≥ grade 3 non-hematological toxicity lasting ≥ 3 days involving a major organ system (brain, heart, kidney, liver, or lung). The maximum tolerated dose of oxaliplatin was used in the phase II portion of the study. The study was conducted based on an outcome-adaptive Bayesian procedure (Thall and Cook) and using the program “efficacy toxicity dose finding” (MD Anderson, Department of Biostatistics website).

Twenty-seven patients were treated: phase I, n=12 (3 patients per oxaliplatin dose level); and phase II, n=15. The median age was 58 years (range, 6–71). Six patients were ≥ 65 years. There were 11 men and 16 women. Six patients had performance status (PS) 0, 16 had 1 and 5 patients had PS 2. Twenty-one patients had complex cytogenetics (CG), 3 normal and 3 hyperdiploid. All patients were pretreated, including 11 patients who had prior allogeneic stem cell transplantation (SCT). DLTs were Grade 3 transaminitis; Grade 3 hyperbilirubinemia; and Grade 3 renal insufficiency and were all noted at the 35mg/m²/d oxaliplatin dose level. Therefore, the phase II recommended dose of oxaliplatin was 30 mg/m²/day. No DLT was noted in 18 patients treated at oxaliplatin 30 mg/m²/day dose level. Grade 3–4 non-hematologic toxicity was noted as follows: diarrhea (4 of 27 patients), hyperbilirubinemia (3 of 27 patients) and transaminitis (3 of 27 patients). Five of 27 (18.5%) patients responded to FAO (CR, n=3; CRp, n=2). Three of the 5 responders had prior SCT. Characteristics and clinical outcomes of responders are shown in Table:

The Phase II recommended dose of FAO was fludarabine 30mg/m² IV (Days 2–6); cytarabine 500mg/m² IV continuous infusion (Days 2–6); and oxaliplatin 30mg/m²/day IV (Days 1–4) and it was well tolerated. FAO had significant antitumor activity in selected patients with heavily pretreated relapsed or refractory poor-risk AML and warrants further investigation.

Tsimberidou:Sanofi: Research Funding. Off Label Use: Oxaliplatin - off-label use in a Phase I-II clinical trial (combined with fludarabine and cytarabine) for patients with relapsed/refractory AML or high-risk MDS.