Clofarabine in Combination with a Standard Remission Induction Regimen (AraC and idarubicin) in Patients with Previously Untreated Intermediate and Bad Risk Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS):Phase I Results of An Ongoing Phase I/II Study of the EORTC-LG and GIMEMA(EORTC GIMEMA 06061/AML-14A trial)

Remission induction treatment in previously untreated intermediate/bad risk AML or high risk MDS needs continuous improvement. Clofarabine is a nucleoside analog with proven activity in acute leukemias. The aim of the study was to determine the recommended/maximum tolerated dose (MTD) of Clofarabine when administered with standard remission induction regimen (Ara-C and Idarubicin) in patients suffering from AML/MDS.

This open label, 2-arm, multi-center, phase I trial included adult patients (pts) with previously untreated intermediate/bad risk AML or high risk MDS. All FAB subtypes except M3 and the cytogenetic groups, t(8;21) or inv(16) with WBC<100×10⁹/l, were eligible. Pts with blast crisis of CML or CNS leukemia were excluded. Arm A: 1h infusion Clofarabine (10 mg/m²/d and 15 mg/m²/d) on d2, d4, d6, d8, d10; Ara-C continuous infusion (c.i.): 100 mg/m²/d on d1-d10, Idarubicin (i.v): 10 mg/m²/d, on d1, d3, d5. Arm B: push injection Clofarabine (10 mg/m²/d and 15 mg/m²/d on d2, d4, d6, d8, d10); Ara-C and Idarubicin same regimen as in arm A. A minimum of 3 pts per arm were to be included at each dose level. The next dose level was visited if none of the first 3 patients experienced a Dose Limiting Toxicity (DLT) at a certain dose level. DLT was defined as treatment-related adverse events: non-hematological grade III-IV toxicity (CTCAE 3.0) occurring during 8 weeks (except grade III events resolving to grade < III within 4 weeks) after the start of the remission induction, and/or hematological toxicity defined as bone marrow hypoplasia leading to neutrophil or platelet recovery (ANC > 0.5 × 10⁹/l and platelets >50 × 10⁹/l) later than 8 weeks after start of remission induction. If 1 out of the first 3 pts experienced a DLT, 3 additional pts were added (a maximum of 6 pts per dose level) in order to ensure the safety profile of this dose level. If a second patient experienced a DLT, no further pts were entered at that particular dose level. Dose escalation stopped and additional pts included at the previous lower dose to have a minimum of 6 pts treated at the recommended dose.

25 pts have been entered into this phase I part in 3 participating sites. WHO PS status was 0 (N=16), 1 (N=8) or 2 (N=1). Age range was 25–60 years (median 55 years). 20 pts had de novo AML, 3 pts had secondary AML, 2 pts had de novo MDS (WHO RAEB-2). 7 pts had high cytogenetic risk features. In arm A and in arm B 10 mg/m²/d Clofarabine, and in arm A 15 mg/m²/d Clofarabine 6 pts each have been included. In arm B 15 mg/m²/d Clofarabine 7 pts were included, as one patient was substituted since she received 60% of total dose of Clofarabine and refused further treatment with Clofarabine due to related adverse event. All 25 pts were evaluable for DLT analysis. Overall, 5 pts with DLTs were observed: 1 in Arm A 10mg/m²/d Clofarabine, 3 in Arm A 15 mg/m²/d Clofarabine, 1 in Arm B 15 mg/m²/d Clofarabine. One patient with prolonged hematological toxicity as DLT reported in Arm A 10mg/m²/d Clofarabine. Two deaths in cytopenia/aplasia and one toxic death following sepsis/multiorgan failure have been reported as DLTs in 3 patients in both Arm A and B 15 mg/m²/d Clofarabine. The 5th patient had grade 4 anorexia, diarrhea, infection, prolonged hypoplasia and grade 3 confusion which classified as DLT in Arm A 15 mg/m²/d Clofarabine. In addition, three pts in the 15 mg/m²/d Clofarabine arms needed to be withdrawn from Clofarabine due to adverse events not classified as DLT. Main toxicity was bone marrow toxicity resulting in prolonged aplasia. Out of 25 pts, complete remission (CR) following induction 1/2 has been achieved in 19 pts: in 10/12 pts using 10 mg/m²/d Clofarabine (5 pts each in Arm A and Arm B) and in 9/13 pts using 15 mg/m²/d Clofarabine (4 pts in Arm A and 5 pts in Arm B). In addition CR with incomplete blood count recovery (CRi) following induction 1/2 was observed in 2 pts: 1 in Arm A 10 mg/m²/d Clofarabine and 1 in Arm B 15 mg/m²/d Clofarabine.

Infusion of 15 mg/m²/d Clofarabine resulted in a high rate of DLTs (4/13 pts) and early treatment withdrawals (3/13 pts). The infusion of 10 mg/m²/d Clofarabine had an acceptable rate of DLTs (1/12 pts), no early treatment withdrawals occurred, and a high CR/CRi rate (11/12 pts) was observed. Therefore the MTD of Clofarabine in combination with Ara-C and Idarubicin is defined at 10 mg/m²/d and will be the recommended dose for the phase II part of this study.

Willemze:Genzyme: member advisory committee clofarabine. Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.