Updated Results of a Phase I/II, Randomized Study of Clofarabine Combined with Idarubicin and Cytarabine (CIA) or Fludarabine Combined with Idarubicin and Cytarabine (FIA) for the Treatment of Patients (pts) with Newly Diagnosed or Relapsed/Refractory (RR) Acute Myeloid Leukemia (AML)

Standard treatment for pts with AML involves combination chemotherapy with idarubicin (I) plus cytarabine (A). However, most pts relapse, necessitating improved frontline therapeutic strategies. The management of relapse depends on the duration of first complete remission (CR) and prior treatment. Cladribine, fludarabine (F), and clofarabine (C) are all purine analogs which have been shown to act synergistically with cytarabine. Recently, results from a phase III study have shown that the addition of cladribine to 7 + 3 leads to improved overall survival (OS) in younger pts with newly diagnosed AML. In this study, we randomized both newly diagnosed and RR pts to receive CIA or FIA.

Phase I of the study was aimed at determining the MTD of C. All pts in the phase I had RR AML. The starting dose of C was 15 mg/m², with subsequent escalation up to 25 mg/m² or until DLTs were observed. Once the MTD was established, pts with newly diagnosed or RR AML were randomized using a Bayesian design to either CIA (C at MTD daily for 5 days, I 10 mg/m² daily for 3 days, A 1,000 mg/m² daily for 5 days) or FIA (F 30 mg/m² daily for 5 days, I 10 mg/m² daily for 3 days, A 1,000 mg/m²daily × 5 days). Pts could receive up to 6 cycles of consolidation, which involved the same drugs given according to an attenuated schedule. Dose adjustments were made for organ function and PS. Primary objective was overall response rate (ORR), defined as CR, CR with incomplete platelet recovery (CRp), or CR with incomplete neutrophil recovery (CRi); secondary objectives were event free survival (EFS), OS, remission duration, and toxicity.

During phase I, 9 pts were evaluated (n=6 at 15 mg/m², n=3 at 20 mg/m²). There were multiple DLTs experienced at 20 mg/m², including hand and foot syndrome (HFS), hyperbilirubinemia, and prolonged myelosuppression. Therefore, the MTD was established at 15 mg/m²for phase II. ORR on the phase I was 44%.

28 pts with newly diagnosed AML were enrolled (n=17 CIA, n=11 FIA). Baseline characteristics of the pts were similar. The majority of pts were less than 60 years of age (median age 55 years CIA, 54 years FIA). Approximately 50% of pts had a diploid karyotype (10 to 20% had abnormalities on chromosomes 5 or 7). The CR rates were 76% and 82% for CIA and FIA, respectively (P=NS), (Table 1). Median time to recovery of platelets and neutrophils was less than 30 days for both groups. Minimal residual disease (MRD) by flow cytometry performed on the post-induction bone marrow sample was available for 11/13 responders on CIA and 5/9 responders on FIA. There was a high rate of MRD negative status in both groups (91% CIA, 100% FIA). With median follow up of 5 to 6 months, there have been 0 relapses on CIA, and 3 relapses on FIA. 4-week mortality rates were 0 for both groups. Median OS has not been reached for either group.

49 pts with RR AML were enrolled (n=25 on CIA, n=24 on FIA). Baseline demographic characteristics were similar. Most pts were younger than 60 years of age (median 58 years CIA, 56 years FIA). There were more pts in the CIA group with abnormalities on chromosomes 5 or 7. Salvage status and first CR duration was similar between groups. A similar number of pts on each arm had received prior C or F. The ORR was similar between groups (44% for CIA, 38% for FIA) (Table 1). 4-week mortality rates were 16% for CIA, and 4% for FIA. Median OS was 4 and 5 months for CIA and FIA, respectively. Several pts from each group were able to move forward to allo-SCT (20% on CIA, 29% on FIA). The median time to recovery of all lineages for both groups was less than 40 days.

Grades 3/4 toxicities for the entire cohort were low, but differed between groups. Transaminitis occurred more often in the FIA group (11% compared to 5% on CIA). This is potentially explained by a departmental policy to withhold triazole antifungals during the administration of C. Grades 3/4 mucositis also appeared to be more prevalent on the FIA arm (11% versus 0% on CIA). HFS did not occur in either group.

CIA and FIA are effective regimens for newly diagnosed or RR AML with manageable toxicity profiles and low early mortality rates. There was a trend for better outcome in favor of the CIA regimen. This study continues to accrue, and an update will be presented at the meeting.

Off Label Use: Clofarabine for AML.