Feasibility and Safety Profile of Intensive Consolidation with Clofarabine and Intermediate-Dose Cytarabine (CLARA) in Younger Patients with AML in First Complete Remission (AML-CR1).

Introduction. One frequent option for consolidation chemotherapy in younger patients with AML-CR1 is based on repeated cycles of high-dose cytarabine (HDAC), according to the CALGB schedule (RJ. Mayer, NEJM 1994). Nevertheless, relapse incidence remains high, especially in those with non-favorable AML. CLARA combination (1,000 mg/m²/d cytarabine d1-5, 40 mg/m²/d clofarabine d2-6) has been associated with promising response rate in high-risk AML patients (S. Faderl, Blood 2005 and 2006). In this pilot study, we compared the feasibility and safety of CLARA vs HDAC for CR1 consolidation.

Methods. Between 2004 and 2007, 36 patients aged 17–63y (median, 38y) with AML-CR1 (16 favorable, 12 intermediate, 8 unfavorable cytogenetics) and non eligible for allogeneic transplantation received a total of 75 consolidation cycles (12 CLARA, 63 HDAC). All had previously received remission induction according to ALFA protocols. As CLARA was tested only in non-favorable patients, cytogenetics was unbalanced (P=0.004). Approximately half of HDAC patients but no CLARA patient had CBF-AML. However, median age was similar between both groups. All patients received oral antibacterial prophylaxis with amoxicillin or levofloxacin.

Results. Grade ≥ 2 nausea/vomiting was observed during most CLARA cycles while not during HDAC. Myelosuppression appeared to be more rapid and profound but not longer after CLARA as compared to HDAC. After CLARA, the median time to reach a PMN count < 0.5 × 10⁹/L was 8 days (6–10), while it was 11 days (5–20) after HDAC (P=0.0001). The percentage of patients requiring platelet transfusion was 100% in the CLARA group vs 52% in the HDAC group (P=0.001). A trend for a more rapid recovery (PMN count ≥ 0.5 × 10⁹/L) was observed after CLARA (P=0.07). At day 30 after the onset of chemotherapy, all CLARA patients had recovered while 25% of HDAC patients had not. This trend was observed after the first as well as after subsequent cycles. Median time between recovery and onset of the subsequent cycle was 6 days (3–10) and similar in both groups. Mucositis (mostly Grade 1) was more frequent after CLARA than after HDAC (58% vs 5%; P<0.001). Infectious events were more frequent after CLARA. Incidence of septicemia was 50% in the CLARA group (6 Gram negative bacteria) vs 14% in the HDAC group (8 Gram negative bacteria, 1 staphylococcus aureus) (P=0.01). The overall rate of patients presenting at least one Grade 3–4 infection was 67% in the CLARA group (including 2 invasive pulmonary aspergillosis) versus 24% in the HDAC group (no aspergillosis) (P=0.006). No toxic death was observed. Interestingly, in the HDAC group, the rate of Grade 3–4 infection was significantly lower in patients with CBF-AML (12% vs 37%, P=0.04), leading to a less marked difference between both groups when limiting the comparison to non-favorable AML (67% vs 37%, P=0.10).

Conclusion. Administration of repeated CLARA consolidation cycles is feasible in younger AML-CR1 patients. However, the high rate of infection leads to recommend a careful patient monitoring avoiding out-patient management, as it may be done in some patients receiving HDAC. A randomized Phase 2 trial will be initiated in Q4 2007 by the ALFA group in order to prospectively compare these two consolidation approaches in terms of anti-leukemic efficacy (ALFA-0702 trial).