Phase I/II Study of Clofarabine Combined with Standard Dose Cytarabine as Remission Induction Therapy of De Novo AML in Elderly Patients ≥60 Years.

Despite significant advances in the treatment of acute myeloid leukemia (AML) in younger adults, there has been little progress in the treatment of older patients (age≥60 years), who comprise the majority of those with the disease. Clofarabine is a purine nucleoside analog with single agent activity in patients with relapsed AML. In addition, clofarabine potentiates Ara-C cytotoxicity in vitro through increased intracellular Ara-CTP accumulation, making this an attractive combination.

A phase I/II study has therefore been initiated combining clofarabine with standard dose cytarabine (100mg/m²/day x 7) in pts age ≥60 years with de novo AML. The starting dose of clofarabine was 30mg/m²/day x 5 beginning on day 2 (Dose level I). Patients were accrued in cohorts of 3–6 to establish dose limiting toxicity (DLT); cohort expansion at the maximum tolerated dose (MTD) is planned in phase II using a Simon 2-stage design. Detailed plasma and intracellular pharmacokinetics were performed during induction therapy with Ara-C alone (day 1), and following the addition of clofarabine (day 2) to determine the effect of clofarabine on intracellular Ara-CTP accumulation. Pts with residual AML on d14–21 restaging bone marrow (BM) biopsy were eligible to receive Re-Induction with 5 days of clofarabine & Ara-C. Those achieving complete remission were also eligible to receive 1–2 cycles of consolidation with Ara-C (d1–5) & clofarabine (total 3 cycles of planned therapy).

Dose limiting toxicity was encountered at dose level I (see Table 1). 2/4 pts achieved CR, in 1 case with residual cytogenetic abnormality, and there were 2 treatment-related deaths from infxn (culture neg sepsis, n=1; Candida tropicalis, n=1). In the latter case (pt 4), BM aplasia was achieved, but the pt died on d25 prior to hematologic recovery. In view of the DLT, the protocol has therefore been amended to allow 25% dose de-escalation of clofarabine to Dose Level -I (22.5mg/m²/day x 5), and to limit eligibilty to pts age 60–75 yrs inclusive. Routine use of aggressive pre-hydration and antibiotic and antifungal prophylaxis is now mandated.

Clofarabine & cytarabine is a highly active induction regimen in older adults age ≥60 yrs with de novo AML, but has significant myelosuppressive and infectious toxicity. The study is proceeding in phase I at Dose Level -I to establish the MTD.