Clofarabine Plus Anthracycline Combinations in Acute Myeloid Leukemia (AML) Salvage.

Clofarabine (CLO) is a second-generation nucleoside analog with activity in acute leukemias. Whereas it has received FDA approval in children with relapsed acute lymphoblastic leukemia, the focus of clinical research in adults has shifted to AML. To improve single agent activity, various CLO combinations are being studied. Here we present the results of two dose-finding phase I studies, exploring combinations of CLO with idarubicin (IDA) [CI] and CLO+IDA+Ara−C [CIA] in patients (pts) with relapsed or refractory AML and high-risk MDS. Eligibility for CI required previous Ara-C and primary refractory disease, or relapsed AML with first remission duration (CRD1) < 12 mos. Eligibility for CIA required either no previous Ara-C or Ara-c with CRD1 ≥ 12 mos. Maximum tolerated dose (MTD) was determined by “3+3” method. Forty-four pts (CI 23; CIA 21) have been accrued and are evaluable. The median age of pts on CI was 56 yrs (range 24–71), 9 were primary refractory and 14 in first relapse (median CRD1 2 mos. [0–9]). Fifteen pts had abnormal cytogenetics (including 6 with -5, -7, or 11q23). Sixteen pts had intermediate- or high-dose Ara-C-based prior therapy, 2 relapsed from allogeneic transplant (SCT). The median age of pts on CIA was 56 yrs (23–78), 8 were primary refractory and 13 in first relapse (median CRD1 9 mos [0–61]). Twelve pts had an abnormal karyotype (-5, -7, or 11q23 in 6 pts). Twelve pts received intermediate dose Ara-C-based prior therapy and 2 failed unrelated donor SCT. The starting dose level of the CI group was CLO 22.5 mg/m² iv daily x 5d and IDA 12 mg/m² iv daily x 3d. Three DLTs occurred (diarrhea, rash, ↑ bilirubin) requiring dose de-escalation to CLO 15 mg/m²/d x 5d and IDA 8 mg/m²/d x 3d. Gradual re-escalation led to CLO 30 mg/m²/d x 5d and IDA 10 mg/m²/d x 3d where 2/5 pts experienced DLTs (↑ SGPT, ↑ bilirubin, headache). MTD was defined by the next lower dose level: CLO 22.5 mg/m²/d x 5d and IDA 10 mg/m²/d x 3d. Three (13%) CR occurred. The CIA group started at CLO 22.5 mg/m²/d x 5d, IDA 8 mg/m²/d x 3d, and Ara-C 1g/m²/d x 5d. Two pts developed DLTs (diarrhea, ↑ bilirubin, renal failure) requiring de-escalation to CLO 15 mg/m²/d x 5d, IDA 6 mg/m²/d x 3d, and Ara-C 0.75 g/m²/d x 5d. Re-escalation to CLO 30mg/m²/d x 5d, IDA 6mg/m²/d x 3d, and Ara-C 0.75 g/m²/d x 5d revealed DLTs in 2/6 pts (diarrhea, mucositis, ↑ bilirubin). MTD was thus defined at next lower dose level of CLO 22.5 mg/m²/d x 5d, IDA 6 mg/m²/d x 3d, and Ara-C 0.75 g/m²/d x 5d. Ten (48%) responses (9 CR, 1 CRp) occurred. The higher response rate of CIA may be due to the difference in pt characteristics between the two trials. A phase II study is now in progress adaptively randomizing patients with AML relapse to CI versus CIA versus CLO (40 mg/m²/d x 5d) plus Ara-C (1 g/m²/d x 5d) (as established in an earlier study) to assess activity of the combinations.