Clofarabine-Induced Remission in Relapsed Pediatric Acute Myelogenous Leukemia

Abstract Despite improvements, the prognosis for children with recurrent or progressive acute myeloid leukemia (AML) remains poor; the 5-year relative survival rate for children under age 15 years is 54% (Jemal, et al., Ca Cancer J Clin 2008). Early relapse, defined as relapse within less than 18 months from time of initial diagnosis, is associated with a second CR rate of about 50% and an overall survival of 10% or less (Stahnke, K. et al. Leuk 1998). The second generation purine nucleoside analog clofarabine was designed to improve on the efficacy and safety of cladribine and fludarabine. Interest in assessing the utility of clofarabine in the treatment of pediatric patients with AML was stimulated by its Food and Drug Administration approval for the treatment of pediatric patients with relapsed acute lymphoblastic leukemia previously treated with at least 2 regimens. We report on our experience using clofarabine in 6 pediatric patients with relapsed AML, 4 of whom achieved complete remission (CR) with this single agent (Table 1). All patients received clofarabine IV at the recommended dosage of 52 mg/m2/day ′ 5 days, with cycles repeated every 2 to 6 weeks depending on count recovery. Patient 1, who had Dandy Walker Syndrome and never achieved CR with prior therapies, received clofarabine after she relapsed 6 months following a bone marrow transplant (BMT); she achieved CR after 2 treatment cycles. Despite CR, the condition of this severely ill patient worsened and she died following multiple organ failure, pneumonia, and sepsis. Patient 2 obtained a CR after the first cycle of clofarabine and the CR continues after 7 cycles. However, the original plan to maintain this patient on clofarabine for 1 year was not achieved because of chronic thrombocytopenia requiring platelet transfusions. Patient 3 achieved a CR after one cycle of clofarabine and received one additional cycle of clofarabine as maintenance while awaiting BMT. Patient 4 had a CR with one cycle of clofarabine following a relapse after a first BMT. The patient received 2 additional cycles of clofarabine as maintenance before proceeding to a 2nd BMT. This patient relapsed after the second BMT and is currently receiving induction with clofarabine. Patients 5 and 6 had not responded well to previous treatments and failed to respond to a single cycle of clofarabine. Patient 5 never achieved CR despite gemtuzumab and BMT. Patient 6 had an unsustained CR2 with gemtuzumab and failed subsequent therapies. Our experience indicates that single-agent clofarabine as induction therapy can provide durable CRs in pediatric patients with relapsed AML and provide a bridge to subsequent BMT. Table 1. Pt # Age at diagnosis Marrow cytogenetics Prior Treatment (Response) Response to CLO (# of cycles to achieve response) Current Status 1 11 11q23 1-Ara-C/Dauno/6-TG (induction failure) 2. BMT CR (2) Died with fungal sepsis 2 8 11q23 1-Ara-C/Dauno/VP/L-ASP (CR-1) 2-BMT 3-Gemtuzumab (persistent disease) CR (1) CR continues after 7 cycles of CLO but has chronic thrombocytopenia 3 13 t(8;21) 1-Ara-C/Dauno/etoposide/IT+Ara-C/Mito (CR-1) CR (1) In CR, undergoing BMT 4 4 Monosomy 7 1-Ara-C/VP/Dauno/etoposide (CR-1) 2-BMT CR (1) Relapsed after 2nd BMT, undergoing induction with 5 10 Monosomy 5, +8 1-Ara-C/etoposide/6-TG/Dauno/gemtuzumab/Mito/IT + Ara-C (PR) 2-BMT No response (1) Died of progressive disease and toxicities following BMT 6 1.5 Non-informative 1-Ara-C/Dauno/etoposide/6-TG/Mito/IT+Ara-C (CR-1) No response (1) Died of progressive disease CLO: clofarabine; Ara-C: cytarabine; Dauno: daunorubicin; 6-TG: 6-thioguanine; CR: complete remission; VP: etoposide + cisplatin; L-ASP: L-asparaginase; IT: ifosfamide + paclitaxel; Mito: mitoxantrone; PR: partial response