Clofarabine in Combination with Etoposide and Cyclophosphamide (CLOVE) in Pediatric Patients with Relapsed Acute Leukemia: 4 Italian Pediatric AIEOP Centers’ Experience

Clofarabine is a new promising chemotherapic agent active in the treatment of pediatric acute leukemia. We planned to utilize the same drugs’ combination currently evaluated in USA as phase II study salvage therapy: clofarabine (40mg/m²/day) in combination with etoposide (100mg/m²/day) and Cyclophosphamide (440mg/m²/day) (CLOVE). We planned to treat the patients (pts) (aged 1–18) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) with 1 or 2 induction cycles (5 days chemotherapy) to reach complete remission (CR) or complete remission without platelet recovery (CRp) and with 1 or 2 consolidation cycles (4 days chemotherapy). ALL patients (pts) received intrathecal methotrexate at day 6 and AML patients intrathecal cytarabine at Day 0. Prednisone was added (0,5 mg/Kg/day) to prevent systemic inflammatory response syndrome (SIRS). Fourteen children (5 AML, 9 ALL) were treated, median age 5,7 years (range 1,75–16,5), 7 pts in first, 3 pts in second and 4 pts in third relapse. Four AML pts had one prior bone marrow transplantation (BMT): 1 autologous, 1 matched familiar donor and 2 matched unrelated donor (MUD) transplants. Five ALL pts had one prior BMT : 2 autologous, 1 syngenic and 2 MUD. The AML pts were in first relapse, and three of them were refractory to FLAG-X protocol: 3/5 (60%) achieved remission (1CRp, 2 CR), response data are currently pending for1 patient (day + 20 first induction), and 1 patient died for disease progression. The remission rate of nine ALL pts was 66% (4 CR, 2CRp). Infection grade 3 was observed in one patient, diarrhea and abdominal pain occurred in 4 pts. Febrile neutropenia was e common toxicity. Severe muscles pain with functional impairment was observed in two pts (1 AML, 1 ALL) 7 days post induction cycle: the gabapentin therapy in association with prednisone was efficient and the symptom quickly disappeared. One ALL patient refractory to first induction cycle, died after second cycle (day + 6) for cardiac failure. One ALL patient relapsed after CLOVE induction, after two more cycles he obtained partial response (BM Blast cells 10% ), and he underwent MUD transplantation and died for infection. The overall survival is 58 %, 7/9 (77 %) responders are alive. The median survival is 3 months (range 20 days –10 months). Four out 9 responding patients proceeded to BMT from unrelated donor, and three of them are alive and in CR. No unexpected transplant related toxicity was encountered. We confirm that the association of Clofarabine with Etoposide and Cyclophosfamide is active in heavily pretreated relapsed or refractory pediatric acute leukemia. patients.