Phase II Trial of Clofarabine in Combination with Topotecan, Vinorelbine, and Thiotepa (TVTC) in Pediatric Patients with Refractory or Relapsed Acute Leukemia

Outcomes for children with relapsed/refractory acute leukemia remain dismal. Clofarabine has been approved for the treatment of relapsed acute lymphoblastic leukemia (ALL). However activity in pediatric acute myelogenous leukemia (AML), and optimal combination chemotherapy regimens have yet to be established. We previously reported a 36% complete remission (CR) rate with gemcitabine in combination with topotecan, vinorelbine, and thiotepa (TVTG) in relapsed/refractory pediatric acute leukemias. In an effort to improve on the outcomes of TVTG, we substituted clofarabine for the gemcitabine to create the TVTC protocol.

Following completion of a phase I study, a phase II trial of TVTC was conducted. Patients with relapsed/refractory ALL or AML were eligible. Patients were treated at the maximum tolerated dose (MTD) as determined from the preceding phase I study: clofarabine 40mg/m2/day IV × 5 days, topotecan 1mg/m2/day IV continuous infusion × 5 days, vinorelbine 20mg/m2/week IV × 3, and thiotepa 15mg/m2/day IV × 1 day. The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). 17 patients were enrolled. The median age was 10 years (8 months – 24 years). 12 patients had AML, 4 had pre-B ALL, and 1 had biphenotypic leukemia. 13 patients had relapsed disease, and 4 had refractory disease. 2 of the 17 patients were inevaluable for response; one patient was enrolled with minimal residual disease positivity of leukemia, and one patient is currently undergoing therapy.

Of the 15 patients evaluable for response, the ORR was 73% (10 CR, 1 CRp). Among the 11 responders, 10 (91%) proceeded to stem cell transplantation. Of the 4 non-responders, 2 patients had no detectable leukemia in their follow-up marrow samples, but failed to have count recovery. The other 2 patients were refractory to therapy. 16 of the 17 patients were evaluable for overall survival (OS), as one patient is currently undergoing therapy. The OS of the 16 evaluable patients is 53%, with a median OS time of 16.2 months (1.5 – 57.7 months). The most common grade 3 or higher toxicities included febrile neutropenia (69%), transient transaminase elevation (50%), and catheter-related infection (44%). One of the patients died from cardiac arrest 45 days after beginning TVTC. There were no cases of VOD.

TVTC demonstrates significant activity in patients with relapsed/refractory acute leukemia. Infectious complications occurred at similar rates to previously reported clofarabine combination studies. The activity seen in relapsed/refractory AML patients was very encouraging, with 8 of 11 (73%) evaluable patients achieving a CR/CRp. Given the high response and stem cell transplantation rates in relapsed AML patients on this study, patients with high risk de novo AML may benefit from incorporation of TVTC therapy into their treatment regimens. This regimen warrants further exploration in a larger cohort of relapsed leukemia patients.

Off Label Use: Use of Clofarabine for patients with AML. Steinherz:Genzyme: Research Funding.