Background: We determined the maximum tolerated dose (MTD) of clofarabine when administered with topotecan, vinorelbine, thiotepa, and dexamethasone (TVTC) for children with relapsed or refractory acute leukemia, and observed the efficacy and toxicities of this therapy.
Procedure: Twelve patients with acute lymphoblastic or myeloblastic leukemia were given a 14-day remission induction therapy. Clofarabine was administered at a dose of 30 or 40 mg/m(2)/day over 2 hr for five consecutive days in six patients each. Patients who achieved a remission proceeded to a stem cell transplant (HSCT). A second cycle could be administered prior to HSCT.
Results: Of the six patients at the 30 mg/m(2) clofarabine dose, two achieved a complete response (CR) and one a PR and proceeded to BMT. Three patients had progressive disease. Five of the six patients at the 40 mg/m(2) achieved a CR. Four proceeded to HSCT, and one relapsed prior to HSCT. One patient died on day 45 with marrow hypoplasia without evidence of leukemia. Hematologic and infectious adverse events were universal. The one dose limiting non-infectious toxicity observed was prolonged marrow hypoplasia.
Conclusion: TVTC has significant anti-leukemic activity in both acute lymphoblastic and myeloblastic leukemia. The MTD of clofarabine is 40 mg/m(2)/day in this combination. This is the recommended dose for the phase II study in patients with refractory or relapsed leukemia, a population which has limited therapeutic options.