Low Dose Clofarabine Causes Significant Hematologic Toxicity in a Phase II Study of Relapsed or Refractory Multiple Myeloma.

Clofarabine (Clolar™) is a purine nucleoside analog recently approved for the treatment of refractory pediatric ALL. The compound is structurally related to fludarabine and cladribine and has demonstrated activity in refractory adult and pediatric acute leukemias. In phase I studies of adults with clofarabine administered on days 1–5 of a 28 day cycle, the dose limiting toxicity (DLT) among patients with solid tumors and lymphoproliferative disorders was myelosuppression with a maximum tolerated dose (MTD) of 2 mg/m² and 4 mg/m² respectively. In contrast, for patients with acute leukemia the DLT was hepatotoxicity with the MTD of 40 mg/m². Based on in vitro toxicity against myeloma cell lines and its activity in lymphoid malignancies, we initiated a phase II open-label study of low dose clofarabine in patients with relapsed or refractory multiple myeloma. This trial was designed using an optimal two-stage design (alpha =0.05 and power=0.9) with response rate as the primary endpoint. Nine patients will be enrolled in stage I. If one or more responses are observed, an additional 8 patients will be enrolled in stage II. Clofarabine 4mg/m²/day was given on days 1–5 of a 28 day cycle for up to 12 cycles or until disease progression. Eight patients have been enrolled to date. Baseline characteristics are as follows: median age 49 years (range 43–67), IgG (6 patients), IgA (1), light chain only (1). All had Stage IIIA disease and had previously undergone autologous transplants with a median of 3.5 (range 2–6) prior chemotherapy regimens. Hematologic toxicities were common in the first 6 patients treated. One patient developed Grade 3 thrombocytopenia (≤ 75,000/mm³), but all six had a >50% decrease in their platelet counts with recovery by day 28 of therapy. All six patients also developed neutropenia, Grade 3 (ANC ≤ 1000/mm³) in 4 patients and Grade 4 (ANC ≤ 500/mm³) in 2 patients. Interestingly, the timing of cytopenias was discordant between platelet and neutrophil counts. While platelet counts nadir on day 15, neutrophil counts nadir at day 25–28 of chemotherapy as platelet recovery is occurring. Dose delays of 1 to 2 weeks and dose reduction to 2 mg/m2/day have been required of all patients. Low dose clofarabine 4 mg/m² x 5 days results in significant marrow suppression with a dose limiting toxicity of neutropenia. Alternative dosing schedules should be studied in future trials with clofarabine. Response data and toxicities for stage I will be complete and updated at the time of presentation.