Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia

Abstract

In a phase 2 study, 62 patients with relapsed and refractory acute myeloid leukemia (AML; n ‫؍‬ 31), myelodysplastic syndrome (MDS; n ‫؍‬ 8), chronic myeloid leukemia in blastic phase (CMLBP; n ‫؍‬ 11), and acute lymphocytic leukemia (ALL; n ‫؍‬ 12) received 40 mg/m 2 clofarabine intravenously over 1 hour daily for 5 days, every 3 to 6 weeks. Twenty patients (32%) achieved complete response (CR), 1 had a partial response (PR), and 9 (15%) achieved CR but without platelet recovery (CRp), for an overall response rate of 48%. In AML, responses were noted in 2 (18%) of 11 patients in first salvage with short first CR (< 12 months), in 7 (87%) of 8 patients with longer first CR, and in 8 (67%) of 12 patients in second or subsequent salvage. Responses were observed in 4 of 8 patients with high-risk MDS (50%), in 7 (64%) of 11 with CML-BP, and in 2 (17%) of 12 with ALL. Severe reversible liver dysfunction was noted in 15% to 25%. After the first clofarabine infusion, responders accumulated more clofarabine triphosphate in blasts compared with nonresponders (median 18 vs 10 M; P ‫؍‬ .03). This increased only in responders (median, 1.8-fold; P ‫؍‬ .008) after the second clofarabine infusion. In summary, clofarabine is active in acute leukemias and MDS; cellular pharmacokinetics may have prognostic significance. (Blood.

Mechanisms of anti-cancer action and pharmacology of clofarabine

“…A phase II study in 62 adult patients with relapsed or refractory acute leukemia and myelodysplastic syndrome who received clofarabine at 40 mg/m 2 IV once daily for 5 days every 3 to 6 weeks demonstrated a total response rate of 48% [68]. After the first clofarabine infusion, responders accumulated more clofarabine triphosphate in blasts than non-responders.…”

Phase 2 study of intensified chemotherapy and allogeneic hematopoietic stem cell transplantation for older patients with acute lymphoblastic leukemia

“…After induction chemotherapy, we introduced a consolidation cycle that incorporated clofarabine, previously demonstrated to be well-tolerated in older adults and efficacious against ALL, as well as prednisone and asparaginase. 33,34 Following these initial two courses of treatment, patients, regardless of cytogenetics or other risk profiles, could proceed to allogeneic HCT. Those who did not undergo HCT remained on study to receive subsequent therapy.…”

New agents in acute myeloid leukemia and other myeloid disorders

“…8 In the subsequent Phase II study of clofarabine given at a dose of 40 mg/m 2 daily for 5 days, 62 patients with recurrent or refractory acute leukemia, high-risk MDS, or CML in blast phase (CML-BP) were treated. 9 Seventeen of 31 patients (55%) with AML, 4 of 8 patients (50%) with MDS, and 7 of 11 patients (64%) with CML-BP achieved a CR. Another 9 patients (15%) achieved a CR without full platelet recovery.…”

“…Grade 3-4 toxicities included skin rashes, transient liver dysfunction, and nausea/emesis. 9 Ongoing studies are investigating clofarabine in combination with ara-C and anthracyclines for patients with AML as front-line and salvage therapy. …”