Cytarabine and clofarabine after high‐dose cytarabine in relapsed or refractory AML patients

Abstract

Clofarabine has been shown to be effective in AML patients, either as single agent or, mainly, in association with intermediate dose cytarabine. Based on these reports, we conducted a preliminary study combining clofarabine and intermediate dose cytarabine in AML patients who relapsed or failed to respond to at least two induction therapies. We treated 47 patients affected by relapsed/refractory AML with a regimen including clofarabine at 22.5 mg/m2 daily on days 1–5, followed after 3 hr by cytarabine at 1 g/m2 daily on days 1–5. Ten patients received a further consolidation cycle with clofarabine at 22.5 mg/m2 and cytarabine at 1 g/m2 day 1–4. Among the 47 patients, 24/47 (51%) achieved a complete remission, 5/47 (10.5%) a partial response, 10/47 (21%) had a resistant disease, and 6/47 (13%) died of complications during the aplastic phase. The most frequent nonhematologic adverse events were vomiting, diarrhea, transient liver toxicity, febrile neutropenia, and infections microbiologically documented. Among the 24 patients who obtained a CR 13 underwent allogeneic bone marrow transplantation. In 14 patients, complete remission duration was shorter than 12 months, whereas 10 patients experienced longer complete remission duration. These very preliminary results suggest that clofarabine‐cytarabine regimen is effective in this particularly poor prognosis category of patients, representing a potential “bridge” toward bone marrow transplant procedures. Safety data were consistent with previously reported salvage therapies. Further studies and a longer follow up are warranted. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.

Low efficacy and high mortality associated with clofarabine treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes

“…Investigators have examined clofarabine's role in relapsed or refractory AML in multiple phase I-II studies and a single randomized controlled trial [6]. The ranges for overall response and complete response rates assessing the combination of clofarabine with cytarabine are 40-61% and 24-46%, respectively [5,[7][8][9][10][11][12]. The largest trial of clofarabine to date in the relapsed/refractory setting, CLASSIC I, was the only randomized controlled trial of this agent in the AML setting: in CLASSIC I, the combination of clofarabine and cytarabine was associated with overall and complete response rates of 47% and 35%, respectively, compared to 22% and 18% with cytarabine monotherapy.…”

Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

“…GCLAC—Clofarabine is a second-generation deoxyadenosine analog that is characterized by high resistance to phosphorolytic cleavage by bacterial purine nucleoside phosphorylase, potent inhibition of DNA synthesis, prolonged retention of clofarabine triphosphate in leukemic blasts [ 34 ] and, similar to fludarabine and cladribine, can inhibit RNR reductase and increase the intracellular concentration of ara-CTP when administered prior to cytarabine [ 94 ]. Studies evaluating clofarabine with intermediate-dose cytarabine (1 gm/m 2 ) have found CR rates 35%–51% [ 33 , 34 , 35 ] ( Table 1 ). GCLAC is a regimen containing clofarabine, high dose cytarabine (2 g/m 2 ), and G-CSF that has resulted in comparable CR rates (46% in a phase I/II study) [ 36 ] ( Table 1 ).…”

Approach to patients with primary refractory acute myeloid leukemia

“…As salvage chemotherapy outcomes for patients with PRD are dismal, there is accumulating evidence to suggest that HSCT with active disease is a viable strategy that consistently leads to a long-term OS of approximately 20% with studies identifying multiple prognostic factors (Table 3) 3-year OS for all patients was 19% with the following relevant risk factors on multivariate analysis: complete remission less than 6 months (for those without PRD), circulating blasts, nonhuman leukocyte antigen identical sibling donor, Karnofsky performance status less than 90%, and poor-risk cytogenetics. Given the increased efficacy of Clo in the salvage setting and tolerability in an elderly population [39,40,41 & ,55,58,59 & ], it has generated interest as conditioning chemotherapy prior to allogeneic HSCT. Utilization of this prognostic scoring system was subsequently externally validated in a large cohort of Italian patients [50 && ] that also included patients receiving reduced-intensity conditioning regimens or cord blood as a stem cell source.…”