The role of clofarabine in acute myeloid leukemia

Abstract

Clofarabine is a second-generation purine nucleoside analog that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared to its precursors, clofarabine has an increased resistance to deamination and phosphorolysis, and hence better stability as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. Since the initiation of the first phase I study of clofarabine in 1993 in patients with hematologic and solid malignancies, clofarabine has demonstrated single-agent antitumor activity in adult acute leukemia, including acute myeloid leukemia (AML). Due to its unique properties of biochemical modulation when used in combination with other chemotherapy drugs, mainly cytarabine, combination regimens containing clofarabine have been evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This review describes the development, pharmacology and clinical activity of clofarabine, as well as its emerging role in the treatment of adult patients with AML and myelodysplastic syndrome.

How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach

“…67,68 A protective role for GM-CSF against infectious-related toxicities is strongly suggested in an RCT of older AML patients undergoing remission-induction therapy. 69 G-CSF-elicited granulocyte transfusions may serve as a bridge in severely neutropenic patients, in whom neutrophil recovery is not expected within 3 to 4 days.…”

Results from a clofarabine-busulfan-containing, reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: the phase 2 prospective CLORIC trial

“…Lymphoblasts may not be as sensitive as the malignant cells in AML/MDS to clofarabine. One of the reasons may be that, while the anti-apoptotic Bcl2 protein seems to play a crucial role in the survival of lymphoid cells, 36 Bcl2 over-expression itself confers resistance to clofarabine in the particular setting of ALL.37 Thus, anti-Bcl2 therapy, such as ABT-737 may overcome the resistance to clofarabine in ALL patients, 37 and should be tested as part of the conditioning regimen.One possible way of improving the results of the current CloB2A2 regimen for both myeloid and lymphoid acute leukemia could be to increase the dose of either clofarabine (given for 5 days rather than 4 days, for example), as is already the case when considering induction or salvage chemotherapy for patients with de novo or relapsed disease, [12][13][14] or busulfan, as has been tested recently by our group (the FB3A2 regimen), 38 or of both drugs (CloB3 or CloB4 regimens). 39,40 Another way would be to administer clofarabine and busulfan concomitantly since it has been demonstrated that there is a synergistic effect between the two drugs.…”

“…One possible way of improving the results of the current CloB2A2 regimen for both myeloid and lymphoid acute leukemia could be to increase the dose of either clofarabine (given for 5 days rather than 4 days, for example), as is already the case when considering induction or salvage chemotherapy for patients with de novo or relapsed disease, [12][13][14] or busulfan, as has been tested recently by our group (the FB3A2 regimen), 38 or of both drugs (CloB3 or CloB4 regimens). 39,40 Another way would be to administer clofarabine and busulfan concomitantly since it has been demonstrated that there is a synergistic effect between the two drugs.…”

Low-dose clofarabine in combination with a standard remission induction in patients aged 18–60 years with previously untreated intermediate and bad-risk acute myeloid leukemia or high-risk myelodysplastic syndrome: combined phase I/II results of the EORTC/GIMEMA AML-14A trial

“…[1][2][3][4] Clofarabine is a purine nucleoside analog that is highly active as a single agent in AML. 5 Furthermore, synergy between clofarabine and Ara-C has been demonstrated in vitro 6 and in AML patients. [6][7][8] We have recently reported the results of the randomized phase I part of the EORTC/GIMEMA-AML-14A trial and identified clofarabine at 10 mg/m 2 /day on days 2, 4, 6, 8 and 10 as the maximum tolerated dose (given either in a 1-hour infusion or as push injection) in combination with Ara-C and idarubicin.…”

“…5 Furthermore, synergy between clofarabine and Ara-C has been demonstrated in vitro 6 and in AML patients. [6][7][8] We have recently reported the results of the randomized phase I part of the EORTC/GIMEMA-AML-14A trial and identified clofarabine at 10 mg/m 2 /day on days 2, 4, 6, 8 and 10 as the maximum tolerated dose (given either in a 1-hour infusion or as push injection) in combination with Ara-C and idarubicin. 9 We decided to administer clofarabine on these five days because we hypothesized that the synergy between clofarabine and Ara-C would be more effective when clofarabine was present in the leukemic cells during the entire period of Ara-C administration.…”