Clofarabine in the treatment of acute myeloid leukemia in older adults

Abstract

Objective: To review the literature evaluating the efficacy and tolerability of clofarabine as a single agent and in combination therapy for older patients with acute myeloid leukemia (AML). Method: A literature search of the PubMed database (1996–April 2012) using the search terms clofarabine and acute myeloid leukemia was performed. All relevant English language articles were reviewed. Clinical trials with patients aged 50 years or older diagnosed with AML were included. Results: Two studies evaluating clofarabine as monotherapy and five studies evaluating clofarabine in combination with cytarabine were reviewed. Clofarabine demonstrated activity in older adults with AML. Response rates and median overall survival (OS) for patients receiving clofarabine were similar to those for patients receiving conventional induction chemotherapy. The induction mortality rate with clofarabine was lower than that seen with intensive chemotherapy. However, clofarabine was associated with a significant risk of severe complications including myelosuppression and sepsis. Conclusion: Clofarabine is an active agent for the treatment of older patients with AML as a single agent or in combination therapy. Based on published data and side-effect profiles, clofarabine may be an appropriate alternative to intensive chemotherapy for older patients with AML, offering similar response rates to traditional 7+3 chemotherapy with potentially decreased induction mortality. The use of clofarabine in combination with newer agents including DNA methyltransferase inhibitors like decitabine is a promising approach for older patients who are not eligible for intensive chemotherapy. Additional randomized controlled trials are needed to directly compare the efficacy of clofarabine as a single agent and in combination therapy compared with intensive chemotherapy regimens.

Feasibility and efficacy of outpatient therapy with intermediate dose cytarabine, fludarabine and idarubicin for patients with acute myeloid leukaemia aged 70 or older

“…Recent treatments are now available for elderly patients with AML, including azacitidine, decitabine or clofarabine in combination or as monotherapy (21)(22)(23)(24)(25)(26). Clofarabine plus LDAC in combination with decitabine showed a 58% CR rate in a study of 60 patients with median age of 70 yr with newly diagnosed AML (21).…”

Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia

“…Furthermore, standard intensive post-remission, cytarabine-based consolidation in patients older than 60 are plagued by short remission durations (9 months (7), with a four year disease-free probability of 16% (8)) and toxicity, with patients often unable to tolerate more than 1 course (8). A recent post hoc analysis of older patients with AML treated with clofarabine induction followed by post-remission IV clofarabine consolidation (20 mg/m 2 IV days 1-5 of a 28 day cycle, with up to 5 cycles) demonstrated the feasibility of administering this consolidation regimen in the outpatient setting, although the most common adverse events included nausea, vomiting, diarrhea, febrile neutropenia, edema, hypokalemia, and pneumonia (17, 20, 28). While hematologic toxicity was frequent in the oral clofarabine regimen reported here, there were no episodes of febrile neutropenia and a low incidence of infection observed.…”

“…Clofarabine is superior to fludarabine in inhibiting ribonucleotide reductase and superior to cladribine in the inhibition of DNA polymerase alpha (16). The IV formulation of clofarabine has shown acceptable tolerability and single-agent activity in older patients with AML (17-20). Clofarabine therapy in previously untreated elderly AML patients deemed unfit for intensive therapy resulted in a CR rate of 48%,(18) and in a study of patients over 60 with at least one unfavorable prognostic factor the overall response rate (CR + CRp) was 46% (17).…”

Phase I Study of Oral Clofarabine Consolidation in Adults Aged 60 and Older With Acute Myeloid Leukemia

“…Furthermore, standard intensive post-remission, cytarabine-based consolidation in patients older than 60 are plagued by short remission durations (9 months (7), with a four year disease-free probability of 16% (8)) and toxicity, with patients often unable to tolerate more than 1 course (8). A recent post hoc analysis of older patients with AML treated with clofarabine induction followed by post-remission IV clofarabine consolidation (20 mg/m 2 IV days 1-5 of a 28 day cycle, with up to 5 cycles) demonstrated the feasibility of administering this consolidation regimen in the outpatient setting, although the most common adverse events included nausea, vomiting, diarrhea, febrile neutropenia, edema, hypokalemia, and pneumonia (17,20,28). While hematologic toxicity was frequent in the oral clofarabine regimen reported here, there were no episodes of febrile neutropenia and a low incidence of infection observed.…”