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Clofarabine shows promise as alternative chemotherapy for younger patients with AML
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Clofarabine-based combination therapy may serve as a new option for chemotherapy among younger patients with acute myeloid leukemia in their first remission, study data showed.
“Postremission chemotherapy of younger adults with AML is not fully standardized,” Xavier Thomas, MD, PhD, of Lyon-Sud University Hospital, France, and colleagues wrote. “Until now, no alternative postremission chemotherapy, including multiagent regimens, has demonstrated any benefit compared with high-dose cytarabine in randomized trials. … Clofarabine is a deoxyadenosine nucleoside analog that has been shown to be effective as a single agent or in combination with cytarabine in various populations of patients with AML.”
Thomas and colleagues randomly assigned 221 patients aged 18 to 59 years to receive either three clofarabine (n = 107) or three high-dose cytarabine cycles (n = 114). All patients had either intermediate or unfavorable risk AML in first remission and no eligible donors for allogeneic stem-cell transplantation.
RFS served as the primary outcome. Researchers adjusted hazard ratios to account for the confounding effect of stem-cell transplantation in patients with late donor identification.
Patients assigned clofarabine experienced higher RFS than those assigned high-dose cytarabine (58.5% vs. 46.5%).
Fifty-five patients in each arm (n = 110) underwent stem-cell transplantation in first remission. The hazard ratio of clofarabine over high-dose cytarabine either before or in the absence of stem-cell transplantation was 0.65 (95% CI, 0.43-0.98).
A sensitivity analysis showed that when patients who received stem-cell transplantation were censored at time of transplantation, two-year RFS was 53.3% (95% CI, 39-66) in the clofarabine arm and 31% (95% CI, 19-43) in the high-dose cytarabine arm (HR = 0.63; 95% CI, 0.41-0.98). The researchers wrote that the gains in survival may be related to lower cumulative incidence of relapse in the clofarabine arm than in the cytarabine arm (33.9% vs. 46.4% at 2 years; cause-specific HR = 0.61; 95% CI, 0.4-0.94). Clofarabine cycles were associated with higher hematologic and nonhematologic toxicity than cytarabine.
“Although high-dose cytarabine represented an advance in the early 1990s, it is certainly time for another move forward in AML chemotherapy,” the researchers wrote. “We have shown here that clofarabine-based consolidation may improve relapse-free survival in younger patients with intermediate and unfavorable-risk AML as compared with high-dose cytarabine. Thus, clofarabine combination might be considered as a good option for postremission therapy in these patients, especially when a donor for allogeneic stem cell transplantation is not identified at the time when first remission is achieved.” – by Andy Polhamus
Disclosure: Thomas reports honoraria and consulting or advisory roles with Amgen, Celgene, Erytech Pharma, Pfizer and Sunesis; and travel, accommodations and expenses from Amgen, Astellas, Erytech Pharma, Pfizer, Roche, Seattle Genetics and Sunesis. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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This is the first positive trial in many years showing improvement in post induction therapy for intermediate and high-risk patients with acute myeloid leukemia. It has been estimated that 25% of patients in need of allogeneic stem cell transplant will not find a suitable donor. In the era of unrelated cord blood transplantation and haplo-identical transplantation the donor pool has been expanded, nonetheless there remains a significant population in need of better post remission therapy.
In this randomized phase 2 trial, the authors compared the standard high dose cytarabine (HIDAC) with the combination of Clofarabine and intermediate dose cytarabine (CLARA). RFS improved significantly in the CLARA arm 58% vs. 46%. The researchers noted no OS benefit at 2 years.
Grade 3 and 4 gastrointestinal and liver toxicity increased, in addition to longer time to white blood cell and platelet count recovery. This included higher rate of febrile neutropenia and documented infection, and required more platelet and red blood cell transfusion. The toxicity did not result in an observable increase in death in remission.
It should be noted that the patient population studied comprised a highly selected group of younger patients (aged 35-55 years) who had achieved remission after intensive induction therapy and maintained good health and performance status. Due to concern about additional toxicity, this data may not be broadly applicable to older or sicker populations who may be ineligible for transplantation due to health or age. It is, in fact, that subgroup of patients who would be more likely to benefit from more efficacious post remission therapy.
Given the lack of improvement in OS and the fact that the effect of allogeneic stem cell transplantation appeared to erase the CLARA arm’s beneficial effect on RFS, it would seem that the main niche for the CLARA remains restricted to providing more time to find a suitable donor in the era of expanded allogeneic donor pools. Though CLARA may represent a small incremental improvement, an ideal treatment would show improvement in OS and alleviate the need for stem cell transplantation in such a terrible disease affecting many young patients.
In the era of next generation sequencing and precision medicine, clinical trials focusing on molecular targeted therapies and biomarker driven therapies may offer more robust survival improvements in in more narrowly selected patient populations.
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