Therapy for older patients with acute myeloblastic leukemia: a problem in search of a solution

Acute myelogenous leukemia (AML) is characterized by numerous cytogenetic, molecular and epigenetic aberrations that aff ect clinical outcome [1]. Although novel therapies targeting the key molecular defects have recently made headlines, conventional chemotherapy with cytarabine or cytarabine-containing regimens even today continues to provide the cornerstone for curative therapy in this disease. Cytarabine is given at intensive doses in combination with other agents, and elicits initial remissions in 40 – 80% of all patients [2]. Post-remission consolidation therapy again relies on cytarabine to eradicate leukemic cells and achieve durable remissions. However, the majority of studies that established these favorable outcomes were conducted in younger adults ( 65 years), whereas elderly patients with AML tended to have a poor prognosis. In elderly patients, intensive cytarabine therapy was feasible for only 30 – 60%, and while it often induced remission rates similar to those seen in younger patients, it was at the cost of serious therapy related complications. Over the course of multiple trials, it was established that elderly patients were less able to tolerate intensive cytarabine therapy, and suff ered higher toxicities, poorer responses and treatment related mortalities of 10 – 25% [2]. Th e most likely reasons for these poor outcomes were probably the presence of a lower performance status, concomitant comorbidities, unfavorable cytogenetics and a higher intrinsic resistance of leukemic blasts to therapy [3]. Th erefore, there is a great and unmet need for eff ective, nonintensive therapies that may improve survival in this group. Th e earliest non-intensive therapy employed low-dose cytarabine, which provided a limited survival advantage over the best supportive care, plus hydroxyurea, and therefore remained a viable option for those who could not tolerate intensive therapy [4]. Other trials used the related nucleoside agent clofarabine, and determined that it was a well-tolerated therapy for the elderly, and that in combination with low-dose cytarabine increased the event-free survival but had no benefi t on overall survival [5]. More recently, a large randomized trial demonstrated the benefi t of the chromatin modulating demethylating agent, azacitidine, over conventional chemotherapy in improving overall survival in elderly patients with AML [6]. In extending these trials, demethylating agents were combined with other chromatin modulators such as inhibitors of the histone deacetylases (HDACi) and other drugs, which showed promising results, achieving complete or partial responses of 26% [7]. However, there were no systematic trials that evaluated HDACi in combination with cytarabine, a drug with proven therapeutic benefi t. In the present study, Lane et al . [8] carried out in vitro investigations to determine a rational basis for the combination of HDACi such as valproic acid (VA) with low-dose cytarabine for the therapy of AML. Th e addition of VA to cytarabine increased the levels of cell death in primary AML samples obtained from patients who had standard or favorable cytogenetics, but not in those with poor cytogenetics. Exposure to VA inhibited proliferation and promoted diff erentiation in all AML cells tested; however, samples with poor cytogenetics exhibited a lesser inhibition of their proliferative index. Finally, in keeping with its action as a histone deacetylase inhibitor, exposure to VA increased the levels of acetylation on histone H3 in AML cells. Th ese data established the ability of VA to modulate the chromatin and potentiate the toxicity of cytarabine against AML cells in vitro . Based on these data, the authors conducted a clinical trial using a regimen of oral VA at 600 – 100 mg/day in combination with subcutaneous cytarabine at 10 mg/m 2 for 14 days in 15 patients who were ineligible for intensive therapy. Onethird of the patients had refractory disease and a majority harbored adverse cytogenetic features. Th e drug concentrations were chosen based on their ability to achieve therapeutically relevant serum concentrations of VA and cytarabine when assessed at 28 days. However, there were no clinical responses in any of the patients entered on this trial. Th e toxicities were tolerable, but median survival was poor (93 days), and there were four deaths due to disease progression or treatment related