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 affect 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 suffered higher toxicities, poorer responses and treatment related mortalities of 10–25% [2]. The 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]. Therefore, there is a great and unmet need for effective, non-intensive therapies that may improve survival in this group.

The 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 benefit on overall survival [5]. More recently, a large randomized trial demonstrated the benefit 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 benefit.

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. The 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 differentiation 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. These 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/m² for 14 days in 15 patients who were ineligible for intensive therapy. One-third of the patients had refractory disease and a majority harbored adverse cytogenetic features. The 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. The toxicities were tolerable, but median survival was poor (93 days), and there were four deaths due to disease progression or treatment related complications. It is possible that the levels of VA achieved in the serum of patients entered on this trial were insufficient to mimic the apoptotic and antiproliferative actions of VA in vitro. However, increasing the dose of VA was not feasible due to issues with tolerance of the drug. More significantly, these results differed considerably from the results of another phase II study [9], which reported that VA in combination with low-dose cytarabine produced a remission rate of 35% in elderly AML that lasted for up to 23 months. This cohort of patients received a higher dose and longer duration of cytarabine, and may have included a higher percentage of patients with favorable cytogenetics, explaining the positive results.

In conclusion, the results of this study highlight the challenges of finding an effective treatment that provides a survival benefit for elderly patients with AML, who have adverse risk factors. Additional studies with larger cohorts of unselected patients may be needed to identify subsets of elderly patients with AML that are likely to benefit from combination therapy with VA and low-dose cytarabine.

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