Is Less More? Combination Biologics in Elderly AML

Azacitidine Plus Lenalidomide Combination in Elderly Patients with Previously Treated AML and High-Risk MDS (VIREL2 Trial)

Principal Investigator: Bruno Carneiro de Medeiros, Stanford University, Stanford, CA

NCT01442714

Stanford Cancer Institute (Celgene, Inc. is the provider of azacitidine and lenalidomide for this investigator-initiated trial.)

This trial uses a Simon two-stage minimax design with a total enrollment goal of 53 patients.

This is a phase II, non-randomized, open-label study. Patients are eligible if they meet the following disease-specific criteria: 1) age > 60 and not an immediate candidate for allogeneic stem cell transplantation; 2) de novo or secondary AML or high-risk myelodysplastic syndrome (HR-MDS); 3) prior treatment with hypomethylating agents for AML or HR-MDS, or lenalidomide for del(5q) and non-del(5q) HR-MDS. Prior cytotoxic chemotherapy is not permitted. Patients receive azacitidine 75 mg/m2 daily SC or IV on days 1-7 followed by lenalidomide 50 mg PO on days 8-28 of a 42-day cycle. If a complete response (CR), CRp, partial response, hematologic improvement, or stable disease is documented after six total cycles, patients continue treatment until evidence of disease progression, provided they are tolerating treatment. Patients with progressive or relapsed disease after the sixth cycle are discontinued from the study, and patients with excessive toxicity at any time are removed from the trial. The primary objective is to determine overall response rate. The secondary objectives are: 1) 42-day survival rate, and 2) duration of remission. Safety and tolerability of the combination will also be assessed.

AML primarily afflicts older individuals (median age at diagnosis in the mid-60s). In this population, standard induction chemotherapy elicits a complete remission rate of ~40 percent with a higher early death rate compared with younger patients. In addition, median survival is one year or less, and long-term overall survival is observed in only 5 to 10 percent of patients. Because there is no standard of care for such patients, participation in a clinical trial is the treatment recommendation of the National Comprehensive Cancer Network for most patients with AML over the age of 60.

In older AML patients who were considered poor-risk candidates for induction chemotherapy, single-agent azacitidine exhibited a CR rate of 20 percent and a median survival over 15 months in responders (Sudan et al. Cancer, 2006). The CR rate for single-agent, high-dose lenalidomide in elderly patients with AML was 30 percent (Fehniger et al. Blood, 2011). In 18 high-risk MDS patients who received both azacitidine and lenalidomide, the CR rate was 44 percent (Sekeres et al. J Clin Oncol, 2010). Investigators of this current highlighted trial recently published a phase I study of sequential combination of azacitidine plus lenalidomide in 18 previously untreated, elderly AML patients (Pollyea et al. Leukemia, 2011). A maximum tolerated dose was not reached. Ten patients responded (56%), and the rate of CRs or CRs with incomplete recovery of blood counts (CRi) among evaluable patients was 44 percent (7/16). The median response duration was 6.2 months. These data provide an impetus for studying the combination of azacitidine plus lenalidomide in patients who have failed prior therapy for MDS or AML with either one of these agents.

Poor outcomes related to high rates of both disease- and treatment-related mortality plague the experience with intensive chemotherapy in elderly patients with AML. This trial of combination biologic therapy with sequential azacitidine and lenalidomide therapy in previously treated patients is one example of several studies (Table) that aim to address basic questions about the role of biologics in elderly AML induction. The aggregate data that develop from these trials should help clarify whether “less is more” for older patients with AML who have traditionally been steered toward either cytotoxic chemotherapy or supportive care.