Epigenetic Therapy for Elderly Patients With AML

Decitabine With or Without Bortezomib in Treating Older Patients With Acute Myeloid Leukemia

NCT01420926

Alliance for Clinical Trials in Oncology (This is a U.S. Cooperative Group focused on performance of clinical trials that replaced the former Cancer and Leukemia Group B. This group receives funding from the National Cancer Institute.)

More than 20 centers around the United States currently

172 patients will be enrolled (86 per treatment arm); this trial is currently actively recruiting new patients.

This trial seeks to enroll patients 60 years and older with acute myeloid leukemia (AML) who are FLT3 negative, CBF negative, and PML/RAR-α negative as assessed by a central reference laboratory. Patients with treatment-related AML are eligible as well. Patients may have had select prior therapy for myelodysplastic syndrome but not for AML. This is a phase II study with a primary endpoint of survival for patients treated with a combination of decitabine and bortezomib compared with those treated with decitabine alone. Patients are randomized to receive either decitabine alone given as a 10-day infusion or this same schedule of decitabine with subcutaneous bortezomib given on days 1, 4, 8, and 11. Cycles are repeated every 28 days. Once response is obtained, consolidation therapy consists of the same agent(s) on an abbreviated dosing schedule. Secondary endpoints include response rate, progression-free survival, and frequency of serious adverse events. This trial will also examine a variety of traditional and new biomarkers, assessing their capacity to predict response to therapy. Finally, a geriatric assessment process will aid our understanding of how older AML patients tolerate the disease and its treatment.

AML is the most common type of acute leukemia diagnosed in the elderly and represents a major treatment challenge. Elderly patients with AML often have significant co-morbidities and an increased frequency of high-risk cytogenetic and molecular features that together explain their poor response to traditional cytotoxic therapy. A major driving force in the pathogenesis of both myelodysplastic syndromes and AML in the elderly is epigenetic silencing of cell-cycle regulatory elements and tumor suppressor genes as a consequence of promoter methylation or chromatin modification. Aberrant activity of transcription factors such as NF-κB also contribute to the underlying pathobiology of these diseases. Likewise, non-coding RNAs are known to have an important role in disease pathogenesis and response to treatment. These observations have prompted clinical investigations using therapeutics such as hypomethylating agents (decitabine and 5 azacytidine) that reverse gene silencing, histone deacetylase inhibitors that restrict chromatin modification, and direct or indirect inhibitors of NF-κB. Several studies with hypomethylating agents in AML have shown modest clinical activity, but unfortunately, treatment schedules were not optimized to achieve the goal of reversing epigenetic gene silencing. Subsequent studies optimized the hypomethylating activity of decitabine (Blum W et al. J Clin Oncol. 2007), and a single institution phase II study based on that work demonstrated that a 10-day schedule of decitabine given as induction to elderly AML patients was not only acceptably tolerated but also produced complete response rates and progression-free survival durations similar to those observed in patients treated with standard chemotherapy (Blum W et al. Proc NatlAcad Sci USA. 2010). A follow-up to this trial incorporated bortezomib with decitabine based on the hypothesis that the combination would enhance the reversal of epigenetic silencing and thereby improve response rates. The current study compares decitabine alone to the combination of decitabine plus bortezomib in a randomized phase II study aimed at identifying the best regimen that will then be used in a subsequent phase III study.

Despite progress made in the management of many other hematologic malignancies, the high morbidity and mortality associated with standard induction regimens and the high frequency of treatment failure with this approach highlight the need for novel therapeutic approaches to the treatment of elderly patients with AML. This trial targets AML using a different therapeutic strategy in which decitabine or decitabine in combination with bortezomib is used to modify gene expression through effects on epigenetic silencing. While these regimens have some of the same risks as standard cytotoxic therapy (e.g., cytopenias and infections), they lack many of the other toxicities associated with aggressive chemotherapy. Consequently, administration of this therapy is more feasible in elderly patients and in those with co-morbid conditions. With any new treatment approach, it is important to verify that an initial promising result based on a single institution study is reproducible when the regimen is tested in a large, multicenter trial.

This trial will meet this goal and inform us as to whether either of these treatment regimens warrants future clinical investigation. In addition, the laboratory correlates and the geriatric assessment studies, performed in a uniform manner, may identify subsets of patients who particularly benefit from one of these approaches to treatment. Taking an entirely different approach to treatment of elderly patients with AML, as is done in this trial, is justified based upon the limited success of other treatment approaches that are currently available to this patient population.