Hypomethylating agents in acute lymphoblastic leukemia: untapped potential?

Based on pre-clinical data showing patterns of aberrant methylation in myelodysplastic syndromes (MDS) and evidence of cellular differentiation associated with reversal of methylation by decitabine [1–3], MDS became a prime candidate for development of the hypomethylating agents decitabine and 5-azacytidine. Noteworthy, albeit fewer, reports have been published which suggest that acute lymphoblastic leukemia (ALL) might also be amenable to intervention with these agents. Some of these reports provide evidence that promoter regions of genes associated with biological and prognostic importance in ALL are methylated and can be demethylated with exposure to decitabine, including the putative tumor suppressor gene FHIT in pediatric ALL [4,5], and ERG isoforms and BMP-6 in T-ALL [6,7]. Arraybased approaches have also identified a multitude of additional aberrantly methylated genes in ALL that may warrant further investigation [8,9]. There are few reports of clinical investigations exploring the activity of decitabine or 5-azacytidine monotherapy in ALL. The authors of a Letter to the Editor in this issue of Leukemia and Lymphoma cite the report of a single pediatric patient with ALL who achieved a complete response (CR) with decitabine and dexamethasone, and an older study wherein two responses were seen among 23 patients with ALL receiving three different schedules of 5-azacytidine. Additional patients with ALL may be included in acute leukemia studies, such as the one patient who was treated in a phase 1 decitabine study, but was not listed among the responders [10], but response data are not yet available for a uniformly treated cohort with ALL. More recently, interim data from a phase 1 study of decitabine in relapsed and refractory ALL was reported in abstract form in 2009 [11], and updated results should be forthcoming. In this Letter to the Editor, the authors describe the clinical course of a single adult patient with concurrent MDS and ALL who achieved a morphologic remission of ALL with MDS-directed 5-azacytidine therapy [12]. Post-treatment, the patient had cytogenetic evidence of persistent MDS with residual cytopenias, presumably due to MDS. This observation, in addition to available pre-clinical data and earlier clinical reports, provides a hint that the epigenetic regulation of genes contributing to the pathophysiology of ALL should be further and more systematically studied, and that consideration be given to continued testing of DNA methyltransferase inhibitors in pediatric and adult patients with ALL in the context of clinical trials. For example, future trials could target untreated older patients with ALL, given their characteristic relative intolerance to standard therapeutic approaches and the acceptable toxicity of these agents in MDS trials in which the median age was approximately 70 years. Younger patients would also benefit from more treatment options. In the arena of new drug development for acute leukemias, ALL often ‘takes a back seat’ to acute myeloid leukemia. Although hypomethylating agents have secured their place in the management of acute myeloid leukemia and MDS, this report and others suggest that the potential of the hypomethylating agents in ALL and other lymphoid malignancies may be untapped.