Abstract

Acute lymphocytic leukemia (ALL) is characterized by concomitant aberrant methylation of multiple promoter associated CpG islands. Specific DNA methylation patterns predict for poor prognosis. Furthermore, reactivation of epigenetically repressed molecular pathways results in in-vitro selective induction of leukemia cell death (Kuang et al. Oncogene 2007). In vitro modeling in ALL indicates that more frequent dosing of 5-aza-2′-deoxycitidine (DAC) results in increased control of leukemia cell proliferation and induction of cell death (Yang H. Leuk Res 2005). Based on all this data, we designed a phase I clinical trial of DAC for patients (pts) with relapsed or refractory ALL. Pts of any age are eligible for this study. There are no requirements in terms of performance status or prior therapies. DAC is infused over 1 hour daily × 5 every other week. One cycle of therapy is considered as 4 weeks. Pts that do not respond or progress after single agent DAC can participate in a sequential phase I study of DAC in combination with standard hyperCVAD therapy. In that phase of the study, DAC is administered daily × 5 concomitantly with hyperCVAD once per course. DAC is escalated using a conventional “3+3” design in both portions of the study. Thirteen pts have been treated so far. Nine of these pts have also been treated on the sequential phase I portion of the combination of DAC with hyperCVAD. Their median age is 33 years (range 8–66); number of prior therapies 2 (range 1–8); 2 pts had diploid cytogenetics;1 t(4;11) and the rest had complex alterations. No pts was BCR/ABL positive. Pretreatment median WBC was 5 (range 0.5–97). Single agent DAC has been escalated up to doses of 60 mg/m2 IV daily × 5 every other week (total per course= 600 mg/m2). No dose limiting toxicities have been observed. When used in combination with hyperCVAD, DAC doses of 15 mg/m2 daily × 5 (total: 75 mg/m2) have not been associated with significant drug-related toxicities either. Four pts (30%) achieved a complete marrow response (no morphological evidence of leukemia in the marrow) with single agent DAC. Hematological control with single agent DAC was also achieved in pts with rapidly proliferating disease with or without steroid support. Three pts of 9 (30%) achieved a complete remission with DAC + HCVAD. One of these pts had previously achieved a marrow response with single agent DAC. The effect of DAC on DNA hypomethylation induction was measured using the LINE bisulfite pyrosequencing assay. Of importance, no plateau in terms of DNA hypomethylation induction has been detected at doses up to 60 mg/m2 IV × 5 every other week. Based on the lack of toxicity and continuous pharmacodynamic effect, dose escalation continues for both the single agent DAC portion and the DAC + hyperCVAD combination. These results indicate that DAC administered every other week, or in combination with hyperCVAD, is safe and associated with clinical activity in pts with advanced relapsed/refractory ALL. These data also suggest that the optimal dose of hypomethylating agent is disease dependent.

Author notes

Disclosure:Consultancy: GGM and HK have served as consultants for MGI, the maker of 5-aza-2′-deoxycitidine. Research Funding: This study is funded by the NCI. Off Label Use: Use of 5-aza-2′-deoxycitidine for the treatment of acute lymphocytic leukemia.