Final Report of a Phase I Trial of Decitabine with or without hyperCVAD In Relapsed Acute Lymphocytic Leukemia (ALL)

Aberrant DNA methylation is a common feature of ALL. In vitro, decitabine has significant cytotoxic activity against ALL-derived cell lines. Exposure to decitabine results in global and gene specific induction of hypomethylation.

Based on this data, we conducted a phase I trial of decitabine in relapsed ALL. Any patient with relapsed or refractory ALL qualified for the study regardless of performance status, age, renal or hepatic function or presence of CNS disease. During the study, patients not responding to single agent decitabine or that lost response to it could then be treated in a sequential phase of the trial with the combination of decitabine and hyperCVAD. Both the single agent and the decitabine+hyperCVAD combination phases followed a “3+3” dose escalation rule. Starting dose for the single agent decitabine was 10 mg/m² IV daily × 5 every 14 days. Steroids were allowed during first cycle of therapy. For the combination it was 5 mg/m² IV daily × 5 with hyperCVAD. Both given on a 28 day cycle. The dose of decitabine could be escalated until toxicity was documented (2 out of 3 or 6 patients with grade 3 or 4 toxicity) or until identification of an optimal dose. Once the highest or optimal dose of decitabine alone or in combination was defined, the study was to treat 7 additional patients at that dose both for decitabine alone and the combination. Standard doses of hyperCVAD and MTX/ara-c were used. Analysis of global and gene specific methylation was performed as pharmacodynamic endpoints.

39 patients have been treated. Characteristics are as follows: median age 33 years (range 4–67), median WBC 5.3 K/uL (0-132), median peripheral blasts 23% (0-99), median BM blasts 75% (0-99), median creatinine 0.8 mg/dL (0.3-1.8), median bilirubin 0.5 (0.1-1.9), median number of prior therapies 3 (1 to 7): 25 (70%) patients had received more than 1 salvage. Cytogenetics: 5 patients (12%)diploid, 4 (10%) Ph+ and the rest complex. The following dose levels were studied with single agent decitabine: 10, 20, 40, 60, 80, 100 and 120 mg/m² daily × 5 every other week (ie total dose per course 1200 mg/m² at the last dose level). No significant grade 3 or 4 non-hematological toxicity was observed. Significant control of peripheral blood proliferative compartment was observed with single agent decitabine. Seven of 30 patientss (23%) treated with decitabine alone achieved complete marrow responses. These responses were transient and were observed at all dose levels. Because of lack of toxicity, the 60 mg/m² IV daily × 5 every 14 was selected as the optimal dose as it was the most effective in inducing global hypomethylation (below). Of the 30 patientss treated with decitabine alone, 16 patients went to receive decitabine and hyperCVAD sequentially. Additionally 9 patients were treated directly with decitabine and hyperCVAD as the decitabine cohort was already completed. With decitabine and hyperCVAD, we studied the following dose levels 5, 10, 15, 20, 40, 60 mg/m² IV qd × 5 with hperCVAD. The dose was not escalated further as this was the optimal dose with single agent decitabine. No significant toxicity related to the combination was observed either. With the combination, 13 of 25 patientss (52%) achieved a response including 4 CR (16%), 2 (8%) CRp and 7 (28%) complete marrow responses. Median duration of responses is 4+ months (2+ to 8). The optimal dose of decitabine in combination was 40 mg/m² IV x5. Global and gene specific methylation was analyzed on days 0, 2,5, 14,16,19 and 28 of cycle 1. Samples were collected from 18 consenting patients. Global methylation was analyzed using the LINE bisulfite pyrosequencing assay. Induction of methylation was observed at all those levels: median day 0 methylation was 63%, declined to 55% (p=0.01) on day 14 and increased to 61% on day 28. The most effective dose in inducing global hypomethylation was 60 mg/m2 : 61% baseline to 21% on day 15.

Decitabine as single agent and in combination with hyperCVAD is safe in patients with refractory ALL. Single agent decitabine was associated with control of proliferative component of disease and transient marrow responses. The combination of decitabine and hyperCVAD had significant clinical activity in this group of patients with refractory disease universally treated previously with hyperCVAD. Induction of DNA hypomethylation is observed at all dose leves even at doses considered to be cytotoxic.

No relevant conflicts of interest to declare.