Phase I, Dose Escalation Study of Decitabine

Decitabine is a hypomethylating agent with significant anti-leukemic effect in MDS and AML. Additionally, aberrant DNA methylation has been identified in high risk childhood ALL, and therefore, DNA hypomethylating agents, such as decitabine, have been identified as therapeutic agents. Moreover, decitabine has immunomodulatory effects by enhancement of class I human leukocyte antigen (HLA) antigen expression on cancer cells, which increases their susceptibility to immune surveillance mechanisms, such as graft-versus-leukemia effect of donor cells in allogeneic transplantation and by augmentation of natural killer (NK), T and B lymphocyte reactivity. We hypothesize that decitabine delivered after allo-HSCT in patients with leukemia will enhance disease control by the allogeneic immune system and lead to a longer disease free survival. However, a safety study is needed to determine appropriate decitabine dosing in the post-transplant period. Low doses of decitabine are likely better tolerated in the post-transplant setting given risks of myelosuppression. In addition, when administered at lower doses, decitabine's hypomethylation effects are more pronounced in relation to its pyrimidine analog cytotoxic effects. In this study low doses of decitabine will be administered beginning 6 weeks to 100 days post-transplant. Measures of gene methylation and immune reconstitution will be conducted to define biologically active doses. Results from this trial will provide new clinical data regarding the effects of decitabine on gene methylation and immunoreactivity, will establish a maximally tolerated dose in the post-transplant setting, will define biologically active doses, and will serve as a basis for future efficacy trials.

Inclusion criteria

• Age: greater than 1 and less than 31 years of age;
• Diagnosis: history of ALL, AML or MDS, currently in a complete remission (CR) following allo-HSCT (bone marrow leukemic blasts less than 5% by morphology), with high risk features including:
• Status post allogeneic HSCT
• GVHD prophylaxis:
• Karnofsky or Lansky performance scores more than 50%. Karnofsky scores will be used for patients > 16 years of age and Lansky scores for patients ≤ 16 years of age;
• Platelet count ≥ 50,000 (untransfused);
• Absolute neutrophil count ≥ 1000; and;
• Hemoglobin ≥ 8 g/dL (un-transfused);

Exclusion criteria

• Progressive disease;
• Philadelphia chromosome positive ALL (these patients receive tyrosine kinase inhibitor posttransplant);
• Known hypersensitivity to any components of decitabine;
• Uncontrolled grade 3-4 graft versus host disease;
• Uncontrolled infection;
• Serum creatinine > 2 mg/dL or glomerular filtration rate (GFR) less than 60 mL/min/1.73m2 ;
• Alanine Aminotransferase (ALT) greater than 3 times normal or serum total bilirubin greater than 2 mg/dL;