Abstract

Abstract 4307

DNA hypermethylation and histone de-acetylation are mechanisms involved in gene expression silencing and subsequent drug resistance in leukemia. Agents which target these mechanisms have been investigated in myeloid malignancies but few studies have addressed whether they have a role in lymphoid leukemia. We conducted a clinical trial evaluating the tolerability and efficacy of Decitabine and Vorinostat followed by chemotherapy for relapsed/refractory acute lymphoblastic leukemia (ALL). Patients 0–60 years of age were eligible. Protocol therapy included Decitabine (15mg/m2 iv) and Vorinostat (230mg/m2 PO div BID) days 1–4 followed by vincristine, prednisone, PEG-Asparaginase and doxorubicin. Fourteen patients with a median age of 16 (range, 3 – 54) years have been enrolled to date. Five patients failed prior allogeneic transplantation. The most common non-hematological toxicities (grade >3) at least possibly related to Decitabine and/or Vorinostat were infection (grade 3; n=6) and fever (grade 3; n=3). There was a single grade 5 toxicity related to the chemotherapy backbone. Bone marrow samples (n=11) were evaluated using the DNA LINE global methylation analysis. A decrease in total methylation was found in 10 patients comparing baseline and day 5 (4/10 showing significant reductions in hypermethylation (T-test p<0.01). Eight patients were evaluable for response. Complete remission without platelet recovery (CRp) was achieved in 4 patients, PR in 2 patients, SD and PD in 1 patient each for an overall response rate (CRp + PR) of 75%. Six patients were inevaluable for response based on not having an end of treatment marrow evaluation due to disease progression (n=2; days 4 and 16), toxic death (n=1), ineligibility (n=1) and physician/family request (n=2). The combination of Decitabine and Vorinostat for patients with relapsed ALL leads to changes in methylation patterns in the leukemic blasts. The use of these agents followed by chemotherapy appears tolerable and efficacious in patients with relapsed ALL. This study is continuing to accrual and is registered at www.clinicaltrials.gov as NCT00882206.

Disclosures:

Off Label Use: decitabine for relapsed ALL vorinostat for relapsed ALL.