Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML.

We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m² by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m² for 7 days) and daunorubicin (60 mg/m² × 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastro-intestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34(+) bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials.gov as NCT00538876.

High-dose topotecan, melphalan and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of multiple myeloma.

The goal of this trial was to assess the toxicity and potential efficacy of high-dose topotecan, melphalan and cyclophosphamide as a preparative regimen for patients with multiple myeloma undergoing autologous stem cell transplantation. Eighteen patients were treated, 8 for first remission consolidation, 4 with relapse sensitive disease, 3 primary refractory and 3 relapsed refractory. The median age was 56 (38 - 65) and the median number of prior regimens was 3 (1 - 8). Patients received cyclophosphamide 1 g/m2/d on days -6, -5, -4; melphalan 70 mg/m2 on days -3, -2 and topotecan 3.0 to 3.5 mg/m2/d on days -6 to -2. Peripheral blood stem cells were infused on day 0. Toxicity (Bearman Toxicity Criteria) was mostly limited to grade 1 - 2 mucositis and grade 1 diarrhea. There were no transplant-related deaths. The overall response rate at 3 months post transplantation was 89% with 17% CR, 2 of those in refractory patients. The overall response rate in refractory patients was 67%. With a median follow up of 12.3 months, 89% of patients are alive. The TMC regimen is well tolerated and produces high response rates. Further evaluation of TMC to fully assess response and survival is ongoing.