A Phase II Trial of Epigenetic Priming in Patients With Newly Diagnosed Acute Myeloid Leukemia

Brief Summary

Detailed Description

To determine tolerability, priming with DMTi (azacitidine or decitabine) will be limited to Induction I and II during Part 1 of the study. If DMTi treatment is tolerated during Part 1, the investigators will go on to an Expansion Phase (Part 2) that includes DMTi priming prior to all chemotherapy blocks. Treatment will consist of 5 blocks of conventional chemotherapy: Induction I, Induction II, Intensification I, Intensification II, and Intensification III over approximately 5 months. RANDOMIZATION: Patients will be randomized to receive one of two DMTi (azacitidine or decitabine) for 5 days prior to Induction I. Intrathecal (ITHMA) treatments will be given right before treatment on this study or on Day 1 of Induction I treatment. Leucovorin will be given 24-30 hours following ITHMA. INDUCTION I CHEMOTHERAPY: Patients receive cytarabine, daunorubicin, and etoposide. INDUCTION II CHEMOTHERAPY; Patients receive their assigned DMTi for 5 days followed by fludarabine, cytarabine, G-CSF, and idarubicin. Patients are then evaluated and assigned to either the low-risk arm, intermediate-risk arm, or the high-risk arm for Intensification therapy. Patients with ≥ 5% blasts following Induction II will be considered refractory and will go off therapy. The rare high risk patient with an MRD \< 0.1% following Induction I may proceed directly to stem cell transplant (SCT) after Induction II - if a suitable donor is available and the transplant can be performed without delay. MDS patients may proceed to SCT once they have achieved MRD \<0.1% irrespective of the number of chemotherapy courses received. INTENSIFICATION I CHEMOTHERAPY - LOW-RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive cytarabine and etoposide. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to cytarabine and etoposide. INTENSIFICATION II CHEMOTHERAPY - LOW RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive mitoxantrone and cytarabine. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine. INTENSIFICATION I CHEMOTHERAPY - HIGH-RISK AML with a donor: Patients receive mitoxantrone and cytarabine followed by stem cell transplant (SCT). Treatment related AML patients and patients with treatment related MDS who have a donor but are not able to receive a SCT without delay will proceed to HR Intensification III and receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine or erwinia asparaginase and cytarabine. Treatment related AML patients and treatment related MDS patients that are not able to receive a SCT should go off treatment following Intensification II. INTENSIFICATION III CHEMOTHERAPY - INTERMEDIATE-RISK AML and HIGH-RISK AML with no donor: Patients receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to erwinia asparaginase and cytarabine.

Primary Outcomes

Secondary Outcomes

• Proportion of MRD-evaluable subjects with detectable minimal residual disease after receiving five days of a single agent DMTi followed by araC+daunorubicin+etoposide.(MRD will be measured after completion of DMTi+araC+daunorubicin+etoposide (up to 6 weeks after the start of therapy))
• Kaplan-Meier estimate of event-free survival(From diagnosis to the first of the following events: death, relapse, resistant disease, second malignancy, or last follow-up (up to 3 years after completion of therapy))
• Kaplan-Meier estimate of overall survival(From diagnosis to the first of the following events: death or last follow-up (up to 3 years after completion of therapy))