Genomic Predictors of Decitabine Response in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

Phase 2

Completed

Brief Summary: This clinical trial studies potential genetic markers which might be used to predict which patients with acute myeloid leukemia or myelodysplastic syndromes respond to decitabine. This study will contribute to the efforts to find effective and less toxic therapies to provide durable remissions in a significant proportion of elderly AML patients.

Recruitment & Eligibility

Inclusion Criteria

All of the following:

Patient must have non-M3 AML or MDS
An adverse risk karyotype defined by:
- Complex karyotype by cytogenetics, or
- Deletion of all or part of chromosome 5, 7, 12, or 17 defined by FISH or cytogenetics, or
- Somatic TP53 mutation

All of the following:

Patient must have an ECOG performance status ≤ 2.
Patient must have >10% disease burden measured by cytomorphology, flow cytometry, or cytogenetics.
Patient must have peripheral white blood cell count < 50,000/mcl.
Patient must have adequate organ function, defined as:
1. Total bilirubin < 1.5 x ULN
2. AST/ALT < 2.5 x ULN
3. Serum creatinine < 2.0 x ULN
Patient must have undergone ≤ 2 cycles of prior hypomethylating agent (decitabine or azacitidine).
Patient must be enrolled in HRPO# 201011766 ("Tissue Acquisition for Analysis of Genetic Progression Factors in Hematologic Diseases").
Patient must be > 18 years of age.
Patient must be able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria

Patient must not be pregnant or nursing
Patient must not have acute promyelocytic leukemia or t(15;17) observed by FISH.
Patient must not have known central nervous system (CNS) leukemia
Patient must not have a history of positive human immunodeficiency virus (HIV) serology
Patient must not have a history of positive hepatitis C serology
Patient must not have undergone prior allogeneic stem cell transplant
Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, ongoing or active graft-versus-host disease (GVHD), congestive heart failure of New York Heart Association (NYHA) class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements
Patient must not have had radiation therapy within 14 days of enrollment
Patient must not have received any chemotherapy within 21 days of enrollment and any acute treatment-related toxicities must have returned to baseline. Patients may be receiving hydrea at time of enrollment.

Arm && Interventions

Group	Intervention	Description
Decitabine	decitabine	Patients receive decitabine IV over 1 hour on days 1-10 of a 28-day cycle. Treatment continues for 2 cycles. Patients then receive decitabine IV over 1 hour on days 1-10, 1-5, or 1-3 (depending on response). Treatment continues in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Correlation of Patient Specific Mutations With Overall Response Rate	4 months (4 treatment cycles)	-Best response after 4 treatment cycles as assessed according to International Working Group (IWG) criteria; bone marrow for gene sequencing will be collected at baseline; mutations will be correlated with overall response rate --Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Marrow complete remission (mCR), Partial remission (PR), Stable disease (SD), Progressive disease (PD)

Secondary Outcome Measures

Name	Time	Method
Change in Bone Marrow Methylcytosine	Baseline and Day 10	-Change of total bone marrow deoxyribonucleic acid (DNA) methylcytosine from baseline to Day 10
Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls)	4 months (4 treatment cycles)	The overall response rate (CR/CRi/mCR/PR) and complete response rate (CR/CRi/mCR) will be compared with historical controls. Response assessed according to IWG criteria.
Rate of Mutation Clearance During Treatment	Up to Day 56	Samples collected at baseline and after 10, 28 and 56 days of therapy; the rate of mutation clearance was measured as mean VAF change per day of treatment and was estimated using linear mixed model for repeated measurement data .
Peripheral Blood Decitabine Plasma Levels	Day 4	* To determine whether steady state serum concentrations of decitabine correlated with responses * Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Partial remission (PR), Stable disease (SD), Progressive disease (PD), Not applicable (NA) - assessed according to International Working Group (IWG) criteria