This study uses a two-stage eligibility process. Step 1 assesses eligibility prior to the MyeloSeq-HD assay being performed, while Step 2 assesses eligibility of MRD-positive patients for the intervention arm and MRD-negative patients for the observation arm. Patients who are MRD-positive who are determined to be ineligible to continue into the intervention arm must satisfy the eligibility criteria for the observation arm in order to be enrolled in that arm.

Eligibility Criteria for MyeloSeq-HD Assay (Step 1)

• Diagnosis of myelodysplastic syndromes (MDS) based on World Health Organization classification (2016 revision) who have received an allogeneic hematopoietic cell transplant. Any stem cell source, conditioning regimen, and immunosuppression regimen as determined by the treating physician, per institutional guidelines, is permitted. Patients may have received any therapy, or no therapy, prior to transplant.
• 18 to 75 years of age.
• Must have undergone gene panel testing prior to the start of transplant conditioning and must have at least one somatically acquired mutation that is interrogated by the MyeloSeq-HD panel. If the patient has a variant that is known to be a germline/inherited myeloid predisposition gene in that patient, this variant cannot and will not be used as evidence of MRD positivity. If the pre-transplant gene panel testing is a next-generation sequencing panel other than the MyeloSeq platform, the outside report will be reviewed by the PI and the molecular pathologists at the McDonnell Genome Institute to ensure eligibility.
• Willing to comply with the treatment assignment:
• • Intent to proceed with DEC-C therapy if one or more variants detected prior to transplant persists at Day 30 post-transplant with a variant allele frequency of ≥ 0.5%.
  • Intent to proceed with standard of care as determined by the treating physician on the observation arm (no DEC-C intervention) if no variants detected prior to transplant persist at Day 30 post-transplant with a variant allele frequency of ≥ 0.5%, or if the other inclusion criteria are not met.
• Not currently receiving any investigational agents.
• Ability to understand and willingness to sign an IRB-approved written informed consent document (or that of legally authorized representative, if applicable).

Eligibility Criteria for Step 2 Step 2A Inclusion Criteria (DEC-C Intervention Arm)

• One or more somatically acquired variants that were present prior to transplant detected by the MyeloSeq-HD panel at Day 30 post-transplant, with a variant allele frequency of ≥ 0.5%
• Within Days 42-100 post-transplant.
• ≤ 5 % bone marrow myeloblasts on the Day 30 post-transplant biopsy.
• Absolute neutrophil count (ANC) ≥ 1.0 X 109/L and platelets ≥ 50 X 109/L.
• Only patients with adequately controlled GVHD ≤ Grade 2 are eligible for the DEC-C intervention arm. Patients with active grade 3 or higher GVHD are ineligible for the DEC-C intervention arm.
• ECOG performance status ≤ 2
• Adequate renal and hepatic function as described below:
  • Total bilirubin ≤ 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 IULN
  • Creatinine clearance ≥ 30 mL/min using Cockcroft-Gault Formula below:
  • CrCl = [(140-age) x body weight in kg]/(serum creatinine in mg/dL x 72) x 0.85 if female
  • NOTE: If, in the opinion of the treating physician, bilirubin is elevated secondary to hemolysis or Gilbert's disease, the patient may be eligible after discussion with the Washington University PI
• Decitabine has been shown to be teratogenic in animal studies and use of IV decitabine in the first trimester of pregnancy has been associated with major birth defects. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 6 months after completion of the study.

Step 2B Inclusion Criteria (Observation Arm)

• EITHER ≤ 5 % bone marrow myeloblasts on the Day 30 post-transplant biopsy OR enrolled in the study with > 5% bone marrow myeloblasts on the Day 30 post-transplant biopsy but not meeting eligibility criteria for the intervention arm.
• Not receiving any investigational agents.

Step 2A Exclusion Criteria

• Currently receiving any other investigational agents.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to DEC-C or other agents used in the study.
• Concomitant administration of drugs metabolized by cytidine deaminase
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test no more than 10 days prior of the start of the first cycle of DEC-C.