5-Azacitidine and Decitabine Epigenetic Therapy for Myeloid Malignancies

Inclusion Criteria:

• Participants must have MDS or MDS/myeloproliferative overlap disorder with potentialsensitivity to HMA therapy, defined as prior published evidence of response to HMA

• Myelodysplastic Syndromes:

• As classified by hematopathology review of WHO categories,myelodysplastic/myeloproliferative neoplasm unclassifiable, refractoryanemia with ring sideroblasts and thrombocytosis, refractory cytopeniawith unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multi-lineage dysplasia (RCMD),refractory anemia with excess blasts (RAEB), myelodysplastic syndrome withisolated del(5q), myelodysplastic syndrome unclassifiable (MDS-U).

• Participant with MDS who are IPSS-R high and very high risk or IPSSintermediate 2 risk and higher are excluded given proven overall survivalbenefit in higher risk MDS from AZA-001 with this treatment

• Myelodysplastic/myeloproliferative neoplasm overlap disorders ---MDS/MPNcrossover syndromes with limited evidence of extramedullary hematopoiesis (maynot have palpable splenomegaly) and reticulin fibrosis of grade 1 or lesswithout evidence of progression to accelerated phase. These may include but maynot be limited to RARS-T, CMML, Atypical CML (BCR-ABL negative), and MDS/MPNNOS

• Indication for HMA therapy: Symptomatic anemia OR thrombocytopenia with a plateletcount of <100 x 109/L OR transfusion dependence for red-cells OR transfusiondependence for platelets OR absolute neutrophil count < 1.0 x 109/L

--Participants with lower risk MDS must have must have failed or havecontraindications to available therapies (e.g. lenalidomide, epoetin if indicatedfor symptomatic anemia and/or transfusion dependence of red cells) known to beeffective for treatment of their disease

• Participants must have performance status of 60% or greater by Karnofsky PerformanceStatus (KPS)

• Must have adequate end organ function defined as:

• AST and ALT < 3× the upper limit of normal (ULN)

• Bilirubin ≤ 1.5× the ULN. If elevated bilirubin is due to impaired conjugation (e.g Gilbert's disease or concomitant medication) or disease related hemolysis,then direct bilirubin ≤ 1.5× the ULN

• As azacitidine and decitabine have little renal metabolism, and have provensafety even in dialysis participants, renal function is not an inclusion orexclusion criteria

• Subjects must have the ability to understand and the willingness to sign a writteninformed consent document and complete study related procedures.

Exclusion Criteria:

• MDS with IPSS-R high or very high risk, or IPSS intermediate-2 or high risk disease

• Prior Treatment with azacitidine, decitabine or investigational HMA therapy withoverlapping mechanism of action (e.g. guadecitibine)

• No other disease directed therapy, save for hydroxyurea, including experimental orinvestigational drug therapy for 14 days prior to study entry.

• Toxicity (grade 2 or higher) from prior therapies including chemotherapy, targetedtherapy, immunotherapy, experimental therapy, radiation or surgery must be resolvedto grade 1 or less.

• Currently pregnant or breast-feeding. Females of child bearing (FOCBP) potentialmust have negative serum pregnancy test within 72 hours from treatment start. (NOTE:FOCBP is any biologic female, regardless of sexual or gender orientation, havingundergone tubal ligation, or remaining celibate by choice, who has not undergone adocumented hysterectomy or bilateral oophorectomy or has had a menses any time inthe preceding 12 months (therefore not naturally post-menopausal for > 12 months)

• Uncontrolled intercurrent illness that could limit life expectancy or ability tocomplete study correlates. This includes, but is not limited to:

• Ongoing or active infection. As participants with MDS and MDS/MPNs are prone toinfections, if participants are actively being treated with appropriateantibiotics or antifungal therapy with clinical evidence of infection control,then they will be considered eligible for study.

• Uncontrolled concurrent malignancy

• Congestive heart failure of NYHA class III/IV. Participants with compensatedheart failure are permitted.

• Unstable angina pectoris

• New or unstable cardiac arrhythmia. Stable or controlled arrhythmias arepermitted

• Decompensated liver cirrhosis (Child-Pugh score ≥12 or a MELD score ≥21)

• Psychiatric illness/social situations that would limit compliance with studyrequirements.

• Any other prior or ongoing condition, in the opinion of the investigator, thatcould adversely affect the safety of the participant or impair the assessmentof study results.

• WOCBP and males that are unwilling to agree to use dual contraceptive measures (i.e., hormonal or barrier method of birth control; abstinence, condom) prior tostudy entry and for the duration of study participation. Should a female subjectbecome pregnant or suspect she is pregnant while participating in this study, sheshould inform the treating physician immediately

• Sexually active male who is unwilling to use a condom when engaging in any sexualcontact with a female with child-bearing potential, beginning at the screening visitand continuing until 4 weeks after taking the last dose of 5AZA-alt-DEC.

• Participants with known active HIV infection, as this will further increase the riskfor opportunistic infections. However, participants with chronic HIV withundetectable viral load by PCR, without opportunistic infection, and on a stableregimen of antiretroviral therapy would be eligible.

• Known allergy or hypersensitivity to any component of azacitidine or decitabineformulations