Venetoclax and Azacitidine for the Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Inclusion Criteria:

1. Participants with post HMA-failure high-risk MDS (Int-2 or high risk by the IPSSwith overall score >/=1.5) with excess blasts >5% with failure defined as priorreceipt of 4 cycles of HMA therapy with failure to attain a response, or progressionof disease or relapse at any time after prior response to HMA therapy.

2. Participants with relapsed/refractory chronic myelomonocytic leukemia (CMML) andtherapy-related MDS are also eligible.

3. Hydroxyurea is allowed to lower the white cell count </= 10,000/µl prior toinitiation of venetoclax.

4. Adequate hepatic function including total bilirubin ≤ 2.0 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement, andALT/AST ≤ 3.0 x ULN unless considered due to leukemic involvement.

5. Adequate renal function as calculated using the modified Cockcroft-Gault equation of ≥ 30ml/min, OR creatinine < 2x ULN, unless related to the disease.

6. Signed written informed consent.

7. Females must be surgically or biologically sterile or postmenopausal (amenorrheicfor at least 12 months) or if of childbearing potential, must have a negative serumor urine pregnancy test within 72 hours before the start of the treatment. Women ofchildbearing potential must agree to use an adequate method of contraception duringthe study and until 3 months after the last treatment.

8. Males must be surgically or biologically sterile or agree to use an adequate methodof contraception during the study until 3 months after the last treatment.

9. Age >/= 18 years of age.

10. ECOG/PS ≤2

Exclusion Criteria:

1. Participants having received any prior BCL2 inhibitor therapy.

2. Participants with MDS with IPSS risk categories Low or Int-1 (overall IPSS score < 1.5).

3. Participants with known HIV infection (due to potential drug-drug interactionsbetween antiretroviral medications and venetoclax). HIV testing will be performed atscreening, only if required per local guidelines or institutional standards.

4. Participants known to be positive for hepatitis B or C infection [HCV Ab indicativeof a previous or current infection; and/or positive HBs Ag or detected sensitivityon HBV-DNA PCR test for HBc Ab and/or HBs Ab positivity] with the exception of thosewith an undetectable viral load within 3 months of screening. (Hepatitis B or Ctesting is not required). Subjects with serologic evidence of prior vaccination toHBV [i.e., HBs Ag-, and anti-HBs+] may participate.

5. Participants has received strong and/or moderate CYP3A inducers within 7 days priorto the initiation of study treatment.

6. Participants has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior tothe initiation of study treatment.

7. Participants has a cardiovascular disability status of New York Heart AssociationClass > 2. Class 2 is defined as cardiac disease in which patients are comfortableat rest but ordinary physical activity results in fatigue, palpitations, dyspnea, oranginal pain.

8. Participant has chronic respiratory disease that requires continuous oxygen, orsignificant history of renal, neurologic, psychiatric, endocrinologic, metabolic,immunologic, hepatic, cardiovascular disease, any other medical condition or knownhypersensitivity to any of the study medications including excipients of azacitidinethat in the opinion of the investigator would adversely affect his/her participatingin this study.

9. Participant has a malabsorption syndrome or other condition that precludes enteralroute of administration.

10. Participant exhibits evidence of other clinically significant uncontrolled systemicinfection requiring therapy (viral, bacterial or fungal).

11. Participant has received a live attenuated vaccine within 4 weeks prior to the firstdose of study drug.

12. Participant has a history of other malignancies within 2 years prior to study entry,with the exception of:

• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situof breast;

• Basal cell carcinoma of the skin or localized squamous cell carcinoma of theskin;

• Previous malignancy confined and surgically resected (or treated with othermodalities) with curative intent; requires discussion with TA MD.

13. Participant has a white blood cell count > 10 × 109/L. (Hydroxyurea or leukapheresisare permitted to meet this criterion)

14. Female subject has positive results for pregnancy test.

15. Participants with (Grade > 1) unresolved from prior treatment (includingchemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, orsurgery)