Venetoclax and Azacitidine for the Treatment of High-Risk Recurrent or Refractory Myelodysplastic Syndrome

Inclusion Criteria:

• For phase I, patients can be HMA-naive high-risk MDS (Int-2 or high risk by theInternational Prognostic Scoring System [IPSS] with overall score >= 1.5) withexcess blasts > 5%, or relapsed/refractory MDS post-HMA 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) with > 5%blasts

• For phase II, patients will be divided into 2 cohorts: Cohort A: patients withHMA-naive high-risk MDS (Int-2 or high risk by the IPSS with overall score >= 1.5)with excess blasts > 5%. Cohort B: patients with relapsed/refractory MDS post-HMAfailure (defined as prior receipt of 4 cycles of HMA therapy with failure to attaina response, or progression of disease or relapse at any time after prior response toHMA therapy) with > 5% blasts are eligible. Note: Patients with chronicmyelomonocytic leukemia (CMML) and therapy-related MDS are eligible. Hydroxyurea isallowed to lower the white cell count =< 10,000/ul prior to initiation of venetoclax

• Total bilirubin < 3 x upper limit of normal (ULN) unless increase is due toGilbert's disease or leukemic involvement

• Alanine aminotransferase (ALT) < 4 x ULN unless considered due to leukemicinvolvement

• Creatinine < 2 x ULN unless related to the disease

• Signed written informed consent. Consent may be translated for Non-English SpeakingPatients per institutional policy.

• 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

• 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

Exclusion Criteria:

• Patients having received any prior BCL2 inhibitor therapy

• Patients with MDS with IPSS risk categories low or Int-1 (overall IPSS score < 1.5)

• Pregnant or breastfeeding

• Cognitively impaired patients