Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML)

Inclusion Criteria:

1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell \[WBC\] \<13,000/microliter \[mcL\]) or low-blast acute myelogenous leukemia (AML).
2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):

   * Very high (\>6 points).
   * High (\>4.5-6 points).
   * Intermediate (\>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of \>=5% bone marrow myeloblasts.
3. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2.
4. Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score \>=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers.

Calculation of TRM score:

* 0 for (age \<61 years), +2 for (age 61-70 years), +4 for (age \>=71 years).
* \+ 0 for (PS=0), +2 for (PS=1), +4 for (PS \>1).
* \+ 0 for (platelets \<50), +1 for (platelets \>=50).

Exclusion Criteria:

1. Has previous treatment for HR MDS or CMML or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug.
2. Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
3. Participants with AML with a WBC count \>50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria.
4. Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors:

   * Age \>75.
   * Comorbidities.
   * Inability to tolerate intensive chemotherapy (e.g., participants with AML with 20%-30% blasts and TRM \>=4).
   * Physician decision (e.g., lack of available stem cell donor).
   * The reason a participant is not eligible should be documented in the electronic case report form (eCRF).
5. Has either clinical evidence of or history of central nervous system involvement by AML.
6. Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
7. Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease.
8. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
9. Has prothrombin time (PT) or aPTT \>1.5× upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
10. Has known human immunodeficiency virus (HIV) seropositive.
11. Has known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
12. Has known hepatic cirrhosis or severe preexisting hepatic impairment.
13. Has known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension.
14. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.