The purpose of this study is to assess the safety, pharmacokinetic profile of Lisaftoclax (APG-2575) single agent and in combination with HHT/AZA in patients with relapsed/refractory AML and related myeloid malignancies.

This is an open-label, multi-center Phase Ib study of safety, PK of Lisaftoclax (APG-2575) as single agent or in combination with HHT or AZA in relapsed/refractory AML and related myeloid malignancies patients.

This study consists of three stages: The first stage is the Lisaftoclax (APG-2575) single agent dose-escalation study. The second stage is the Lisaftoclax (APG-2575) combined with HHT/AZA dose-escalation study. The third stage is the MTD/RP2D expansion cohort study of the combination regimen.

Inclusion Criteria:

Subjects who meet each of the following inclusion criteria are eligible to participate in this study:

1. In accordance with the World Health Organization (WHO) 2016 diagnostic criteria for relapsed or refractory acute myeloid leukemia (AML), Mixed phenotype acute leukemia(MPAL), Chronic myelomonocytic leukemia (CMML), Higher-risk myelodysplastic syndrome (HR-MDS) , Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and naïve AML ineligible for treatment with a standard chemotherapy due to age or comorbidities.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 -2 (0 to 3 for participants >= 60 to 74 years of age who are evaluated as ineligible for treatment with standard chemotherapy).
3. Subjects can accept oral administration of Lisaftoclax (APG-2575).
4. Life expectancy ≥ 3 months.
5. Adequate renal and liver function.
6. Males, female patients of childbearing potential (postmenopausal women who must have been menopausal for at least 12 months to be considered infertile) and their partners voluntarily take contraception which the investigator considers effective during treatment and at least three months after the last dose of study drug.
7. Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any study-specific procedures).
8. Willingness and ability to comply with study procedures and follow-up examination.

Exclusion Criteria:

Patients who meet any of the following exclusion criteria are not to be enrolled in this study:

1. Patients diagnosed with acute promyelocytic leukemia or t(9;22)(q34.1;q11.2); BCR-ABL1 positive AML patients.
2. The persistent toxicities caused by previous chemotherapy or radiotherapy has not been restored to lower than grade 2 by CTCAE 5.0 (except for alopecia).
3. Known leukemia infiltration of the central nervous system.
4. Symptomatic active fungal, bacterial and/or viral infections.
5. Prior history of allogeneic hematopoietic stem cell transplantation or adoptive cell immunotherapy, autologous hematopoietic stem cell transplantation within 12 months.
6. Within 14 days before the first dose of study drug, received chemotherapy (hydroxyurea is permitted more than 24 hours before the first dose of study drug), radiotherapy, surgery, immunotherapy, targeted therapy, biological therapy or any investigational treatment.
7. Within 7 days before the first dose of study drug, received a strong and/or moderate CYP3A inducer and/or Inhibitor.
8. At the discretion of the investigator, gastrointestinal diseases that affect the absorption of Lisaftoclax (APG-2575).
9. Any other condition or circumstance, at the discretion of the investigator, that patients would be unsuitable for participation in the study.