Study to assess venetoclax + azacitidine and donor lymphocyte infusion (DLI) in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in relapse after allohematopoietic stem cell transplantation (AHSCT).

A phase I-II study to assess venetoclax + azacitidine and donor lymphocyte infusion (DLI) in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in relapse after allohematopoietic stem cell transplantation (AHSCT).

Inclusion Criteria:

1. Documented cytologic relapse of MDS according to FAB/WHO classification 2016 (including CMML with WBC < 13000/mm3) or AML, with WBC < 15000/mm3, after allo-SCT.

   Relapse of MDS or AML is defined as :

   • Return to pretreatment bone marrow blast percentage
   • Decrement of at least 50% from maximum remission

2. Age ≥ 18 years.

3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

4. Patient must have adequate organ function:

   • Serum creatinine < 2 mg/dL or calculated creatinine clearance ≥ 30 mL/min for patients with creatinine levels > 1.5 times Upper Limit of Normal
   • Serum total bilirubin ≤ 2.5 times Upper Limit of Normal or direct bilirubin ≤ Upper Limit of Normal for patients with total bilirubin levels ≥ 2 mg/d
   • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 times Upper Limit of Normal
   • Alkaline phosphatase ≤ 5 times Upper Limit of Normal (if > 2.5 times Upper Limit of Normal, then liver fraction should be ≤ 2.5 times Upper Limit of Normal).

5. Patient not refractory to platelet transfusions.

6. Female subject of childbearing potential must practice at least one protocol specified method of birth control, starting on Study Day 1 through at least 30 days after the last dose of venetoclax or 6 months after the last dose of azacitidine.

   Not being of childbearing potential is defined as:

   • Age > 55 years with no menses for 12 or more months without an alternative medical cause, or
   • Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an Follicle Stimulating Hormone (FSH) level > 40 IU/L, or
   • Permanent surgical sterility (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

7. Female subjects of childbearing potential must have negative results for pregnancy test performed:

   • At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
   • Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results.

   Female subjects who are not of childbearing potential at Screening do not require pregnancy testing.

8. Male subjects sexually active with female partner(s) of childbearing potential, must agree from first dose of study drug(s) through at least 30 days after the last dose of venetoclax or 3 months after the last dose of azacitidine, whichever is later, to practice the protocol specified contraception.

9. Patient is available for periodic blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.

10. Patient has the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.

11. Patient is able to swallow capsules.

Exclusion Criteria:

1. Patient has active and uncontrolled infection.
2. Patient has active acute or chronic Graft-versus-Host-Disease (GVHD).
3. Patient receives more than 1mg/kg/day prednisolone.
4. Patient has uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.
5. Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug.
6. Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy.
7. Patient has clinically active hepatitis B or hepatitis C infection.
8. Patient has a known allergy or hypersensitivity to any component of venetoclax or azacitidine.
9. Patient with a "currently active" second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for > 2 years or are considered by their physician to be at less than 30% risk of relapse.
10. Patient has received growth factors such as erythropoietin alfa (EPO) or granulocyte colony-stimulating factor (G-CSF) or has received non cytotoxic agents (including low dose oral chemotherapy) in the 30 days before inclusion. In case of previous cytotoxic treatment, an interval of 3 months is required.
11. Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs.
12. Patients with clinical evidence of Central Nervous System leukemia.
13. Patient has a history of Gastrointestinal surgery or other procedures that might interfere with the absorption or swallowing of the study drugs.
14. Subject has received strong or moderate CYP3A (Cytochrome P450, family 3, subfamily A) inhibitors within 3 days prior to the first dose of study drug.
15. Patient is unable to take and/or tolerate oral medications on a continuous basis.
16. Patient is pregnant or breastfeeding within the projected duration of the study.
17. Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.
18. Absence of social security.