Pilot Study of Reduced Venetoclax Exposure

A pilot single-arm clinical trial is proposed to assess the primary objective: the tolerability of 14-day Venetoclax cycles in acute myeloid leukemia (AML) patients who have achieved remission and are ineligible for intensive treatment. Participants in the study will transition to a maintenance regimen that reduces the Venetoclax dosage to 14 days per cycle while continuing the hypomethylating agent (HMA) used during induction. Treatment cycles will occur every 28 days. Participants will continue treatment on study until experiencing a grade 4 cytopenic event lasting more than 7 days, an adverse event requiring regimen modification, relapse, or death.

Our primary hypothesis posits that AML patients receiving Venetoclax for 14 days per cycle will exhibit improved treatment tolerability with a reduced rate of grade 4 cytopenia compared to historical data from the VIALE A trial.

Inclusion Criteria:

1. Stated willingness to comply with all study procedures and availability for the duration of the study

2. Ability to take oral medication and be willing to adhere to the study regimen

3. Diagnosed by current WHO or ICC criteria with Acute Myeloid Leukemia and treated for initial induction therapy with one of two regimens:

   1. 5-Azacitidine administered subcutaneously at a dose of 75mg/m2/day X 7 days in combination with VEN (21-28 days/cycle)
   2. Decitabine administered intravenously at a dose of 20mg/m2/day administered in combination with VEN (21-28 days/cycle)

4. Achieving morphological CR/CRi by bone marrow biopsy with <5% blasts within 3 cycles. See Appendix 2 for definitions.

5. Consent to be obtained within 10 days (+/- 3 days) of bone marrow biopsy report showing morphological remission. C1D1 of trial to be initiated within 10 days (+/- 7 days) of bone marrow biopsy report showing morphological remission.

6. ECOG 0-3

7. Intensive treatment ineligible; transplant ineligible or refusal of transplant

8. Patient must be able to understand and sign informed consent and additional study documents

9. On C1D1 of trial, patient must have count recovery with ANC >1000, platelets > 50, Hemoglobin > 7.7 and without transfusion support for 7 days.

10. No growth factor (G-CSF) use in 14 days prior to C1 D1 of trial.

Exclusion Criteria:

1. Treatment with another investigational drug

2. Use of growth factor (G-CSF) within the last 14 days prior to C1D1 of trial treatment.

3. On concomitant targeted therapy such as FLT3 inhibitor or IDH1/2 inhibitor.

4. Subject has received treatment prior to induction with the following:

   i. Prior hypomethylating agent or BCL-2 inhibitor for either AML or MDS other than for induction prior to enrollment.

   ii. Prior CAR-T cell therapy. iii. Experimental or investigational drug therapy for 14 days prior to study entry leukemia-directed therapies.

5. Subject has:

   i. Acute promyelocytic leukemia (APL) with t(15;17). ii. Presence of t(9;22) given the potential indication for concurrent tyrosine kinase therapy.

   iii. Known active CNS involvement with AML.