# Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $270,880

## Abstract

PROJECT SUMMARY
The outcomes of elderly patients and relapsed/refractory patients with either acute myeloid leukemia (AML) or
myelodysplastic syndromes (MDS) remain poor. Venetoclax is a selective BCL-2 inhibitor that recently
demonstrated impressive activity when combined with hypomethylating agents decitabine or 5-azacitidine;
however, outcomes remained more modest among patients with unfavorable risk cytogenetics or with TP53
mutations. Building on recent findings that increasing the schedule of decitabine from days 1-5 to days 1-10 of
28 day cycles was associated with improved overall responses and survival among patients with unfavorable-
risk cytogenetics and TP53 mutations, we hypothesize that concomitant use of venetoclax and 10-day
decitabine will improve the response and survival rates, especially in patients with high-risk karyotypes or TP53
mutations. We designed a Phase II trial that will enroll four parallel, open-label cohorts, each with 40 patients
consisting of high-risk AML or MDS patients, either with advanced age or with relapsed/refractory disease. The
primary objective is to determine the composite overall response rate; secondary objectives include determining
disease-free and overall survival, and the impact of high-risk karyotypes on response and survival. In addition,
two molecular hypotheses will be tested. First, that clearance of exome-defined founding clone mutations from
the peripheral blood provides a consistent and quantified response end-point that circumvents many sources of
inter-patient response variability, and that combination venetoclax and decitabine will be associated with
increased rate and depth of mutation clearance vs. single-agent decitabine. Determining whether a
hypomethylating doublet has improved outcomes vs. single-agent has been challenging for all but large
randomized studies, partially due to clinical confounders such as hemodilute aspirates and poor count recovery
in older and heavily pre-treated patients. This novel approach to response determination isolates anti-leukemic
activity from other factors, thus improving statistical power of the study. Second, we will determine whether
responses to combination venetoclax and decitabine correlate with leukemic dependence on BCL-2 activity or
on other anti-apoptotic proteins. We will apply dynamic BH3 profiling to determine the dependence of AML blasts
on BCL-2, BCL-XL or MCL-1 and correlate these results with response, survival, and mutation patterns. Further,
we will apply CyTOF analysis to serial bone marrow samples obtained during therapy and at relapse. We will
quantify leukemia stem cell subpopulations and the expression of BCL-2 family proteins within bulk AML cells
vs. leukemia stem cells. These data will determine whether combination venetoclax and decitabine leads to
elimination of both bulk and leukemia stem cell populations, and whether sensitivity within subpopulations
corresponds with intracellular levels of BCL-2 family proteins. Co...

## Key facts

- **NIH application ID:** 10745877
- **Project number:** 7R01CA235622-05
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Marina Y Konopleva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $270,880
- **Award type:** 7
- **Project period:** 2019-06-17 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745877

## Citation

> US National Institutes of Health, RePORTER application 10745877, Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen (7R01CA235622-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10745877. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*