Azacitidine + Venetoclax vs Stem Cell Transplant for Acute Myeloid Leukemia

Recruiting at 6 trial locations

Overseen By Roni Tamari, MD

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Azacitidine, Venetoclax

Disqualifiers: Prior allo-HCT, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle for maintenance therapy; up to 6 weeks for transplant preparation

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments to determine which better prevents the recurrence of acute myeloid leukemia (AML). One group receives a stem cell transplant (allogeneic hematopoietic stem cell transplantation), while the other continues with daily medications azacitidine and venetoclax. It targets adults diagnosed with AML who have already undergone treatment with azacitidine and venetoclax. Participants should have no significant issues with major organs and need a suitable donor for the transplant option. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires treatment with azacitidine and venetoclax for acute myeloid leukemia. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of azacitidine and venetoclax is generally well-tolerated by patients. Studies indicate that this treatment remains safe, even at lower doses. Compared to other treatments, patients using azacitidine and venetoclax experienced fewer unwanted side effects.

For the stem cell transplant option, transplants are complex and can sometimes cause complications. However, they are a common treatment for certain types of leukemia and have been safely used in many patients.

Both treatment options have undergone safety studies, providing confidence in their use in clinical settings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Acute Myeloid Leukemia (AML) because they offer innovative approaches compared to the traditional standard of care, which often includes chemotherapy followed by an allogeneic stem cell transplant. The combination of Azacitidine and Venetoclax is unique because it targets cancer cells in two different ways: Azacitidine affects the DNA within cancer cells to stop them from growing, while Venetoclax works by blocking a protein that helps cancer cells survive. This dual approach could be more effective for certain patients and may offer an option with potentially fewer side effects compared to conventional chemotherapy. On the other hand, allogeneic hematopoietic stem cell transplantation (Allo-HCT) remains a cornerstone treatment but is being evaluated alongside these new drug therapies to potentially improve outcomes for AML patients.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

This trial will compare two treatment options for acute myeloid leukemia (AML): azacitidine combined with venetoclax and allogeneic hematopoietic stem cell transplantation. Studies have shown that azacitidine and venetoclax together can effectively treat AML. More than half of the patients who received this treatment went into remission, meaning their cancer was no longer detectable. In one study, patients lived for a median of 16.9 months, while those on a placebo lived for a median of 9.6 months. This suggests that azacitidine and venetoclax can help manage AML effectively.

For the stem cell transplant option, research indicates that allogeneic hematopoietic stem cell transplantation can be a strong treatment for AML. This involves replacing diseased bone marrow with healthy cells from a donor, which can help prevent the cancer from returning. This approach is often considered for patients who are healthy enough for the procedure and can lead to long-term remission. Participants in this trial will be randomized to receive either the azacitidine and venetoclax combination or the stem cell transplant. ^{1 2 3 6 7}

Who Is on the Research Team?

Roni Tamari, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for people aged 65 and older with Acute Myeloid Leukemia (AML). Participants should be eligible for a stem cell transplant or able to receive maintenance therapy. Specific inclusion and exclusion criteria details are not provided, but typically include factors like overall health status, prior treatments received, and the presence of other medical conditions.

Inclusion Criteria

Subject is willing and able to adhere to the study visit schedule and other protocol requirements

I have been diagnosed with acute myeloid leukemia.

I will begin the study treatment 28-42 days after my second AZA/VEN cycle, with a possible third cycle if there's a delay in my transplant.

Exclusion Criteria

I have had a bone marrow transplant from another person.

My cancer has affected my brain or spinal cord at some point.

I am planned for a treatment that is not AZA/VEN.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either an allogeneic stem cell transplant or maintenance therapy with azacitidine and venetoclax

28 days per cycle for maintenance therapy; up to 6 weeks for transplant preparation

Follow-up

Participants are monitored for relapse-free survival and overall survival

1 year for primary outcome, up to 3 years for secondary outcome

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic hematopoietic stem cell transplantation
• Azacitidine
• Venetoclax

Trial Overview The study is comparing two approaches: one group will undergo an allogeneic hematopoietic stem cell transplant (HSCT), while another will receive maintenance therapy using azacitidine (AZA) combined with venetoclax. The goal is to see which method better prevents AML from returning.

How Is the Trial Designed?

Group I: maintenance arm Azacitidine and Venetoclax (AZA/VEN) Experimental Treatment 2 Interventions

Patients randomized to the maintenance arm (AZA/VEN) will be treated with azacitidine given daily for 7 days starting on Day 1 of each Cycle (7 consecutive days or a total of 7 days with a 2 day break due to weekends or holidays is permissible). Venetoclax will be taken orally daily for 28 days. A cycle will be considered 28 days.

Group II: Allogeneic hematopoietic stem cell transplantation (Allo-HCT arm) Experimental Treatment 1 Intervention

Patients who are randomized to the transplant arm will start the conditioning regimen no later than 6 weeks (day 42) after C2D1 of AZA/VEN.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

The VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

In the HiDDAV study involving 42 newly diagnosed AML patients, higher doses of venetoclax (600 mg daily) were found to be tolerable but did not show significant clinical improvement compared to the standard 400 mg dose.

The study revealed that using minimal residual disease (MRD) status to guide the discontinuation of azacitidine did not lead to better outcomes in terms of duration of response or overall survival, suggesting that alternative strategies are needed to optimize treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia. Gutman, JA., Winters, A., Kent, A., et al.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., et al.[2023]

In a study of 20 elderly patients with relapsed refractory acute myeloid leukemia (AML), the combination of azacytidine and venetoclax showed a total treatment efficiency of 90%, significantly higher than the 40% efficiency observed with azacytidine alone.

The combination treatment improved hematological parameters, such as platelet and white blood cell counts, while maintaining a similar safety profile to azacytidine alone, indicating it is a promising option for enhancing treatment efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the Clinical Efficacy of Azacytidine + Venetoclax in the Treatment of Elderly Patients with Relapsed Refractory Acute Myeloid Leukemia. Wang, W., Luo, Q., Chen, Q., et al.[2023]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40951718/

Real-world outcomes of azacitidine plus venetoclax in ... After treatment, more than half went into remission (the cancer was no longer detectable), and those with newly diagnosed AML had better ...

2. nature.com nature.com/articles/s41375-025-02730-3

Outcomes of patients treated with venetoclax plus ... Efficacy, including composite complete remission and overall survival, were improved with venetoclax plus azacitidine vs. placebo plus ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2012971

Azacitidine and Venetoclax in Previously Untreated Acute ... At a median follow-up of 14.9 months, the median overall survival was 16.9 months. This confirmatory trial (VIALE-A) was designed to evaluate ...

4. hematologyadvisor.com hematologyadvisor.com/news/combination-azacitidine-venetoclax-acute-myeloid-leukemia-aml-treatment-risk/

Combination Azacitidine, Venetoclax Effective in AML ... Analysis showed that the overall response rates in the azacitidine plus venetoclax, chemotherapy, and azacitidine monotherapy groups were 38.5%, ...

5. ashpublications.org ashpublications.org/bloodneoplasia/article/1/3/100017/516192/Real-world-outcomes-of-newly-diagnosed-AML-treated

Real-world outcomes of newly diagnosed AML treated with ... In the VIALE-A study, venetoclax combined with azacitidine improved the median overall survival (OS) from 9.6 to 14.7 months, compared with placebo.2 When ...

6. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... Overall, venetoclax plus azacitidine at the RP2D was well tolerated and had favorable outcomes. A phase 3 study (NCT04401748) is ongoing to ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18509

Comparative safety and effectiveness of azacitidine plus ... In AML patients aged 60–75 years, HMA&Ven demonstrated comparable all-cause mortality to IC and significantly lower risk of several adverse events.