Decitabine + Venetoclax for Acute Myeloid Leukemia Maintenance Therapy

Overseen By Benjamin Tomlinson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Benjamin Tomlinson

Must not be taking: HMA/VEN therapy

Disqualifiers: Pregnancy, Active infection, Uncontrolled malignancy, Congestive heart failure, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year or until relapse or unacceptable toxicity

20 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this interventional clinical trial is to determine if low doses of gentle chemotherapy after bone marrow transplant may prevent relapse and promote an increase in survival and decrease in side effects in participants with acute myeloid leukemia and myelodysplastic syndromes. The main question it aims to answer is whether or not providing a new, gentler way of administering chemotherapy will help control leftover cancer with minimal side effects. This treatment involves decitabine and venetoclax. Participants will receive standard post-transplant care. Participants will be administered decitabine once per week with normal transplant follow up visits, and then will take a venetoclax pill about 6 to 8 hours later. Participants will meet their study team at the beginning, midway, and at the end of the trial to receive bone marrow testing. Participants will receive treatment until either one year of therapy, relapse, or recurrent dose limiting toxicity (DLT) despite dose reduction.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on other planned post-transplant maintenance therapy, you may not be eligible to participate.

What data supports the effectiveness of the drug combination of Decitabine and Venetoclax for Acute Myeloid Leukemia maintenance therapy?

Research shows that combining Venetoclax with Decitabine is effective for older patients with acute myeloid leukemia (AML), with a significant number achieving complete remission. This combination is particularly beneficial for those who are not fit for intensive chemotherapy, improving remission rates and survival. ^{1 2 3 4 5}

Is the combination of Decitabine and Venetoclax safe for humans?

The combination of Decitabine and Venetoclax has been studied in elderly patients with acute myeloid leukemia (AML) and was generally well tolerated. Common side effects included nausea, diarrhea, constipation, fever with low white blood cell count (febrile neutropenia), fatigue, low potassium levels (hypokalemia), decreased appetite, and a decrease in white blood cell count. No cases of tumor lysis syndrome (a serious condition caused by the rapid breakdown of cancer cells) were observed. ^{1 2 3 6 7}

How is the drug Decitabine + Venetoclax unique for treating acute myeloid leukemia?

Decitabine + Venetoclax is unique because it combines a hypomethylating agent (decitabine) with a BCL-2 inhibitor (venetoclax) to target leukemia cells in elderly or unfit patients who cannot undergo intensive chemotherapy. This combination has shown promising results in achieving remission in high-risk patients and offers a new standard of care for those who are not candidates for traditional treatments. ^{1 2 3 8 9}

Research Team

Benjamin Tomlinson, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Claudio Brunstein, MD, PhD

Principal Investigator

Cleveland Clinic Foundation, Case Comprehensive Cancer Center

James Ignatz-Hoover, MD, PhD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults over 18 with acute myeloid leukemia or related conditions, who've had a bone marrow transplant. They should be at high risk of cancer returning but currently without severe infection or organ rejection (GVHD grade II+). Participants need proper liver and kidney function, good physical health (ECOG 0-1), and must not be pregnant or breastfeeding.

Inclusion Criteria

Your total bilirubin level is less than 2.0 mg/dL, unless you have a known condition called Gilbert's syndrome.

Your kidneys work well enough to filter out waste products from your blood.

You can understand and sign a paper that explains the study and your decision to take part in it.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive low dose decitabine once weekly followed by venetoclax orally approximately 6 hours afterwards as maintenance therapy post-transplant

1 year or until relapse or unacceptable toxicity

Weekly visits for decitabine administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• Decitabine
• Venetoclax

Trial Overview The study tests if low-dose chemotherapy with decitabine and venetoclax can prevent cancer from coming back after a bone marrow transplant. Patients will get standard care plus weekly decitabine followed by venetoclax pills, continuing up to one year unless the disease returns or they experience significant side effects.

Participant Groups

Group I: Low dose maintenance chemotherapy Experimental Treatment 2 Interventions

Participants will receive low dose chemotherapy as a maintenance therapy post-transplant. Participants must enroll by post-transplant day 40. Treatment will consist of once weekly 5 mg/m2 decitabine followed by 400 mg venetoclax orally approximately 6 hours afterwards. Participants will continue maintenance therapy for one year or unacceptable toxicity. Participants will otherwise receive post Allogeneic hematopoietic stem cell transplant (alloSCT) care and disease monitoring as per institutional standards.

Who Is Running the Clinical Trial?

Benjamin Tomlinson

Lead Sponsor

Trials

4

Recruited

110+

Findings from Research

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

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]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., 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]

Venetoclax, a BCL-2 inhibitor, shows promise in combination therapies for newly diagnosed or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving high remission rates and deep molecular responses.

Despite these encouraging results, there are concerns about side effects such as incomplete blood count recovery and increased infection rates, particularly when used with chemotherapy, and more research is needed to understand the long-term effectiveness and durability of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Shimony, S., Stone, RM., Stahl, M.[2023]

A once-weekly low-dose decitabine (LDDec) combined with venetoclax (VEN) showed high efficacy in treating elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving an overall response rate of 88% for AML and 64% for MDS in a retrospective study of 39 patients.

Patients receiving the LDDec/VEN regimen experienced longer treatment durations and a trend towards higher transfusion independence compared to those on standard dosing, suggesting that this approach may reduce severe myelosuppression while maintaining effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML. Levitz, D., Saunthararajah, Y., Fedorov, K., et al.[2023]

In a study of 81 patients with acute myeloid leukemia (AML) receiving venetoclax with decitabine or azacitidine, 72.8% experienced infections, with the most common pathogens being Candida albicans and Klebsiella pneumonia.

The study found that the incidence of infectious complications was lower with this treatment compared to conventional chemotherapy, and high leukemia burden and fever were identified as significant risk factors for developing infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. Zhu, LX., Chen, RR., Wang, LL., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]

4. United States 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. [2023]

5. China pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

A real-world study of infectious complications of venetoclax combined with decitabine or azacitidine in adult acute myeloid leukemia. [2022]