Venetoclax + Chemotherapy for AML and MDS

Overseen By Uday R. Popat

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: HIV, Cognitive impairments, 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: 22 days

324 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs for individuals with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing a stem cell transplant. Researchers aim to determine if adding venetoclax, a targeted therapy, to the standard chemotherapy drugs—busulfan, cladribine, and fludarabine—will better control these conditions. The trial seeks participants with AML or MDS who have specific high-risk features, such as not achieving complete remission after initial treatments or possessing certain genetic mutations. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants the potential benefit of a promising new therapy.

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, you should avoid grapefruit, Seville oranges, and star fruit within 3 days before starting the study drug.

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

Research has shown that combining venetoclax with busulfan, cladribine, and fludarabine may help treat serious conditions like high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). One study examined this combination before stem cell transplants and suggested it might help manage these diseases.

The FDA has already approved venetoclax for another use, confirming its safety. Past patients have tolerated these drugs, but side effects can occur. Common side effects include tiredness, nausea, or low blood cell counts. Monitoring for anything unusual when taking these medications together is important.

This trial is in phase 2, indicating that the treatment has been tested for safety before. This phase focuses more on effectiveness, but safety remains a priority. Discussing any concerns with a healthcare provider before joining a trial is advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) because it combines venetoclax with chemotherapy agents in a novel way. Unlike traditional treatments that primarily rely on chemotherapy alone, this approach integrates venetoclax, which specifically targets and disrupts cancer cell survival pathways. This combination aims to enhance the effectiveness of chemotherapy by making cancer cells more vulnerable to treatment. Additionally, incorporating venetoclax may potentially reduce the duration and intensity of chemotherapy needed, offering a promising alternative with potentially fewer side effects.

What evidence suggests that this trial's treatments could be effective for high-risk acute myeloid leukemia or myelodysplastic syndrome?

Research has shown that venetoclax may help treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In this trial, participants will receive a combination of venetoclax, busulfan, fludarabine, and cladribine. One study found that combining venetoclax with azacitidine led to a 62% positive response rate, with some patients achieving complete remission. Busulfan, commonly used in stem cell transplants, has improved patient outcomes at various doses. Adding cladribine to chemotherapy has benefited AML patients, particularly those eligible for a stem cell transplant. Fludarabine, when combined with other treatments, has increased survival rates for patients with certain genetic profiles. Together, these treatments aim to enhance the effectiveness of stem cell transplants for high-risk AML and MDS patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Uday R. Popat

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), who've had previous treatments. Eligible participants must have certain genetic mutations, adequate liver and kidney function, and not be in complete remission. Pregnant women can't join, nor those with HIV, active infections, heart or lung issues below specified levels.

Inclusion Criteria

My liver and kidney functions are within normal ranges.

My kidneys work well, with a creatinine clearance rate of at least 50 mL/min.

My condition is a type of blood cancer caused by previous cancer treatment.

Exclusion Criteria

I have been treated with gemtuzumab ozogamicin or inotuzumab ozogamicin.

I have a heart condition that needed treatment or my heart pumps less efficiently.

Corrected DLCO < 65% or FEV1 < 65%

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax, busulfan, fludarabine, and cladribine followed by stem cell transplantation

22 days

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety, engraftment, and survival outcomes post-transplant

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Cladribine
• Fludarabine Phosphate
• Venetoclax

Trial Overview The study tests venetoclax combined with busulfan, cladribine, and fludarabine in patients undergoing stem cell transplant to treat AML/MDS. It aims to see if adding venetoclax improves outcomes compared to the standard care regimen.

How Is the Trial Designed?

Group I: Treatment (venetoclax, busulfan, fludarabine, cladribine) Experimental Treatment 6 Interventions

Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.

Busulfan is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of 218 patients undergoing allogeneic stem cell transplantation, pharmacokinetic (PK)-guided dosing of IV busulfan led to improved overall survival and progression-free survival compared to fixed dosing, particularly benefiting patients with MDS and those with AML not in remission.

The PK-guided approach did not increase the risk of toxicity or graft-versus-host disease (GvHD), suggesting it is a safer and more effective alternative to traditional fixed-dose busulfan administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Andersson, BS., Thall, PF., Valdez, BC., et al.[2019]

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]

Combining the alkylating agents busulfan and 4-hydroperoxycyclophosphamide, or busulfan and fludarabine, with the BCL2 inhibitor ABT199/venetoclax significantly enhances cytotoxic effects and apoptosis in acute myeloid leukemia (AML) cells, indicating a promising strategy for treatment.

The study demonstrated that these drug combinations not only increased cell death but also inhibited pro-survival pathways, suggesting they could be effective pre-transplant conditioning regimens for AML patients without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells. Valdez, BC., Murray, D., Yuan, B., et al.[2023]

Venetoclax, a BCL-2 inhibitor, has significantly improved remission rates and overall survival in older patients with acute myeloid leukemia (AML) who are not suitable for intensive chemotherapy, highlighting its efficacy in this vulnerable population.

The use of venetoclax-based combinations is rapidly expanding in both research and clinical practice, with ongoing investigations aimed at enhancing cure rates across various AML patient subgroups, including those in frontline treatment and post-transplant settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions. Samra, B., Konopleva, M., Isidori, A., et al.[2020]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[2023]

In a study of 118 patients with relapsed and refractory acute myeloid leukemia (R/R AML), the combination of fludarabine, cytarabine, and idarubicin with venetoclax (FLAVIDA) resulted in a significantly higher overall response rate (78%) compared to the standard FLA-IDA treatment (47%).

Both treatment regimens led to similar rates of measurable residual disease negativity and event-free survival, but FLAVIDA was effective in quickly identifying chemosensitive patients, making it a promising option for inducing remission in R/R AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia. Shahswar, R., Beutel, G., Gabdoulline, R., et al.[2023]

The study of 49 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a conditioning regimen of busulfan and increased-dose fludarabine showed high efficacy, with overall survival (OS) at 3 years reaching 71.1% and disease-free survival (DFS) at 66.7%.

The treatment demonstrated a low transplant-related mortality (TRM) of 4.1% at 100 days and 8.2% over a median follow-up of 14 months, indicating a favorable safety profile with manageable complications such as acute graft-versus-host disease (GVHD) occurring in 28.6% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combination of busulfan with increased-dose of fludarabine as conditioning regimen for MDS and MDS-AML patients with allo-HSCT]. Yuan, J., Ren, H., Qiu, Z., et al.[2020]

The study evaluates the safety and efficacy of venetoclax combined with oral azacitidine as maintenance therapy for patients with acute myeloid leukemia (AML) who are in complete remission but have incomplete blood count recovery after intensive treatment.

The primary goal of the trial is to assess relapse-free survival, with secondary outcomes including overall survival and quality of life, highlighting the potential of this combination therapy to prevent relapse in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia. Ivanov, V., Yeh, SP., Mayer, J., et al.[2022]

In a retrospective study of 40 patients with relapsed/refractory acute myeloid leukemia (AML) treated with venetoclax, 76% of those who survived more than two cycles achieved neutrophil recovery, indicating a positive response to the treatment.

Venetoclax demonstrated safety and efficacy in advanced AML, with a median overall survival of 5.5 months for all patients and 6.5 months for those who survived beyond two months, suggesting it can be a viable option for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax is safe and efficacious in relapsed/refractory AML. Ganzel, C., Ram, R., Gural, A., et al.[2021]

Venetoclax is an oral medication with a favorable side-effect profile that shows promise in treating acute myeloid leukemia (AML), particularly for patients with refractory or relapsed cases.

This drug can serve as a bridge to hematopoietic cell transplant for curative treatment and may significantly extend survival for older patients who cannot tolerate more aggressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? Pullarkat, VA., Newman, EM.[2021]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

The combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and venetoclax showed a high overall response rate of 75% in relapsed/refractory acute myeloid leukemia (R/R-AML) and 97% in newly diagnosed acute myeloid leukemia (ND-AML), indicating its efficacy as a treatment option.

Patients with ND-AML and R/R-AML who underwent allogeneic hematopoietic stem-cell transplantation after this treatment had significantly improved overall survival rates, with 1-year survival rates of 94% for ND-AML and 78% for R/R-AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia. DiNardo, CD., Lachowiez, CA., Takahashi, K., et al.[2022]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23562738/

Busulfan dose intensity and outcomes in reduced ... In this retrospective analysis, we investigated the effect of i.v. busulfan dosing (total dose 3.2 mg/kg versus 6.4 mg/kg) in RIC regimens that combined ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1083879113001420

Busulfan Dose Intensity and Outcomes in Reduced ... In this retrospective analysis, we investigated the effect of i.v. busulfan dosing (total dose 3.2 mg/kg versus 6.4 mg/kg) in RIC regimens that combined ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7051

Myeloablative fractionated busulfan-based conditioning ... Results: A total of 116 patients were randomized, 59 to the shorter day -13 arm and 57 to the longer day -20 arm. Median age was 59 in the day -13 arm and 57 in ...

4. journals.lww.com journals.lww.com/hosct/fulltext/2020/13030/comparative_effectiveness_of.6.aspx

Comparative effectiveness of busulfan/cyclophosphamide... We compared the effectiveness of these regimens with a focus on quality of life (QOL). Methods: This was a single center, retrospective analysis of adult acute ...

5. researchgate.net researchgate.net/publication/274030893_Busulfan_Does_Intensity_and_Outcomes_in_Reduced_Intensity_Allogeneic_Stem_Cell_Transplantation_for_MDSAML

(PDF) Busulfan Does Intensity and Outcomes in Reduced ... Busulfan Does Intensity and Outcomes in Reduced Intensity Allogeneic Stem Cell Transplantation for MDS/AML. February 2013; Biology of Blood ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04708054

Study Details | NCT04708054 | Venetoclax to Improve ... This phase II trial studies the effect of venetoclax together with busulfan, cladribine, and fludarabine in treating patients with high-risk acute myeloid ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02250937

Venetoclax and Sequential Busulfan, Cladribine ... This randomized phase II trial studies how well venetoclax and sequential busulfan, cladribine, and fludarabine phosphate before donor stem cell transplant ...

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04708054/

Clinical Trial: NCT04708054 This phase II trial studies the effect of venetoclax together with busulfan, cladribine, and fludarabine in treating patients with high-risk acute myeloid ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10939475/

ABT199/venetoclax synergism with thiotepa enhances the ... The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells.

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Venetoclax (ABT-199), a BH3-mimetic and selective BCL-2 inhibitor, was recently approved by the US Food and Drug Administration (FDA) for the treatment of acute ...