Venetoclax + Chemotherapy Before Stem Cell Transplant for Leukemia

Overseen By Uday Popat, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Prior transplantation, Uncontrolled infections, HIV, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments to prepare patients with acute myeloid leukemia or myelodysplastic syndrome for a stem cell transplant. The researchers aim to determine how effectively venetoclax, combined with chemotherapy drugs like busulfan, cladribine, and fludarabine, can eliminate cancer cells and create space for healthy donor stem cells to grow. This approach seeks to improve the chances of successful recovery and remission. Suitable participants have these conditions and can receive a donor stem cell transplant from a matched sibling or unrelated donor. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to advancements in therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that the treatments studied in this trial have different safety records from earlier studies.

For venetoclax, past research in patients with acute myelogenous leukemia (AML) found side effects like low white blood cell counts and nausea, which were usually manageable with supportive care.

Busulfan, a chemotherapy drug, works well but can cause side effects such as low blood counts and liver problems. Its safety is well understood due to its use in similar situations before.

Cladribine, another chemotherapy drug, has helped some AML patients achieve complete remission. Side effects may include low blood counts and a higher risk of infection, but these were expected and manageable.

Fludarabine phosphate, also a chemotherapy drug, has been used in combination treatments for leukemia. It can cause low blood counts and a higher risk of infection, similar to other chemotherapy drugs.

In summary, while all these treatments can have side effects, they are generally expected and manageable with proper care. Previous studies support their safety in humans, although monitoring and supportive care are important for managing any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for leukemia because it includes venetoclax, which uniquely targets a protein called BCL-2 that helps cancer cells survive. Unlike standard chemotherapy options, which often attack rapidly dividing cells indiscriminately, venetoclax specifically disrupts the survival mechanism of leukemia cells, potentially leading to more effective cancer cell elimination. This regimen also strategically incorporates chemotherapy agents like busulfan, cladribine, and fludarabine phosphate to enhance the treatment's overall impact before a stem cell transplant. By combining these therapies, the approach aims to intensify the attack on leukemia cells while maintaining precision, offering hope for improved outcomes.

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

This trial will evaluate the effectiveness of venetoclax combined with chemotherapy drugs such as busulfan, cladribine, and fludarabine before stem cell transplants for patients with acute myelogenous leukemia (AML). Studies have shown that venetoclax, which blocks a protein called BCL-2, can improve treatment outcomes for AML. Participants in this trial will receive venetoclax with these chemotherapy drugs in various regimens. Research indicates that this combination can enhance the success of stem cell transplants by destroying more cancer cells and creating space for healthy cells. Early findings suggest that this treatment approach may increase remission chances in high-risk AML patients. Overall, these results are promising for improving treatment effectiveness before stem cell transplants. ^{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 acute myelogenous leukemia or myelodysplastic syndrome, either untreated or in remission. They must have a matched donor for stem cell transplant and good organ function (heart, liver, kidneys). Children may join after safety checks on adults. Exclusions include previous transplants, HIV positivity, severe comorbidities, uncontrolled infections, and heart disease.

Inclusion Criteria

I, or someone legally allowed, can sign the consent form; if I'm 7-17, I can also agree to participate.

I am mostly active and can care for myself.

Forced expiratory volume in 1 second (FEV1) >= 50% of expected corrected for hemoglobin and/or volume

Exclusion Criteria

I have had a stem cell transplant before.

I have had heart disease related to my arteries.

I am HIV positive.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Participants receive venetoclax, busulfan, cladribine, and fludarabine as conditioning before stem cell transplant

3 weeks

Transplant

Participants undergo allogeneic peripheral blood stem cell transplant

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

2.5 years

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic Hematopoietic Stem Cell Transplantation
• Busulfan
• Cladribine
• Fludarabine Phosphate
• Peripheral Blood Stem Cell Transplantation
• Venetoclax

Trial Overview The study tests venetoclax combined with chemotherapy (busulfan, cladribine, fludarabine phosphate) before a donor stem cell transplant to treat blood cancers. The goal is to see if this approach better eliminates cancer cells and supports healthy bone marrow growth compared to current methods.

How Is the Trial Designed?

Group I: Arm II (busulfan days -20 and -13 before PBSCT) Experimental Treatment 8 Interventions

PREPARATIVE REGIMEN: Patients receive venetoclax PO QD on days -22 to -3 and busulfan IV over 3 hours on days -20 and -13. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0.

Group II: Arm I (busulfan days -13 and -12 before PBSCT) Experimental Treatment 8 Interventions

PREPARATIVE REGIMEN: Patients receive venetoclax PO QD on days -22 to -3 and busulfan IV over 3 hours on days -13 and -12. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3. TRANSPLANT: Patients undergo allogeneic PBSCT 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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

In a study of 31 patients with acute myeloid leukemia evolving from myeloproliferative neoplasms, venetoclax showed some efficacy in newly diagnosed patients, achieving complete remission in 6 patients with a median overall survival of 7 months, but no formal responses in relapsed/refractory patients with a median survival of only 3 months.

The treatment was associated with significant hematologic toxicities, with 83% of patients experiencing severe infections and 14 patients suffering from severe hemorrhagic complications, highlighting the need for safer and more effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs. Masarova, L., DiNardo, CD., Bose, P., et al.[2021]

In a retrospective study of 34 adult patients with various types of non-Hodgkin lymphoma treated off-label with venetoclax, the overall response rate was 26%, indicating modest efficacy in heavily pretreated patients.

Adverse events occurred in 76% of patients, with higher incidence than reported in clinical trials, highlighting the need for further investigation into the safety and dosing strategies of venetoclax in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. Hughes, ME., Landsburg, DJ., Rubin, DJ., et al.[2020]

In a study of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL), Venetoclax combined with multidrug chemotherapy resulted in a 67.7% overall response rate and a 60% complete response rate, indicating significant efficacy.

The treatment was found to be safe, with manageable hematological toxicities and no severe adverse reactions, suggesting that Venetoclax combined with chemotherapy could be a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. Kong, JY., Zong, LH., Pu, Y., et al.[2023]

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]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Citations

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Busulfan - StatPearls - NCBI Bookshelf - NIH Busulfan is a crucial medication for treating these conditions, which warrants a review of its indications, mechanisms of action, and contraindications.

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

Busulfan Dose Intensity and Outcomes in Reduced ... Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity.

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.e19032

Busulfan versus treosulfan conditioning for acute myeloid ... Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD.

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Outcomes of Melphalan Versus Busulfan with Fludarabine ... Our findings suggest that melphalan, compared to busulfan, with fludarabine RIC allo-HCT significantly decreases relapse rates; however, the overall survival ...