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

116 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Venetoclax when used in combination with chemotherapy for leukemia?

Research shows that Venetoclax, when combined with multidrug chemotherapy, has been effective in treating patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia, achieving a 67.7% overall response rate. Additionally, Venetoclax has shown promise in treating chronic lymphocytic leukemia and acute myeloid leukemia, indicating its potential effectiveness in various types of leukemia. ^{1 2 3 4 5}

Is the combination of Venetoclax and chemotherapy safe for leukemia patients undergoing stem cell transplant?

Research shows that Venetoclax, when combined with chemotherapy, has an acceptable safety profile in various conditions, including leukemia. Common side effects include neutropenia (low white blood cell count), mucositis (mouth sores), diarrhea, and liver issues, but these are manageable. No dose-limiting toxicities were observed, indicating it is generally safe for use in humans. ^{2 3 6 7 8}

What makes the drug Venetoclax combined with chemotherapy unique for leukemia treatment?

Venetoclax is unique because it is a BCL-2 inhibitor that targets a specific protein to help kill cancer cells, and when combined with chemotherapy, it offers a novel approach for treating leukemia, especially in cases where other treatments have failed. This combination is particularly promising for patients with relapsed or refractory leukemia, providing a new option where standard treatments may not be effective. ^{1 3 5 9 10}

What is the purpose of this trial?

This randomized phase II trial studies how well venetoclax and sequential busulfan, cladribine, and fludarabine phosphate before donor stem cell transplant work in treating patients with acute myelogenous leukemia or myelodysplastic syndrome. Giving chemotherapy before a donor peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells.

Research Team

Uday R. Popat

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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, 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]

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 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 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 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]

References

1. China 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]. [2023]

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

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

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

4. England pubmed.ncbi.nlm.nih.gov

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia. [2022]

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

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

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

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]

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

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. [2020]

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

Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active. [2023]

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

Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs. [2021]

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

Venetoclax is safe and efficacious in relapsed/refractory AML. [2021]