Combination Chemotherapy for Chronic Myelomonocytic Leukemia & Myelodysplastic Syndrome

Overseen by Guillermo M. Bravo

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled infection, Heart failure, Pregnancy, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial uses a combination of four drugs to treat certain blood cancers in patients who have not responded to other treatments or are at high risk. The drugs work together to kill cancer cells and stop their growth.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any other investigational agents or chemotherapy, radiotherapy, or immunotherapy during the trial.

What data supports the effectiveness of the drug combination used in the clinical trial for Chronic Myelomonocytic Leukemia and Myelodysplastic Syndrome?

Venetoclax, one of the drugs in the combination, has shown effectiveness in treating acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) when used with other agents like azacitidine, achieving complete remission rates of up to 66.4% in some studies. Although these results are from different conditions, they suggest potential benefits of venetoclax in similar blood-related diseases. ^{1 2 3 4 5}

Is the combination chemotherapy involving Venetoclax generally safe for humans?

Venetoclax, when used in combination with other drugs, has been shown to have an acceptable safety profile in patients with conditions like chronic lymphocytic leukemia and acute myeloid leukemia. However, some patients may experience serious side effects such as infections and blood-related issues, so careful monitoring and management are important. ^{1 2 4 6 7}

What makes the combination chemotherapy of Cladribine, Cytarabine, and Venetoclax unique for treating chronic myelomonocytic leukemia and myelodysplastic syndrome?

This treatment is unique because it combines Cladribine and Cytarabine, which are chemotherapy drugs, with Venetoclax, a targeted therapy that inhibits BCL2 (a protein that helps cancer cells survive). This combination may offer a novel approach by targeting cancer cells more effectively than traditional chemotherapy alone. ^{1 4 8 9 10}

Research Team

Guillermo M. Bravo

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with higher-risk chronic myelomonocytic leukemia (CMML) or myelodysplastic syndromes (MDS) who have not responded to previous treatments. Participants must be over 18, have a white blood cell count under 50,000/L, and an ECOG performance status of <=2. They should also have adequate kidney and liver function and agree to use contraception if they can reproduce.

Inclusion Criteria

I have been diagnosed with MDS or CMML.

I can take care of myself and perform daily activities.

My liver is functioning well.

Exclusion Criteria

Receiving other investigational agents or therapies

Positive for hepatitis B surface antigen or active hepatitis C infection

Reproductive potential patients not following contraception requirements

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cladribine, cytarabine, and venetoclax for 2 cycles, followed by azacitidine and venetoclax for 2 cycles, repeated for up to 18 cycles

Approximately 72 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Azacitidine (DNA Methyltransferase Inhibitor)
• Cladribine (Anti-metabolites)
• Cytarabine (Anti-metabolites)
• Venetoclax (BCL-2 Inhibitor)

Trial Overview The trial is testing whether a combination of drugs—cladribine, cytarabine, venetoclax, and azacitidine—is effective in controlling higher-risk MDS with excess blasts or CMML. It aims to find out if this drug regimen can help patients who haven't had success with other therapies.

Participant Groups

Group I: cladribine, cytarabine, venetoclax, and azacitidine Experimental Treatment 4 Interventions

Participants will receive cladribine, cytarabine, and venetoclax for 2 cycles and then azacitidine and venetoclax for 2 cycles. Participants will repeat this pattern of 2 cycles each for up to a total of 18

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Findings from Research

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]

In a real-world study of 24 patients with acute myeloid leukemia (AML) treated with the oral BCL2 inhibitor venetoclax (VEN) combined with hypomethylating agents (HMAs), 52% achieved complete remission, indicating significant efficacy for patients unfit for intensive chemotherapy.

However, the treatment was associated with a high rate of adverse drug reactions, with 79% of patients experiencing serious side effects, including a notable incidence of febrile neutropenia, which led to 3 deaths, highlighting the need for careful monitoring of safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. Gozzo, L., Vetro, C., Brancati, S., et al.[2021]

Venetoclax (VEN) is FDA approved for treating newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML) when combined with hypomethylating agents, showing complete remission rates of 28.3% and overall survival improvements in a phase-3 study.

While VEN has demonstrated effectiveness in various myeloid malignancies, including relapsed AML and high-risk myelodysplastic syndromes, remissions are often short-lived, typically lasting less than a year, but can facilitate transitions to allogeneic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points. Gangat, N., Tefferi, A.[2023]

In a study of 60 patients with high-risk MDS and AML, venetoclax demonstrated a 35% overall response rate, indicating its efficacy as a treatment option for these conditions.

However, the treatment was associated with significant hematologic toxicity, with 86.7% of patients experiencing grade 2 or higher side effects, and infections, particularly pneumonia, being the most common nonhematologic complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. Gemici, A., Ozkalemkas, F., Dogu, MH., et al.[2022]

In a study of eight pediatric patients with high-grade myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), the combination of venetoclax and 5-azacitidine was well tolerated, with gastrointestinal and hematologic adverse events being the most common.

The treatment led to positive outcomes, with six patients showing morphologic responses, including all four AML responders becoming minimal residual disease negative, suggesting that this regimen is promising and warrants further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. Winters, AC., Maloney, KW., Treece, AL., et al.[2020]

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]

Venetoclax, an oral BCL2 inhibitor, has been approved for older patients with acute myeloid leukemia (AML) who cannot undergo intensive chemotherapy, showing higher rates of complete remission (54% with LDAC and 67% with HMA) compared to traditional treatments.

The median overall survival for patients treated with venetoclax in combination with LDAC or HMA was significantly improved, at 10.4 months and 17.5 months respectively, while the most common side effects were manageable gastrointestinal symptoms and myelosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy. Richard-Carpentier, G., DiNardo, CD.[2020]

In a phase 2 trial involving 33 adults with newly diagnosed acute myeloid leukaemia, the combination of venetoclax with daunorubicin and cytarabine (DAV regimen) achieved a remarkable composite complete remission rate of 91% after one cycle of treatment.

The treatment was found to be safe, with no treatment-related deaths reported, although all patients experienced grade 3 or worse adverse events, such as neutropenia and thrombocytopenia, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. Wang, H., Mao, L., Yang, M., et al.[2022]

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]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. [2021]

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

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points. [2023]

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

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. [2022]

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

Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. [2020]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. [2022]

9. England 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. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Tumor lysis syndrome risk in outpatient versus inpatient administration of venetoclax and hypomethlators for acute myeloid leukemia. [2021]