Combination Chemotherapy for Chronic Myelomonocytic Leukemia & Myelodysplastic Syndrome

Overseen By Guillermo Bravo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled infection, Heart failure, Pregnancy, 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: Approximately 72 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of four drugs—cladribine, cytarabine, venetoclax, and azacitidine—can help manage certain blood disorders. It targets individuals with higher-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) who haven't responded to other treatments. Participants typically have MDS or CMML with specific characteristics, such as a high number of immature blood cells or certain high-risk features. For those with these conditions where previous treatments have been ineffective, this trial might be suitable. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research shows that a combination of four drugs—cladribine, cytarabine, venetoclax, and azacitidine—is being tested for safety in treating certain blood disorders, such as higher-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML).

Studies indicate that this drug combination has been used in patients with similar conditions and is generally well-tolerated. Some patients have experienced side effects, which are common in cancer treatments, like low blood counts or fatigue. However, serious side effects occur less frequently.

Overall, this treatment appears promising, and research suggests it might help manage these blood disorders. Those interested should consult a healthcare provider to understand the potential risks and benefits for their situation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cladribine, cytarabine, venetoclax, and azacitidine because it introduces a fresh approach to treating Chronic Myelomonocytic Leukemia (CMML) and Myelodysplastic Syndrome (MDS). Unlike the usual treatments that often rely on single-agent therapies such as azacitidine or decitabine, this combination uses multiple drugs to target the cancer cells more aggressively. Venetoclax, in particular, is a standout because it works by inhibiting a protein called BCL-2, which helps cancer cells survive. By using venetoclax alongside traditional chemotherapy agents like cladribine and cytarabine, the treatment aims to enhance the overall effectiveness and potentially improve patient outcomes.

What evidence suggests that this trial's treatments could be effective for higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia?

This trial will evaluate the effectiveness of a combination of four drugs—cladribine, cytarabine, venetoclax, and azacitidine—in treating higher-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Participants will receive cladribine, cytarabine, and venetoclax for 2 cycles, followed by azacitidine and venetoclax for 2 cycles, repeating this pattern for up to 18 cycles. Previous studies have found that cladribine, when combined with low-dose cytarabine and venetoclax, can destroy cancer cells in similar conditions by targeting and eliminating the abnormal blood cells causing the disease. Azacitidine, another drug in the mix, stops these abnormal cells from growing. Early results suggest that using these medicines together may control the disease better than using each one alone. ^{1 4 6 7 8}

Who Is on the Research Team?

Guillermo M. Bravo

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Cladribine
• Cytarabine
• Venetoclax

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.

How Is the Trial Designed?

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

Cladribine is already approved in United States, European Union for the following indications:

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

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

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 (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]

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 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 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]

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 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]

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]

In a study of 43 patients with acute myeloid leukemia (AML) treated with venetoclax and hypomethylating agents (HMAs), outpatient initiation of venetoclax was found to be safe, with only one case (2.5%) of laboratory tumor lysis syndrome (TLS) and no clinical TLS episodes reported.

The 30-day mortality rate after starting venetoclax was 0%, indicating that the outpatient ramp-up approach does not compromise patient safety in this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor lysis syndrome risk in outpatient versus inpatient administration of venetoclax and hypomethlators for acute myeloid leukemia. Pelcovits, A., Moore, J., Bakow, B., et al.[2021]

Citations

1.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6503

Phase II study of cladribine, low-dose cytarabine, and ...

Cladribine (CDA) induces monocyte apoptosis and is active in AML when combined with low dose cytarabine (LDAC) and venetoclax (VEN).

2.

ashpublications.org

ashpublications.org/blood/article/142/Supplement%201/1876/505014/Results-of-a-Phase-II-Study-of-Cladribine-Low-Dose

Results of a Phase II Study of Cladribine, Low Dose ...

We aimed to evaluate the safety and activity of cladribine, LDAC and venetoclax in HR-MDS and CMML. METHODS: We designed a phase II basket ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05365035

NCT05365035 | A Phase II Study of Cladribine and Low ...

To determine the efficacy, safety and tolerability of the combination of cladribine, cytarabine and venetoclax in higher-risk MDS with excess ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S0006497123084793

Results of a Phase II Study of Cladribine, Low Dose ...

We designed a phase II basket clinical trial of cladribine combined with LDAC and venetoclax alternating with azacitidine and venetoclax for pts with HR-MDS or ...

5.

mdanderson.org

mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-1116.html

A Phase II Study of Cladribine and Low Dose Cytarabine in ...

The combination of cladribine, cytarabine, venetoclax, and azacitidine can help to control higher-risk myelodysplastic syndrome (MDS) with excess blasts.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06504459

Study Details | NCT06504459 | Venetoclax in Combination ...

Giving venetoclax with cladribine and cytarabine alternating with azacitidine and venetoclax may kill more cancer cells in patients with newly diagnosed ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/35704787/

Phase II Study of Venetoclax Added to Cladribine Plus Low ...

Venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA is an effective regimen among older or unfit patients with newly diagnosed ...

8.

asco.org

asco.org/abstracts-presentations/ABSTRACT502254

Phase II study of cladribine, low-dose cytarabine, and ...

Phase II study of cladribine, low-dose cytarabine, and venetoclax, alternating with azacitidine and venetoclax, in higher-risk chronic myelomonocytic leukemia ...