Combination Chemotherapy for Acute Myeloid Leukemia

Overseen By Tapan Kadia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Pregnancy, Uncontrolled illness, Hypersensitivity, 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

508 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well cladribine, idarubicin, cytarabine, and venetoclax work in patients with acute myeloid leukemia, high-risk myelodysplastic syndrome, or blastic phase chronic myeloid leukemia. Drugs used in chemotherapy, such as cladribine, idarubicin, cytarabine, and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

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, it allows prior use of certain drugs like hydroxyurea and azacytidine, suggesting some medications might be continued. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination for treating acute myeloid leukemia?

Research shows that adding venetoclax to other treatments like cladribine and low-dose cytarabine can improve remission rates and survival in older patients with acute myeloid leukemia. Another study found that venetoclax combined with low-dose cytarabine significantly improved remission rates and overall survival compared to low-dose cytarabine alone. ^{1 2 3 4 5}

Is the combination chemotherapy for acute myeloid leukemia safe?

Venetoclax-based combinations for acute myeloid leukemia have been studied and are generally considered safe, though hematologic toxicities (blood-related side effects) are common. These combinations have been used effectively in both newly diagnosed and relapsed cases, with safety data available from studies conducted in various settings. ^{6 7 8 9 10}

How is the drug combination of Cladribine, Idarubicin, and Venetoclax unique for treating acute myeloid leukemia?

This drug combination is unique because it includes Venetoclax, which is known to improve remission rates and survival in older or unfit patients with acute myeloid leukemia when combined with other drugs like azacitidine. Venetoclax works by targeting and inhibiting a protein that helps cancer cells survive, making it a novel addition to traditional chemotherapy regimens. ^{2 4 6 11 12}

Research Team

Tapan Kadia, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with acute myeloid leukemia, high-risk myelodysplastic syndrome, or blastic phase chronic myeloid leukemia. Eligible participants must have certain levels of liver and kidney function, a heart ejection fraction >= 45%, an ECOG performance status of =< 2 (which means they can do some activities), and no severe allergies to the drugs used. Pregnant or breastfeeding women cannot join, and participants must agree to use contraception.

Inclusion Criteria

I have been diagnosed with AML, acute biphenotypic leukemia, high risk MDS, or CML in myeloid blast phase.

I can take care of myself but might not be able to do heavy physical work.

A negative urine pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial

Exclusion Criteria

Pregnant women are excluded from this study due to potential teratogenic or abortifacient effects; breastfeeding should also be avoided

Patient with documented hypersensitivity to any of the components of the chemotherapy program

I am using contraception or agree to use it during the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive cladribine, cytarabine, and idarubicin intravenously, with additional treatments for specific mutations, repeated every 28 days for up to 2 cycles

8 weeks

Multiple visits for IV administration

Consolidation

Patients receive cladribine, cytarabine, and idarubicin intravenously, with additional treatments for specific mutations, repeated every 28 days for up to 5 cycles

20 weeks

Multiple visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6-12 months

Treatment Details

Interventions

• Cladribine
• Idarubicin
• Venetoclax

Trial Overview The study tests how well a combination of chemotherapy drugs—cladribine, idarubicin, cytarabine—and venetoclax work in treating specific blood cancers. It's designed to see if these drugs can stop cancer cells from growing by killing them or preventing their division and spread.

Participant Groups

Group I: Treatment (cladribine, cytarabine, idarubicin) Experimental Treatment 7 Interventions

INDUCTION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-5 and idarubicin IV over 30-60 minutes on days 1-3. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD on days 1-14. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-3 and idarubicin IV over 30-60 minutes on days 1-2. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 3 trial involving 211 adults with acute myeloid leukemia (AML) who were not eligible for intensive chemotherapy, the combination of venetoclax and low-dose cytarabine (LDAC) showed a clinically meaningful improvement in overall survival, with a median survival of 8.4 months compared to 4.1 months for LDAC alone.

The treatment also resulted in higher remission rates, with 48% of patients achieving complete remission or complete remission with incomplete blood count recovery, while maintaining a manageable safety profile, despite some significant adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Wei, AH., Montesinos, P., Ivanov, V., et al.[2021]

In a study comparing treatment regimens for relapsed/refractory acute myeloid leukemia (R/R AML), the venetoclax (VEN) combination therapy showed a comparable overall response rate (59.3%) to intensive chemotherapy (IC) (44.0%), suggesting it is an effective alternative for patients who have failed previous treatments.

Patients receiving the VEN combination had a significantly higher percentage of successful stem cell transplants at blast clearance (86.5% vs. 62.3% for IC), indicating better disease control and potentially lower treatment-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Park, S., Kwag, D., Kim, TY., et al.[2022]

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]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a phase Ib trial, the combination of the BCL2 inhibitor venetoclax and the MDM2 inhibitor idasanutlin showed a response rate of 35.9% in patients with relapsed or refractory acute myeloid leukemia, indicating potential efficacy in this difficult-to-treat population.

The side effects of this combination therapy were reported to be manageable, suggesting a favorable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2/MDM2 Inhibitor Combo Effective in AML. [2019]

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., 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]

In a comparison of two combination therapies for acute myeloid leukemia—glasdegib+low-dose cytarabine (LDAC) and venetoclax+LDAC—no statistically significant differences in overall survival or complete remission rates were found, suggesting similar efficacy.

When choosing between these treatments, factors like safety profiles, ease of administration, and patient preferences will be important since both therapies appear equally effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. Tremblay, G., Daniele, P., Bell, T., et al.[2021]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

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 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 phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

References

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

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. [2021]

2. England pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). [2022]

3. Italy pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia. [2023]

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

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. [2023]

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

BCL2/MDM2 Inhibitor Combo Effective in AML. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]

7. China 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]. [2023]

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

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. [2023]

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

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

11. 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]

12. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]