Chemotherapy for Acute Myeloid Leukemia in Young Patients with Down Syndrome

Not currently recruiting at 209 trial locations

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Disqualifiers: Promyelocytic leukemia, Prior therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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 type of chemotherapy for treating acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in young patients with Down syndrome. The goal is to evaluate how well different drugs work together to stop cancer cell growth and to tailor treatment based on initial patient responses. The study includes different groups, each receiving various drugs such as cytarabine (Cytosar-U, Depocyt, or Tarabine PFS) and daunorubicin (Cerubidine), to identify the most effective approach with the fewest side effects. Participants must have Down syndrome and be newly diagnosed with AML or MDS without prior treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that children who have previously received chemotherapy, radiation therapy, or any anti-leukemic therapy are not eligible, except for cytarabine for treating transient myeloproliferative disorder.

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

Previous studies have shown varying levels of safety for the treatments used in this trial. Cytarabine, a key chemotherapy drug, has proven safe and effective. High doses can be well-tolerated but require careful monitoring due to possible side effects like infections. Daunorubicin is also safe and effective when combined with other treatments. Adjusting the dosage in similar studies has not negatively affected outcomes.

Thioguanine, part of the chemotherapy mix, is generally safe but needs monitoring for side effects like liver issues. Etoposide, another drug in the mix, can cause infections, especially in children with Down syndrome, so monitoring is crucial.

Mitoxantrone has been successfully used to treat types of leukemia. It is effective but can increase the risk of developing another type of leukemia, so weighing the benefits and risks is important.

Finally, Asparaginase, including its variant from Erwinia chrysanthemi, has been safely used in leukemia treatments for years. It is generally well-tolerated, though some people may have allergic reactions.

All these treatments are part of a phase 3 trial, indicating they have been tested in earlier studies for safety. While side effects are possible, the known profiles of these drugs help doctors manage them during treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia (AML) in young patients with Down syndrome because they explore different chemotherapy combinations that could potentially improve outcomes. Unlike the standard treatment options, which typically revolve around a set regimen of chemotherapy drugs, this trial includes the use of asparaginase and its variant, asparaginase Erwinia chrysanthemi, which might offer new ways to target leukemia cells. Additionally, the trial uses high-dose cytarabine, which could enhance the effectiveness of the treatment by aggressively targeting cancer cells. By combining these drugs in novel ways, researchers hope to discover more effective treatment protocols that are specifically tailored to the unique needs of patients with Down syndrome.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia or myelodysplastic syndrome in young patients with Down syndrome?

Research has shown that cytarabine, a key chemotherapy drug, yields promising results for patients with Down syndrome and acute myeloid leukemia (AML). Studies have found a high remission rate, with 88.8% of children with AML responding well to treatment. Additionally, 62% of these children survive for at least five years. For myeloid leukemia specific to Down syndrome, 89.9% of children remain free of major health events for five years, and 93.0% survive for at least five years. In this trial, participants in Arm A (standard risk) will receive cytarabine along with daunorubicin and thioguanine, while participants in Arm B (high risk) will receive high-dose cytarabine with mitoxantrone and etoposide. Daunorubicin has proven effective even at lower doses without worsening outcomes. Etoposide and mitoxantrone also improve survival rates when combined with other drugs. Overall, these treatments show strong potential in improving outcomes for younger patients with Down syndrome facing AML or related conditions. ^{1 6 7 8 9}

Who Is on the Research Team?

Jason N Berman

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for young patients with Down syndrome who have newly diagnosed acute myeloid leukemia or myelodysplastic syndrome. They must not have received any anti-leukemic therapy except cytarabine for transient myeloproliferative disease, and they should not have promyelocytic leukemia. Patients need to show a certain percentage of blasts in their bone marrow or blood and meet specific diagnostic criteria.

Inclusion Criteria

It has been over 8 weeks since my temporary blood disorder with high blast cells resolved.

I have a new diagnosis of AML with more than 20% bone marrow blasts.

I have Down syndrome confirmed by genetic testing.

Exclusion Criteria

I received my last cytarabine dose for TMD treatment within the last 30 days.

I have been diagnosed with a specific type of leukemia (FAB M3).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction I

Patients receive cytarabine intrathecally and intravenously, daunorubicin hydrochloride, and thioguanine orally. Induction I continues for a minimum of 28 days.

4 weeks

Induction II

Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine. Induction II continues for a minimum of 28 days.

4 weeks

Induction III

Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days.

4 weeks

Intensification I

Patients receive cytarabine and etoposide. Intensification I continues for a minimum of 28 days.

4 weeks

Intensification II

Patients receive cytarabine and etoposide. Intensification II continues for a minimum of 28 days.

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes visits at 1 month, monthly for 12 months, every 3 months for 12 months, every 6 months for 3 years, and annually for 10 years.

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Asparaginase
• Asparaginase Erwinia chrysanthemi
• Cytarabine
• Daunorubicin Hydrochloride
• Etoposide
• Mitoxantrone Hydrochloride
• Thioguanine

Trial Overview The study tests response-based chemotherapy using drugs like Asparaginase Erwinia chrysanthemi, Cytarabine, Daunorubicin Hydrochloride, among others. It aims to categorize patients by risk based on their initial treatment response and adjust subsequent treatments accordingly to reduce side effects while treating the cancer effectively.

How Is the Trial Designed?

Group I: Arm B (high risk) Experimental Treatment 5 Interventions

INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days. INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi IM or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days.

Group II: Arm A (standard risk) Experimental Treatment 5 Interventions

INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II continues for a minimum of 28 days. INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days. INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days. (This arm is closed to accrual and treatment with amendment #4A 01/07/2019)

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Vyxeos (CPX-351) received FDA approval for treating adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), based on a study involving 309 patients aged 60-75 that showed improved overall survival (9.6 months vs. 5.9 months with standard treatment).

The safety profile of Vyxeos was comparable to the standard treatment, but it was associated with longer periods of neutropenia and thrombocytopenia, highlighting the need for careful monitoring and a warning against switching between different formulations of daunorubicin and cytarabine during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. Krauss, AC., Gao, X., Li, L., et al.[2020]

Gemtuzumab ozogamicin (Mylotarg) has been approved for treating acute myeloid leukemia (AML) in patients aged 15 and older, showing significant improvements in event-free survival and reduced relapse risk based on a meta-analysis of 3,325 patients.

While Mylotarg is effective, it is associated with common side effects such as hemorrhage and infection, particularly when used in combination with other chemotherapy drugs like daunorubicin and cytarabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA Review of Mylotarg (Gemtuzumab Ozogamicin) for the Treatment of Acute Myeloid Leukemia. Ali, S., Dunmore, HM., Karres, D., et al.[2020]

Glasdegib, an oral Hedgehog pathway inhibitor, has shown promising response rates in treating acute myeloid leukemia (AML) in elderly patients, with moderate toxicity and reduced early mortality compared to standard treatments.

Approved by the FDA and EMA for use with low-dose cytarabine in patients aged 75 and older or those unfit for intensive chemotherapy, glasdegib represents a significant advancement in AML therapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on glasdegib in acute myeloid leukemia - broadening horizons of Hedgehog pathway inhibitors. Fersing, C., Mathias, F.[2023]

Vyxeos, a liposomal formulation combining daunorubicin and cytarabine, significantly improves overall survival in patients aged 60-75 with untreated high-risk acute myeloid leukemia (AML), showing a median survival of 9.56 months compared to 5.95 months with standard chemotherapy.

The study demonstrated that Vyxeos not only enhances survival rates but also increases the likelihood of patients undergoing hematopoietic stem cell transplantation, which is crucial for potentially curing AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes. Tzogani, K., Penttilä, K., Lapveteläinen, T., et al.[2022]

CPX-351, a liposomal-encapsulated combination of daunorubicin and cytarabine, has been approved for treating therapy-related acute myeloid leukemia (tAML) and AML with myelodysplasia-related changes (AML-MRCs), showing improved overall survival and remission rates in older patients compared to the traditional '7 + 3' treatment.

In a Phase III trial involving patients aged 60-75, CPX-351 demonstrated higher rates of complete remission and event-free survival, suggesting that its fixed 5:1 drug ratio may enhance efficacy in these challenging subgroups of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. Chen, EC., Fathi, AT., Brunner, AM.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02521493

Study Details | NCT02521493 | Response-Based ... This phase III trial studies response-based chemotherapy in treating newly diagnosed acute myeloid leukemia or myelodysplastic syndrome in younger patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8500660/

Outcomes of patients with Down syndrome and acute leukemia The overall survival rates in children with DS-ALL and DS-AML were 35.7% and 57.1%, respectively (P = .438). The overall survival rate was ...

3. nyaspubs.onlinelibrary.wiley.com nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111/nyas.12496

Development of asparaginase Erwinia chrysanthemi for the ... The anti-asparagines antibodies correlate with L-asparagines activity and may affect clinical outcome of childhood acute lymphoblastic leukemia.

4. haematologica.org haematologica.org/article/view/haematol.2022.282324/75849

the amazing journey of the therapeutic anti-leukemia ... Asparaginase Erwinia chrysanthemi as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0959804921005529

How much asparaginase is needed for optimal outcome in ... This review provides an overview of asparaginase dose intensity, ie duration of exposure in weeks and level of exposure reflected by dose and/or asparaginase ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/asparaginase-erwinia-chrysanthemi-injection-route/description/drg-20075340

Asparaginase erwinia chrysanthemi (injection route) Asparaginase Erwinia chrysanthemi is used together with other cancer medicines to treat a certain type of blood cancer called acute lymphoblastic leukemia (ALL ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5348069/

Safety, efficacy, and clinical utility of asparaginase in the ... It is a safe and effective agent in the treatment of younger adults with ALL with response rates in the frontline setting ranging from 78% to 96%.

8. go.drugbank.com go.drugbank.com/drugs/DB08886

Asparaginase Erwinia chrysanthemi Asparaginase Erwinia chrysanthemi is an asparaginase-specific enzyme derived from Erwinia chrysanthemi used as an anticancer agent.

9. haematologica.org haematologica.org/article/view/11165

Back to the future: the amazing journey of the therapeutic ... Asparaginase (ASNase) is a therapeutic enzyme used now for over 50 years as a component of multi-agent chemotherapy for children with ALL.