Combination Therapy for Acute Lymphoblastic Leukemia

Overseen By Seth E. Karol, MD

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Pregnant, Breastfeeding, Prior cancer therapy, 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: 1

Duration: 1 week

850 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this study is to provide sufficient therapy during the time a patients' B-cell Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LLy) risk category is being determined. The term "risk" refers to the chance of the ALL or LLy coming back after treatment. Primary Objectives * To provide sufficient therapy to enable testing of newly diagnosed acute lymphoblastic leukemia/lymphoma and mixed phenotype acute leukemia/lymphoma tumor samples to determine eligibility and appropriate risk stratification for SJALL therapeutic studies. * To develop a central database of genomic and clinical findings. Secondary Objectives * To assess event free and overall survival data of patients enrolled on this study.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does allow for some prior treatments like one dose of certain chemotherapy drugs or steroids. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination therapy for acute lymphoblastic leukemia?

Research shows that using methotrexate and mercaptopurine, which are part of the combination therapy, can help children with high-risk acute lymphoblastic leukemia achieve remission. In one study, 97% of patients achieved remission, and the 4-year event-free survival rate was around 69% for a similar drug combination. ^{1 2 3 4 5}

Is the combination therapy for acute lymphoblastic leukemia safe?

The combination therapy, including drugs like methotrexate and cytarabine, has shown some side effects such as neutropenia (low white blood cell count) and fever, which were significant but manageable. Other side effects noted in different studies include infections, gastrointestinal issues, and some skin, eye, and liver problems, but overall, the treatment was considered to have tolerable toxicity. ^{1 3 6 7 8}

What makes the combination therapy for acute lymphoblastic leukemia unique?

This combination therapy for acute lymphoblastic leukemia is unique because it uses a mix of drugs, including Cytarabine, Daunorubicin, Dexamethasone, Methotrexate, and Vincristine, which work together to target cancer cells in different ways. This approach aims to improve outcomes by using multiple mechanisms to attack the leukemia, potentially leading to better event-free survival rates compared to standard treatments. ^{5 6 9 10 11}

Research Team

Seth E. Karol, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and teens aged 1 to nearly 19 with newly diagnosed acute leukemia or lymphoma, including ALL with significant bone marrow involvement, LLy with less than 25% bone marrow blasts, or MPAL. It's not for those who are pregnant/breastfeeding, have had certain cancer treatments already (except limited cases), are ineligible for related studies, can't consent, or have specific pre-existing conditions.

Inclusion Criteria

I have been diagnosed with acute leukemia or lymphoma.

My leukemia involves over 25% of my bone marrow or is present in my blood.

I have a type of leukemia that may or may not affect my bone marrow.

Exclusion Criteria

Pregnant or breastfeeding

I've had limited cancer treatment, excluding steroids, which I may have received.

Known to be currently ineligible for available SJALL therapeutic studies (e.g. receipt of prohibited therapy, no appropriate SJALL therapeutic study available, enrolled on competing trial, etc.)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Participants receive 7 days of chemotherapy including dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy

1 week

Daily visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Regular visits (in-person)

Long-term follow-up

Participants are monitored for overall survival and event-free survival

5 years

Treatment Details

Interventions

• Cytarabine
• Daunorubicin
• Dexamethasone
• Methotrexate
• Vincristine

Trial Overview The study tests initial therapy while determining the risk category of B-cell Acute Lymphoblastic Leukemia/Lymphoblastic Leukemia. It involves drugs like Dexamethasone and Vincristine among others. The aim is to gather data on the disease and survival rates while creating a database of genomic/clinical information.

Participant Groups

Group I: Newly diagnosed ALL, LLy, and MPAL patients Experimental Treatment 6 Interventions

All eligible patients receive the following intervention: Dexamethasone, Vincristine, Daunorubicin, Intrathecal triple therapy (methotrexate + hydrocortisone + cytarabine)

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

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

In a study of 83 children with higher-risk B-lineage acute lymphoblastic leukemia (ALL), 98% achieved remission after receiving intensive intravenous methotrexate (MTX) and mercaptopurine (MP) treatment, indicating high efficacy of this regimen.

The 4-year event-free survival rate was 57.4%, and the treatment was associated with generally mild toxicities, suggesting that intensive MTX/MP is an effective and relatively safe option for postremission therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study. Camitta, B., Mahoney, D., Leventhal, B., et al.[2017]

In a study involving 490 children with high-risk B-precursor acute lymphoblastic leukemia (ALL), two treatment regimens were compared, showing that both regimens achieved a high remission rate of 97%.

While regimen B, which involved more intensive myelosuppressive combinations, showed a higher estimated 4-year event-free survival (EFS) of 69.4% compared to 61.6% for regimen A, the difference was not statistically significant, and regimen B was associated with more frequent toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Lauer, SJ., Shuster, JJ., Mahoney, DH., et al.[2019]

A study involving 428 children with acute lymphoblastic leukemia (ALL) compared two chemotherapy schedules using intermediate-dose methotrexate and cytarabine, finding that both regimens had similar efficacy in maintaining remission but differed in toxicity profiles.

The front-loading regimen resulted in a significantly higher incidence of central nervous system (CNS) toxicity, including permanent leukoencephalopathy in one patient, highlighting the need to balance efficacy with safety in treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of two schedules of intermediate-dose methotrexate and cytarabine consolidation therapy for childhood B-precursor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Land, VJ., Shuster, JJ., Crist, WM., et al.[2017]

In a study of 88 children with acute lymphoblastic leukemia, two treatment protocols showed high complete remission rates of 92-96%, with protocol 0276/A demonstrating a significantly lower relapse rate of 4% compared to 28% in protocol 0171.

The long-term outcomes were promising, with 60% of children from protocol 0171 remaining alive in complete remission for over 10 years, while protocol 0276/A showed even better results with over 70% of complete responders in continuous remission for up to 57 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of acute lymphoblastic leukemia in children. Long-term results of two trials. Cáp, J., Koza, I., Misíková, Z., et al.[2007]

In a study involving 105 children with late bone marrow relapses of acute lymphoblastic leukemia (ALL), 97% achieved a second complete remission, indicating that retreatment can be effective.

The trial did not conclusively determine a superior treatment regimen between doxorubicin/prednisone and cytarabine/teniposide, but identified key prognostic factors such as age under 10, lower white blood cell count at relapse, and longer initial remission duration that are associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Sadowitz, PD., Smith, SD., Shuster, J., et al.[2021]

In a pilot study involving 106 children with newly diagnosed non-T-, non-B-cell acute lymphoblastic leukemia, the addition of intermediate-dose methotrexate and cytosine arabinoside to standard therapy showed manageable toxicity, primarily neutropenia and fever.

The study found that event-free survival rates at 4 years were 71% for standard-risk patients and 53% for poor-risk patients, suggesting that this treatment approach may be beneficial and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of intermediate-dose methotrexate and cytosine arabinoside, "spread-out" or "up-front," in continuation therapy for childhood non-T, non-B acute lymphoblastic leukemia. A Pediatric Oncology Group study. Krance, RA., Newman, EM., Ravindranath, Y., et al.[2019]

In a study of 31 pediatric patients with relapsed acute lymphoblastic leukemia (ALL), topotecan administered before standard induction therapy resulted in an impressive 89.3% response rate, significantly reducing circulating blast cells.

The combination of topotecan with standard induction therapy led to a 74.2% complete response rate, indicating that this regimen is effective and well-tolerated, despite some hematologic and gastrointestinal toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse. Hijiya, N., Stewart, CF., Zhou, Y., et al.[2015]

In a study of 33 patients with relapsed acute lymphoblastic leukemia (ALL), 64% achieved complete remission after a combination treatment involving multiple chemotherapy agents, indicating the treatment's efficacy.

While the treatment was effective in inducing remissions, it was associated with significant side effects, particularly hematological issues and infections, suggesting that while the therapy is tolerable, improvements in disease-free survival are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of relapsed acute lymphocytic leukemia in adults. Freund, M., De Boben, M., Diedrich, H., et al.[2019]

In a study of 36 patients with relapsed or refractory acute lymphoblastic leukemia (ALL) treated with an idarubicin-based regimen, the 'ABC' phase II trial achieved a complete remission (CR) rate of 61%, indicating that this treatment approach can be effective for some patients.

Despite the treatment's feasibility and a median overall survival of 7.6 months, there were no long-term survivors, highlighting the ongoing challenge of curing refractory or relapsing ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplant-finalized salvage of adult acute lymphoblastic leukemia: results of a mitoxantrone- and methotrexate-based regimen in 36 patients. Di Bona, E., Pogliani, E., Rossi, G., et al.[2019]

The study found that sequential treatment with methotrexate (MTX) followed by 6-mercaptopurine (6MP) significantly increased apoptosis in a human T-cell leukemia line compared to using each drug alone, suggesting a more effective treatment strategy for childhood acute lymphoblastic leukemia.

Similarly, sequential exposure to tiazofurin (TF) followed by 6-thioguanine (TG) also resulted in a greater induction of apoptosis, indicating that the order of drug administration is crucial for maximizing therapeutic efficacy in leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy in childhood leukaemia: in vitro studies of thiopurines and inhibitors of purine metabolism on apoptosis. De Abreu, RA., Trueworthy, RC., van Kuilenburg, AB., et al.[2017]

A new treatment protocol using teniposide (VM-26) and cytarabine (ara-C) significantly improved event-free survival (EFS) rates in children with acute lymphoblastic leukemia and high initial leukocyte counts, achieving a 44% EFS rate compared to just 10% in matched controls after 4 years.

The combination therapy was well tolerated, with most complications being manageable, and 25 patients from the treatment group survived without adverse events for up to 6.8 years, indicating a promising long-term outcome for this high-risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Teniposide plus cytarabine improves outcome in childhood acute lymphoblastic leukemia presenting with a leukocyte count greater than or equal to 100 x 10(9)/L. Dahl, GV., Rivera, GK., Look, AT., et al.[2017]

References

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

Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study. [2017]

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

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. [2019]

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

Comparison of two schedules of intermediate-dose methotrexate and cytarabine consolidation therapy for childhood B-precursor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. [2017]

4. Slovakia pubmed.ncbi.nlm.nih.gov

Treatment of acute lymphoblastic leukemia in children. Long-term results of two trials. [2007]

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

Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. [2021]

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

A pilot study of intermediate-dose methotrexate and cytosine arabinoside, "spread-out" or "up-front," in continuation therapy for childhood non-T, non-B acute lymphoblastic leukemia. A Pediatric Oncology Group study. [2019]

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

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse. [2015]

8. Germany pubmed.ncbi.nlm.nih.gov

Treatment of relapsed acute lymphocytic leukemia in adults. [2019]

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

Transplant-finalized salvage of adult acute lymphoblastic leukemia: results of a mitoxantrone- and methotrexate-based regimen in 36 patients. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Combination therapy in childhood leukaemia: in vitro studies of thiopurines and inhibitors of purine metabolism on apoptosis. [2017]

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

Teniposide plus cytarabine improves outcome in childhood acute lymphoblastic leukemia presenting with a leukocyte count greater than or equal to 100 x 10(9)/L. [2017]