Non-TBI Conditioning for HCT in Acute Lymphoblastic Leukemia

Recruiting at 24 trial locations

Overseen By Liz Gourdine

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Pediatric Transplantation & Cellular Therapy Consortium

Disqualifiers: Pregnancy, HIV, Active CNS leukemia, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 43

Duration: Variable, based on conditioning regimen

95 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates a new method for preparing patients with Acute Lymphoblastic Leukemia (ALL) for a hematopoietic cell transplant (HCT) without total body irradiation (TBI). The aim is to determine if this non-TBI approach, known as myeloablative allogeneic HCT with a non-TBI conditioning regimen, is effective for patients at low risk of leukemia relapse. A special test checks for minimal residual disease (tiny amounts of cancer cells) to assess this risk. If the test detects no residual disease, patients may receive the non-TBI treatment before their transplant. This trial suits patients with ALL who are preparing for an HCT and have no detectable cancer cells in their bone marrow, as confirmed by the test. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor to get specific guidance based on your situation.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that the treatment plan used in this trial, which includes thiotepa, busulfan, and fludarabine, is generally safe and well-tolerated. Previous studies found that this combination has acceptable side effects for patients with acute lymphoblastic leukemia (ALL). These studies suggest that the treatment is promising, with manageable side effects.

Additionally, this treatment approach has been successfully used in various transplant situations, making it a reliable choice for patients undergoing blood cell transplants. While side effects can occur, this drug combination is considered a safe alternative to total body irradiation (TBI), especially for patients with a lower risk of disease recurrence. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute lymphoblastic leukemia?

Researchers are excited about this treatment for acute lymphoblastic leukemia because it uses a myeloablative conditioning regimen without total body irradiation (TBI), which is the traditional approach. The study focuses on using a combination of busulfan, fludarabine, and thiotepa, offering a potentially less toxic alternative to TBI that could reduce long-term side effects. This approach is particularly promising as it could allow more patients to undergo transplantation by minimizing the harmful impact on non-cancerous cells, making the treatment more tolerable and safer.

What evidence suggests that this non-TBI conditioning regimen could be an effective treatment for acute lymphoblastic leukemia?

This trial will compare two approaches for patients with acute lymphoblastic leukemia (ALL) undergoing stem cell transplant. One arm involves an observational approach using the NGS-MRD test to determine eligibility for the treatment arm. Studies have shown that a combination of drugs—thiotepa, busulfan, and fludarabine—can serve as an alternative to total body irradiation (TBI) for patients needing a stem cell transplant. Research suggests that TBI is often more effective for young patients with ALL. However, the treatment arm in this trial will use a myeloablative non-TBI conditioning regimen with thiotepa, busulfan, and fludarabine for eligible patients who have no detectable cancer cells before the transplant. While researchers continue to study the effectiveness of this non-TBI method, it provides another option for those who cannot undergo TBI. Results can vary, and further research is needed to confirm its benefits for this specific group. ^{5 6 7 8 9}

Who Is on the Research Team?

Abdel-Azim Hisham, MD

Principal Investigator

Loma Linda University

Troy Quigg, DO, MS

Principal Investigator

Helen DeVos Children's Hospital

Are You a Good Fit for This Trial?

This trial is for children, adolescents, and young adults aged 1-25 with B-ALL leukemia who are candidates for a stem cell transplant. They must have low relapse risk indicated by negative NGS-MRD (a type of genetic test) in their bone marrow before the transplant. Participants need to be in first or second remission and have good organ function. Those with certain conditions like CNS relapse history or HIV are not eligible.

Inclusion Criteria

My family or doctor decided against a specific treatment even though tests showed I might benefit from it.

I am receiving my first bone marrow transplant for T-ALL or MPAL.

I have ALL and am undergoing a specific bone marrow transplant.

Exclusion Criteria

I haven't had any cancer, except for skin cancer, in the last 5 years.

I have not had a CNS relapse while in my second complete remission.

I received inotuzumab treatment before my stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive a myeloablative non-TBI conditioning regimen with busulfan, fludarabine, and thiotepa prior to hematopoietic cell transplantation

Variable, based on conditioning regimen

Follow-up

Participants are monitored for safety and effectiveness after treatment, with NGS-MRD testing at specified intervals

1 year

Multiple visits for NGS-MRD testing at days 42, 100, 180, 270, and 365 post-HCT

Long-term follow-up

Participants are followed for outcome for up to 5 years to estimate event-free survival

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Myeloablative allogeneic HCT with a non-TBI conditioning regimen
• NGS-MRD

Trial Overview The study tests if a non-TBI (no total body irradiation) conditioning regimen before hematopoietic cell transplantation can work for patients with B-ALL who show no minimal residual disease through next-generation sequencing. It compares this approach against standard treatments that include TBI.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 2 Interventions

Patients enrolled to the observational arm that are NGS-MRD pre-HCT are considered for the Treatment Arm. Patients will receive a myeloablative non-TBI conditioning regimen prior to the transplant consisting on busulfan, fludarabine and thiotepa. Patients will be followed for outcome for up to 5 years.

Group II: Observational Arm Experimental Treatment 1 Intervention

Patients are enrolled to the observational arm to proceed with NGS-MRD testing pre-HCT. If NGS-MRD negative, eligible patients may be considered for the Treatment Arm to receive a myeloablative non-TBI conditioning regimen prior to HCT. If NGS-MRD positive, patients may continue in the observational arm and receive HCT under the direction of their transplant physician and followed on the study for outcome.

Myeloablative allogeneic HCT with a non-TBI conditioning regimen is already approved in United States, European Union for the following indications:

Approved in United States as Myeloablative allogeneic HCT with non-TBI conditioning for:

• B-cell acute lymphoblastic leukemia (B-ALL) in NGS-MRD negative patients

Approved in European Union as Myeloablative allogeneic HCT with non-TBI conditioning for:

• B-cell acute lymphoblastic leukemia (B-ALL) in NGS-MRD negative patients

Who Is Running the Clinical Trial?

Pediatric Transplantation & Cellular Therapy Consortium

Lead Sponsor

Children's Hospital Los Angeles

Lead Sponsor

Trials

257

Recruited

5,075,000+

Published Research Related to This Trial

A non-myeloablative conditioning regimen using fludarabine, cytarabine, and melphalan (FLAG combined with L-PAM) was successfully administered to 10 pediatric patients with acute leukemia, resulting in 100% engraftment and 80% overall survival after a median follow-up of 126 months.

This approach minimized late adverse effects typically associated with conventional myeloablative treatments like busulfan and total body irradiation, with no treatment-related mortality reported, indicating a safer alternative for children undergoing allogeneic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and melphalan (FALG with L-PAM) as a reduced toxicity conditioning regimen in children with acute leukemia. Kato, K., Yoshida, N., Matsumoto, K., et al.[2014]

Nonmyeloablative regimens for allogeneic hematopoietic cell transplantation (HCT) resulted in significantly lower regimen-related toxicities and nonrelapse mortality compared to myeloablative regimens, with 3% NRM at day 100 for nonmyeloablative patients versus 23% for myeloablative patients.

Despite nonmyeloablative patients being at higher risk due to factors like age and comorbidities, they experienced less severe toxicities across multiple organ systems, suggesting that these regimens are safer and could be beneficial for patients who are ineligible for more intensive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Diaconescu, R., Flowers, CR., Storer, B., et al.[2021]

In a study of 278 adult patients with acute lymphoblastic leukemia (ALL) undergoing radiation-free myeloablative conditioning for allogeneic stem cell transplantation, outcomes such as overall survival and disease-free survival were similar for patients with and without central nervous system (CNS) involvement.

Pre-HSCT cranial radiation therapy did not significantly reduce the risk of post-transplant CNS relapse, indicating that TBI-free conditioning can be a viable option for ALL patients with CNS involvement, without compromising long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation-Free myeloablative allogeneic hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia: A comparison of outcomes between patients with and without central nervous system involvement. Esfandbod, M., Enshaei, M., Monzavi, SM., et al.[2022]

In a study involving 5,629 pediatric patients with acute lymphoblastic leukemia (ALL), total body irradiation (TBI)-based conditioning regimens before allogeneic hematopoietic stem cell transplant (HSCT) showed significantly better overall survival and event-free survival compared to chemotherapy (CHT) alone.

Both TBI and CHT conditioning had similar risks for complications like acute graft-versus-host disease and nonrelapse mortality, indicating that while TBI is more effective, it does not increase the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis. Rehman, MEU., Chattaraj, A., Mahboob, A., et al.[2023]

Nonmyeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) provide a safer alternative for older or medically unfit patients with hematologic malignancies, allowing them access to potentially curative treatment that was previously too risky due to high toxicity.

These regimens utilize donor T-cells to target and eliminate malignant cells without the need for intensive chemotherapy or radiotherapy, demonstrating a promising graft-versus-tumor effect and improving the eligibility of patients for HSCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of "minitransplantation": nonmyeloablative allogeneic hematopoietic stem cell transplantation. Georges, GE., Storb, R.[2019]

A reduced-toxicity myeloablative conditioning regimen using dose-adjusted busulfan, fludarabine, antithymocyte globulin, and total body irradiation was evaluated in 40 pediatric patients with high-risk leukemias, showing overall survival rates of 67% at two years and 51% at five years post-transplant.

The regimen demonstrated safety with a transplant-related mortality of 8% at 100 days and 13% at one year, and it was particularly effective for patients with myeloid disease who achieved a busulfan exposure above 4000 μmol*min/day, leading to a two-year relapse-free survival rate nearing 80%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-toxicity conditioning regimen with busulfan, fludarabine, rATG, and 400 cGy TBI in pediatric patients undergoing hematopoietic stem cell transplant for high-risk hematologic malignancies. Rossoff, J., Jacobsohn, D., Kwon, S., et al.[2022]

A systematic review of 8 studies involving over 5000 patients indicates that total body irradiation (TBI)-based conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) in acute lymphoblastic leukemia (ALL) patients significantly improve overall survival (OS) and progression-free survival (PFS) while reducing relapse rates compared to chemotherapy-only regimens.

While TBI-based regimens do not increase the risk of nonrelapse mortality or lower-grade graft-versus-host disease (GVHD), they are associated with a higher risk of severe acute GVHD, suggesting a need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis. Khimani, F., Dutta, M., Faramand, R., et al.[2021]

In a study of 104 patients with high-risk acute leukemia, those who underwent standard myeloablative conditioning regimens had significantly better overall survival rates (52%) compared to those who received alternative regimens (25%).

The alternative regimens were associated with a higher risk of relapse (58% vs 34%) and worse survival outcomes, indicating that these alternative treatments did not improve patient outcomes in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia. Mengarelli, A., Iori, A., Guglielmi, C., et al.[2019]

Myeloablative Total Body Irradiation (TBI) is primarily used for conditioning in high-risk acute lymphoblastic leukemia (ALL) patients, but it is not recommended for children under 3-4 years old due to higher toxicity risks.

The recommended TBI dose for children is between 12-14.4 Gy, with specific dose reductions for sensitive organs, and advanced techniques like TomoTherapy and VMAT TBI are encouraged to improve safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children. Hoeben, BAW., Pazos, M., Seravalli, E., et al.[2022]

In a study comparing 27 patients under 60 who received reduced intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (HCT) to 226 age-matched controls who received myeloablative conditioning (MAC), the RIC group showed significantly lower 2-year overall survival rates (29% vs. 63%).

The RIC group also experienced higher rates of treatment-related mortality (41% vs. 24%) and a trend towards increased risk of relapse, indicating that RIC with T-cell depletion (TCD) may lead to worse outcomes in younger ALL patients undergoing HCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inferior outcomes with reduced intensity conditioning followed by allogeneic hematopoietic cell transplantation in fit individuals with acute lymphoblastic leukemia: a Canadian single-center study and a comparison to registry data. Pasic, I., Paulson, K., Dozois, G., et al.[2021]

Allogeneic hematopoietic cell transplantation using nonmyeloablative or reduced-intensity conditioning regimens has shown promising 2-year survival rates of 48% to 79% for older patients and those with medical comorbidities with acute myeloid leukemia in first complete remission.

Retrospective studies indicate that outcomes for patients receiving nonmyeloablative conditioning are comparable to those receiving traditional myeloablative conditioning, suggesting a potential shift in treatment approaches for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic cell transplantation after reduced-intensity conditioning for older adults with acute myeloid leukemia in complete remission. Baron, F., Storb, R.[2016]

Reduced intensity and nonmyeloablative regimens for allogeneic hematopoietic cell transplantation (HCT) are designed to treat older patients or those with comorbidities by minimizing regimen-related side effects while still achieving tumor reduction through graft-versus-tumor (GVT) effects.

Current challenges in these approaches include managing graft-versus-host disease (GVHD) while promoting GVT, and future clinical trials will compare these new regimens with traditional myeloablative conditioning to broaden treatment options for standard-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning for allogeneic hematopoietic cell transplantation: current perspectives. Sandmaier, BM., Mackinnon, S., Childs, RW.[2018]

Citations

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Myeloablative conditioning with thiotepa-busulfan-fludarabine ... Myeloablative conditioning with thiotepa-busulfan-fludarabine does not improve the outcome of patients transplanted with active leukemia.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723015828

Thiotepa-Based Regimens Are Valid Alternatives to Total ... Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) ...

3. astctjournal.org astctjournal.org/article/S1083-8791(17)30872-8/fulltext

Intravenous Busulfan Compared with Total Body Irradiation ... Thus, we compared the outcomes of adult patients with ALL who received allogeneic HCT after treatment with myeloablative TBI-based conditioning versus i.v. Bu- ...

4. nature.com nature.com/articles/s41409-023-01966-w

Total body irradiation versus busulfan based intermediate ... Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL).

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/57/NCT01991457/Prot_SAP_002.pdf

Single Arm Phase II Study of Myeloablative Allogeneic ... We will investigate the safety and efficacy of a myeloablative regimen of Flu TBI 12 Gy regimen for ALL patients who are not eligible for Cy TBI ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36224494/

Thiotepa, busulfan and fludarabine conditioning-regimen is ... Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity.

7. astctjournal.org astctjournal.org/article/S1083-8791(19)30151-X/fulltext

Thiotepa, Busulfan, and Fludarabine Conditioning ... Thiotepa, busulfan, and fludarabine conditioning is safe in a haploidentical transplantation setting. •. Antithymocyte globulin (ATG) prophylaxis seems ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S1083879117308728

Intravenous Busulfan Compared with Total Body Irradiation ... An updated analysis of MD Anderson data with Bu-Clo transplant conditioning for ALL patients in CR1 (n = 62) or CR2 (n = 28) revealed 2-year overall survival ( ...

9. nature.com nature.com/articles/s41409-024-02378-0

Comparing transplant outcomes in ALL patients after ... Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL.