Stem Cell Addback for Leukemia

Overseen By Megan Atkinson

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Genetic disorders, Hodgkin lymphoma, pregnant, others

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

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to assist leukemia patients receiving a donor stem cell transplant. The aim is to enhance immune recovery and reduce the risk of serious infections post-transplant. The study employs a process called TCRαβ + T Cell and CD45RA Depleted Peripheral Stem Cell Addback, which reintroduces specific immune cells (T cells) to bolster the immune system. It targets patients with high-risk acute leukemia or similar blood cancers undergoing their first stem cell transplant. Participants must have a suitable donor and no certain genetic disorders.

As an unphased trial, this study allows patients to contribute to pioneering research that could improve immune recovery following stem cell transplants.

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.

What prior data suggests that this stem cell addback is safe for leukemia patients?

Research has shown that using specially treated stem cells, known as TCRαβ and CD45RA depleted stem cells, may benefit patients undergoing stem cell transplants. Studies indicate that this method can reduce the risk of graft vs host disease (GVHD) and deaths unrelated to cancer recurrence, leading to fewer complications and deaths from other causes.

In one study, patients who received these treated stem cells had survival rates similar to those who underwent other types of transplants, suggesting the treatment is generally safe and effective.

Another report found that using TCRαβ-depleted stem cells did not significantly increase the risk of serious infections or other major side effects. This finding is important because it indicates the treatment does not add extra risk.

Overall, the evidence suggests this stem cell treatment is safe for humans, appearing to be well-tolerated with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the stem cell addback treatment for leukemia because it uses a unique combination of TCRαβ + T Cell and CD45RA depleted peripheral stem cells. Unlike traditional chemotherapies and radiation treatments, which broadly target and destroy cancer cells, this approach focuses on enhancing the body's own immune system to more precisely attack leukemia. By selectively depleting certain cell types, this treatment aims to reduce the risk of graft-versus-host disease, a common complication of stem cell transplants, potentially leading to better patient outcomes and fewer side effects.

What evidence suggests that this trial's treatment could be effective for leukemia?

Research has shown that adding back certain cells after a stem cell transplant can help the immune system recover faster. In this trial, participants will receive a TCRαβ + T Cell and CD45RA Depleted Peripheral Stem Cell Addback, which aims to lower the risk of graft-versus-host disease (GVHD) while also helping the body fight infections. Studies have found that removing specific cells from donor stem cells can prevent problems like GVHD. Early results suggest this approach may improve immune function more quickly. This method is believed to retain important immune cells that protect against disease while reducing harmful side effects. ^{3 4 6 7 8}

Who Is on the Research Team?

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for patients under 25 years old who are undergoing their first allogeneic HSCT and have high-risk acute leukemias or certain hematologic malignancies. They must meet specific health criteria and be able to consent if over 18. It's not for those with Hodgkin lymphoma, non-Burkitts/non-lymphoblastic lymphomas, genetic disorders like Fanconi anemia, or without a suitable stem cell donor.

Inclusion Criteria

My leukemia is at high risk of coming back or has already relapsed.

My organs are healthy and I don't have infections, as per the bone marrow transplant guidelines.

I am younger than 25 years old.

Exclusion Criteria

I have a genetic disorder related to DNA repair, like Fanconi anemia.

I don't have a matching donor for a stem cell transplant.

I have Hodgkin lymphoma or a type of non-Burkitts, non-lymphoblastic lymphoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Transplantation

Patients receive T depleted hematopoietic stem cell transplant followed by CD45RA depleted donor peripheral stem cells

Immediate

GVHD Prophylaxis

A short course of GVHD prophylaxis is administered after CD45RA depletion

Short-term

Follow-up

Participants are monitored for incidence of acute graft vs. host disease (GVHD) and immune reconstitution

Up to 100 days post-transplantation

What Are the Treatments Tested in This Trial?

Interventions

• TCRαβ + T Cell and CD45RA Depleted Peripheral Stem Cell Addback

Trial Overview The trial tests the CliniMACS Cell Processing System for TCRαβ+ T Cell/CD45RA Depleted Peripheral Stem Cell Addback post-transplant to prevent GVHD while reducing infection risks by potentially improving immune reconstitution in young patients with leukemia or other related conditions.

How Is the Trial Designed?

Group I: TBI regimen Experimental Treatment 1 Intervention

Standard of care myeloablative regimens will be used based on disease type and clinical status at time of transplant. Patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma will receive total body irradiation (TBI) regimen (thiotepa, cyclophosphamide, TBI).

Group II: TBI or busulfan regimen Experimental Treatment 1 Intervention

Standard of care myeloablative regimens will be used based on disease type and clinical status at time of transplant. Patients not diagnosed with ALL or lymphoblastic lymphoma may receive either total body irradiation (TBI) regimen (thiotepa, cyclophosphamide, TBI) or busulfan containing regimen (thiotepa, cyclophosphamide, busulfan).

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Published Research Related to This Trial

In a study involving 33 children with high-risk acute myeloid leukemia (AML) who received TCR-alpha/beta and CD19-depleted grafts, primary engraftment was achieved in all patients, indicating the effectiveness of this graft manipulation method.

The cumulative incidence of acute graft-versus-host disease (aGvHD) was 39%, with a 10% transplant-related mortality rate, while the overall survival rate at 2 years was 67%, suggesting that this approach is both safe and effective for improving outcomes in pediatric AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Maschan, M., Shelikhova, L., Ilushina, M., et al.[2022]

A new strategy has been developed to create virus-specific T cells from donor blood that can be genetically modified to target leukemia cells, specifically those expressing the CD19 marker, which could help prevent or treat leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

The modified T cells showed similar activation and effectiveness in killing leukemia cells when stimulated through either the chimeric antigen receptor (CAR) or their natural T cell receptor (TCR), indicating that this approach could provide a robust method for targeted leukemia therapy while minimizing the risk of graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Terakura, S., Yamamoto, TN., Gardner, RA., et al.[2023]

In a phase 1 study involving 12 pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), the autologous CD19-CAR T-cell therapy was well tolerated, with low rates of cytokine release syndrome (6 patients) and neurotoxicity (3 patients).

75% of the patients achieved a minimal residual disease-negative complete response in the bone marrow, although higher disease burden before treatment was linked to more side effects and lower response rates, emphasizing the importance of pre-infusion disease status on treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Talleur, AC., Qudeimat, A., Métais, JY., et al.[2022]

T-cell depletion in HLA-identical sibling bone marrow transplants significantly reduces the incidence of acute and chronic graft-versus-host disease (GVHD), but it also increases the risk of graft failure and leukemia relapse, particularly in patients with acute leukemia or chronic myelogenous leukemia.

Among T-cell-depleted transplant recipients, certain factors like higher radiation doses and specific post-transplant immune suppression strategies were associated with fewer treatment failures, suggesting that careful management of these variables could improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell depletion of HLA-identical transplants in leukemia. Marmont, AM., Horowitz, MM., Gale, RP., et al.[2023]

A unique population of CD19+/CD3+ T cells was identified in a patient undergoing CAR T-cell therapy after receiving haploidentical HSCT, suggesting that these cells originated from a previous treatment with a genetically modified T-cell product (RivoCel).

The presence of these CD19-expressing T cells may complicate CAR T-cell therapy, as they were eliminated during the CAR transduction process, indicating that using alternative markers instead of CD19 for tracking post-transplant T cells could be beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of dual positive CD19+/CD3+ T cells in a leukapheresis product undergoing CAR transduction: a case report. Schultz, L., Patel, S., Davis, KL., et al.[2021]

In a study involving 213 children with acute leukemia, TCRαβ/CD19 cell depletion during HLA-haploidentical hematopoietic stem cell transplantation showed promising long-term outcomes, with a projected 10-year overall survival rate of 75.4% and a disease-free survival rate of 71.6%.

The incidence of severe complications such as acute and chronic graft-versus-host disease was low (14.7% and 8.1%, respectively), indicating that this graft manipulation technique is both safe and effective for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Merli, P., Algeri, M., Galaverna, F., et al.[2023]

In a study of 143 pediatric and young adult patients undergoing haploidentical hematopoietic cell transplantation, selective T-cell depletion targeting CD45RA led to significantly improved 3-year overall survival (78.9%) and event-free survival (77.7%) compared to historical cohorts (46.7% and 42.7%, respectively).

The enhanced survival rates were mainly attributed to reduced transplant-related mortality, while the rates of graft-versus-host disease (GVHD) did not significantly increase, indicating a safer and more effective approach to T-cell depletion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival rate in T-cell depleted haploidentical hematopoietic cell transplantation over the last 15 years at a single institution. Mamcarz, E., Madden, R., Qudeimat, A., et al.[2021]

Donor leukocyte infusions (DLI) can effectively induce remission in patients who relapse after bone marrow transplantation (BMT), and using CD34+ cell selection allows for the recovery of functional T cells for immunotherapy.

The study found that the CD34+ cell selection process yielded a high recovery of CD3+ T cells (84% responsive) and a significant T cell depletion (99.8%), making it a promising method for generating T cell products for DLI in patients with acute leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A laboratory comparison of T cell depletion by CD34+ cell immunoaffinity selection and in vitro Campath-1M treatment: clinical implications for bone marrow transplantation and donor leukocyte therapy. Clarke, E., Potter, MN., Oakhill, A., et al.[2019]

Allogeneic CAR-engineered CD45RA-negative T cells effectively target and kill CD19(+) MLL-rearranged leukemia cells, showing promise as a cancer treatment without causing graft-versus-host disease (GVHD).

In mouse models, these CAR(+)CD45RA(-) T cells not only reduced leukemia burdens and improved survival but also maintained their ability to respond to infections, suggesting they could be used safely in non-transplant settings as off-the-shelf therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity. Chan, WK., Suwannasaen, D., Throm, RE., et al.[2021]

In a study involving 60 pediatric and young adult patients undergoing unrelated donor hematopoietic stem cell transplant (HSCT), TCRαβ/CD19 depletion was found to be a safe and effective method, achieving a 4-year overall survival rate of 69% and leukemia-free survival of 64%.

The incidence of severe graft-versus-host disease (GVHD) was relatively low, with only 13% of patients experiencing grade III to IV acute GVHD, suggesting that TCRαβ/CD19 depletion may help mitigate GVHD risks while maintaining effective leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unrelated donor α/β T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia. Leahy, AB., Li, Y., Talano, JA., et al.[2022]

A new automated process using the CliniMACS Prodigy successfully depletes alloreactive T cells from hematopoietic stem cell grafts, achieving a high depletion efficiency of 4 log for both CD45RA+ and TCRαβ/CD19+ cells with minimal manual intervention.

The resulting products maintain a high viability of over 90% for stem cells and retain important immune cells like TCRγδ+ and NK cells, which are crucial for immunological surveillance, making them suitable for haplo-identical hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automatic generation of alloreactivity-reduced donor lymphocytes and hematopoietic stem cells from the same mobilized apheresis product. Wiercinska, E., Quade-Lyssy, P., Hümmer, C., et al.[2023]

In a study of 98 pediatric patients with acute lymphoblastic leukemia (ALL) receiving CD19-targeted CAR T cell therapy, 24 patients (about 24%) experienced hypotension requiring inotropic support, typically occurring around 4.6 days post-infusion.

While 10 patients showed worsened systolic function after treatment, persistent cardiac dysfunction was rare by the 6-month follow-up, indicating that although CAR T therapy can affect heart function, long-term effects are uncommon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac Profile of Chimeric Antigen Receptor T Cell Therapy in Children: A Single-Institution Experience. Burstein, DS., Maude, S., Grupp, S., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03810196

CD45RA Depleted Peripheral Stem Cell Addback for Viral ... Patients will be given CD45RA depleted donor peripheral stem cells (PSCs) following T depleted hematopoietic stem cell transplant (HSCT). A short course of GVHD ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12062598/

Selective TCRαβ+ and CD45RA+ T-cell depletion of ... Selective depletion of TCRαβ+ and CD45RA+ subsets of apheresed hematopoietic progenitor cells, HPC(A), enables haploidentical hematopoietic stem ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1201971224001140

TCRαβ-depleted hematopoietic stem cell transplant and ... TCRαβ-depleted HSCT can treat secondary graft rejection. •. The third-party CD45RA+ depleted adoptive cell therapy is an effective treatment.

4. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/581815

Phase 1/2: CD45RA Depleted Stem Cell Addback to ... The central hypothesis of this study is that an addback of CD45RO memory T lymphocytes, derived from a fraction of the original donor peripheral ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02942173

CD45RA Depleted T-cell Infusion for Prevention of ... Selective depletion of TCR-alpha/beta T-lymphocytes is a new method of hematopoietic stem cell graft manipulation, which is thought to conserve important cell ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06839456

Phase 1/2: CD45RA Depleted Stem Cell Addback to ... The central hypothesis of this study is that an addback of CD45RO memory T lymphocytes, derived from a fraction of the original donor peripheral stem cell ...

7. ashpublications.org ashpublications.org/blood/article/143/3/279/498045/TCR-CD19-cell-depleted-HLA-haploidentical

TCRαβ/CD19 cell–depleted HLA-haploidentical ... TCRαβ/CD19 cell–depleted haploHSCT is characterized by low NRM and acute/chronic GVHD, with OS and DFS similar to other transplants.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8702395/

Results of a multicenter phase I/II trial of TCRαβ and CD19- ... Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients.