Stem Cell Addback for Leukemia

Recruiting in Palo Alto (17 mi)

Overseen by Timothy S Olson, MD, PhD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Genetic disorders, Hodgkin lymphoma, pregnant, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The major morbidities of allogeneic hematopoietic stem cell transplant with non-human leukocyte antigen (HLA) matched siblings are graft vs host disease (GVHD) and life threatening infections. T depletion of the donor hematopoietic stem cell graft is effective in preventing GVHD, but immune reconstitution is slow, increasing the risk of infections. An addback of donor CD45RA (naive T cells) depleted cells may improve immune reconstitution and help decrease the risk of infections.

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 data supports the effectiveness of the treatment TCRαβ + T Cell and CD45RA Depleted Peripheral Stem Cell Addback for leukemia?

Research shows that using TCRαβ/CD19 depletion in stem cell transplants for children with leukemia has led to promising survival rates, with a 5-year overall survival of 75.4% and low rates of severe complications like graft-versus-host disease. Additionally, CD45RA depletion helps preserve important immune cells, improving survival outcomes by reducing transplant-related mortality. ^{1 2 3 4 5}

Is the Stem Cell Addback for Leukemia treatment generally safe in humans?

Research on similar treatments, like CD45RA-negative T cells, shows they can be safe, as they control cancer without causing graft-versus-host disease (a condition where donor cells attack the recipient's body). Additionally, studies on CD19-CAR T-cell therapy, which is related, indicate it is generally well-tolerated, with manageable side effects like cytokine release syndrome (a reaction causing fever and low blood pressure) and neurotoxicity (nerve damage). ^{6 7 8 9 10}

What makes the Stem Cell Addback treatment for leukemia unique?

This treatment is unique because it involves a specific type of stem cell transplantation that depletes certain immune cells (TCRαβ and CD19) to reduce complications like graft-versus-host disease (GVHD) while adding back CD45RA-depleted stem cells to enhance immune recovery and reduce relapse risk. ^{1 2 9 11 12}

Research Team

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• TCRαβ + T Cell and CD45RA Depleted Peripheral Stem Cell Addback (Cell Therapy)

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.

Participant Groups

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+

Joseph W. St. Geme III

Children's Hospital of Philadelphia

Chief Medical Officer since 2021

MD, PhD, MPH

Madeline Bell

Children's Hospital of Philadelphia

Chief Executive Officer since 2015

BSc in Nursing from Villanova University, MSc in Organizational Dynamics from the University of Pennsylvania

Findings from Research

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]

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]

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]

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]

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]

References

1. England 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. [2022]

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

TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. [2023]

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

Unrelated donor α/β T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia. [2022]

4. England 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Automatic generation of alloreactivity-reduced donor lymphocytes and hematopoietic stem cells from the same mobilized apheresis product. [2023]

6. England 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. [2021]

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

Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. [2023]

8. United States 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. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Identification of dual positive CD19+/CD3+ T cells in a leukapheresis product undergoing CAR transduction: a case report. [2021]

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

Cardiac Profile of Chimeric Antigen Receptor T Cell Therapy in Children: A Single-Institution Experience. [2019]

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

T-cell depletion of HLA-identical transplants in leukemia. [2023]

12. England 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. [2019]