Stem Cell Transplant for Bone Marrow Failure Syndrome

(ExpMACs Trial)

Overseen By Megan Atkinson

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Infections, HLA matched sibling, pregnancy

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4-6 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this protocol is to expand access for patients who lack a fully HLA (Human leukocyte antigen) matched sibling donor and who are candidates for allogeneic hematopoietic stem cell transplant (HSCT). These patients have a serious or immediately life-threatening disease for which HSCT is indicated. These patients are not eligible for other Children's Hospital of Philadelphia IRB approved protocols that utilize CliniMACs technology for T depletion.

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 'Stem Cell Transplant for Bone Marrow Failure Syndrome' involving CD3+/CD19+ depletion?

Research shows that depleting specific immune cells (TCRαβ+ T cells and CD19+ B cells) from stem cell transplants can help reduce complications like graft-versus-host disease (a condition where the donor cells attack the recipient's body) and improve outcomes in similar treatments for conditions like leukemia and severe combined immunodeficiency. ^{1 2 3 4 5}

Is the stem cell transplant with CD3+/CD19+ depletion generally safe for humans?

Research shows that using the CliniMACS system for stem cell transplants with CD3+/CD19+ depletion is generally safe. It effectively removes certain immune cells to reduce complications like graft-versus-host disease (a condition where transplanted cells attack the recipient's body) without harming the stem cells' function. ^{1 2 3 5 6}

How is the stem cell transplant treatment with CD3+/CD19+ depletion different from other treatments for bone marrow failure syndrome?

This treatment is unique because it involves selectively removing specific immune cells (T and B cells) from the donor stem cell graft to reduce the risk of complications like graft-versus-host disease, while preserving other beneficial cells like natural killer cells, which can improve patient outcomes. ^{1 2 3 5 7}

Research Team

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for patients without a fully matched sibling donor who need a stem cell transplant due to serious conditions like leukemia, metabolic diseases correctable by HSCT, bone marrow failure, or immune system problems. They must meet specific health criteria and not be pregnant or have uncontrolled infections.

Inclusion Criteria

My organ functions meet the required levels, and I don't have an untreated infection.

You don't have a fully matched sibling for a specific type of stem cell transplant, and you don't meet the requirements for other treatment options at the hospital.

I am capable of becoming pregnant and have a negative pregnancy test.

Exclusion Criteria

My donor cannot give stem cells through their bloodstream.

I am currently pregnant.

I do not have any ongoing serious infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo allogeneic hematopoietic stem cell transplant (HSCT) with CD3+/CD19+ depleted stem cells

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after the transplant, focusing on complications such as graft vs. host disease (GVHD)

12 weeks

Treatment Details

Interventions

• Transplant of stem cells with CD3+/CD19+ depletion (CliniMACs)

Trial Overview The trial provides access to a special stem cell transplant using CliniMACs technology to deplete certain cells (CD3+/CD19+) from the donated material. It's aimed at those who can't participate in other trials but need this potentially life-saving procedure.

Participant Groups

Group I: Expanded access to CliniMACs device for T cell depletion Experimental Treatment 1 Intervention

access for patients who lack a fully HLA matched sibling, and who are candidates for allogeneic hematopoietic stem cell transplant (HSCT). These patients have a serious or immediately life-open protocols that utilize CliniMACs technology for T depletion. Subjects will undergo transplant of stem cells with CD3+/CD19+ depletion.

Transplant of stem cells with CD3+/CD19+ depletion (CliniMACs) is already approved in European Union, United States for the following indications:

Approved in European Union as CD3+/CD19+ depleted PBSC for:

• Hematologic malignancies
• Hemoglobinopathies
• Primary immunodeficiencies

Approved in United States as CD3+/CD19+ depleted PBSC for:

• Hematologic malignancies
• Hemoglobinopathies
• Primary immunodeficiencies

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Findings from Research

The study successfully demonstrated the simultaneous depletion of T and B cells from mobilized peripheral blood stem cells (PBSCs) using the CliniMACS device, achieving a T cell depletion efficiency of 99.98% and B cell depletion of over 99.99%.

Importantly, the depletion process did not adversely affect the function of the remaining hematopoietic stem cells, maintaining a high recovery rate of CD34(+) cells and NK cells, which is crucial for the success of haploidentical stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[An effective method for T-cell and B-cell simultaneous depletion in vitro from mobilized peripheral blood stem/progenitor cell graft for haploidentical transplantation]. Xiao, J., Li, HH., Jin, XS., et al.[2017]

A novel treatment for severe combined immunodeficiency (SCID) using haploidentical hematopoietic stem cell transplantation (HSCT) with selective depletion of GvHD-inducing T-cells showed rapid engraftment and no signs of graft-versus-host disease (GvHD) in a 9-month-old patient.

The addition of donor lymphocyte infusion (DLI) enriched with memory T-cells effectively enhanced the patient's antiviral immunity, leading to increased T-cell counts and clearance of severe viral infections without causing GvHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. Brodszki, N., Turkiewicz, D., Toporski, J., et al.[2018]

The CliniMACS Prodigy® system successfully performed TCRαβ+ T cell and B cell depletion in ten haploidentical stem cell transplants, achieving a median log reduction of TCRαβ+ cells of -4.21, indicating effective cell removal.

The procedure demonstrated reliability and ease of use, with a median CD34 recovery of 83%, although B cell depletion was slightly less efficient with a median log reduction of -3.72.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depletion of αβ+ T and B Cells Using the CliniMACS Prodigy: Results of 10 Graft-Processing Procedures from Haploidentical Donors. Haastrup, E., Ifversen, MRS., Heilmann, C., et al.[2022]

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 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]

The use of the CliniMACS Plus system for CD34+ cell enrichment in allogeneic stem cell transplantation achieved an average product purity of 95.66%, indicating a high-quality process that enhances the potential for using partially matched grafts without increasing the risk of graft-versus-host disease.

All end products tested negative for bacterial contamination and endotoxins, demonstrating the safety and reliability of the manufacturing process, which was validated across six different cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A CD34+ Cell Enrichment Protocol of Hematopoietic Stem Cells in a Well-Established Quality Management System. Kilic, P., Bay, M., Yildirim, Y., et al.[2020]

Aggressive T-cell depletion is crucial for the success of haplo-identical stem cell transplantation, but traditional methods have resulted in high transplant-related mortality, with only a 20% overall survival rate.

The study found that while the recovery of CD34+ and NK cells was generally high, the T- and B-cell depletion process was not consistently effective, leading to the consideration of alternative protocols for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD3/CD19 Depletion for T-cell Reduction of Allogeneic Transplants: Mostly Efficient, but not Robust. Wiercinska, E., Seifried, E., Bonig, H.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

[An effective method for T-cell and B-cell simultaneous depletion in vitro from mobilized peripheral blood stem/progenitor cell graft for haploidentical transplantation]. [2017]

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

Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. [2018]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Depletion of αβ+ T and B Cells Using the CliniMACS Prodigy: Results of 10 Graft-Processing Procedures from Haploidentical Donors. [2022]

4. 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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

A CD34+ Cell Enrichment Protocol of Hematopoietic Stem Cells in a Well-Established Quality Management System. [2020]

7. England pubmed.ncbi.nlm.nih.gov

CD3/CD19 Depletion for T-cell Reduction of Allogeneic Transplants: Mostly Efficient, but not Robust. [2021]