T Cell-Depleted Stem Cell Transplant for Leukemia

Recruiting at 9 trial locations

Overseen By Marie Bleakley

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Tacrolimus, Fludarabine, Methotrexate

Disqualifiers: Active CNS disease, HIV-positive, Uncontrolled infections, Pregnancy, 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: 29

68 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well naive T-cell depletion works in preventing chronic graft-versus-host disease in children and young adults with blood cancers undergoing donor stem cell transplant. Sometimes the transplanted white blood cells from a donor attack the body's normal tissues (called graft versus host disease). Removing a particular type of T cell (naive T cells) from the donor cells before the transplant may stop this from happening.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

What data supports the effectiveness of the T Cell-Depleted Stem Cell Transplant treatment for leukemia?

Research shows that using blood stem cell grafts and tacrolimus can lead to faster recovery and reduced early mortality in leukemia patients. Additionally, a combination of fludarabine, busulfan, and low-dose total body irradiation has been associated with a lower relapse rate compared to other regimens, suggesting potential effectiveness in leukemia treatment. ^{1 2 3 4 5}

Is T Cell-Depleted Stem Cell Transplant for Leukemia safe for humans?

Research shows that T Cell-Depleted Stem Cell Transplant, using various conditioning regimens, is generally safe in humans. Studies report successful engraftment with low organ toxicity and manageable side effects like graft-versus-host disease (GVHD), which can often be controlled with medication. ^{6 7 8 9 10}

How is the T Cell-Depleted Stem Cell Transplant for Leukemia treatment different from other treatments?

This treatment is unique because it involves a T cell-depleted stem cell transplant, which aims to reduce the risk of graft-versus-host disease (GVHD) by removing specific immune cells (T cells) from the donor's stem cells. It combines multiple drugs and therapies, including busulfan, cyclophosphamide, fludarabine, and total-body irradiation, to prepare the body for the transplant, potentially offering a curative option for leukemia patients. ^{1 8 11 12 13}

Research Team

Marie Bleakley

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for children and young adults aged 6 months to 22 years with certain blood cancers who need a stem cell transplant. They must have good heart function, lung capacity, liver and kidney function, and not be pregnant or breastfeeding. Participants need a matched donor available in the US.

Inclusion Criteria

I am between 6 months and 22 years old.

My planned infusion will use stem cells from bone marrow or blood, not cord blood.

I have a donor who is a perfect match for my bone marrow transplant.

Exclusion Criteria

You have HIV.

I am not pregnant or breastfeeding.

My brain or spinal cord disease is currently under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Patients undergo total body irradiation and receive chemotherapy drugs as part of the conditioning regimen

10 days

Daily visits for treatment

Transplant

Patients receive either naive T-cell depleted PBSCs or unmanipulated T cell-replete BM

1 day

1 visit (in-patient)

GVHD Prophylaxis

Patients receive tacrolimus and methotrexate to prevent graft-versus-host disease

50 days

Multiple visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Visits at days 28, 56, 90, 180, 270, 365, and months 15, 18, 21, 24

Treatment Details

Interventions

• Allogeneic Bone Marrow Transplantation
• Busulfan
• Cyclophosphamide
• Fludarabine
• Methotrexate
• Naive T Cell-Depleted Hematopoietic Stem Cell Transplantation
• Tacrolimus
• Thiotepa
• Total-Body Irradiation

Trial Overview The study tests if removing naive T-cells from donor cells before transplant can prevent chronic graft-versus-host disease in patients undergoing stem cell transplants for blood cancer treatment.

Participant Groups

Group I: Arm I (chemotherapy, naive T-cell depleted PBSC) Experimental Treatment 12 Interventions

CONDITIONING REGIMEN A: Patients undergo TBI BID on days -10 to -7, then receive thiotepa IV over 3 hours QD on days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2. CONDITIONING REGIMEN B: Patients undergo TBI BID on days -8 to -5, then receive fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on days -3 and -2. CONDITIONING REGIMEN C: Patients receive fludarabine IV over 30 minutes QD on days -6 to -2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID on day -1. TRANSPLANT: Patients receive naive T-cell depleted PBSCs on day 0. GVHD PROPHYLAXIS: All patients receive tacrolimus IV beginning on day -1 and methotrexate IV on days 1, 3, 6, and 11. Additionally, patients undergo ECHO and CSF collection at baseline as well as blood sample collection and bone marrow aspiration with or without biopsy throughout the trial.

Group II: Arm II (chemotherapy, unmanipulated T cell replete BM) Active Control 12 Interventions

CONDITIONING REGIMEN A: Patients undergo TBI BID on days -10 to -7, then receive thiotepa IV over 3 hours QD on days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2. CONDITIONING REGIMEN B: Patients undergo TBI BID on days -8 to -5, then receive fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on days -3 and -2. CONDITIONING REGIMEN C: Patients receive fludarabine IV over 30 minutes QD on days -6 to -2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID on day -1. TRANSPLANT: Patients receive unmanipulated T cell-replete BM on day 0. GVHD PROPHYLAXIS: All patients receive tacrolimus IV beginning on day -1 and methotrexate IV on days 1, 3, 6, and 11. Additionally, patients undergo ECHO and CSF collection at baseline as well as blood sample collection and bone marrow aspiration with or without biopsy throughout the trial.

Allogeneic Bone Marrow Transplantation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Blood cancers
• Leukemia
• Lymphoma
• Myelodysplastic syndromes
• Aplastic anemia

Approved in European Union as Allogeneic Bone Marrow Transplant for:

• Haematological malignancies
• Leukaemia
• Lymphoma
• Myelodysplastic syndromes
• Aplastic anaemia

Approved in Canada as Donor Stem Cell Transplant for:

• Blood cancers
• Leukemia
• Lymphoma
• Myelodysplastic syndromes
• Aplastic anemia

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 359 patients who received bone marrow transplants, a higher dose of CD34+ cells was linked to better platelet engraftment and lymphocyte recovery, indicating its importance in the success of the transplant.

However, the study found no significant relationship between donor cell subsets and overall survival or donor chimerism, suggesting that while graft composition affects certain outcomes, it may not influence long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of bone marrow CD34+cells and T-cell subsets on clinical outcomes after myeloablative allogeneic hematopoietic cell transplantation. Patel, SS., Rybicki, LA., Corrigan, D., et al.[2022]

In a Phase II study involving 85 adults with advanced leukemia, the use of filgrastim-mobilized blood stem cells (SCT) led to faster neutrophil recovery compared to bone marrow transplants (BMT), with recovery occurring on average by day 10 versus day 17.

The prophylactic use of tacrolimus (FK506) significantly reduced the incidence of grades 2-4 graft-versus-host disease (GVHD) compared to cyclosporine (CsA), and SCT recipients using FK506 showed improved survival rates at day 180 post-transplant (84% vs. 53%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus. Przepiorka, D., Ippoliti, C., Khouri, I., et al.[2019]

In a study of 30 patients undergoing matched sibling or alternative donor transplantation with a conditioning regimen of fludarabine, thiotepa, and total body irradiation, most patients achieved prompt engraftment, but there were significant complications, including regimen-related toxicity leading to 18 deaths.

The 12-month progression-free survival rates were 47% for HLA-identical sibling transplants and 30% for all patients, but due to high rates of complications and relapses, the researchers decided to discontinue this conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. van Besien, K., Devine, S., Wickrema, A., et al.[2013]

In a study of 146 adults with acute lymphoblastic leukemia undergoing transplantation, both conditioning regimens (Cyclophosphamide/Total Body Irradiation vs. Fludarabine/Busulfan/Low-dose TBI) showed similar overall and progression-free survival rates, indicating comparable efficacy.

However, the Fludarabine/Busulfan/Low-dose TBI regimen resulted in a significantly lower relapse rate (18.5% vs. 31.5% for Cy/TBI), suggesting it may be a safer option, especially for patients with poorer performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, busulfan, and low-dose TBI conditioning versus cyclophosphamide and TBI in allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. Speziali, C., Daly, A., Abuhaleeqa, M., et al.[2020]

In a study of 119 adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation, the TBI/Cy conditioning regimen resulted in a median overall survival of 11 months, compared to 6.2 months for the Bu/Cy regimen.

Although both conditioning regimens showed no statistically significant differences in overall survival and disease-free survival, the Bu/Cy regimen was associated with a higher risk of relapse, indicating a potential disadvantage in using this non-TBI approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irradiation free conditioning regimen is associated with high relapse rate in Egyptian patients with acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation. Abdelaty, MM., Gawaly, A., Fathy, GM., et al.[2021]

A novel conditioning regimen for allogeneic hematopoietic stem cell transplantation (SCT) in Fanconi anemia patients showed rapid engraftment and stable donor hemopoiesis with minimal short-term toxic complications, indicating its safety and efficacy.

The conditioning regimen, which avoided irradiation and cyclophosphamide, resulted in low organ toxicity and effective immunosuppression, although some patients experienced mild acute graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors. Maschan, AA., Trakhtman, PE., Balashov, DN., et al.[2013]

A new nonmyeloblative stem cell transplantation (NST) protocol was tested on 11 high-risk patients aged 26-58, showing rapid engraftment and full donor chimerism in most cases, despite a high overall mortality rate.

The modified minimally ablative stem cell transplantation (MST) can potentially be used for high-risk patients, but it carries significant risks, including a high incidence of acute graft-versus-host disease (GVHD), with 8 out of 10 evaluable patients experiencing it, and only one patient surviving the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new minimally ablative stem cell transplantation procedure in high-risk patients not eligible for nonmyeloablative allogeneic bone marrow transplantation. Shapira, MY., Or, R., Resnick, IB., et al.[2013]

In a clinical trial involving 16 elderly patients (median age 65) with advanced hematologic malignancies, selectively depleting host-reactive donor T cells from stem cell transplants using an anti-CD25 immunotoxin was shown to be feasible and resulted in sustained engraftment in 15 patients.

The study reported a lower incidence of severe acute graft-versus-host disease (GVHD), with rates of 12% for grades III to IV, suggesting that this method may effectively reduce the risk of severe GVHD while preserving the immune response against leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Solomon, SR., Mielke, S., Savani, BN., et al.[2021]

The new conditioning regimen using thiotepa and fludarabine (TT-FLUDA) was well tolerated in six patients undergoing allogeneic bone marrow transplantation, with successful engraftment and stable donor chimerism in most cases.

Despite the patients being poor candidates for standard treatments, the TT-FLUDA regimen showed no major toxicity, although one patient died from acute graft-versus-host disease (GVHD), indicating a need for careful monitoring of GVHD prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. Alessandrino, EP., Bernasconi, P., Colombo, AA., et al.[2019]

In a study of 31 Japanese patients undergoing reduced intensity allogeneic stem cell transplantation (u-RIST) without total body irradiation (TBI) or T-cell depletion, all patients achieved neutrophil engraftment, indicating effective grafting.

The study reported a manageable incidence of acute graft-versus-host disease (GVHD) at 42%, with 77% of those affected responding well to high-dose steroid treatment, suggesting that this approach may improve outcomes for certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning by fludarabine/busulfan without additional irradiation or T-cell depletion leads to low non-relapse mortality in unrelated bone marrow transplantation. Nakane, T., Nakamae, H., Koh, H., et al.[2021]

In a study of 33 patients with relapsed acute myelogenous leukemia (AML) undergoing matched unrelated donor bone marrow transplant (MUD BMT), selective T-cell depletion (TCD) targeting CD8+ T cells was used, resulting in a 15% rate of graft failure, primarily in patients with HLA-Cw mismatches.

While 67% of patients experienced acute graft-versus-host disease (GVHD), only 19% developed severe forms (grade III-IV), suggesting that selective CD8+ TCD can help manage GVHD while still providing a potentially curative treatment for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens. Kalaycio, M., Rybicki, L., Pohlman, B., et al.[2013]

In a study of 32 patients with acute leukemia and other blood cancers, T lymphocyte depletion achieved a mean of 94%, leading to successful engraftment in all evaluable patients without late graft failure.

Despite the high level of T cell depletion, 88% of patients did not experience significant acute graft-versus-host disease (GVHD), suggesting that complete T cell depletion may not be necessary to prevent this complication in HLA-identical marrow transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful graft-versus-host disease prevention without graft failure in 32 HLA-identical allogeneic bone marrow transplantations with marrow depleted of T cells by monoclonal antibodies and complement. Hervé, P., Cahn, JY., Flesch, M., et al.[2021]

In a study of 30 leukemia patients undergoing T-cell depleted stem cell transplantation, an intensified conditioning regimen using Busulfan, Thiotepa, and Cyclophosphamide showed normal engraftment and moderate regimen-related toxicity, similar to standard protocols.

The overall survival and disease-free survival rates at 60 months were 50%, with only 10% of patients relapsing, suggesting that while the new regimen did not significantly improve outcomes compared to the standard treatment, it remains a viable option for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of thiotepa in allogeneic stem cell transplantation in patients with leukemia. Rosales, F., Naparstek, E., Varadi, G., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Effect of bone marrow CD34+cells and T-cell subsets on clinical outcomes after myeloablative allogeneic hematopoietic cell transplantation. [2022]

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

Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. [2013]

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

Fludarabine, busulfan, and low-dose TBI conditioning versus cyclophosphamide and TBI in allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. [2020]

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

Irradiation free conditioning regimen is associated with high relapse rate in Egyptian patients with acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors. [2013]

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

A new minimally ablative stem cell transplantation procedure in high-risk patients not eligible for nonmyeloablative allogeneic bone marrow transplantation. [2013]

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

Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. [2019]

10. Japan pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning by fludarabine/busulfan without additional irradiation or T-cell depletion leads to low non-relapse mortality in unrelated bone marrow transplantation. [2021]

11. England pubmed.ncbi.nlm.nih.gov

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens. [2013]

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

Successful graft-versus-host disease prevention without graft failure in 32 HLA-identical allogeneic bone marrow transplantations with marrow depleted of T cells by monoclonal antibodies and complement. [2021]

13. England pubmed.ncbi.nlm.nih.gov

The role of thiotepa in allogeneic stem cell transplantation in patients with leukemia. [2022]