Stem Cell Transplant for Leukemia

Overseen By Research Nurse

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Dartmouth-Hitchcock Medical Center

Disqualifiers: Psychiatric disorder, Major organ failure, Refractory infection, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

21 Participants Needed

Trial Summary

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

The trial information does not specify if 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 involving stem cell transplant for leukemia?

Research shows that using fludarabine with total body irradiation (TBI) before stem cell transplants can improve survival rates and reduce relapse in patients with blood cancers compared to TBI alone. Additionally, combining TBI with cyclophosphamide has been associated with a lower risk of cancer returning compared to using fludarabine, suggesting these components can be effective in treating leukemia. ^{1 2 3 4 5}

Is tacrolimus safe for use in humans?

Tacrolimus is commonly used in organ transplants and is generally safe, but it can have toxic side effects, so doctors monitor its levels closely to keep it within a safe range. ^{6 7 8 9 10}

How is the stem cell transplant treatment for leukemia unique?

This treatment combines stem cell transplantation with a mix of drugs and total body irradiation (TBI) to enhance the chances of successful engraftment and reduce the risk of graft rejection or graft-versus-host disease (GVHD). The use of fludarabine and cyclophosphamide, along with TBI, helps in achieving stable engraftment even with mismatched donors, which is a novel approach compared to traditional regimens. ^{2 11 12 13 14}

What is the purpose of this trial?

The standard Johns Hopkins' regimen will be used in study subjects, with the use of donor peripheral blood stem cells, rather than marrow. Clinical outcomes will be defined while focusing efforts on immune reconstitution focusing on immune checkpoint regulators after a related haploidentical stem cell transplant.

Research Team

Kenneth Meehan, MD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Eligibility Criteria

This trial is for people under 75 with certain blood cancers like various leukemias, lymphomas, and myeloma who might benefit from a stem cell transplant. They need to have a related donor that's a partial genetic match (haploidentical), be in decent physical shape without major organ failure or active infections, and not have HIV or hepatitis B/C.

Inclusion Criteria

My major organs are functioning well enough for a transplant.

I have a family member who is a match for my transplant.

I do not have HIV, hepatitis B, or hepatitis C.

Exclusion Criteria

I do not have a major illness or organ failure that would prevent me from surviving a transplant.

I have had infections that didn't respond to treatment.

Psychiatric disorder or mental deficiency affecting compliance and informed consent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants undergo conditioning regimen including cyclophosphamide, fludarabine, total body irradiation, and immune suppression, followed by peripheral blood stem cell transplantation

Approximately 1-2 weeks

Post-Transplant Monitoring

Participants are monitored for engraftment, survival, and immune checkpoint regulator expression. Includes assessment of donor-recipient chimerism and incidence of GVHD

100 days

Regular visits for monitoring at days 30, 60, and 90

Extended Follow-up

Participants are monitored for long-term outcomes including one-year survival and chronic GVHD incidence

Up to 1 year

Exploratory Analysis

Exploratory analysis of immune checkpoint regulators and MDSCs in patients experiencing GVHD

Up to 3 years post-transplant

Treatment Details

Interventions

• cellcept
• Cyclophosphamide
• Fludarabine
• g-csf
• Peripheral Blood Transplant
• Tacrolimus
• Total Body Irradiation

Trial Overview The study tests the standard Johns Hopkins' regimen using donor peripheral blood stem cells instead of marrow for transplants. It aims to observe clinical outcomes and how immune checkpoint regulators behave after the transplant in patients with specific blood disorders.

Participant Groups

Group I: Johns Hopkins' conditioning regimen Experimental Treatment 7 Interventions

Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

Findings from Research

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 involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a study of 85 patients with hematological malignancies, adding fludarabine to a 2-Gy total body irradiation (TBI) regimen before stem cell transplantation resulted in better overall survival (65% vs. 54%) and lower relapse rates compared to TBI alone.

The combination of fludarabine and TBI led to significantly higher levels of donor T cell and NK cell chimerism, indicating improved donor engraftment and a stronger graft-versus-tumor effect, which is crucial for successful transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Kornblit, B., Maloney, DG., Storb, R., et al.[2021]

In a study of 2,255 adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation, conditioning with total body irradiation (TBI) plus cyclophosphamide (Cy) significantly reduced the risk of relapse compared to TBI plus fludarabine (Flu), with a relapse rate of 18% versus 30% at 2 years.

While TBI/Cy was associated with a higher risk of grade 2-4 acute graft-versus-host disease (GVHD), it did not significantly affect other transplantation outcomes, suggesting that TBI/Cy may be a preferable conditioning regimen for patients in complete remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT. Giebel, S., Labopin, M., Socié, G., et al.[2023]

The Waters MassTrak Immunosuppressants assay for measuring tacrolimus levels in whole blood shows good precision and linearity, but it has an average negative bias of 18.5% compared to the Abbott Architect assay, indicating potential discrepancies in results between the two methods.

Both assays are crucial for therapeutic drug monitoring of tacrolimus, which is essential for maintaining organ transplant health, but caution is needed when interpreting results due to their lack of agreement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Waters MassTrak LC-MS/MS Assay for Tacrolimus and a Comparison to the Abbott Architect Immunoassay. Saitman, A., Metushi, IG., Mason, DS., et al.[2017]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

MHC-mismatched stem cells can successfully engraft in leukemia treatment after nonmyeloablative conditioning with fludarabine and low-dose total body irradiation, reducing the risk of graft rejection and graft-versus-host disease (GVHD).

The study demonstrated that pretransplantation fludarabine and posttransplantation cyclophosphamide are crucial for successful engraftment and can enhance donor chimerism while minimizing harmful GVHD reactions, allowing for effective adoptive immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Luznik, L., Jalla, S., Engstrom, LW., et al.[2021]

In a study of 42 patients undergoing allogeneic hematopoietic stem cell transplantation, the combination of busulfan and fludarabine (BuFlu) resulted in significantly lower rates of mucositis compared to the traditional busulfan and cyclophosphamide (BuCy) regimen.

Both BuFlu and BuCy showed similar efficacy in terms of engraftment time, relapse risk, event-free survival, and overall survival, suggesting that BuFlu is a viable alternative to BuCy for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. Lee, JH., Choi, J., Kwon, KA., et al.[2021]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

References

1. 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]

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

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013]

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

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Total body irradiation plus fludarabine versus thiotepa, busulfan plus fludarabine as a myeloablative conditioning for adults with acute lymphoblastic leukemia treated with haploidentical hematopoietic cell transplantation. A study by the Acute Leukemia Working Party of the EBMT. [2022]

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

Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT. [2023]

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

Comparative safety of generic versus brand calcineurin inhibitors in solid organ transplant patients: A systematic review and meta-analysis. [2023]

7. Denmark pubmed.ncbi.nlm.nih.gov

Cyclosporine-induced hemolytic uremic syndrome and hemorrhagic colitis following renal transplantation. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Polyneuropathy due to cyclosporine A in patients with renal transplantation: a case report. [2014]

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

Evaluation of the Waters MassTrak LC-MS/MS Assay for Tacrolimus and a Comparison to the Abbott Architect Immunoassay. [2017]

10. England pubmed.ncbi.nlm.nih.gov

A prospective cohort conversion study of twice-daily to once-daily extended-release tacrolimus: role of ethnicity. [2021]

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

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. [2021]

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

Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. [2021]

13. Korea (South) pubmed.ncbi.nlm.nih.gov

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. [2021]

14. England pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. [2022]