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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating leukemia and similar blood-related conditions using stem cells from a donor's blood instead of bone marrow. The researchers aim to determine how effectively this approach rebuilds the immune system, focusing on specific immune signals that control inflammation and infection responses. Participants should have a condition such as acute or chronic leukemia, myelodysplasia, or lymphoma, and need a compatible family member willing to donate stem cells. The trial seeks to improve outcomes for patients who could benefit from a stem cell transplant. As a Phase 3 trial, this treatment is in the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatment used in the Johns Hopkins plan is generally safe for patients. Some studies have found that using cyclophosphamide and tacrolimus together can help prevent graft-versus-host disease (GVHD), a common issue after stem cell transplants. This combination has been linked to longer periods without disease recurrence compared to other methods.

Patients who received cyclophosphamide after their transplant did not experience worse outcomes in terms of progression-free survival or overall survival. The regimen also includes fludarabine and total body irradiation (TBI), which are standard treatments in stem cell transplants and are usually well-tolerated by most patients.

Overall, these treatment components have been used safely in other studies, but like any medical treatment, there may be some risks. Patients should consult their doctor to learn more about these potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this stem cell transplant regimen for leukemia because it combines several innovative approaches that could enhance patient outcomes. Unlike standard treatments, which often rely on chemotherapy alone, this regimen uses a combination of cyclophosphamide, fludarabine, and total body irradiation to more effectively prepare the body for transplant. Additionally, it incorporates immune suppression with tacrolimus and cellcept, aiming to reduce transplant-related complications. The use of peripheral blood transplant along with granulocyte colony-stimulating factor (G-CSF) is designed to speed up recovery and improve the chances of successful engraftment. This comprehensive approach offers the potential to improve survival rates and quality of life for leukemia patients.

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

Research has shown that the Johns Hopkins treatment plan, a treatment arm in this trial, includes cyclophosphamide, fludarabine, and total body irradiation (TBI), and is effective for leukemia patients receiving stem cell transplants. Studies have found that using cyclophosphamide after the transplant (PTCy) does not harm the transplant's success and can improve survival rates without causing severe graft-versus-host disease, where new cells attack the patient's body. Another study found that combining PTCy with a drug like tacrolimus, also part of this trial's regimen, can help prevent this disease. Overall, the treatment plan aims to help the new cells grow successfully and reduce the chance of cancer returning. Researchers are also exploring the use of stem cells from the bloodstream instead of bone marrow for potentially better immune recovery. ^{1 2 3 5 6}

Who Is on the Research Team?

Kenneth Meehan, MD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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 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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT07214688

Fludarabine and Intermediate-dose TBI Followed by PTCy ... The Flu-TBI 800 trial is a prospective, single-arm, multicenter, interventional phase 2 study to evaluate whether fludarabine plus intermediate-dose total ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06859424

Study Details | NCT06859424 | A Platform Protocol to ... The purpose of this clinical trial is to compare drug combinations to learn which drugs work best to prevent graft-versus-host-disease (GVHD) in people who ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10558021/

Post-Transplant Cyclophosphamide for the Prevention of ... Some studies, mostly retrospective, support that the incorporation of PTCy does not compromise engraftment or lead to worsened progression-free or overall ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10555825/

Haploidentical transplant with posttransplant ... We compare the outcome of haploHCT (n = 40) with ptCY with HCT from HLA-identical MRD (n = 105) and MUD (n = 68).

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2503189

Graft-versus-Host Disease Prophylaxis with ... The combination of post-transplantation cyclophosphamide and a calcineurin inhibitor led to longer GVHD-free, relapse-free survival than standard prophylaxis.

6. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723017116

Post-Transplantation Cyclophosphamide and Tacrolimus ... This study compared the efficacy of graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy) and tacrolimus (Tac) versus ...