Conditioning Regimen for Chimerism in Kidney Transplant

Overseen By Tatsuo Kawai, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Must not be taking: Immunosuppressants, Antivirals

Disqualifiers: HIV, Hepatitis, Cancer, others

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

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it is important to discuss your current medications with the trial team to ensure they do not interfere with the study.

What data supports the effectiveness of the treatment Conditioning Regimen for Chimerism in Kidney Transplant?

Research on conditioning regimens, particularly nonmyeloablative and reduced-intensity types, shows they can be effective in reducing toxicities and improving outcomes in transplants by relying on the body's immune response to fight disease. These regimens have been used successfully in other types of transplants, like stem cell transplants, to reduce complications and improve patient survival. ^{1 2 3 4 5}

Is the conditioning regimen for kidney transplant generally safe for humans?

The conditioning regimens, including those using mycophenolate mofetil (MMF) and sirolimus, have been shown to be safe in kidney transplant patients, with efforts to reduce toxicities associated with other drugs like calcineurin inhibitors. Studies indicate that these regimens can maintain good kidney function and have a similar safety profile over the long term. ^{5 6 7 8 9}

How is the Conditioning Regimen treatment for kidney transplant different from other treatments?

The Conditioning Regimen for kidney transplant is unique because it uses a reduced-intensity approach, which means it involves lower doses of radiation and chemotherapy to prepare the body for the transplant. This makes the treatment safer and more suitable for older patients or those with other health issues, as it reduces the risk of severe side effects compared to traditional high-dose regimens. ^{1 10 11 12 13}

What is the purpose of this trial?

The goal is to investigate the safety of the conditioning regimen, and its ability to induce donor/recipient lymphohematopoietic chimerism without Chimerism Transition Syndrome (CTS), which may result in donor-specific unresponsiveness (tolerance) to the renal allograft in the absence of maintenance immunosuppression.

Eligibility Criteria

This trial is for adults aged 18-60 with chronic kidney disease or end-stage renal disease on dialysis, awaiting their first kidney transplant from a living donor. They must have been exposed to EBV, not be pregnant or breastfeeding, and use approved contraception. Exclusions include poorly controlled diabetes, severe organ dysfunction, certain infections (HIV/Hepatitis), recent cancer history except specific skin/cervical cancers, and allergies to trial drugs.

Inclusion Criteria

I am eligible for a kidney transplant from a donor who doesn't fully match my tissue type.

You need to test negative for COVID-19 before the screening and also 2 days before the procedure.

This is my first time receiving a transplant.

Exclusion Criteria

My kidney disease, like FSGS, has a high risk of returning after a transplant.

I have had cancer before, but it was not skin cancer or early-stage cervical cancer.

Your liver or blood clotting test results are more than twice the normal range.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Participants undergo a conditioning regimen to induce donor/recipient lymphohematopoietic chimerism

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on the absence of Chimerism Transition Syndrome and maintenance immunosuppression

12 months

Treatment Details

Interventions

• Conditioning Regimen

Trial Overview The study tests a conditioning regimen aiming to create mixed chimerism—a state where both donor and recipient cells coexist—without causing Chimerism Transition Syndrome. Success could lead to tolerance of the new kidney without long-term immunosuppression.

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

Nonmyeloablative conditioning regimens for allogeneic transplantation provide effective cytoreduction while significantly reducing toxicity and transplant-related mortality, making them safer for older patients.

These novel regimens not only support donor cell engraftment but also promote a beneficial graft-versus-malignancy effect against various cancers, including myeloid and lymphoid malignancies, as well as metastatic renal cell cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conditioning regimens for allogeneic stem cell transplants. Barrett, AJ.[2019]

Nonmyeloablative and reduced-intensity conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) have shown promise in treating patients with hematologic malignancies who are not suitable for conventional HCT due to age or health issues, focusing on the graft-versus-tumor effect rather than heavy chemotherapy.

While these regimens have led to reduced toxicities and have been curative for some patients, challenges such as graft-versus-host disease, infections, and disease progression still pose significant risks, as highlighted in various phase I and II studies reviewed in the article.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current roles for allogeneic hematopoietic cell transplantation following nonmyeloablative or reduced-intensity conditioning. Baron, F., Storb, R.[2021]

Nonmyeloablative conditioning regimens for allogeneic stem cell transplantation may reduce the risk of bacterial infections linked to mucosal damage and prolonged neutropenia, compared to traditional myeloablative regimens.

Despite the benefits, patients undergoing nonmyeloablative transplantation still face risks of late viral and fungal infections, especially during severe graft versus host disease, indicating a need for ongoing research into infection prevention strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infectious risks and outcomes after stem cell transplantation: are nonmyeloablative transplants changing the picture? Junghanss, C., Marr, KA.[2021]

A minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies showed lasting remissions in 45% to 75% of patients, with a 5-year survival rate ranging from 25% to 60%, indicating its efficacy for those unable to tolerate high-intensity treatments.

The study found that while graft-versus-tumor (GVT) effects were comparable between related and unrelated donor grafts, chronic graft-versus-host disease (GVHD) increased GVT effects but also led to higher nonrelapse mortality, suggesting a need for better GVHD management to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. Storb, R., Gyurkocza, B., Storer, BE., et al.[2023]

Mycophenolate mofetil (MMF) is a highly effective immunosuppressant that helps preserve long-term kidney function in transplant patients while avoiding the nephrotoxicity associated with calcineurin inhibitors (CNIs) and steroids.

Toxicity-sparing regimens that include MMF are showing promise in reducing the side effects linked to long-term use of CNIs and steroids, suggesting a safer approach for maintaining kidney transplant health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity-sparing protocols using mycophenolate mofetil in renal transplantation. Land, W., Vincenti, F.[2022]

In a study of 26 liver transplant patients who experienced nephrotoxicity from calcineurin inhibitors, switching to Sirolimus (SRL) led to significant improvements in kidney function over a mean follow-up of 27.5 months.

While SRL can cause side effects like hypertriglyceridemia and hypercholesterolemia, it is nonnephrotoxic and can also improve glucose tolerance, making it a beneficial alternative for patients with renal dysfunction post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus monotherapy effectiveness in liver transplant recipients with renal dysfunction due to calcineurin inhibitors. Di Benedetto, F., Di Sandro, S., De Ruvo, N., et al.[2014]

In a study of 221 allogeneic hematopoietic cell transplantation (HCT) recipients, the incidence of chronic kidney disease (CKD) was found to be similar between those who underwent myeloablative (MA) conditioning (28%) and those who received reduced-intensity conditioning (RIC) (29%) over a median follow-up of 28 months for MA and 25 months for RIC.

Factors such as older age, acute graft-versus-host disease, prolonged use of cyclosporine, and early acute kidney injury were identified as independent risk factors for developing CKD, highlighting the need for ongoing renal function monitoring in all HCT survivors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar risks for chronic kidney disease in long-term survivors of myeloablative and reduced-intensity allogeneic hematopoietic cell transplantation. Al-Hazzouri, A., Cao, Q., Burns, LJ., et al.[2013]

In a study of 132 live-donor renal transplant recipients over approximately 5 years, a calcineurin inhibitor (CNI)-free regimen using sirolimus and mycophenolate mofetil (MMF) showed similar patient and graft survival rates compared to a regimen including low-dose tacrolimus.

The MMF/sirolimus group demonstrated significantly better renal function and a lower need for changes in immunosuppression compared to the tacrolimus/sirolimus group, indicating that the CNI-free approach may be more beneficial for long-term kidney health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients. Hamdy, AF., Bakr, MA., Ghoneim, MA.[2021]

Transitioning kidney transplant recipients from tacrolimus to sirolimus did not result in a significant difference in renal function improvement after 24 months, with 34% of sirolimus patients and 42% of tacrolimus patients showing improvement.

However, patients on sirolimus experienced higher rates of acute rejection and treatment discontinuation due to adverse events, while they had lower rates of skin squamous cell carcinoma, indicating a complex risk-benefit profile for sirolimus compared to tacrolimus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients. Tedesco-Silva, H., Peddi, VR., Sánchez-Fructuoso, A., et al.[2020]

Reduced-intensity conditioning regimens for stem cell allografting have shown promising results in decreasing morbidity and mortality compared to conventional myeloablative therapies, making them a viable option for patients with hematologic neoplasias and genetic diseases who are ineligible for standard treatments.

The Flu-Cy protocol, which combines high-dose therapy with low-intensity conditioning and donor mobilized stem cell infusion, has demonstrated feasibility in initial studies, particularly in transplants from HLA-identical siblings, suggesting a potential pathway for safer transplant options in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low intensity regimens with allogeneic hematopoietic stem cell transplantation as treatment of hematologic neoplasia. Carella, AM., Giralt, S., Slavin, S.[2013]

A survey of 56 hematopoietic cell transplantation (HCT) professionals revealed that 67% agree on key criteria for defining reduced-intensity conditioning (RIC) regimens, emphasizing reversible myelosuppression and low nonhematologic toxicity.

While there is general acceptance of certain definitions for RIC, only 32% of participants considered the BEAM regimen as RIC, indicating a lack of consensus in the transplant community regarding specific conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Giralt, S., Ballen, K., Rizzo, D., et al.[2022]

The shift from high-dose chemoradiotherapy to reduced-intensity and nonmyeloablative conditioning regimens in hematopoietic cell transplantation (HCT) has expanded the pool of eligible patients, allowing more individuals to benefit from these treatments.

This review highlights the importance of balancing effective treatment with safety, as lower doses can still harness the beneficial graft-versus-tumor effects while reducing the toxicities associated with traditional high-dose regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Gyurkocza, B., Sandmaier, BM.[2022]

Reduced-intensity and nonmyeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) allow for effective treatment of older patients and those with comorbid conditions, minimizing toxicity compared to traditional myeloablative regimens.

These regimens successfully prevent host-versus-graft rejection and promote anti-tumor effects, making them a promising option for patients with hematologic malignancies or inherited blood disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning as treatment for hematologic malignancies and inherited blood disorders. Baron, F., Storb, R.[2021]

References

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

Conditioning regimens for allogeneic stem cell transplants. [2019]

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

Current roles for allogeneic hematopoietic cell transplantation following nonmyeloablative or reduced-intensity conditioning. [2021]

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

Infectious risks and outcomes after stem cell transplantation: are nonmyeloablative transplants changing the picture? [2021]

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

Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. [2023]

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

Toxicity-sparing protocols using mycophenolate mofetil in renal transplantation. [2022]

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

Sirolimus monotherapy effectiveness in liver transplant recipients with renal dysfunction due to calcineurin inhibitors. [2014]

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

Similar risks for chronic kidney disease in long-term survivors of myeloablative and reduced-intensity allogeneic hematopoietic cell transplantation. [2013]

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

Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients. [2021]

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

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients. [2020]

10. Italy pubmed.ncbi.nlm.nih.gov

Low intensity regimens with allogeneic hematopoietic stem cell transplantation as treatment of hematologic neoplasia. [2013]

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

Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. [2022]

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

Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. [2022]

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

Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning as treatment for hematologic malignancies and inherited blood disorders. [2021]