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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment plan, known as a Conditioning Regimen, to help kidney transplant patients accept their new kidney without needing long-term medication to prevent rejection. The research focuses on ensuring the safety of this treatment and preventing a condition called Chimerism Transition Syndrome (CTS), which could lead to the body accepting the transplant more naturally. This trial seeks participants with chronic kidney disease who are on dialysis and receiving their first kidney transplant from a living donor with a different tissue type.

As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative treatment.

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 prior data suggests that this conditioning regimen is safe?

Research has shown that conditioning regimens, the treatments given before a transplant, vary in safety levels. One study found that combining the chemotherapy drugs fludarabine and busulfan led to better survival rates and fewer early complications compared to other treatments, suggesting this regimen might be safe.

Another study found that a reduced-intensity conditioning (RIC) approach, which is gentler on the body, resulted in similar survival rates as more intense treatments, even for older patients. This suggests the treatment may be easier for patients to handle. However, more intense treatments carried a higher risk of long-term issues.

These findings indicate that conditioning regimens can be safe, with some being easier on patients than others. However, since this trial is in an early stage, researchers continue to closely study safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the conditioning regimen for kidney transplants because it aims to improve the integration of donor cells with the recipient's body, potentially reducing the need for long-term immunosuppressive drugs. Unlike standard treatments that primarily focus on suppressing the immune system to prevent rejection, this regimen seeks to create a harmonious coexistence between donor and recipient cells, known as chimerism. This approach could minimize side effects associated with lifelong immunosuppressive therapy and improve transplant outcomes.

What evidence suggests that this conditioning regimen might be an effective treatment for inducing chimerism in kidney transplant patients?

Research shows that certain treatments help the body accept a new kidney after a transplant. Studies have found that these treatments lead to good survival rates and may cause fewer side effects compared to other methods. Evidence suggests these approaches improve overall survival and reduce early complications. This makes them promising options for achieving donor-specific tolerance in kidney transplants without ongoing medication. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

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.

Use of FDA-approved methods of contraception

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4201264/

Comparison of Reduced-Intensity and Myeloablative ... RIC-HCT resulted in comparable <2-year and 2–6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more ...

2. nature.com nature.com/articles/s41409-024-02378-0

Comparing transplant outcomes in ALL patients after ... Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL.

3. astctjournal.org astctjournal.org/article/S1083-8791(16)00143-9/fulltext

Outcome after Transplantation According to Reduced ... Both regimens are reportedly as effective as and less toxic than myeloablative conditioning regimens. Previous studies have compared FB and FM conditioning ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S108387911830569X

The Dilemma of Conditioning Intensity Myeloablative conditioning results in better relapse rates and disease-free survival compared with reduced-intensity conditioning among patients with AML and ...

5. haematologica.org haematologica.org/article/view/haematol.2022.281958

Association between the choice of the conditioning ... Our study demonstrates that fludarabine/busulfan-based conditioning is associated with superior overall survival, lower early non-relapse ...

6. astctjournal.org astctjournal.org/article/S2666-6367(21)00718-1/fulltext

Myeloablative versus Reduced-Intensity Conditioning for ... Our data show that patients who received MAC were at higher risk of late TRM compared with those who received RIC; however, because of the exceedingly high ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0268960X24000560

Current challenges in conditioning regimens for MDS ... We summarized these retrospective and prospective studies and evaluated the limitations of the available evidence to delineate the ideal conditioning regimen.