Bone Marrow Transplant for Kidney Failure

Overseen By Gabriel Impreso Baysa

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Massachusetts General Hospital

Must not be taking: Anticoagulants

Disqualifiers: Cancer, HIV, Hepatitis, Autoimmune, 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 explores the safety and effectiveness of adding a bone marrow transplant to a kidney transplant. The goal is to determine if this approach can protect the new kidney from the body's immune system. Participants will receive an allogeneic bone marrow transplant along with several medications to support the new kidney. The trial seeks kidney transplant recipients with good kidney function and no history of rejection. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

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?

A previous study linked bone marrow transplants to certain risks, particularly concerning kidney health. People undergoing these transplants might experience kidney damage over time. However, the benefits of the transplant often justify considering these risks.

Research has shown that cyclophosphamide is generally safe. It is often used to treat various conditions and has shown positive results in kidney treatments. Some side effects can occur, but they are usually manageable.

Studies have found that fludarabine can cause kidney problems in some cases, including rare instances of acute kidney failure. Therefore, doctors must closely monitor kidney health when using this drug.

Rituximab is usually well-tolerated, with many patients maintaining good kidney function while taking it. However, rare cases of severe kidney issues necessitate careful monitoring.

Research on siplizumab indicates it has a good safety profile. Most side effects are mild to moderate, with no significant increase in infections reported.

Overall, this combination of treatments has been used successfully, but monitoring and managing potential side effects is important for participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for kidney failure focus on managing symptoms and slowing disease progression, often involving dialysis or a kidney transplant. However, researchers are excited about the use of bone marrow transplants as a potential game-changer. Unlike traditional treatments, this approach aims to introduce healthy stem cells that can improve kidney function and potentially reduce the need for long-term immunosuppressive drugs. This treatment utilizes a combination of medications like cyclophosphamide, fludarabine, rituximab, and siplizumab to prepare and support the body in accepting the new cells. This innovative method could revolutionize how kidney failure is treated by targeting the underlying issues rather than just the symptoms.

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

This trial will examine the effects of combining a bone marrow transplant with a kidney transplant to help the body accept the new kidney more easily. Participants may receive medications like cyclophosphamide and fludarabine to prepare for these transplants, as studies have shown these drugs support kidney function. Rituximab, another treatment option in this trial, helps improve the survival rates of the transplanted kidney. Siplizumab is also under study for its potential to enhance kidney acceptance. Together, these treatments aim to protect the transplanted kidney and improve its long-term function. ^{1 2 3 6 7}

Who Is on the Research Team?

Tatsuo Kawai, MD, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults aged 18-65 with kidney failure who've had a transplant and show good renal function, without rejection history or severe health issues. Must have prior EBV exposure, use reliable contraception, and test negative for COVID-19. Living donors must be healthy and meet criteria for stem cell donation; deceased donors' families must consent to bone marrow donation.

Inclusion Criteria

If you're donating stem cells, you must be in good health, not pregnant, and have normal lab test results. You also need to be free of certain infections and have normal heart and lung function.

I will use highly effective birth control starting from treatment until 24 months after my kidney transplant.

You have previously been exposed to the Epstein-Barr virus.

Exclusion Criteria

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

Your lung function test results show that your breathing capacity is less than half of what is expected for someone your age and size.

I have tested positive for HIV, hepatitis B, or hepatitis C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants receive a conditioning regimen including rituximab, fludarabine, cyclophosphamide, thymic irradiation, and Siplizumab, followed by donor hematopoietic stem cell infusion

7 days

Post-Transplant Treatment

Participants receive methylprednisolone and prophylaxis for infections, with blood transfusions restricted to leukocyte-depleted and irradiated products

20 days

Follow-up

Participants are monitored for safety and effectiveness, including renal allograft biopsy at 6 months and potential immunosuppression withdrawal by 9-12 months

12 months

Long-term Follow-up

Participants are monitored for incidence of allograft rejection and infections for 2 years after immunosuppression withdrawal

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Bone Marrow Transplant
• Cyclophosphamide
• Fludarabine
• Peripheral Blood Stem Cell Collection
• Rituximab
• Siplizumab

Trial Overview

The trial tests the safety and effectiveness of a bone marrow transplant following a kidney transplant using additional treatments including an investigational drug to prevent immune attack on the new kidney.

How Is the Trial Designed?

Group I: Kidney and Stem Cell Recipients Experimental Treatment 5 Interventions

Months-Years after standard transplant, patients will undergo bone marrow transplant (either from prospective collection of stem cells from their living donor, or from bone marrow collected at the time of deceased donation)

Group II: Kidney and Stem Cell Donors Experimental Treatment 1 Intervention

PBSC will be collected from the LD via leukapheresis 1-4 weeks before the scheduled HSCT. The donor will first undergo standard GCSF mobilization: GCSF (can be TBO-GCSF) dosed at 10 mcg/kg/d (rounded to nearest pre-filled syringe) administered subcutaneously daily for 5 consecutive days. On the 5th day, the donor will undergo standard large volume leukapheresis. The target yield will be 2-3 x 106 CD34+ cells / kg of actual recipient body weight. A maximum of 3 days of pheresis will be allowed. A minimum of 2 x 106 CD34+ cells / kg of actual recipient body weight will be required to proceed

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

Approved in European Union as Allogeneic Bone Marrow Transplant for:

• Acute Leukemias
• Chronic Leukemias
• Lymphomas
• Multiple Myeloma
• Myelodysplastic Syndromes
• Aplastic Anemia

Approved in United States as Allogeneic Bone Marrow Transplant for:

• Acute Leukemias
• Chronic Leukemias
• Lymphomas
• Multiple Myeloma
• Myelodysplastic Syndromes
• Aplastic Anemia

Approved in Canada as Allogeneic Bone Marrow Transplant for:

• Acute Leukemias
• Chronic Leukemias
• Lymphomas
• Multiple Myeloma
• Myelodysplastic Syndromes
• Aplastic Anemia

Approved in Japan as Allogeneic Bone Marrow Transplant for:

• Acute Leukemias
• Chronic Leukemias
• Lymphomas
• Multiple Myeloma
• Myelodysplastic Syndromes
• Aplastic Anemia

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

ITB-Med LLC

Industry Sponsor

Trials

12

Recruited

390+

Ossium Health, Inc.

Industry Sponsor

Trials

11

Recruited

200+

Published Research Related to This Trial

In a study of 196 patients who underwent allogeneic hematopoietic cell transplant, dose alterations of methotrexate (MTX) and cyclosporin (CYA) for graft-versus-host disease (GVHD) prophylaxis were linked to worse overall survival (OS) and higher non-relapse mortality (NRM). Specifically, MTX dose alterations were associated with a 2.4 times higher risk of inferior OS and a 4.6 times higher risk of NRM.

While dose alterations of MTX and CYA did not significantly affect GVHD rates, they highlight the importance of careful monitoring and management of these medications to improve patient outcomes post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors and outcomes of dose reduction of methotrexate and cyclosporin graft-versus-host disease prophylaxis following allogeneic haemopoietic cell transplantation. Ramanan, R., Lim, ABM., Tan, JLC., et al.[2023]

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 223 kidney transplant recipients followed for 2 years, the combination of tacrolimus and mycophenolate mofetil (MMF) showed the best kidney function and overall outcomes compared to other regimens.

Patients treated with tacrolimus+MMF had a 23% increase in allograft survival in cases of delayed graft function compared to those on cyclosporine+MMF, highlighting the potential benefits of this combination for specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years. Ahsan, N., Johnson, C., Gonwa, T., et al.[2022]

Rituximab is effective for treating CD20+ posttransplant lymphoproliferative disorder and may help with recurrent membranous nephropathy and certain types of vasculitis in kidney transplant recipients, but evidence is limited due to small sample sizes and short follow-up periods.

The combination of Rituximab with IVIg/plasmapheresis can lower antibody levels and improve transplantation success in sensitized recipients, although its role in ABO-incompatible transplants and efficacy in antibody-mediated rejection remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD20 Blocker Rituximab in Kidney Transplantation. Sood, P., Hariharan, S.[2022]

Recent advancements in immunosuppressive therapies, including the use of tacrolimus and mycophenolate salts, have significantly improved patient and graft survival rates in kidney transplantation, reducing acute rejection episodes to less than 10%.

While these newer agents have decreased the incidence of infections compared to older protocols, there remains a concern about adverse effects from prolonged immunosuppression, such as cardiovascular disease and malignancies, highlighting the need for further research on optimal drug combinations and dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Present and future of immunosuppressive therapy in kidney transplantation. Ponticelli, C.[2011]

In a study of 278 kidney transplant recipients, alemtuzumab induction therapy resulted in a lower early rejection rate (4.1%) compared to basiliximab (11.6%), although rejection rates were similar at one year.

Overall, both alemtuzumab and basiliximab showed comparable long-term patient and graft survival rates, indicating that alemtuzumab is as effective as basiliximab in a prednisone-free maintenance immunosuppressive protocol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab induction and prednisone-free maintenance immunotherapy in kidney transplantation: comparison with basiliximab induction--long-term results. Kaufman, DB., Leventhal, JR., Axelrod, D., et al.[2023]

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]

Nephrologists need to enhance their understanding of both established and newer immunosuppressive drugs for kidney transplant patients, as these medications are crucial for patient management and improving clinical outcomes.

Recent advancements in immunosuppressive therapy, including drugs like rapamycin and monoclonal antibodies, offer new options alongside traditional calcineurin inhibitors, highlighting the importance of a comprehensive knowledge of all available treatments to tailor effective regimens for kidney transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New immunodepressant drugs for the prevention and control of kidney transplant rejection]. Segoloni, GP.[2018]

Recent immunosuppressive drugs like mycophenolate mofetil and basiliximab, along with calcineurin inhibitors, have significantly decreased the rates of acute rejection in kidney transplants.

Newly developed agents such as CTLA4-Ig, LEA29Y, rituximab, and FTY720 are being introduced, and there are evolving protocols that allow for the withdrawal of steroids or calcineurin inhibitors, enhancing the safety and efficacy of kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Renal transplantation]. Hattori, R., Ono, Y., Oshima, S.[2014]

In a study of 56 patients with bone marrow failure syndromes, fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell transplantation successfully prevented graft-failure, achieving sustained donor engraftment despite a high rate of pretransplant HLA-alloimmunization (41%).

While the approach was effective, it was associated with a significant incidence of chronic graft-versus-host disease (GVHD) at 72%, particularly in patients with rapid donor T-cell engraftment, indicating a trade-off between successful engraftment and increased GVHD risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes. Pantin, J., Tian, X., Shah, AA., et al.[2021]

In a study of 36 patients undergoing bone marrow transplants for severe aplastic anemia or acute leukemia, those receiving methotrexate (MTX) experienced significantly less renal dysfunction compared to those treated with cyclosporin A (CyA).

CyA recipients exhibited various nephrotoxic effects, including asymptomatic azotaemia and acute renal failure due to infections, highlighting the potential risks associated with CyA in post-transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclosporin A associated nephrotoxicity in the first 100 days after allogeneic bone marrow transplantation: three distinct syndromes. Atkinson, K., Biggs, JC., Hayes, J., et al.[2019]

Tacrolimus significantly improves graft survival and reduces the risk of acute rejection in kidney transplant recipients compared to cyclosporin, with a relative risk of graft loss at six months being 0.56 based on data from 4102 patients across 30 trials.

While tacrolimus is more effective, it is associated with a higher risk of developing insulin-requiring diabetes and other side effects like tremors and gastrointestinal issues, indicating a trade-off between efficacy and safety in post-transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Webster, A., Woodroffe, RC., Taylor, RS., et al.[2022]

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