Bone Marrow Transplant for Kidney Failure

Overseen By Gabriel Impreso Baysa

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Massachusetts General Hospital

Must not be taking: Anticoagulants

Disqualifiers: Cancer, HIV, Hepatitis, Autoimmune, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This study will examine the safety and effectiveness of a bone marrow transplant after kidney transplant (from either a living or deceased donor). An investigational medication and other treatments will be given prior to and after the transplant to help protect the transplanted kidney from being attacked by the body's immune system

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.

What data supports the effectiveness of the treatment Bone Marrow Transplant for Kidney Failure?

The research mentions that Rituximab, a component of the treatment, may be beneficial in certain kidney transplant scenarios, such as treating recurrent membranous nephropathy and recurrent allograft vasculitis, and it appears to help decrease antibody levels in sensitized recipients, potentially increasing the odds of transplantation. ^{1 2 3 4 5}

Is bone marrow transplant generally safe for humans?

Bone marrow transplants, including those using fludarabine and cyclophosphamide, have been performed safely in humans, with some patients experiencing mild to moderate side effects like graft-versus-host disease (GVHD), which can affect the skin and gut. However, these procedures are generally associated with low organ toxicity and effective immune suppression, making them a viable option for treating certain conditions. ^{6 7 8 9 10}

How is the bone marrow transplant treatment for kidney failure different from other treatments?

This treatment is unique because it uses a bone marrow transplant, which is not a standard approach for kidney failure, and combines it with specific drugs like cyclophosphamide, fludarabine, rituximab, and siplizumab to potentially improve outcomes by targeting the immune system differently than traditional kidney transplant immunosuppressive drugs. ^{1 2 5 11 12}

Research Team

Tatsuo Kawai, MD, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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.

The donor is between 18 to 70 years old, has consented to donate vertebral bones, has successfully preserved and saved a certain number of cells needed for the recipient, and has acceptable laboratory test results and negative tests for certain viruses and COVID-19.

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.

Trial Timeline

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

Treatment Details

Interventions

• Bone Marrow Transplant (Procedure)
• Cyclophosphamide (Alkylating agents)
• Fludarabine (Anti-metabolites)
• Peripheral Blood Stem Cell Collection (Procedure)
• Rituximab (Monoclonal Antibodies)
• Siplizumab (Monoclonal Antibodies)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

References

1. United States 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. [2022]

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

Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. [2022]

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

Anti-CD20 Blocker Rituximab in Kidney Transplantation. [2022]

4. Italy pubmed.ncbi.nlm.nih.gov

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

5. Japan pubmed.ncbi.nlm.nih.gov

[Renal transplantation]. [2014]

6. England pubmed.ncbi.nlm.nih.gov

Cyclosporin A associated nephrotoxicity in the first 100 days after allogeneic bone marrow transplantation: three distinct syndromes. [2019]

7. Australia 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. [2023]

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

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

9. England 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. [2013]

10. United States 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. [2021]

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

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

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

Alemtuzumab induction and prednisone-free maintenance immunotherapy in kidney transplantation: comparison with basiliximab induction--long-term results. [2023]