RIC + BMT for Non-Malignant Disorders

Recruiting at 2 trial locations

Overseen By Shalini Shenoy, M.D.

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Disqualifiers: HLA-identical sibling donor, Cirrhosis, Uncontrolled infection, HIV, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 90

29 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is designed to estimate the efficacy and toxicity of familial HLA mismatched bone marrow transplants in patients with non-malignant disease who are less than 21 years of age and could benefit from the procedure.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have received an investigational drug or device within 3 months of enrollment, you may not be eligible to participate.

What data supports the effectiveness of the treatment RIC + BMT for Non-Malignant Disorders?

Research shows that reduced-intensity conditioning (RIC) is effective in making stem cell transplants safer for older or less healthy patients by lowering treatment-related deaths. This approach has been successful in treating blood cancers, suggesting it might also be beneficial for non-malignant disorders. ^{1 2 3 4 5}

Is the reduced-intensity conditioning (RIC) regimen generally safe for humans?

Reduced-intensity conditioning (RIC) regimens are designed to be less harsh than traditional high-dose treatments, aiming to reduce side effects and complications. They are generally considered to have lower toxicity and are safer for patients who cannot tolerate more intense treatments, although they still carry some risks. ^{1 4 5 6 7}

How is the RIC + BMT treatment different from other treatments for non-malignant disorders?

The RIC (Reduced-Intensity Conditioning) regimen is unique because it uses lower doses of chemotherapy and radiation to prepare the body for a bone marrow transplant, reducing the risk of severe side effects. This makes it suitable for older patients or those with other health issues who might not tolerate more intense treatments. ^{1 2 3 4 8}

Research Team

Shalini Shenoy, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for young people (up to age 20.99) with non-malignant disorders like sickle cell disease, bone marrow failure, or metabolic diseases. They must have specific health criteria met such as normal kidney function and no severe liver issues. Participants need a performance score of at least 50 and agree to contraception methods post-transplant.

Inclusion Criteria

My kidney function is within the normal range.

I have had multiple severe episodes of acute chest syndrome.

Written informed consent must be obtained from all recipients in accordance with the guidelines of the institution's Human Studies Committee.

Exclusion Criteria

I have an active autoimmune disease like lupus.

I have a sibling who matches my bone marrow and is willing to donate.

I haven't used any experimental drugs or devices in the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Reduced Intensity Conditioning

Participants receive a reduced intensity conditioning regimen consisting of hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan

3 weeks

Bone Marrow Transplantation

Participants undergo familial HLA-mismatched bone marrow transplantation

1 week

Follow-up

Participants are monitored for safety and effectiveness after transplantation, including donor cell engraftment and organ function

2 years

Multiple visits at 90 days, 180 days, 1 year, and 2 years post-transplant

Treatment Details

Interventions

• GVHD prophylaxis regimen
• RIC regimen

Trial Overview The study tests the effectiveness and safety of familial HLA mismatched bone marrow transplants in patients under 21 with non-cancerous diseases. It includes a reduced intensity conditioning (RIC) regimen before transplant and graft-versus-host disease (GVHD) prevention afterwards.

Participant Groups

Group I: RIC Prep Regimen & GVHD Prophylaxis Experimental Treatment 2 Interventions

Single arm study. All patients receive the same Reduced Intensity Conditioning (RIC) regimen and GVHD prophylaxis regimen

RIC regimen is already approved in European Union, United States for the following indications:

Approved in European Union as Reduced-Intensity Conditioning for:

• Bone Marrow Failure Syndromes
• Myelodysplastic Syndrome
• Acute and Chronic Myeloid Leukemias
• Metabolic Disorders

Approved in United States as Reduced-Intensity Conditioning for:

• Immune Deficiencies
• Pre-Leukemia Syndromes
• Acute Myeloid Leukemia
• Chronic Myeloid Leukemia
• Metabolic Disorders

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Findings from Research

Nonmyeloablative (NM) conditioning resulted in a higher rate of graft failure (25%) compared to reduced-intensity conditioning (RIC) (3%), indicating that RIC may be a safer option for patients undergoing allogeneic hematopoietic stem-cell transplantation.

While NM conditioning led to fewer transfusions and less leukopenia, it was associated with significantly higher rates of acute graft-versus-host disease (GVHD) (59% vs. 12%) and transplant-related mortality (TRM) (42% vs. 20%) compared to RIC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of nonmyeloablative and reduced-intensity conditioning for allogeneic stem-cell transplantation. Le Blanc, K., Remberger, M., Uzunel, M., et al.[2021]

Reduced-intensity conditioning (RIC) transplants allow for effective allogeneic hematopoietic stem cell transplantation with less intense chemotherapy and radiotherapy, reducing treatment-related mortality and making the procedure accessible to older patients and those with co-morbidities.

The evolution of RIC transplants has broadened the patient population eligible for this therapy, indicating that age alone should not determine whether a patient is referred for allogeneic transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Alousi, A., de Lima, M.[2007]

Reduced intensity conditioning (RIC) regimens are associated with lower transplant-related mortality but a higher risk of disease relapse compared to standard myeloablative conditioning (MAC) regimens, based on large retrospective studies.

For adult patients with acute leukemia in remission and myelodysplastic syndrome, RIC regimens provide similar disease-free and overall survival rates as MAC, supporting their use in this population until more definitive data from prospective trials are available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity versus myeloablative allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, myelodysplastic syndrome and acute lymphoid leukemia. Horwitz, ME.[2011]

In a study of 401 patients with acute myeloblastic leukemia (AML) receiving reduced intensity conditioning (RIC) before unrelated donor transplants, younger patients experienced higher relapse rates compared to those receiving myeloablative conditioning (MAC), indicating a need for improved relapse prevention strategies in this age group.

For patients aged 50 and older, RIC resulted in lower non-relapse mortality compared to MAC, suggesting that RIC can be a safer option for older patients undergoing stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. Ringdén, O., Labopin, M., Ehninger, G., et al.[2009]

In a study of 93 patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), reduced-intensity conditioning (RIC) allo-SCT using fludarabine and busulfan showed promising long-term outcomes, with 4-year disease-free survival (DFS) and overall survival (OS) rates of 43% and 45%, respectively.

The development of chronic graft-versus-host disease (GVHD) was associated with lower relapse rates and improved DFS and OS, highlighting its potential role in enhancing the efficacy of RIC allo-SCT for patients who cannot undergo conventional high-dose conditioning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. Valcárcel, D., Martino, R., Caballero, D., et al.[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]

Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplants have been developed to enhance the graft-versus-leukemia (GVL) effect while minimizing toxicity, marking a significant advancement in treatment strategies over the past decade.

Clinical data has shown that RIC regimens can be tailored for effective immunosuppression and antimalignant treatment, allowing for a better understanding of their successes and limitations in stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stem cell transplantation with reduced-intensity conditioning regimens: a review of ten years experience with new transplant concepts and new therapeutic agents. Barrett, AJ., Savani, BN.[2013]

Reduced intensity-conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT) can effectively prevent graft rejection and establish stable donor-derived blood cell production, making it a safer option for children with preexisting health issues.

While RIC-SCT has shown promise for nonmalignant disorders and is now routinely used for conditions like primary immunodeficiencies, its application in pediatric patients with hematologic malignancies is still limited and should be reserved for those who cannot undergo standard myeloablative SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases. Satwani, P., Cooper, N., Rao, K., et al.[2010]

References

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

A comparison of nonmyeloablative and reduced-intensity conditioning for allogeneic stem-cell transplantation. [2021]

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

Reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. [2007]

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

Reduced intensity versus myeloablative allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, myelodysplastic syndrome and acute lymphoid leukemia. [2011]

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

Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. [2009]

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

Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. [2013]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

Stem cell transplantation with reduced-intensity conditioning regimens: a review of ten years experience with new transplant concepts and new therapeutic agents. [2013]

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

Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases. [2010]