RIC + BMT for Non-Malignant Disorders

Recruiting at 3 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of bone marrow transplants for young patients with non-cancerous conditions. It uses a special treatment plan, the reduced-intensity conditioning (RIC) regimen, to prepare the body for the transplant and prevent complications. Suitable candidates include those under 21 with conditions like sickle cell disease, bone marrow failure, or metabolic disorders, especially if they experience severe symptoms such as frequent hospital visits or significant pain. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and assess its effectiveness in an initial, smaller group, offering a chance to contribute to groundbreaking medical advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the Reduced Intensity Conditioning (RIC) regimen used in bone marrow transplants is generally easier for patients to handle. Studies indicate that RIC causes fewer serious side effects on the brain, heart, lungs, liver, and other organs compared to more intense treatments, reducing long-term harmful effects.

For preventing graft-versus-host disease (GVHD), research suggests that a mix of medications, including post-transplant cyclophosphamide, can help patients live longer without severe GVHD. However, about 30-50% of patients still develop some form of GVHD, with 10% experiencing severe cases.

These findings suggest that both the RIC regimen and the GVHD prevention methods have manageable safety profiles, making them potentially safer options for patients undergoing bone marrow transplants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Reduced Intensity Conditioning (RIC) is unique because it offers a less aggressive approach to preparing patients for bone marrow transplants compared to traditional conditioning regimens. Traditional methods often involve high-dose chemotherapy and radiation, which can be harsh and lead to severe side effects. RIC, however, uses lower doses, aiming to minimize toxicity while still effectively preparing the body for transplant. Researchers are excited because this approach could make bone marrow transplants accessible to more patients, including those who might not tolerate standard conditioning methods well. Additionally, the inclusion of GVHD prophylaxis helps manage graft-versus-host disease, a common complication, potentially improving overall outcomes.

What evidence suggests that this trial's treatments could be effective for non-malignant disorders?

Research has shown that the Reduced Intensity Conditioning (RIC) regimen offers health benefits, such as better survival rates and improved quality of life, with fewer side effects on organs. This method is often used in bone marrow transplants for non-cancerous conditions. Studies have found that while RIC doesn't significantly change survival outcomes compared to more intense treatments, it remains effective with less harm to the body. In this trial, all participants will receive the RIC regimen along with GVHD prevention methods. Using RIC with GVHD prevention has been linked to similar survival and disease-free outcomes as other treatments, making it a promising option for young patients who need transplants. ^{2 6 7 8 9}

Who Is on the Research Team?

Shalini Shenoy, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

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]

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]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK76651/

Prophylaxis regimens for GVHD: systematic review and meta ... The authors found that no prophylaxis regimen for acute graft-versus-host disease (aGVHD) investigated was superior for improving survival rates ...

2. ashpublications.org ashpublications.org/bloodadvances/article/7/16/4505/496495/Tacrolimus-methotrexate-vs-tacrolimus-reduced-dose

Tacrolimus/methotrexate vs tacrolimus/reduced-dose ... Key Points. Compared with full-MTX, mini-MTX/MMF was associated with no significant differences in GVHD.Mini-MTX was associated with faster ...

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK608285/

GVHD Prophylaxis - The EBMT Handbook - NCBI Bookshelf Overall, 30–50% of patients undergoing allo-HCT will develop acute GVHD, and around 10% will have severe acute GVHD (grades III–IV). The main ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2215943

Post-Transplantation Cyclophosphamide-Based Graft ... Estimated 1-year overall survival, disease-free survival, and the incidence of transplantation-related death were similar in the two groups.

5. astctjournal.org astctjournal.org/article/S1083-8791(20)30569-3/fulltext

A New Standard in Graft-versus-Host Disease Prophylaxis ... The primary hypothesis of the study is that GRFS at 1 year after transplantation will be at least 15% greater for subjects who received PTCy/Tac/MMF for GVHD ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2503189

Graft-versus-Host Disease Prophylaxis with ... The combination of post-transplantation cyclophosphamide and a calcineurin inhibitor led to longer GVHD-free, relapse-free survival than standard prophylaxis.

7. ashpublications.org ashpublications.org/blood/article/142/12/1037/496953/Novel-developments-in-the-prophylaxis-and

Novel developments in the prophylaxis and treatment of acute ... Acute graft-versus-host disease (GVHD) remains a major barrier to favorable outcomes with allogeneic stem cell transplantation.

8. thelancet.com thelancet.com/journals/lanhae/article/PIIS2352-3026(23)00342-3/abstract

Prophylaxis and management of graft-versus-host disease ... Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations

9. astctjournal.org astctjournal.org/article/S1083-8791(14)00446-7/fulltext

Calcineurin Inhibitor–Free Graft-versus-Host Disease ... Calcineurin inhibitor (CNI)-free GVHD prophylaxis with post-transplant cyclophosphamide (Cy) and brief course sirolimus appears to be a safe and effective ...