Stem Cell Transplant for Sickle Cell Disease

Overseen By Courtney F Joseph, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Disqualifiers: HLA-matched sibling, ECOG 3+, 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: 31

Duration: Approximately 30 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to make stem cell transplants safer for individuals with sickle cell disease (SCD), a condition that causes painful episodes and organ damage due to misshaped red blood cells. The study will test a new combination of drugs with radiation to determine if they can reduce transplant side effects. Participants must have SCD, be eligible for a stem cell transplant, and have a family member who can donate. Those who frequently experience severe pain or organ issues due to SCD might be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new approach.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, since the trial involves a stem cell transplant and new drug treatments, it's possible that some medications may need to be adjusted. Please consult with the trial coordinators for specific guidance.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, since the trial involves a stem cell transplant and new drug treatments, it's possible that some medications may need to be adjusted. It's best to discuss this with the trial team.

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

Research has shown that the drug combination tested in this trial, including briquilimab, abatacept, and alemtuzumab, is part of a less intense approach to stem cell transplants for sickle cell disease (SCD). This gentler method can lead to fewer side effects for patients.

Studies have found that these less intense transplants can be effective while reducing some severe side effects seen with more aggressive treatments. For instance, similar studies have shown that patients often experience better survival rates and fewer complications. This trial uses a mix of drugs and low-dose radiation to make the stem cell transplant process safer.

While all treatments carry potential risks, previous research has shown that these types of transplants are generally well-tolerated. As this trial is in its early stages, safety remains a top priority. Researchers closely monitor for any side effects to enhance the treatment's safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for sickle cell disease, which often include pain management, hydroxyurea, and blood transfusions, this investigational approach uses a stem cell transplant method with a few unique twists. Researchers are excited because it features a non-myeloablative haploidentical hematopoietic cell transplant (HCT), which means it's less intense and potentially less risky for patients. The treatment also utilizes a novel combination of drugs, including the investigational briquilimab antibody and abatacept, alongside an established NIH regimen. This approach aims to reduce complications and improve recovery by minimizing the immune system's aggressive response to the transplant. Additionally, the two different dosing strategies for the drug PT-Cy in the treatment arms offer insights into optimizing the effectiveness and safety of this therapy.

What evidence suggests that this trial's treatments could be effective for sickle cell disease?

Research has shown that hematopoietic cell transplantation (HCT) can potentially cure sickle cell disease (SCD). For children with severe SCD, over 90% of these treatments have yielded good long-term results. This trial will investigate a less intense version of this treatment, called non-myeloablative HCT, which has shown promise in treating SCD with fewer side effects. Participants will receive a combination of drugs, including briquilimab, abatacept, and alemtuzumab, along with radiation, to make HCT safer and more effective for people with SCD. Cohort 1 will receive a single dose of PT-Cy, while Cohort 2 will receive two doses, to evaluate the optimal dosing strategy. ^{1 2 3 6 7}

Who Is on the Research Team?

Courtney F Joseph, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

This trial is for people aged 16+ with Sickle Cell Disease (SCD) at high risk of health issues due to the disease. They need a family donor match who's willing and suitable to donate stem cells. Participants must agree to use birth control post-treatment and be able to follow the study procedures for its duration.

Inclusion Criteria

I am willing and able to follow all study procedures for its duration.

You have a negative pregnancy test.

You must agree to use birth control for 12 months after receiving the drug.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive briquilimab, abatacept, and alemtuzumab along with radiation therapy and undergo HCT

Approximately 30 days

Hospital stay for about 30 days post-HCT

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Non-myeloablative Phase I/II Haploidentical HCT

Trial Overview The trial tests a new drug combo (briquilimab, abatacept, alemtuzumab) plus radiation in HCT for SCD. It aims to make blood stem cell transplants from family donors safer, even when patients have organ damage from SCD.

How Is the Trial Designed?

Group I: Cohort 2 Experimental Treatment 1 Intervention

All participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors. Cohort 2 will receive a total of two doses of PT-Cy; 50mg/kg, on days +3 and +4 (total 100 mg/kg) post-HCT

Group II: Cohort 1 Experimental Treatment 1 Intervention

All participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors. Cohort 1 will receive a single dose of PT-Cy; 50 mg/kg, on day +3 post-HCT

Non-myeloablative Phase I/II Haploidentical HCT is already approved in United States, European Union for the following indications:

Approved in United States as Non-myeloablative Haploidentical HCT for:

• Sickle Cell Disease

Approved in European Union as Non-myeloablative Haploidentical HCT for:

• Sickle Cell Disease
• Hematological Malignancies

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Related haploidentical hematopoietic stem cell transplant (HCT) offers a promising alternative for treating sickle cell disease (SCD), expanding the donor pool to about 90% of eligible patients, including adults with significant health issues.

Three emerging haploidentical HCT strategies show potential for curative therapy in SCD, with nonmyeloablative approaches allowing for better tolerance in adults and reducing treatment-related deaths compared to traditional myeloablative methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The range of haploidentical transplant protocols in sickle cell disease: all haplos are not created equally. Kassim, AA., DeBaun, MR.[2023]

In a study of 23 patients with severe sickle cell disease undergoing haploidentical bone marrow transplant (haplo-BMT), researchers found that immune reconstitution was excellent by 6 months post-transplant, with a 100% engraftment rate and 96% event-free survival.

Despite the successful immune recovery, 70% of patients experienced viral reactivations or infections, highlighting the need for further research to understand the immunologic factors contributing to these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early viral reactivation despite excellent immune reconstitution following haploidentical Bone marrow transplant with post-transplant cytoxan for sickle cell disease. Patel, DA., Dhedin, N., Chen, H., et al.[2023]

Haploidentical hematopoietic stem cell transplantation (HSCT) is a promising treatment for children with non-malignant disorders who do not have an HLA-compatible donor, with recent studies showing effective outcomes for both T cell depleted and unmanipulated HSCT.

The use of post-transplant cyclophosphamide has emerged as an effective strategy to prevent graft-versus-host disease (GvHD) in haploidentical HSCT, addressing concerns about immune recovery and graft failure associated with T cell depletion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T Cell-Depleted and T Cell-Replete HLA-Haploidentical Stem Cell Transplantation for Non-malignant Disorders. Bertaina, A., Pitisci, A., Sinibaldi, M., et al.[2018]

Haploidentical stem cell transplantation (haplo-SCT) is a safe and effective alternative to matched donor stem cell transplantation (matched-SCT) for treating hematological malignancies, based on a review of 25 studies involving 11,359 patients.

Patients receiving haplo-SCT had a lower risk of acute graft-versus-host disease (GVHD) compared to those receiving matched-SCT from related donors, but those undergoing reduced-intensity conditioning (RIC) faced a higher risk of acute GVHD and non-relapse mortality, suggesting haplo-SCT may not be ideal for RIC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical versus matched donor stem cell transplantation for patients with hematological malignancies: a systemic review and meta-analysis. Yang, B., Yu, R., Cai, L., et al.[2020]

A nonmyeloablative bone marrow transplantation approach using related and HLA-haploidentical donors has been developed for sickle cell disease, showing a low risk of complications and allowing for a broader donor pool.

In a study of 17 patients, 11 achieved durable engraftment, with 10 patients remaining asymptomatic and only one case of mild acute graft-versus-host disease, indicating the treatment's safety and potential efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Bolaños-Meade, J., Fuchs, EJ., Luznik, L., et al.[2022]

Haploidentical hematopoietic stem cell transplantation (allo-HSCT) can achieve outcomes comparable to HLA-identical transplantation for chronic myeloid leukemia (CML), providing a viable option for patients without matched donors, as demonstrated in a study of 93 patients.

The study reported a 4-year overall survival rate of 76.5% for patients in chronic phase 1 and 85.7% for chronic phase 2, indicating that even advanced stages of CML can have similar survival outcomes to stable stages when treated with this method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for chronic myeloid leukemia: improved outcomes in patients in accelerated phase and blast crisis phase. Xiao-Jun, H., Lan-Ping, X., Kai-Yan, L., et al.[2022]

Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) has shown to be curative for children with sickle cell disease (SCD), but recent advancements in nonmyeloablative allo-HSCT have made it a viable option for adults, leading to stable mixed hematopoietic chimerism and normalization of blood counts.

The potential for immunologic tolerance in adults receiving nonmyeloablative allo-HSCT suggests that this approach could safely expand treatment options for SCD patients, including the use of alternative donor sources, thereby increasing the accessibility of curative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Hsieh, MM., Fitzhugh, CD., Tisdale, JF.[2021]

In a study of 13 patients with nonmalignant hematologic diseases, HLA haploidentical stem cell transplantation demonstrated effective engraftment and resulted in 11 patients surviving free of disease after a median follow-up of 13 months.

The procedure showed a manageable safety profile, with low incidences of acute and chronic graft-versus-host disease (GVHD), indicating that it is a viable treatment option for conditions like severe aplastic anemia and β thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The outcome of thirteen patients with nonmalignant hematologic diseases treated with HLA haploidentical stem cell transplantation]. Tao, Y., Wu, B., Du, Q., et al.[2018]

Haploidentical hematopoietic stem-cell transplantation offers a viable option for patients lacking HLA-matched donors, with recent advancements reducing issues like graft failure and graft-versus-host disease (GVHD) through improved T cell depletion methods.

Despite these improvements, challenges such as prolonged immune deficiency and increased relapse rates persist, but new strategies like partial T cell depletion and posttransplant therapies show promise for enhancing immune recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical hematopoietic stem-cell transplantation in adults. Alshemmari, S., Ameen, R., Gaziev, J.[2021]

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) was successfully performed in 17 children and adolescents with severe aplastic anemia (SAA), achieving neutrophil engraftment in all patients within a median of 16 days, indicating its efficacy as a treatment option.

The incidence of severe acute graft-versus-host disease (GVHD) was low, with only one patient experiencing grade III-IV aGVHD, suggesting that the treatment regimen, including GVHD prophylaxis, is relatively safe for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Good outcome of haploidentical hematopoietic SCT as a salvage therapy in children and adolescents with acquired severe aplastic anemia. Wang, Z., Zheng, X., Yan, H., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4698790/

Nonmyeloablative HLA-Matched Sibling Allogeneic ... Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10727056/

The range of haploidentical transplant protocols in sickle ... We review the similarities, differences, outcomes, and gaps in knowledge with these 3 haploidentical HCT approaches for SCD.

3. ashpublications.org ashpublications.org/blood/article/143/25/2654/515325/An-international-learning-collaborative-phase-2

An international learning collaborative phase 2 trial for ... Describe event-free survival (EFS) and overall survival (OS) in patients with sickle cell disease (SCD) treated with nonmyeloablative related ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03240731

HLA Haploidentical Bone Marrow Transplant in Patients ... The bone marrow transplantation cures almost 95% of children and adolescents transplant from an HLA-identical siblings. In patients without HLA-identical donor, ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1319016424000999

The effectiveness of hematopoietic stem cell ... Several studies have shown that HSCT, when performed on children with sickle cell disease (SCD), has favorable long-term outcomes, with over 90 % of transplants ...

6. astctjournal.org astctjournal.org/article/S2666-6367(25)01055-3/fulltext

Two Nonmyeloablative HLA-Matched Related Donor ... Two nonmyeloablative HLA-matched related donor allogeneic hematopoietic cell transplantation regimens in patients with severe sickle cell disease.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8582053/

Non-myeloablative human leukocyte antigen-matched related ... Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres · Summary.