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

6 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Non-myeloablative Phase I/II Haploidentical HCT for Sickle Cell Disease?

Research shows that using haploidentical donors (partially matched family members) for stem cell transplants in sickle cell disease can expand the donor pool and is associated with low risk of complications. In a study, most patients became symptom-free, and the treatment was well-tolerated even in adults with other health issues. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment Non-myeloablative Phase I/II Haploidentical HCT for Sickle Cell Disease?

Research shows that using haploidentical donors (partially matched family members) for stem cell transplants in sickle cell disease can expand the donor pool and is associated with low risk of complications. In a study, most patients became symptom-free, and the treatment was well-tolerated even in adults with other health issues. ^{1 2 3 4 5}

Is haploidentical stem cell transplantation generally safe for humans?

Haploidentical stem cell transplantation has been studied for various conditions and is considered a safe option when a matched donor is unavailable. However, it may have risks like graft-versus-host disease (a condition where the donated cells attack the recipient's body) and prolonged immune deficiency, but advances in treatment have reduced these issues. ^{3 4 6 7 8}

Is haploidentical stem cell transplantation generally safe for humans?

Haploidentical stem cell transplantation has been studied for various conditions and is considered a safe option when a matched donor is unavailable. However, it may have risks like graft-versus-host disease (a condition where the donor cells attack the recipient's body) and transplant-related mortality, though advances have reduced these issues. It is important to discuss individual risks with a healthcare provider. ^{3 4 6 7 8}

How is the treatment 'Non-myeloablative Haploidentical Hematopoietic Cell Transplantation' unique for sickle cell disease?

This treatment is unique because it uses a non-myeloablative (less intense) approach, allowing more patients, including adults with existing health issues, to receive a transplant from a partially matched family donor. It expands the donor pool significantly and reduces the risk of severe complications compared to traditional methods, making it a promising option for curing sickle cell disease. ^{1 2 3 9 10}

How is the treatment 'Non-myeloablative Haploidentical Hematopoietic Cell Transplantation' unique for sickle cell disease?

This treatment is unique because it uses a non-myeloablative (less intense) approach, allowing more patients, including adults with other health issues, to receive a transplant from a partially matched family donor, expanding the donor pool and reducing complications compared to traditional methods. ^{1 2 3 9 10}

What is the purpose of this trial?

Background: Sickle cell disease (SCD) is a genetic disorder where red blood cells, that carry oxygen, are stiff and become stuck in small blood vessels. As a result, affected patients can experience severe pain and serious organ damage. SCD can be cured with a hematopoietic cell transplant (HCT), that is, when they receive blood stem cells from a family donor. But HCT can also have serious side effects, especially in people with organ damage. Researchers want to find ways to make HCT safer for everyone. Objective: To test a new combination of drugs (briquilimab, abatacept, and alemtuzumab), used along with radiation, in people undergoing HCT for SCD. Eligibility: People aged 16 and older with SCD. They must be eligible for HCT and have a family member who is a good donor match. Donors must be aged 4 and older. Design: Participants with SCD will be screened. They will have blood tests and tests of organs including their heart and lung function. Donors will have blood drawn. Participants with SCD will have a tube inserted into a blood vessel in their chest (intravenously). This line will remain in place up to 2 months; it will be used to draw blood and administer the donor cells and other medications. Briquilimab will be administered intravenously 1 time, along with other drugs used to prepare for HCT. Participants will receive abatacept 6 times, from just before they receive their donor cells until 6 months after. Participants will undergo radiation therapy and take other drugs that are standard for HCT. Most HCT recipients remain in the hospital for about 30 days after HCT. Follow-up visits will continue for 5 years....

Research Team

Courtney F Joseph, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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 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]

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]

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]

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]

References

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

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

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

HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. [2022]

3. England 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. [2022]

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

T Cell-Depleted and T Cell-Replete HLA-Haploidentical Stem Cell Transplantation for Non-malignant Disorders. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Good outcome of haploidentical hematopoietic SCT as a salvage therapy in children and adolescents with acquired severe aplastic anemia. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[The outcome of thirteen patients with nonmalignant hematologic diseases treated with HLA haploidentical stem cell transplantation]. [2018]

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

Haploidentical versus matched donor stem cell transplantation for patients with hematological malignancies: a systemic review and meta-analysis. [2020]

8. Egypt pubmed.ncbi.nlm.nih.gov

Haploidentical hematopoietic stem-cell transplantation in adults. [2021]

9. Denmark 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. [2023]

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

Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. [2021]