Stem Cell Transplant for Sickle Cell Disease

Overseen By Lisa Pullens, RN

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Prior transplants, Active infection, Malignancy, others

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

Compensation: Varies

Number of Visits: 1

3 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Blood stem cells can produce red blood cells (which carry oxygen), white blood cells of the immune system (which fight infections) and platelets (which help the blood clot). Patients with sickle cell disease produce abnormal red blood cells. A blood stem cell transplant from a donor is a treatment option for patients with severe sickle cell disease. The donor can be healthy or have the sickle cell trait. The blood stem cell transplant will be given to the patient as an intravenous infusion (IV). The donor blood stem cells will then make normal red blood cells - as well as other types of blood cells - in the patient. When blood cells from two people co-exist in the patient, this is called mixed chimerism. Most children are successfully treated with blood stem cells from a sibling (brother/sister) who completely shares their tissue type (full-matched donor). However, transplant is not an option for patients who (1) have serious medical problems, and/or (2) do not have a full-matched donor. Most patients will have a relative who shares half of their tissue type (e.g. parent, child, and brother/sister) and can be a donor (half-matched or haploidentical donor). Adult patients with severe sickle cell disease were successfully treated with a half-matched transplant in a clinical study. Researchers would like to make half-matched transplant an option for more patients by (1) improving transplant success and (2) reducing transplanted-related complications. This research transplant is being tested in this Pilot study for the first time. It is different from a standard transplant because: 1. Half-matched related donors will be used, and 2. A new combination of drugs (chemotherapy) that does not completely wipe out the bone marrow cells (non-myeloablative treatment) will be used to prepare the patient for transplant, and 3. Most of the donor CD4+ T cells (a type of immune cells) will be removed (depleted) before giving the blood stem cell transplant to the patient to improve transplant outcomes. It is hoped that the research transplant: 1. Will reverse sickle cell disease and improve patient quality of life, 2. Will reduce side effects and help the patient recover faster from the transplant, 3. Help the patient keep the transplant longer and 4. Reduce serious transplant-related complications.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use certain investigational agents, chemotherapy, biological therapy, or radiation therapy, and you cannot use moderate and strong CYP3A4 inhibitors. It's best to discuss your current medications with the trial team.

Is haploidentical stem cell transplantation safe for sickle cell disease patients?

Haploidentical stem cell transplantation for sickle cell disease has shown improved safety with low rates of complications like graft failure and graft-versus-host disease (a condition where the donor cells attack the recipient's body). Overall survival rates are high, and advancements in treatment have reduced risks, making it a promising option for patients without matched donors. ^{1 2 3 4 5}

How is the CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant treatment different from other treatments for sickle cell disease?

This treatment is unique because it uses a donor who is only partially matched, which greatly increases the number of potential donors for patients. It also involves removing specific immune cells (CD4+ T-cells) to reduce the risk of complications like graft-versus-host disease, making it a promising option for those who cannot find a fully matched donor. ^{1 5 6 7 8}

What data supports the effectiveness of the treatment CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant for Sickle Cell Disease?

Research shows that haploidentical stem cell transplants, which use a partially matched family donor, have been effective in treating sickle cell disease. Studies indicate high survival rates and low rates of complications like graft-versus-host disease, making it a promising curative option for patients without a fully matched sibling donor. ^{2 4 5 7 9}

Who Is on the Research Team?

Joseph Rosenthal, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with severe sickle cell disease who have had multiple joint issues, strokes, or vaso-occlusive crises despite treatment. They need a related half-matched donor (like a parent or sibling) and can't have had prior transplants. Women must not be pregnant and agree to use contraception.

Inclusion Criteria

I have had a stroke or neurological issues lasting more than a day.

I have been diagnosed with sickle cell disease (SS or S-βº Thalassemia).

My condition is considered severe due to one or more specific factors.

Exclusion Criteria

I have serious liver scarring and have been on blood transfusion therapy for over 6 months.

I am not pregnant or breastfeeding.

I have had a bone marrow transplant in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Non-myeloablative Conditioning

Participants receive a 21-day non-myeloablative conditioning regimen with cyclophosphamide, pentostatin, and rabbit anti-thymocyte globulin

3 weeks

Multiple visits for drug administration

Transplantation

Participants receive a CD4+ T-cell-depleted haploidentical hematopoietic cell transplant

1 day

1 visit (in-patient)

Immunosuppressant Therapy

Participants receive immunosuppressants (tacrolimus and mycophenolate mofetil) starting from Day -1 post-transplant

Until discontinuation post-transplant

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of donor chimerism

Up to 2 years post-transplant

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant
• Cyclophosphamide
• Mycophenolate mofetil
• Pentostatin
• Rabbit anti-thymocyte globulin
• Tacrolimus

Trial Overview The study tests a blood stem cell transplant from a half-matched relative using new chemotherapy that's less harsh on bone marrow. It aims to create mixed chimerism where the patient's body accepts both their own and the donor's blood cells, potentially reversing sickle cell disease.

How Is the Trial Designed?

Group I: COH-MC-17 and immunosuppressants Experimental Treatment 6 Interventions

Participants receive COH-MC-17: a 21-day nonmyeloablative conditioning regimen (cyclophosphamide, pentostatin and rabbit anti-thymocyte globulin), followed by CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant on Day 0. Immunosuppressants (tacrolimus and mycophenolate mofetil) given on Day -1 onwards until discontinuation post-transplant. The minimally manipulated transplant product is manufactured using the CliniMACS device.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

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 50 adult patients with sickle cell disease referred for haploidentical hematopoietic stem cell transplantation (HSCT), only 10 patients underwent the procedure, highlighting challenges such as insurance denial and patient reluctance.

The modified Hopkins regimen used for HSCT resulted in a high engraftment rate of 87.5% and low morbidity, with 87.5% of patients alive at a median follow-up of 16 months, suggesting its potential for broader application in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease. Saraf, SL., Oh, AL., Patel, PR., et al.[2023]

Haploidentical stem cell transplantation (haploHCT) offers a life-saving option for high-risk sickle cell disease patients without matched donors, but it faces challenges like graft failure and graft-versus-host disease (GvHD).

Recent strategies, including T-cell depletion methods and post-transplant cyclophosphamide, aim to improve engraftment rates while minimizing GvHD, and achieving stable mixed chimerism post-transplant has shown promise for better survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical stem cell transplantation for patients with sickle cell disease: current status. Pawlowska, AB., Sun, V., Rosenthal, J.[2022]

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]

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]

Citations

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. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Alternative donor: αß/CD19 T-cell-depleted haploidentical hematopoietic stem cell transplantation for sickle cell disease. [2020]

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

Proceedings From the Fourth Haploidentical Stem Cell Transplantation Symposium (HAPLO2016), San Diego, California, December 1, 2016. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease. [2023]

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

Haploidentical Allogeneic Stem Cell Transplantation in Sickle Cell Disease: A Systematic Review and Meta-Analysis. [2022]

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

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease. [2023]

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

Haploidentical stem cell transplantation for patients with sickle cell disease: current status. [2022]

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

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

9. 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]