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 donor, Infections, Pregnancy, others

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

Compensation: Varies

Number of Visits: 8

57 Participants Needed

Trial Summary

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. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Cyclophosphamide, Cytoxan, Neosar, Endoxan, Pentostatin, Sirolimus, Rapamune for sickle cell disease?

Research shows that using cyclophosphamide and sirolimus in stem cell transplants for sickle cell disease can help patients achieve stable donor cell engraftment, improve quality of life, and reduce complications like graft-versus-host disease, making it a promising treatment option. ^{1 2 3 4 5}

Is stem cell transplant for sickle cell disease generally safe?

Stem cell transplants for sickle cell disease have shown promising safety results, with studies reporting no cases of graft-versus-host disease (GVHD) and high survival rates. Sirolimus, used in these transplants, is generally safe but can have side effects like high blood pressure and liver or kidney issues. ^{4 5 6 7 8}

How is the stem cell transplant treatment with Cyclophosphamide, Pentostatin, and Sirolimus different for sickle cell disease?

This treatment is unique because it uses a nonmyeloablative (less intense) approach to expand the donor pool by allowing the use of HLA-haploidentical (partially matched) donors, which makes stem cell transplantation more accessible for sickle cell disease patients. It also includes post-transplantation high-dose cyclophosphamide to reduce complications like graft-versus-host disease, making it safer for patients. ^{1 2 3 4 9}

What is the purpose of this trial?

Background: Peripheral blood stem cell transplantation procedures are used for people with sickle cell disease. Researchers want to improve the success and reduce the complications for these procedures. This might allow more people to have a transplant. Objective: To see if a new transplant regime is effective, safe and well tolerated in people with sickle cell disease. Eligibility: Adults at least 18 years old with sickle cell disease and certain complications. A relative who is a half tissue match. Design: Participants will be screened with medical history, physical exam, and blood tests. Recipients will also have: * Heart, lung, and mental health tests * Chest x-rays * Bone marrow taken from the pelvic bone * Eyes and teeth checked Recipients will have a large central line inserted into a vein for up to 6 months. Donors will have their veins tested and have an IV inserted for 1 day or on rare occasions 2 days. Donors will get a drug to activate bone marrow. It will be injected for about 6 days. Donors will have at least 1 five-hour procedure where bone marrow stem cells will be collected. Blood will be taken from a vein in one arm or in rare cases from a groin vein and put through a machine. Some blood will be saved and the rest will be returned. Stem cells will be taken from the saved blood in a lab and frozen until ready to give to the recipient. Recipients will have: * Stems cells collected and frozen * Hygiene lessons * Bone density scans * Low-dose radiation * Drugs for their immune system * Donor cells infused through their central line * Transfusions After about 30 days, recipients will leave the hospital. They must stay near NIH for 3 months after the transplant and have frequent visits. After returning home, they will have 8 visits over 5 years, then be contacted yearly.

Research Team

Courtney F Joseph, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

Adults over 18 with sickle cell disease and severe complications like stroke, high blood flow in the lungs, liver issues, serious lung problems or silent strokes on MRI. They need a half-matched relative donor, good heart and kidney function, and can't be pregnant or breastfeeding. People with uncontrolled infections or major illnesses that could interfere with stem cell transplant recovery are excluded.

Inclusion Criteria

My kidney function test shows a filtration rate above 60 mL/min.

My heart pumps blood effectively.

Adjusted DLCO greater than or equal to 35%

Exclusion Criteria

Pregnant or breast-feeding

I have a sibling donor who is a perfect match for me.

I need help with my daily activities due to my health condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for medical history, physical exam, and tests

Pre-Transplant Conditioning

Participants receive pentostatin, oral cyclophosphamide, alemtuzumab, and low-dose radiation to prepare for transplant

3 weeks

Frequent visits for drug administration and monitoring

Transplantation

Donor-derived peripheral blood stem cells are infused, followed by cyclophosphamide and sirolimus administration

1 week

Inpatient stay for stem cell infusion and post-transplant care

Initial Post-Transplant Monitoring

Participants are monitored for engraftment, GVHD, and other complications

100 days

Frequent visits for monitoring and assessments

Follow-up

Participants are monitored for long-term safety and effectiveness, including chimerism and GVHD assessments

5 years

8 visits over 5 years, then annual contact

Treatment Details

Interventions

• Cyclophosphamide
• Pentostatin
• Sirolimus

Trial Overview The trial is testing a new bone marrow transplant method using donors who are half tissue matches for adults with severe sickle cell disease. It includes taking stem cells from the donor's blood after drug stimulation, preparing the recipient's body with radiation and immune system drugs before infusing these cells through a central vein line.

Participant Groups

Group I: Participants with Sickle Cell Disease with Nonmyeloablative Haplo Transplants Experimental Treatment 6 Interventions

Participants will receive pentostatin on days -21, -17, -13, and -9 and oral cyclophosphamide from days -21 to -8. Alemtuzumab to be infused on days -7 to -3, followed by 400 cGy TBI on day -1. Donor-derived peripheral blood stem cells will be given on Day 0 then cyclophosphamide will be given at 50 mg/kg on day +3. Sirolimus loading dose of 5mg PO q4h x three doses at one day after the completion of cyclophosphamide (on day +4) and continued the following day at 5mg PO q24h to maintain trough levels between 5-15 ng/ml.

Group II: Human Leukocyte Antigens (HLA) Haploidentical Related Stem Cell Donor Experimental Treatment 1 Intervention

A haploidentical relative donor will receive filgrastim (G-CSF) 10 to 16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of peripheral blood hematopoietic progenitor cells (PBPC) after the 5th day (and after the 6th day if required).

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

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

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]

In a study involving 13 high-risk adult patients with sickle cell disease, a chemotherapy-free stem cell transplantation regimen resulted in successful engraftment in all patients, with 92% maintaining stable mixed donor/recipient chimerism after a median follow-up of 22 months.

The treatment showed no mortality or graft-versus-host disease, and patients experienced significant improvements in hemoglobin levels and quality of life, including aspects like bodily pain and vitality, highlighting the efficacy and safety of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease. Saraf, SL., Oh, AL., Patel, PR., et al.[2017]

A Phase II clinical trial of haploidentical bone marrow transplantation (BMT) with post-transplantation cyclophosphamide showed a 93% stable donor engraftment rate at 6 months and 100% overall survival among 15 patients, indicating high efficacy for treating severe sickle cell disease (SCD).

The addition of thiotepa to the conditioning regimen reduced the risk of graft rejection, with only 2 patients experiencing severe acute graft-versus-host disease (GVHD), suggesting that this approach minimizes transplantation-related morbidity while improving outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Sickle Cell Anemia: Results of an International Learning Collaborative. de la Fuente, J., Dhedin, N., Koyama, T., et al.[2020]

In a study involving 16 children and adolescents with sickle cell disease, a nonmyeloablative hematopoietic cell transplantation regimen showed 100% event-free and overall survival rates after a median follow-up of 19.5 months, with no observed sickling crises or graft-versus-host disease (GVHD).

All patients achieved mixed donor-recipient engraftment, indicating successful integration of donor stem cells, and sirolimus weaning was possible for most patients, suggesting a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease. Guilcher, GMT., Monagel, DA., Nettel-Aguirre, A., et al.[2020]

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

Four FDA-approved drugs for sickle cell disease—hydroxyurea, L-glutamine, crizanlizumab, and voxelotor—offer safe and effective treatment options, addressing the need for accessible therapies as curative methods remain limited.

Combining these therapies may enhance treatment outcomes, as individual agents have shown limited efficacy when used alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using disease-modifying therapies in sickle cell disease. Rai, P., Ataga, KI.[2023]

References

1. 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]

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

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease. [2017]

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

Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Sickle Cell Anemia: Results of an International Learning Collaborative. [2020]

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

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease. [2020]

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

Abatacept is effective as GVHD prophylaxis in unrelated donor stem cell transplantation for children with severe sickle cell disease. [2022]

6. Denmark pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. [2022]

7. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

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

Successful management of sirolimus toxicity in a hematopoietic stem cell transplant patient using automated red blood cell exchange. [2021]

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

Using disease-modifying therapies in sickle cell disease. [2023]