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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new stem cell transplant approach for people with sickle cell disease. Researchers aim to determine if this method is safe, effective, and reduces complications compared to current procedures. The treatment combines drugs, including Cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan), Pentostatin, and Sirolimus (also known as Rapamune), with donor stem cells to manage the disease. Suitable candidates include adults with sickle cell disease who experience complications affecting daily life and have a relative who is a partial tissue match. As a Phase 1, Phase 2 trial, this study seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

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.

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

Research shows that the treatments used in this trial—pentostatin, cyclophosphamide, and sirolimus—have been studied for safety in people with sickle cell disease.

Pentostatin and cyclophosphamide form part of a treatment plan proven to aid successful transplants. Studies indicate that adults with sickle cell disease can tolerate these drugs well, even with severe organ damage. Notably, no transplant-related deaths have occurred in these cases, indicating good safety.

Sirolimus, another drug in this trial, is generally considered safe but can cause side effects like high blood pressure and potential liver or kidney issues. Discussing these side effects with a healthcare team is important.

Overall, while these drugs can have side effects, they are often well-tolerated in similar situations. It is crucial to consider these findings alongside personal health and consult a doctor about any concerns. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for sickle cell disease because it combines a unique approach with stem cell transplants. Unlike traditional treatments that mainly focus on managing symptoms, this method uses a nonmyeloablative haploidentical stem cell transplant, which aims to replace damaged cells without fully wiping out the patient's existing bone marrow. Key components like a combination of cyclophosphamide, pentostatin, and sirolimus work together to facilitate the transplant process while minimizing the side effects typically associated with more aggressive conditioning regimens. This approach could potentially offer a curative option, transforming the disease management landscape for patients with sickle cell disease.

What evidence suggests that this transplant regime might be an effective treatment for sickle cell disease?

In this trial, participants with sickle cell disease will receive a combination of three drugs—pentostatin, cyclophosphamide, and sirolimus—as part of a nonmyeloablative haplo transplant. Research has shown that this combination can be very effective in stem cell transplants for sickle cell disease. One study found that 95% of patients were still alive one year after receiving this treatment. This approach helps the donor's cells successfully take over and function well in the patient's body by reducing the risk of rejection through lowering certain immune cells. These results are promising for patients with sickle cell disease. ^{6 7 8 9 10}

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?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12424894/

Nonmyeloablative Pentostatin-Cyclophosphamide ... One-year overall survival was 95%; in the first year, there was 1 death on each protocol. Table 2 summarizes the post-HCT outcomes. At one-year post-HCT, there ...

2. medrxiv.org medrxiv.org/content/10.1101/2025.08.31.25334807v1.full.pdf

Nonmyeloablative Pentostatin-Cyclophosphamide ... donor transplantation in sickle cell disease: outcomes from three independent centres. Br. 431. J Haematol, 2021. 192(4): p. 761-768. 432. 18 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4592398/

High-Dose Sirolimus And Immune Selective Pentostatin Plus ... Pentostatin plus low-dose, dose-adjusted Cy yielded sufficient host T cell depletion and suppression to permit prompt donor T cell engraftment. The PC regimen ...

4. withpower.com withpower.com/trial/phase-2-anemia-sickle-cell-3-2017-f7125

Stem Cell Transplant 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 ...

5. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT02105766

NCT02105766 | Nonmyeloablative Peripheral Blood ... This modified regimen consists of pentostatin and oral cyclophosphamide, which we hypothesize will reduce both the T cells that mediate leukocyte rejection and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5727815/

Cyclophosphamide improves engraftment in patients with ... Patients with SCD and severe organ damage can tolerate nonmyeloablative conditioning with no transplant-related mortality.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9820909/

Long-term health outcomes following curative therapies for ... We summarize the limited data reported on health outcomes following HSCT for SCD and emphasize the need for more research within this area.

8. hopkinsmedicine.org hopkinsmedicine.org/news/newsroom/news-releases/2023/12/a-cure-for-sickle-cell-disease

A Cure for Sickle Cell Disease Of the 42 participants, 95% were still alive two years after transplant, and 88% have not seen their sickle cell disease return and are ...

9. astctjournal.org astctjournal.org/article/S1083-8791(17)30799-1/fulltext

Outcomes of Unrelated Donor Stem Cell Transplantion with ... This preparative regimen along with the use of post-transplant cyclophosphamide offers a promising approach for unrelated donor transplants in patients with SCD ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S2666636725014472

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell ... This systematic review and meta-analysis present strong evidence for the safety and efficacy of allo-HSCT in SCD treatment, with an OS of 94% ...