Stem Cell Transplant for Sickle Cell Disease

Overseen By Damiano Rondelli, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Illinois at Chicago

Disqualifiers: HIV-positive, Pregnant, HLA-matched sibling, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating sickle cell disease using a combination of drugs, low-dose radiation, and a stem cell transplant (also known as stem cell infusion). The goal is to determine how effectively the new treatment plan helps the body accept the stem cell transplant by Day 60. Individuals with sickle cell disease who frequently experience pain episodes, strokes, or other serious complications might be suitable candidates for this trial. Participants should not have a fully matched sibling donor but need a partly matched (haploidentical) family member willing to donate stem cells. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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

The trial information does not specify if you need to stop 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 has shown that donor stem cell transplants are generally safe for treating sickle cell disease. A large review of studies found a high survival rate of 94%, indicating most patients did well and survived after the procedure.

Previous studies have noted that certain complications, such as graft failure (when the new stem cells don't work) and graft-versus-host disease (when the new cells attack the body), can be minimized with proper care.

Cyclophosphamide and fludarabine, chemotherapy drugs often used in these transplants, help the body accept the new stem cells. While generally safe, these drugs can cause side effects like nausea or low blood cell counts, but these are usually manageable.

In summary, despite some risks, research suggests that this treatment is well-tolerated and effective for many people with sickle cell disease. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this stem cell transplant treatment for sickle cell disease because it offers a potentially curative approach, unlike standard treatments that mainly manage symptoms. This investigational treatment uses a combination of cyclophosphamide, fludarabine, and total body irradiation to prepare the body for the infusion of healthy stem cells, aiming to replace the patient's defective cells with healthy ones. Additionally, the inclusion of graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, sirolimus, and mycophenolate mofetil is designed to reduce complications, which is a major advancement over traditional options. This innovative approach could mean not just improved symptom relief but a possible long-term solution for patients with sickle cell disease.

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

Research has shown that stem cell transplants hold promise for treating sickle cell disease. Studies indicate that over 90% of transplants in children result in favorable long-term outcomes. Survival rates are high, with overall survival at 94% and event-free survival at about 86%. This trial will evaluate a specific regimen involving stem cell infusion, where participants receive a conditioning regimen of ATG, fludarabine, cyclophosphamide, and total body irradiation. The method has low rates of complications, such as graft-versus-host disease, where the donor's cells attack the recipient's body. These findings suggest that stem cell transplants could be a strong option for those with sickle cell disease. ^{6 7 8 9 10}

Who Is on the Research Team?

Damiano Rondelli, MD

Principal Investigator

University of Illinois at Chicago

Are You a Good Fit for This Trial?

This trial is for people aged 16-60 with severe sickle cell disease, who have complications like stroke, recurrent pain episodes, or organ damage. They must not be pregnant, HIV-negative, and without a fully HLA-matched sibling donor but have an HLA-haploidentical relative willing to donate stem cells.

Inclusion Criteria

I have sickle cell disease with serious complications like stroke, frequent pain, or vision loss.

ALT ≤ 3x upper limit of normal

HIV-negative

Exclusion Criteria

My donor relative is not a close enough genetic match for the transplant.

I have a sibling who is a complete HLA match and willing to donate stem cells.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Patients receive intensity modulated total body irradiation (TBI) at a dose of 3 Gy with standard fludarabine/i.v. cyclophosphamide conditioning prior to HLA-haploidentical hematopoietic stem cell transplant (HSCT)

6 days

Transplantation

HLA-haploidentical hematopoietic stem cell transplant (HSCT) is performed

1 day

Post-Transplant Evaluation

Post-transplant evaluation with data collection at days 30, 60, 100, 180, 365, and annually thereafter

Up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to Day +60

What Are the Treatments Tested in This Trial?

Interventions

• ATG
• Cyclophosphamide
• Fludarabine
• Mycophenolate Mofetil
• Sirolimus
• Stem cell infusion
• Total body irradiation

Trial Overview The study tests a new way of transplanting stem cells from half-matched relatives in patients with aggressive sickle cell disease. It involves low-dose body radiation and drugs like fludarabine and cyclophosphamide before the transplant, followed by post-transplant medication to help the body accept the new cells.

How Is the Trial Designed?

Group I: Subject treatment Experimental Treatment 7 Interventions

Patients will receive the following conditioning regimen: ATG, fludarabine (6 days before stem cell infusion), cyclophosphamide, and total body irradiation. The stem cell product will be infused according to BMT unit policy. Patients will also receive GVHD prophylaxis which will consist of cyclophosphamide, sirolimus, and mycophenolate mofetil according to the protocol. Post-transplant evaluation will be done as per standard care with study data collected at days 30, 60, 100, 180, 365, and annually thereafter.

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?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

Published Research Related to This Trial

In a study of 102 patients undergoing hematopoietic cell transplantation (HCT) with fludarabine and low-dose total body irradiation, significant variability was observed in pharmacological biomarkers related to fludarabine metabolism, indicating that individual responses to the drug can differ widely.

Despite the variability in biomarkers such as F-ara-A area under the curve and F-ara-ATP accumulation, no significant associations were found between these biomarkers and clinical outcomes like acute graft-versus-host disease or overall mortality, suggesting that these pharmacological measures may not predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. McCune, JS., Mager, DE., Bemer, MJ., et al.[2018]

Two adult patients with sickle cell disease (SCD), including one with end-stage renal disease (ESRD), successfully underwent fludarabine-based nonmyeloablative stem cell transplantation (SCT) from matched siblings, achieving full donor chimerism and normal blood counts without immunosuppressive medications.

The study demonstrated that with a 20% reduction in fludarabine dosage and aggressive dialysis, it is possible to safely manage fludarabine toxicity in patients with ESRD, making SCT a feasible option for adults with SCD even in the presence of significant comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics. Horwitz, ME., Spasojevic, I., Morris, A., et al.[2021]

A population pharmacokinetic/pharmacodynamic model was developed using data from 41 hematopoietic cell transplant recipients to understand how different concentrations of F-ara-A affect lymphocyte suppression.

The model successfully characterized the variability in absolute lymphocyte counts during treatment, indicating that the specific HCT protocol significantly influenced lymphocyte kill rates and could help optimize future fludarabine-based conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. McCune, JS., Vicini, P., Salinger, DH., et al.[2021]

A new conditioning regimen combining fludarabine with reduced doses of busulfan and cyclophosphamide (BU-FLU-CY-ATG) shows promise in treating children with sickle cell disease, achieving 100% disease-free survival in a small trial of 14 patients.

This modified regimen resulted in no severe toxicity, suggesting it may be a safer alternative to the traditional high-dose BU-CY-ATG regimen, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial. Horan, JT., Haight, A., Dioguardi, JL., et al.[2015]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a study involving 16 patients with hematological malignancies, the pharmacokinetics of fludarabine were assessed before and after administration of busulfan, showing no significant changes in key parameters such as clearance and half-life.

The results suggest that there is unlikely to be a clinically relevant drug interaction between busulfan and fludarabine, supporting their combined use in conditioning regimens for stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bonin, M., Pursche, S., Bergeman, T., et al.[2013]

In a study of 4 children with severe sickle cell disease undergoing unrelated donor hematopoietic cell transplantation, a new treatment regimen led to successful engraftment in 3 patients, who have remained disease-free for a median of 2.5 years.

Remarkably, none of the engrafted patients experienced acute or chronic graft-versus-host disease (GVHD), suggesting that the combination of the novel immunosuppressive regimen and post-transplant cyclophosphamide may improve safety and efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Unrelated Donor Stem Cell Transplantion with Post-Transplant Cyclophosphamide for Graft-versus-Host Disease Prophylaxis in Patients with Severe Sickle Cell Disease. Rangarajan, HG., Abu-Arja, R., Pai, V., et al.[2019]

Fludarabine phosphate, an antimetabolite derived from adenosine arabinoside, has been found to be safe at a dose of 20 mg/m2 administered every 12 hours for 6 doses in good-risk patients during a phase I trial.

The main side effect of fludarabine phosphate is myelosuppression, which can become severe at higher doses, highlighting the need for careful dose management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine (2-fluoro-ara-AMP). Kavanagh, JJ., Krakoff, IH., Bodey, GP.[2019]

The increased-intensity FBCA conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 22 patients with severe aplastic anemia resulted in prompt and sustained hematopoietic reconstitution, with median neutrophil and platelet engraftment times of 15 and 16 days, respectively.

The study reported a low incidence of graft-versus-host disease (GVHD) at 9.1% for acute and 15.8% for chronic cases, with a 13.6% transplantation-related mortality rate, indicating that the regimen is effective with manageable safety outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fludarabine-based increased-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in acquired severe aplastic anemia]. Sun, C., Lin, X., Huang, Y., et al.[2014]

Citations

1. 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10988128/

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 ...

3. astctjournal.org astctjournal.org/article/S2666-6367(25)01447-2/fulltext

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell ... Allo-HSCT in SCD has OS, EFS, and mortality rates of 94%, 86% and 6%, respectively. •. NMA conditioning has the lowest aGVHD, cGVHD, and ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11057353/

Hematopoietic Stem Cell Transplantation in Sickle Cell Disease At the last follow-up, OS and EFS were 100% and 88.9%, respectively. These findings indicate that NMA preparative regimen is safe, feasible, and ...

5. ashpublications.org ashpublications.org/bloodadvances/article/9/4/877/526317/Is-allogeneic-transplantation-for-sickle-cell

Is allogeneic transplantation for sickle cell disease still ... Five participants died from infectious complications for an overall 2-year event-free survival (EFS) of 83% and an overall survival (OS) of 94%.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40953733/

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell ... The findings of this study show that allo-HSCT is safe and efficacious in curing SCD with an OS of 94%. GF and GVHD issues could be reduced by ...

7. 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% ...

8. astctjournal.org astctjournal.org/article/S2666-6367(25)01447-2/fulltext?rss=yes

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell ... The meta-analysis of 58 studies (n=7931) revealed allo-HSCT to have 94%, 86%, 20%, 14%, 9%, 6% for overall survival (OS), event-free survival ( ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3766347/

Hematopoietic stem-cell transplantation for sickle cell disease Though human leukocyte antigen (HLA) matched sibling donor (MSD) transplants offer the best outcomes for SCD, less than 14% of patients with SCD have such ...

10. tandfonline.com tandfonline.com/doi/full/10.1080/16078454.2022.2163357

A systematic review comparing allogeneic hematopoietic ... Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta- ...