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

Trial Summary

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.

What data supports the effectiveness of the treatment Stem Cell Transplant for Sickle Cell Disease?

Research shows that fludarabine, a component of the treatment, is effective in conditioning regimens for stem cell transplants, helping to prevent graft rejection and achieve successful donor cell integration in patients with severe aplastic anemia. This suggests potential effectiveness in similar transplant settings, like sickle cell disease. ^{1 2 3 4 5}

Is stem cell transplant for sickle cell disease generally safe in humans?

Stem cell transplants, which often use drugs like fludarabine and cyclophosphamide, have been studied for safety in humans. While these treatments can be effective, they may have side effects such as myelosuppression (a decrease in bone marrow activity leading to fewer blood cells). Some studies show that higher doses of these drugs can lead to worse outcomes, so careful monitoring and dose adjustments are important to ensure safety. ^{1 4 5 6 7}

How is the stem cell transplant treatment for sickle cell disease different from other treatments?

This treatment is unique because it combines stem cell transplantation with a specific regimen of drugs, including cyclophosphamide and fludarabine, and total body irradiation to prepare the body for the transplant. This approach aims to reduce the risk of rejection and graft-versus-host disease (a condition where the donor cells attack the recipient's body), which are common challenges in treating sickle cell disease with unrelated donor transplants. ^{1 4 8 9 10}

What is the purpose of this trial?

The study is a Phase II clinical trial. Patients will receive intensity modulated total body irradiation (TBI) at a dose of 3 Gy with standard fludarabine/ i.v. cyclophosphamide conditioning prior to human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplant (HSCT). The primary objective of the study is to determine the engraftment at Day +60 following HLA-haploidentical hematopoietic stem cell transplant protocol using immunosuppressive agents and low-dose total body irradiation (TBI) for conditioning and post-transplant cyclophosphamide in patients with sickle cell disease.

Research Team

Damiano Rondelli, MD

Principal Investigator

University of Illinois at Chicago

Eligibility Criteria

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

Patient is not pregnant

Patient is able and willing to sign informed consent

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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 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]

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]

References

1. United States 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. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Fludarabine-based increased-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in acquired severe aplastic anemia]. [2014]

4. England pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013]

5. Germany pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. [2018]

6. England pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. [2013]

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

Phase I study of fludarabine (2-fluoro-ara-AMP). [2019]

8. United States 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. [2015]

9. United States 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. [2019]

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

Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics. [2021]