Stem Cell Transplant for Sickle Cell Disease

(Sickle-AID Trial)

Overseen By Greg Guilcher, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Calgary

Must not be taking: Sirolimus

Disqualifiers: Noncompliance, Sirolimus hypersensitivity, 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

12 Participants Needed

Trial Summary

What is the purpose of this trial?

The aim of this study to evaluate the safety and efficacy of a nonmyeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with sickle cell disease (SCD) who have a matched related major ABO-incompatible donor. The nonmyeloablative regimen will use alemtuzumab, total body irradiation (TBI) and sirolimus for immune suppression. This study will expand the access of HSCT for patients with SCD who are currently not eligible because of donor restrictions.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that sickle cell complications should be present despite the use of hydroxyurea, suggesting you might continue it unless advised otherwise by the study team.

What data supports the effectiveness of this treatment for sickle cell disease?

Research shows that using a combination of alemtuzumab, sirolimus, and total body irradiation in children with sickle cell disease led to successful stem cell transplants without sickling crises, and all patients survived without major complications over a median follow-up of 19.5 months. ^{1 2 3 4 5}

Is stem cell transplant for sickle cell disease using alemtuzumab and sirolimus safe?

Alemtuzumab, used in stem cell transplants, can cause delayed immune recovery and increase the risk of infections. In a study with children and adolescents with sickle cell disease, no serious complications like graft-versus-host disease were observed, and survival rates were high, but long-term safety is still being studied. ^{1 2 5 6 7}

How is the stem cell transplant treatment for sickle cell disease unique?

This treatment is unique because it combines alemtuzumab, sirolimus, and total body irradiation to prevent complications like graft-versus-host disease, while allowing for successful stem cell engraftment without sickling crises. It uses a nonmyeloablative approach, meaning it is less intense and potentially safer for children, with promising early results showing no cases of graft failure or GVHD. ^{1 2 4 5 8}

Eligibility Criteria

This trial is for children with sickle cell disease aged 1 to less than 19 years who have had complications like pain crises, stroke, or organ damage despite treatment. They must be eligible for a stem cell transplant and have a related donor who doesn't match their blood type.

Inclusion Criteria

I have sickle cell disease, confirmed by a specific blood test.

I am eligible for a stem cell transplant due to my severe sickle cell disease complications.

Exclusion Criteria

Patients who are unable to comply with or follow the study protocol

You are allergic to sirolimus or any of its ingredients.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Non-myeloablative Conditioning

Participants undergo non-myeloablative conditioning using alemtuzumab, total body irradiation (TBI), and sirolimus for immune suppression

6 weeks

Hematopoietic Stem Cell Transplantation

Participants receive hematopoietic stem cell transplantation from a matched related major ABO-incompatible donor

Immediate post-conditioning

Follow-up

Participants are monitored for safety and effectiveness, including monitoring for pure red cell aplasia (PRCA) and graft failure

24 months

Treatment Details

Interventions

• Alemtuzumab
• Sirolimus
• Total Body Irradiation

Trial Overview The study tests a nonmyeloablative transplant approach using alemtuzumab (an antibody), low-dose total body irradiation, and sirolimus (for immune suppression) in pediatric patients with SCD having ABO-incompatible donors.

Participant Groups

Group I: Non-myeloablative conditioning Experimental Treatment 3 Interventions

Non-myeloablative conditioning

Alemtuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Campath for:

• Chronic lymphocytic leukemia
• Multiple sclerosis

Approved in European Union as Lemtrada for:

• Multiple sclerosis

Approved in European Union as Campath for:

• Chronic lymphocytic leukemia

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Findings from Research

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 population pharmacokinetic model for alemtuzumab was developed using data from 206 pediatric patients, revealing that body weight significantly affects the drug's clearance and distribution, which can lead to variable drug exposure.

The study suggests that the current standard dosing method may not be optimal for all children, and individualized dosing based on this model could improve treatment outcomes and reduce toxicity associated with alemtuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. Admiraal, R., Jol-van der Zijde, CM., Furtado Silva, JM., et al.[2023]

Alemtuzumab, when used in reduced-intensity conditioning for allogeneic stem cell transplantation, significantly reduces the incidence of graft-versus-host disease (GvHD) and treatment-related mortality (TRM), improving patient outcomes in hematological diseases.

However, while it effectively prevents GvHD, alemtuzumab can lead to increased disease relapse and slower immune recovery, necessitating careful monitoring for opportunistic infections and managing the risk of disease recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in allogeneic hematopoetic stem cell transplantation. Poiré, X., van Besien, K.[2021]

CAMPATH-1H (alemtuzumab) is effective in depleting lymphocytes and is licensed for treating chronic lymphocyte leukemia, showcasing its efficacy in managing blood cancers.

Short-term use of alemtuzumab has shown long-term benefits in various autoimmune conditions, suggesting it may help in reducing the need for ongoing immunosuppressive drugs in transplantation and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAMPATH: from concept to clinic. Waldmann, H., Hale, G.[2018]

Alemtuzumab (Campath 1H), a monoclonal antibody targeting CD52 on B and T cells, is increasingly used as a conditioning agent for bone marrow transplantation, but it can have serious side effects.

In a case study of a 37-year-old woman, acute renal failure and disseminated intravascular coagulation (DIC) occurred after receiving Campath, leading to the abortion of her transplant and ongoing dialysis, highlighting the need for caution and further investigation into its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. Osborne, WL., Lennard, AL.[2017]

Patients receiving alemtuzumab induction therapy after renal transplantation showed significantly higher stability rates (96.6%) compared to those on conventional immunosuppressive therapy (75.7%), indicating better outcomes with alemtuzumab.

The ImmuKnow assay revealed that ATP levels, which reflect immune function, were significantly lower in the alemtuzumab group compared to the conventional group at 180 days post-transplant, suggesting that while alemtuzumab effectively maintains stability, it may also lead to reduced immune responsiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of the ImmuKnow assay to evaluate the effect of alemtuzumab-depleting induction therapy on cell-mediated immune function after renal transplantation. Zhou, H., Lin, J., Chen, S., et al.[2021]

In a study of 11 kidney transplant recipients, alemtuzumab induction led to a high patient and graft survival rate of 91% at one year, indicating its efficacy as an induction agent in renal transplantation.

The use of alemtuzumab was found to be safe, with no serious adverse events such as hyperlipidemia or new-onset diabetes, and no cases of acute rejection were observed, even among recipients of extended criteria donor kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab induction in deceased donor kidney transplantation. Shin, M., Song, SH., Kim, JM., et al.[2017]

Alemtuzumab (CAMPATH-1H) is an effective monoclonal antibody for depleting T-cells in stem cell transplantation, significantly reducing the risk of graft-versus-host disease (GVHD) while maintaining low rates of graft rejection.

Current protocols for using alemtuzumab, either added to stem cell infusions or administered before transplantation, show excellent control of GVHD and have been associated with reduced transplant-related mortality, particularly from infections, although further clinical trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in stem cell transplantation. Hale, G.[2021]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Alemtuzumab in allogeneic hematopoetic stem cell transplantation. [2021]

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

CAMPATH: from concept to clinic. [2018]

5. Italy pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. [2017]

6. Japan pubmed.ncbi.nlm.nih.gov

Use of the ImmuKnow assay to evaluate the effect of alemtuzumab-depleting induction therapy on cell-mediated immune function after renal transplantation. [2021]

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

Alemtuzumab induction in deceased donor kidney transplantation. [2017]

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

Alemtuzumab in stem cell transplantation. [2021]