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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to stem cell transplants for children with sickle cell disease. The goal is to determine if a milder method of preparing the body for a stem cell transplant is safe and effective. This method uses specific drugs, including Alemtuzumab (also known as Campath, Lemtrada, or MabCampath) and Sirolimus (also known as Rapamune), along with Total Body Irradiation (TBI), to help manage the immune system. It may suit children and teens with sickle cell disease who experience complications like frequent pain episodes, strokes, or lung problems, even while on regular medication. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from a potentially effective new therapy.

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.

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

Previous studies have shown that alemtuzumab can cause serious side effects, including immune system problems, infusion reactions, and even strokes. It is typically given to patients who have not responded to other treatments. Sirolimus, in contrast, may cause allergic reactions, nausea, weakness, and skin rashes, but it shows potential benefits for patients with sickle cell disease. Researchers have studied total body irradiation (TBI) at various doses to assess its effectiveness in stem cell transplants, and it has been used safely at lower doses for this purpose.

In summary, while each treatment carries risks, they are employed in specific ways to expand the availability of stem cell transplants for more people with sickle cell disease. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sickle cell disease?

Researchers are excited about this treatment for sickle cell disease because it involves using a combination of stem cell transplant with alemtuzumab, sirolimus, and total body irradiation. Unlike traditional treatments like hydroxyurea or blood transfusions that primarily manage symptoms, this approach aims to correct the underlying genetic cause of the disease. The use of non-myeloablative conditioning is particularly innovative because it is less intense than traditional methods, potentially reducing side effects and making the procedure safer for more patients. This novel strategy could offer a long-term solution, potentially leading to a cure rather than just symptom management.

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

In this trial, participants will receive a combination of alemtuzumab, sirolimus, and total body irradiation (TBI) as part of a non-myeloablative conditioning regimen for stem cell transplants to treat sickle cell disease. Research has shown that alemtuzumab helps the new stem cells settle successfully in the patient's body. Sirolimus increases fetal hemoglobin, which benefits people with sickle cell disease, and also reduces the risk of graft-versus-host disease (GVHD). When used carefully, TBI has led to successful long-term outcomes in over 90% of children receiving stem cell transplants for sickle cell disease. Overall, these treatments hold promise for improving patients' lives by making stem cell transplants safer and more effective. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39904467/

Comparison of outcomes following subcutaneous or ... We found that subcutaneous alemtuzumab administration elicited fewer infusion-related reactions than intravenously administered drug.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9338787/

Alemtuzumab clearance, lymphocyte count, and T-cell ... Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0966327425000073

Comparison of outcomes following subcutaneous or ... Subcutaneous administration of alemtuzumab for children undergoing transplant for sickle cell disease is safe and effective. Introduction. Alemtuzumab is a ...

4. astctjournal.org astctjournal.org/article/S1083-8791(15)00597-2/fulltext

Nonmyeloablative Stem Cell Transplantation with ... No treatment-related mortality or graft-versus-host disease occurred after alemtuzumab/total body irradiation conditioning in sickle cell disease adults. •.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06358638

NCT06358638 | Sickle Cell Disease Transplant Using a ... This is a phase 2 study given that the studied nonmyeloablative conditioning backbone (alemtuzumab, 300 cGY TBI, sirolimus) has been previously used effectively ...

6. lemtrada.com lemtrada.com/about/safety-side-effects

Safety & Side Effects: LEMTRADA® (alemtuzumab) LEMTRADA can cause serious side effects including autoimmune problems, infusion reactions, stroke, tears in your arteries that supply blood to your brain.

7. go.drugbank.com go.drugbank.com/drugs/DB00087

Alemtuzumab: Uses, Interactions, Mechanism of Action Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2001/alemmil050701LB.htm

Campath (ALEMTUZUMAB) Package Insert Safety data, except where indicated, are based on 149 patients with B-CLL enrolled in studies of Campath as a single agent administered at a ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/24797180/

Reduced toxicity, myeloablative conditioning with BU, ... We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, ...