Transplant Method for Sickle Cell Disease

(SUN Trial)

Recruiting at 7 trial locations

Overseen By Fahmida Hoq, MBBS

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Robert Nickel

Disqualifiers: HIV, Hepatitis B/C, Pregnancy, 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

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new transplant method for children with sickle cell disease (SCD) that may reduce harmful side effects. It combines alemtuzumab (also known as Campath, Lemtrada, or MabCampath), low-dose radiation, and sirolimus (also called Rapamune) to determine if this approach can effectively cure SCD. Children who have experienced severe symptoms, such as multiple pain crises, strokes, or frequent hospitalizations due to SCD, may be suitable candidates for this trial. The goal is to find a safer, more effective treatment option for children facing this challenging condition. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering hope for improved treatment options.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves a transplant procedure, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.

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

Research has shown that the treatment plan for this trial, called the SUN regimen, appears promising in terms of safety based on past studies. Alemtuzumab, a key component of this plan, has been used in children with sickle cell disease. Studies have found it safe and effective when administered as an injection under the skin.

Another part of the treatment is low-dose total body irradiation, which has been used in similar situations and is generally considered safe, especially at low doses. This approach helps reduce side effects while maintaining effectiveness.

Lastly, sirolimus, a medication in the regimen, has been studied for its effects on sickle cell disease. Research has shown it to be safe for long-term use, particularly when the dose is carefully controlled.

These findings from past research suggest that the treatments in the SUN regimen are generally well-tolerated and safe for children with sickle cell disease. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for sickle cell disease, which often involves blood transfusions and hydroxyurea, the SUN regimen uses a combination of alemtuzumab, low dose total body irradiation, and sirolimus. This method focuses on a nonmyeloablative approach, meaning it aims to reduce toxicity while maintaining a high cure rate. Researchers are excited about this approach because it uses HLA-identical sibling donor transplantation, which could offer a more targeted and potentially safer alternative for children with sickle cell disease. By minimizing the harsh side effects typically associated with transplants, this regimen offers hope for better outcomes and improved quality of life.

What evidence suggests that this transplant method is effective for sickle cell disease?

Research has shown that the SUN regimen, which participants in this trial will receive, uses a less intense treatment combination of alemtuzumab, low-dose total body irradiation, and sirolimus, and can be effective for sickle cell disease. Previous studies found that this combination lowers transplant-related risks and improves patient outcomes. Importantly, no treatment-related deaths or severe complications, such as graft-versus-host disease (where donor cells attack the patient's body), occurred in adults with sickle cell disease. These findings suggest that this treatment could be a safer and effective option for children with sickle cell disease. ^{2 6 7 8 9}

Who Is on the Research Team?

Robert Nickel, MD

Principal Investigator

Children's National Research Institute

Are You a Good Fit for This Trial?

This trial is for children with Sickle Cell Disease who have had complications like stroke, frequent pain or acute chest syndrome despite treatment. They must not have severe liver, heart, kidney, lung problems or a history of certain blood reactions and should not be pregnant.

Inclusion Criteria

I have received 8 or more blood transfusions in the last year.

I have had two or more episodes of severe chest pain in my life.

I have had two or more acute coronary syndrome episodes in the last 2 years.

Exclusion Criteria

- General: Life expectancy less than 6 months. Pregnant or breastfeeding patients.

I do not have any uncontrolled infections or active Hepatitis B/C or HIV.

My lung function is severely reduced.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo nonmyeloablative conditioning with alemtuzumab, low dose total-body irradiation, and sirolimus

1-2 weeks

Transplantation

HLA-identical sibling donor transplantation is performed

1 day

Post-Transplant Monitoring

Participants are monitored for acute GVHD and other outcomes

100 days

Regular visits for monitoring

Follow-up

Participants are monitored for long-term outcomes including donor engraftment and quality of life

365 days

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Low Dose Total Body Irradiation
• Sirolimus

Trial Overview The study tests a transplant method using alemtuzumab (an antibody), low dose radiation, and sirolimus (an immune system regulator) in siblings with matching tissue types to treat SCD with potentially less toxicity than traditional methods.

How Is the Trial Designed?

Group I: SUN regimen Experimental Treatment 1 Intervention

Alemtuzumab, low dose total body irradiation, Sirolimus HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).

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?

Robert Nickel

Lead Sponsor

Trials

1

Recruited

100+

Allistair Abraham, MD

Lead Sponsor

Trials

1

Recruited

100+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

The Children's Hospital at Montefiore

Collaborator

Trials

3

Recruited

5,002,000+

Morgan Stanley Children's Hospital

Collaborator

Trials

10

Recruited

5,012,000+

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

Alberta Children's Hospital

Collaborator

Trials

58

Recruited

44,700+

The Hospital for Sick Children

Collaborator

Trials

724

Recruited

6,969,000+

Levine Children's Hospital

Collaborator

Trials

4

Recruited

560+

Ann & Robert H Lurie Children's Hospital of Chicago

Collaborator

Trials

275

Recruited

5,182,000+

Published Research Related to This Trial

Alemtuzumab (CAMPATH-1H) has shown significant clinical activity in treating mature T-cell diseases, with over two-thirds of patients with T-cell prolymphocytic leukemia (T-PLL) and more than 50% of patients with cutaneous T-cell lymphoma (CTCL) responding to treatment.

The safety profile of alemtuzumab is generally acceptable, with manageable side effects such as infusional reactions and prolonged lymphopenia, which can be mitigated through careful monitoring and prophylactic measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in peripheral T-cell malignancies. Dearden, C.[2017]

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]

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]

CAMPATH (alemtuzumab) is an effective treatment for chronic lymphocytic leukemia (CLL), particularly in cases that are resistant to chemotherapy, and it has an acceptable safety profile.

This monoclonal antibody targets CD52, which is found on many lymphocytes but not on hematopoietic progenitor cells, allowing for effective treatment of CLL while sparing the cells needed for blood production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAMPATH (alemtuzumab) for the treatment of chronic lymphocytic leukemia and beyond. Dumont, FJ.[2017]

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]

Alemtuzumab induction therapy in kidney transplantation significantly reduces the risk of biopsy-proven acute rejection (BPAR) compared to interleukin-2 receptor antibodies (IL-2RAs), with a relative risk of 0.54 based on a systematic review of 10 randomized controlled trials involving 1223 patients.

There was no significant difference in the risk of BPAR when comparing alemtuzumab to rabbit antithymocyte globulin (rATG), and other outcomes like graft loss and patient death were similar across induction methods, suggesting that safety and cost may guide the choice of induction therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Morgan, RD., O'Callaghan, JM., Knight, SR., et al.[2018]

In a study of 10 kidney transplant recipients treated with alemtuzumab, long-term immunosuppressive therapy was found to influence the balance of T-regulatory and Th17 cells, which are important for immune response regulation.

The research demonstrated that T-regulatory cells can effectively suppress Th17 cell activity, suggesting a potential mechanism for managing immune responses in patients undergoing long-term immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Th17 cells in alemtuzumab-treated patients: the effect of long-term maintenance immunosuppressive therapy. Hester, J., Mills, N., Shankar, S., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06358638

NCT06358638 | Sickle Cell Disease Transplant Using a ... The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26348889/

Nonmyeloablative Stem Cell Transplantation with ... Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1083879115005972

Adult 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.

4. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT06358638/

Trial | NCT06358638 The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8459571/

Stem cell transplantation in sickle cell disease - PubMed Central Allogeneic transplantation in SCD has evolved and improved over the last two decades, now offering a standard of care curative option using an HLA-matched ...

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

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

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

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

8. astctjournal.org astctjournal.org/article/S1083-8791(19)30136-3/fulltext

Nonmyeloablative Matched Sibling Donor Hematopoietic ... The study is a retrospective single center analysis of alemtuzumab/300 cGy total body irradiation (TBI) matched sibling donor peripheral blood hematopoietic ...

9. researchgate.net researchgate.net/publication/281621630_Non-Myeloablative_Stem_Cell_Transplant_with_AlemtuzumabLow_Dose_Irradiation_to_Cure_and_Improve_the_Quality_of_Life_of_Adults_with_Sickle_Cell_Disease

Non-Myeloablative Stem Cell Transplant with ... Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely performed in adult patients with sickle cell disease (SCD).