Transplant Method for Sickle Cell Disease

(SUN Trial)

Recruiting at 6 trial locations

Overseen By Fahmida Hoq, MBBS

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Robert Nickel

Disqualifiers: HIV, Hepatitis B/C, Pregnancy, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial uses a combination of drugs and mild radiation to help children with sickle cell disease receive treatment from a sibling. It aims to reduce side effects while maintaining high cure rates. The focus is on children who need a safer treatment option.

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.

What data supports the effectiveness of the drug Alemtuzumab (Campath) in treating sickle cell disease?

Alemtuzumab has been shown to effectively deplete lymphocytes, which helps in immunosuppression during transplants, and has demonstrated clinical activity in certain T-cell diseases, improving survival in some patients. This suggests it may help in managing immune responses in sickle cell disease transplants. ^{1 2 3 4 5}

Is the transplant method for sickle cell disease using Alemtuzumab generally safe in humans?

Alemtuzumab has been used in various transplant settings, but it can cause serious side effects like delayed immune recovery, viral infections, and in rare cases, kidney failure and blood clotting issues. Its safety profile includes significant immune system suppression, which can lead to infections. ^{2 3 4 5 6}

How is the treatment for sickle cell disease using Alemtuzumab, Low Dose Total Body Irradiation, and Sirolimus different from other treatments?

This treatment is unique because it combines Alemtuzumab, which depletes immune cells to prevent rejection, with low-dose total body irradiation and Sirolimus to prevent graft-versus-host disease, offering a nonmyeloablative (less intense) approach that has shown promising results in children with sickle cell disease, achieving high survival rates without sickling crises. ^{2 3 5 7 8}

Research Team

Robert Nickel, MD

Principal Investigator

Children's National Health System

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Alemtuzumab (Monoclonal Antibodies)
• Low Dose Total Body Irradiation (Other)
• Sirolimus (Other)

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.

Participant Groups

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).

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+

Findings from Research

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]

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]

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 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]

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]

References

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

Alemtuzumab in peripheral T-cell malignancies. [2017]

2. Italy pubmed.ncbi.nlm.nih.gov

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

3. 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]

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

Th17 cells in alemtuzumab-treated patients: the effect of long-term maintenance immunosuppressive therapy. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. [2018]

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

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

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

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