Low-Dose Radiation + Immunosuppressants for Sickle Cell Disease

Recruiting at 1 trial location

Overseen By Christina C Luckett

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

130 Participants Needed

Trial Summary

What is the purpose of this trial?

People with severe congenital anemias, such as sickle cell anemia and beta-thalassemia, have been cured with bone marrow transplantation (BMT). The procedure, however, is limited to children younger than the age of 16 because the risks are lower for children than for adults. The purpose of this study is to explore the use of a BMT regimen that, instead of chemotherapy, uses a low dose of radiation, combined with two immunosuppressive drugs. This type BMT procedure is described as nonmyeloablative, meaning that it does not destroy the patient s bone marrow. It is hoped that this type of BMT will be safe for patients normally excluded from the procedure because of their age and other reasons. To participate in this study, patients must be between the ages of 18 and 65 and have a sibling who is a well-matched stem-cell donor. Beyond the standard BMT protocol, study participants will undergo additional procedures. The donor will receive G-CSF by injection for five days; then his or her stem cells will be collected and frozen one month prior to BMT. Approximately one month later, the patient will be given two immune-suppressing drugs, Campath 1-H and Sirolimus, as well as a single low dose of total body irradiation and then the cells from the donor will be infused. Prior to their participation in this study, patients will undergo the following evaluations: a physical exam, blood work, breathing tests, heart-function tests, chest and sinus x-rays, and bone-marrow sampling. ...

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, since the study involves taking immunosuppressive drugs and radiation, it's best to discuss your current medications with the study team to ensure there are no interactions.

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

Research shows that using a combination of low-dose radiation, immunosuppressants like Alemtuzumab and Sirolimus, and a stem cell transplant from a matched sibling donor can be effective for treating sickle cell disease. In a study with children and adolescents, this approach led to 100% survival rates without sickling crises, and no cases of graft-versus-host disease were observed. ^{1 2 3 4 5}

Is the treatment with Alemtuzumab generally safe for humans?

Alemtuzumab has been used in various treatments and is generally considered to have an acceptable safety profile, but it can cause side effects like delayed immune recovery, viral reactivations, and infusion reactions. In rare cases, it has been associated with serious conditions like acute kidney failure and blood clotting issues. Careful monitoring and preventive measures can help manage these risks. ^{2 5 6 7 8}

How is the treatment for sickle cell disease using low-dose radiation and immunosuppressants different from other treatments?

This treatment is unique because it combines low-dose total body irradiation with immunosuppressants like Alemtuzumab and Sirolimus to prepare the body for a peripheral blood stem cell transplant, aiming to cure sickle cell disease. Unlike traditional treatments, this approach uses a nonmyeloablative regimen, meaning it is less intense and potentially safer, especially for children, while still achieving successful engraftment without sickling crises. ^{1 2 5 6 9}

Research Team

John F Tisdale, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for adults aged 18-65 with severe congenital anemias like sickle cell disease, who have a sibling as a stem-cell donor. Participants must meet specific health criteria such as normal organ function and not be pregnant or lactating. Those with uncontrolled infections or significant heart/lung problems are excluded.

Inclusion Criteria

I am over 18 and have high ferritin or bilirubin levels indicating liver issues.

I need regular blood transfusions.

You must have one of the following diseases:

Exclusion Criteria

Recipient:

Transaminases greater than 5 times the upper limit of normal for age

Baseline oxygen saturation or less than 85% or PaOa2 less than 70

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-transplant Preparation

Donor receives G-CSF injections for five days, and stem cells are collected and frozen one month prior to BMT. Patients undergo evaluations including physical exam, blood work, and imaging.

4-5 weeks

Transplantation

Patients receive two immune-suppressing drugs, a single low dose of total body irradiation, and infusion of donor stem cells.

1 week

Daily visits during treatment

Follow-up

Participants are monitored for safety, effectiveness, and engraftment success. Monitoring includes assessment of donor-host chimerism and incidence of GVHD.

Up to 2 years

Regular visits (frequency not specified)

Treatment Details

Interventions

• Alemtuzumab
• Peripheral blood hematopoietic progenitor cell Apherisis
• Peripheral blood hematopoietic progenitor cell (PBPC) transplant
• Sirolimus
• Total Body Irradiation

Trial Overview The study tests a bone marrow transplant (BMT) method using low-dose radiation and immunosuppressive drugs Alemtuzumab and Sirolimus, instead of chemotherapy. This nonmyeloablative BMT aims to be safer for patients normally too old for traditional BMT.

Participant Groups

Group I: Participants with Severe Beta-globin Disorders in Allogeneic Peripheral Blood Stem Cell Transplants Experimental Treatment 3 Interventions

Nonmyeloablative transplant regiment, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells from human leukocyte antigen-matched siblings.

Group II: Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor Experimental Treatment 1 Intervention

Participants received Filgrastim to mobilize peripheral blood stem cells for apheresis collection. Collected stem cells of donor will then be infused to HLA matched sibling.

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?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

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]

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]

In a study of 22 adult patients with sickle cell disease undergoing matched related donor HSCT, higher levels of alemtuzumab 14 days post-transplant were associated with better T-cell engraftment at 2 and 4 months, indicating that adequate lymphodepletion may improve transplant outcomes.

The pharmacokinetics showed that alemtuzumab was detectable for up to 28 days post-HSCT, with significant differences in serum levels and half-lives between two treatment regimens, suggesting that the choice of regimen can impact drug clearance and potentially influence patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab clearance, lymphocyte count, and T-cell chimerism after hematopoietic stem cell transplant in sickle cell disease. Furstenau, D., Peer, CJ., Hughes, TE., et al.[2022]

A reduced-toxicity conditioning regimen (BFA) before HLA-matched sibling donor transplantation in children with sickle cell disease resulted in a 100% event-free survival (EFS) and overall survival (OS) over two years, indicating high efficacy.

The study, involving 18 pediatric patients, showed a low incidence of grade II-IV acute graft-versus-host disease (GVHD) at 17%, along with stable or improved organ function, highlighting the safety of the BFA regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. Bhatia, M., Jin, Z., Baker, C., 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]

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) 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]

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]

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

Alemtuzumab clearance, lymphocyte count, and T-cell chimerism after hematopoietic stem cell transplant in sickle cell disease. [2022]

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

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. [2021]

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. 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 in peripheral T-cell malignancies. [2017]

8. England pubmed.ncbi.nlm.nih.gov

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

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

Clinical evaluation of busulfan, cladribine and alemtuzumab as reduced intensity conditioning for stem cell transplantation. [2017]