Low-Dose Radiation + Immunosuppressants for Sickle Cell Disease

Not currently 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)

Must be taking: Immunosuppressants

Disqualifiers: Pregnancy, Infections, Organ failure, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find a safer bone marrow transplant (BMT) method for adults with severe sickle cell disease or beta-thalassemia. Instead of chemotherapy, the study tests a combination of low-dose radiation and two immunosuppressive drugs, Alemtuzumab (also known as Campath, Lemtrada, or MabCampath) and Sirolimus (also known as Rapamune), to make BMT possible for those typically excluded due to age or health reasons. Patients with severe complications from sickle cell disease, such as frequent painful crises or organ damage, and who have a well-matched sibling donor, may be good candidates for this study. As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in treatment.

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.

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

Research has shown that the combination of treatments tested in this trial has promising safety results. Alemtuzumab, used in transplant procedures, was well tolerated by patients, with no severe reactions and relatively short hospital stays.

Sirolimus, another drug in the trial, has been studied for sickle cell disease. It proved helpful and did not interfere with other important body functions, suggesting its safety in this context.

Low-dose total body irradiation (TBI) has also been studied and suggested as a safe option for similar transplant procedures. At the doses used in this study, it remains safe and effective without significant side effects.

Overall, these treatments have been well tolerated in past studies, indicating a good safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for sickle cell disease because it combines low-dose radiation with immunosuppressants and a stem cell transplant. Unlike the standard of care, which often includes hydroxyurea or blood transfusions, this approach uses a nonmyeloablative regimen, meaning it’s less intense and potentially safer for patients. The use of alemtuzumab, sirolimus, and total body irradiation in this combination aims to prepare the body to accept healthy stem cells without the harsh side effects of traditional high-dose chemotherapy. Importantly, the infusion of stem cells from an HLA-matched sibling could offer a more effective long-term solution by addressing the root cause of the disease rather than just managing symptoms.

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

Studies have shown that bone marrow transplants (BMT) can cure severe blood disorders like sickle cell disease, especially in children. This trial includes a treatment arm exploring a new BMT method using low-dose radiation and two drugs, alemtuzumab and sirolimus, which might be safer for adults. Alemtuzumab has reduced complications after BMT in sickle cell patients, with no treatment-related deaths reported. Sirolimus helps increase fetal hemoglobin, which benefits sickle cell disease management. Using low doses of radiation aims to lower the risks usually linked with BMT. This combination may offer a promising alternative for adults who are typically at higher risk with traditional BMT methods. ^{2 3 6 7 8}

Who Is on the Research Team?

John F Tisdale, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1.

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.

2.

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.

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06358638

NCT06358638 | Sickle Cell Disease Transplant Using a ...

This multicenter prospective study seeks to determine if daratumumab given, prior to HLA-identical sibling donor transplantation using alemtuzumab, low dose ...

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.

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.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8582053/

Non-myeloablative human leukocyte antigen-matched related ...

In summary, alemtuzumab, low-dose TBI and sirolimus were applied to the largest group of adult patients with SCD; half of them were older than 30 years old. The ...

7.

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.

8.

astctjournal.org

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

Nonmyeloablative Matched Sibling Donor Hematopoietic ...

All recipients tolerated the conditioning regimen well, with no grade 3 or 4 reactions to alemtuzumab. The median length of hospital stay was 7 days from stem ...