Reduced Toxicity Conditioning for Thalassemia

Recruiting at 1 trial location

Overseen By Yogi Chopra, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: The Hospital for Sick Children

Disqualifiers: Cardiac dysfunction, Renal impairment, Hepatic dysfunction, Active infections, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new transplant approach for people with thalassemia who rely on regular blood transfusions. It focuses on reducing transplant side effects using two medications, abatacept (Orencia) and sirolimus (Rapamune), to prevent post-procedure complications. Participants should have confirmed thalassemia with high-risk factors, such as difficulty managing iron levels or severe transfusion reactions. Those with these thalassemia-related challenges and a compatible family member donor may find this trial suitable. As a Phase 1/Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that abatacept is generally safe for patients. In studies, it extended patients' lives and reduced the risk of complications after transplants. Some participants experienced infections such as colds or bronchitis, but these were uncommon. Research in individuals with thalassemia demonstrated that sirolimus positively affected blood health. Sirolimus is also under study for its effects on the immune system. Both treatments have undergone safety testing and appear to be well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of abatacept and sirolimus for thalassemia because this approach aims to reduce the toxicity traditionally associated with conditioning regimens used before bone marrow transplants. Unlike standard treatments that often involve high-dose chemotherapy or radiation, this regimen incorporates pre-transplant immunosuppression to prepare the body, which may lead to fewer side effects. Additionally, by using abatacept and sirolimus as graft-versus-host disease (GVHD) prophylaxis, the treatment targets the immune system more precisely, potentially reducing the risk of GVHD while maintaining transplant effectiveness. This innovative angle could improve the safety and success rates of transplants for patients with thalassemia.

What evidence suggests that this trial's treatments could be effective for thalassemia?

This trial will evaluate a treatment regimen involving abatacept and sirolimus for patients undergoing transplants. Research has shown that abatacept can extend patient survival by reducing the risk of graft-versus-host disease (GVHD), a common and serious issue. One study found that 100% of patients survived without thalassemia when using abatacept, compared to 71% without it. For sirolimus, studies indicate it benefits patients with beta-thalassemia by improving blood levels, such as hemoglobin and red blood cells, which are often low in these patients. Together, these treatments aim to make transplants safer and more successful for people with thalassemia. ^{1 3 4 6 7}

Who Is on the Research Team?

Yogi Chopra, MD

Principal Investigator

The Hospital for Sick Children

Are You a Good Fit for This Trial?

This trial is for kids and teens (1-18 years old) with high-risk thalassemia, which requires regular blood transfusions. They should have a sibling or family donor for bone marrow transplant, not be eligible for gene therapy, and able to take oral meds. Excluded are those with severe organ dysfunction, active infections like HIV/hepatitis B/C, previous transplants or gene therapy, pregnant women or significant allergies to the treatment drugs.

Inclusion Criteria

I can take pills and will follow the study plan.

I've had a full iron status check and recent MRI scans of my heart and liver.

I am not eligible for gene therapy.

Exclusion Criteria

Patients will be excluded if they demonstrate significant functional deficits in major organs, which could interfere with the outcome following bone marrow transplant, including: Cardiac: Evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of < 50% with absence of improvement with exercise), marked cardiomegaly or uncontrollable hypertension. Renal: Evidence of > 50% reduction in expected creatinine clearance or GFR < 60mL/min/1.73m2. Hepatic: Evidence of hepatic dysfunction evidenced by a serum direct (conjugate) bilirubin of > 2.5 mg/dl, or ALT > 5 times the upper limit of normal for age. Pulmonary: Evidence of focal or diffuse active infection or pneumonitis and the patient demonstrates a FEV1 < 50% or carbon monoxide diffusing capacity (DLCO) of < 50% predicted value (adjusted for hemoglobin). The patient should not require ventilation support. Presence of donor specific antibody (DSA) with mean fluorescence intensity (MFI) greater than 3,000. Previous stem cell transplant or gene therapy. Presence of cardiomyopathy with a T2* < 10ms per Cardiac MRI. Presence of significant liver iron deposition defined as liver iron content >15mg/g liver dry weight. If iron chelation were optimized and reassessment within 6 months shows a decrease of LIC to <15 with no evidence of cardiomyopathy, patient may still be considered for enrollment. Active HIV, hepatitis B or hepatitis C disease. Severe liver cirrhosis or bridging fibrosis on liver biopsy if previously done. Prior or current malignancy or myeloproliferative or immunodeficiency disorder. Evidence of active, deep seated, life-threatening infections despite therapy (e.g., certain fungal species, HIV, etc.). Patients will be excluded if they are women of childbearing potential who are currently pregnant (b-HCG+) or who are not practicing adequate contraception. Any condition that would preclude serial follow up. Patients with a known life-threatening allergy to components of the pre transplant immunosuppression (fludarabine), conditioning (treosulfan, cyclophosphamide or anti-thymocyte globulin) or graft versus host prophylactic regimen (abatacept, sirolimus). Any condition or diagnosis, that could in the opinion of the Principal Investigator or delegate interfere with the participant's ability to comply with study instructions, might confound the interpretation of the study results, or put the participant at risk

My eligibility is not affected by my sex, race, or ethnicity.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-transplant Immunosuppression

Administration of pre-transplant immunosuppression as part of the reduced-toxicity conditioning regimen

2 weeks

Transplant and GVHD Prophylaxis

Allogeneic transplant with abatacept and sirolimus as GVHD prophylaxis

100 days

Follow-up

Participants are monitored for safety and effectiveness after transplant, including immune reconstitution and GVHD assessment

365 days

What Are the Treatments Tested in This Trial?

Interventions

• Abatacept
• Sirolimus

Trial Overview The study tests a new transplant method using two drugs: Abatacept and Sirolimus in children with thalassemia who need frequent blood transfusions. The goal is to see if this approach can improve long-term outcomes after bone marrow transplantation from family donors.

How Is the Trial Designed?

Group I: PTIS followed by abatacept and sirolimus Experimental Treatment 2 Interventions

Administration of reduced-toxicity conditioning regimen combined with pre-transplant immunosuppression, followed by abatacept and sirolimus as graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant with either Human Leukocyte Antigen (HLA)-matched sibling donors or haploidentical donors

Abatacept is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in United States as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in Canada as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Approved in Japan as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

Thalassemia Foundation of Canada

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

In a pilot clinical trial involving 8 patients with β-thalassemia, low-dose sirolimus (1 mg/day) significantly increased the expression of γ-globin mRNA, which is beneficial for patients as it can lead to higher fetal hemoglobin levels.

Sirolimus treatment also reduced markers of ineffective erythropoiesis and decreased the transfusion demand in 7 out of 8 patients, demonstrating its potential efficacy and safety, with only minor side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin). Zuccato, C., Cosenza, LC., Zurlo, M., et al.[2022]

In a pilot study of 10 children with severe aplastic anemia, the combination of extended T cell costimulation blockade (COSBL) using Abatacept with post-transplantation cyclophosphamide (PTCy) significantly reduced the incidence of acute graft-versus-host disease (GVHD) to 10.5%, compared to 50% in the control group.

The COSBL group also showed improved outcomes with lower rates of chronic GVHD (12.5% vs 56%) and cytomegalovirus (CMV) reactivation (30% vs 80%), along with a higher percentage of regulatory T cells (Tregs), suggesting that this treatment may enhance transplantation tolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Jaiswal, SR., Bhakuni, P., Zaman, S., et al.[2018]

A new approach to allogeneic hematopoietic stem cell transplantation (allo-SCT) for severe thalassemia using haploidentical donors resulted in over 96% overall and event-free survival at 3 years among 83 patients, demonstrating high efficacy.

The introduction of pharmacologic adjustments, including bortezomib and rituximab for patients with high anti-donor-specific HLA antibodies, eliminated graft failures in the last 52 patients, indicating a safe and effective strategy for improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using a Novel Conditioning Regimen. Anurathapan, U., Hongeng, S., Pakakasama, S., et al.[2021]

In a study of 24 children with beta-thalassemia major undergoing stem cell transplants, adding abatacept to standard GVHD prophylaxis resulted in a significant reduction in severe acute GVHD incidence by day +100, with no cases of grades III-IV GVHD compared to 50% in the standard group.

The addition of abatacept did not affect engraftment rates and led to a higher thalassemia-free survival rate of 100% in the abatacept group versus 62.5% in the standard group, indicating its potential as a safe and effective enhancement to GVHD prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Graft-versus-host Disease Prophylaxis With Abatacept Reduces Severe Acute Graft-versus-host Disease in Allogeneic Hematopoietic Stem Cell Transplant for Beta-thalassemia Major With Busulfan, Fludarabine, and Thiotepa. Khandelwal, P., Yeh, RF., Yu, L., et al.[2021]

Sirolimus treatment in β-Thalassemia patients positively affects the activity and quantity of memory CD4+ and CD8+ T cells, enhancing their ability to release IFN-γ in response to antigenic stimulation.

This study suggests that Sirolimus may improve immune responses in β-Thalassemia patients, who are typically at risk for immune deficiency, indicating its potential as a therapeutic strategy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Sirolimus treatment on patients with &#946;-Thalassemia: Lymphocyte immunophenotype and biological activity of memory CD4+ and CD8+ T cells. Zurlo, M., Nicoli, F., Proietto, D., et al.[2023]

Drug repositioning offers a promising strategy for developing treatments for β-thalassemia, as it utilizes existing drugs that have already undergone extensive safety testing, significantly reducing the risk of project failure.

Repurposed drugs, like sirolimus (rapamycin), not only have established safety profiles but also can expedite the time to market, making them attractive options for treating rare diseases like β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs. Prosdocimi, M., Zuccato, C., Cosenza, LC., et al.[2022]

Citations

1. ashpublications.org ashpublications.org/bloodadvances/article-pdf/doi/10.1182/bloodadvances.2025017197/2412364/bloodadvances.2025017197.pdf

Abatacept Improves Post-Transplant Survival and Reduces ... We hypothesized that the addition of abatacept to standard GVHD prophylaxis would reduce the incidence of endothelial injury syndromes and improve survival ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2473952925005750/pdf?md5=9e93b1503eeeb7e792353630ba0b7d83&pid=1-s2.0-S2473952925005750-main.pdf

Abatacept Improves Post-Transplant Survival and Reduces ... Thalassemia-free survival was 100% in the abatacept cohort and 71% in the no abatacept cohort. Addition of abatacept to calcineurin inhibitor based acute GVHD ...

3. answers.childrenshospital.org answers.childrenshospital.org/gvhd-abatacept/

Abatacept prevents GVHD after bone marrow transplant The drug abatacept appears to block GVHD pathways, making bone marrow transplant an option for people with an imperfect (7/8) donor match.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9943961/

Role of abatacept in the prevention of graft-versus-host disease The results of the study showed abatacept to be safe. The results also led to improved chronic scores (44%) and a significant reduction ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa050524

Abatacept for Rheumatoid Arthritis Refractory to Tumor ... At six months, all primary and secondary outcomes were improved in the abatacept group as compared with the placebo group. Clinical improvements in ACR 20 and ...

6. cri-net.com cri-net.com/ckfinder/userfiles/files/fiches-pratiques/abatacept_english_feb2012/10_Specific_situations_dialysis_hemoglobinopathy_splenectomy.pdf

Specific situations: dialysis, hemoglobinopathy, splenectomy The risk of fluid overload with cardiac decompensation after intravenous abatacept administration is low in hemodialysis patients, as the amount of saline ...

7. orenciahcp.com orenciahcp.com/safety-data.html

Safety Data | ORENCIA® (abatacept) The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1%), bronchitis (0.7%), and herpes zoster (0.7%).