What side effects are associated with this type of intervention?

Common side effects of stem cell transplantation treatments involving low dose radiation and immunosuppressive drugs such as cyclophosphamide, pentostatin, and sirolimus include increased risk of infections due to immunosuppression, gastrointestinal issues like nausea and diarrhea, liver enzyme elevation, and potential bone marrow suppression. Specific to cyclophosphamide, there can be risks of hemorrhagic cystitis and cardiotoxicity. Sirolimus may cause hyperlipidemia, hypertension, and delayed wound healing. Overall, patients may also experience fatigue, hair loss, and mucositis. Close monitoring and supportive care are essential to manage these side effects.

What prior FDA approvals exist?

FDA approvals for treatments related to stem cell transplantation often include the use of immunosuppressive drugs and conditioning regimens to enhance donor stem cell acceptance. For instance, cyclophosphamide is a commonly approved immunosuppressive agent used in various conditioning regimens. Sirolimus, another immunosuppressive drug, is also approved and used to prevent graft-versus-host disease (GVHD) post-transplant. While specific approvals for low dose radiation in this context are less common, the combination of these immunosuppressive drugs with radiation is a recognized strategy to improve engraftment and reduce transplant-related complications.

What other types of research exist?

Promising novel alternatives for enhancing donor stem cell acceptance in stem cell transplantation patients include nonmyeloablative regimens, which use lower intensity conditioning to reduce toxicity while maintaining efficacy. Additionally, novel agents like imetelstat, an antisense oligonucleotide targeting telomerase, have shown potential in clinical studies. The 'Beijing Protocol' for haplo-identical hematopoietic stem cell transplantation is another innovative approach that has been refined to improve outcomes. These strategies aim to enhance donor stem cell acceptance with reduced treatment-related toxicity.

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Immunosuppressive Agent

Nonmyeloablative Stem Cell Transplant for Sickle Cell Anemia and Thalassemia

Phase 2

Waitlist Available

Led By Matthew M Hsieh, M.D.

Research Sponsored by National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

-Age greater than or equal to 4 years

--E. Sickle hepatopathy defined as EITHER ferritin >1000mcg/L OR direct bilirubin >0.4 mg/dL at baseline

Must not have

Major anticipated illness or organ failure incompatible with survival from PBSC transplant

ECOG performance status of 3 or more

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests if using low dose radiation and certain drugs can help patients with beta-thalassemia or sickle cell disease better accept donor stem cells. The treatment aims to suppress the immune system to reduce rejection of the new cells.

Who is the study for?

This trial is for people aged 4 and older with severe sickle cell disease or beta-thalassemia, who are at high risk of complications not improved by other treatments. They must have a matched family donor willing to donate stem cells. Exclusions include serious infections within the last month, pregnancy, lactation, or any major illness that could interfere with transplant survival.

What is being tested?

The study tests a new transplant method using low-dose radiation and immunosuppressive drugs (cyclophosphamide, pentostatin, sirolimus) to see if they help patients better accept donated stem cells. Participants will undergo various procedures including blood tests and bone marrow sampling before receiving the treatment in hospital.

What are the potential side effects?

Potential side effects may include reactions to medication like cyclophosphamide or alemtuzumab such as nausea and hair loss; organ inflammation from sirolimus; skin irritation from radiotherapy; immune system weakening leading to increased infection risk.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am at least 4 years old.

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I have sickle cell-related liver issues with high ferritin or bilirubin levels.

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I have kidney problems due to sickle cell disease, including high creatinine, low filtration rate, or need for dialysis.

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I have a family donor who is a complete match for my transplant.

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I have beta-thalassemia with moderate to severe iron overload.

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I have severe sickle cell disease with major organ damage or complications not improved by current treatments.

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I have had a stroke confirmed by an MRI or need regular transfusions due to artery issues in my brain.

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I have severe sickle cell disease not improved by standard treatments.

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I have beta-thalassemia with significant iron overload.

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I have had acute chest syndrome twice or once while on hydroxyurea.

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My liver extends more than 2cm below my rib cage.

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I've been hospitalized at least 3 times last year for pain crises, even while on treatment.

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I need regular blood transfusions and my hemoglobin doesn't improve much on hydroxurea.

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I have had at least 2 long-lasting erections.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have any major illnesses or organ failures that would make a stem cell transplant impossible.

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I need considerable assistance and am unable to carry out any work activities.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Number of Participants With Donor Red Cells at 2 Years Post Stem Cell Transplant

Number of Patients Who Have Sustained Donor Type Hemoglobin at One Year Post Transplant

Secondary study objectives

Mean CD3+ Cell Dose

Mean CD34+ Cell Dose

Median Day to Neutrophil Recovery

+10 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplantExperimental Treatment5 Interventions

Participants with pre-existing antibodies and Sickle Cell Disease (SCD) or Beta-thalassemia receiving stem cell transplant. Pentostatin given on days -21, -17, -13, -9 and oral cyclophosphamide from days -21 to -8, with the intention to be administered in the outpatient setting. Alemtuzumab on days 7 to 3, and 300 cGy TBI on day 2. Sirolimus started at a loading dose of 5mg PO every 4 hours for three doses on day -1 and adjusted to maintain trough levels between 10-15 ng/mL. The PBSC graft targeted to deliver .10 x 106 CD34+ cells/kg (minimum .5 x 106) and infused on day 0.

Group II: Human Leukocyte Antigens (HLA) Matched Related Stem Cell DonorExperimental Treatment1 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.

Group III: Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donorExperimental Treatment5 Interventions

Female participants with Sickle Cell Disease (SCD) or Beta-thalassemia receiving stem cell transplant with male donor. Pentostatin given on days -21, -17, -13, -9 and oral cyclophosphamide from days -21 to -8, with the intention to be administered in the outpatient setting. Alemtuzumab on days 7 to 3, and 300 cGy TBI on day 2. Sirolimus started at a loading dose of 5mg PO every 4 hours for three doses on day -1 and adjusted to maintain trough levels between 10-15 ng/mL. The PBSC graft targeted to deliver .10 x 106 CD34+ cells/kg (minimum .5 x 106) and infused on day 0.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Filgrastim

2000

Completed Phase 3

~3690

Alemtuzumab

2004

Completed Phase 4

~1880

Sirolimus

2013

Completed Phase 4

~2750

Cyclophosphamide

2010

Completed Phase 4

~2310

Pentostatin

2000

Completed Phase 3

~1300

Radiotherapy

2017

Completed Phase 3

~2610

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments in stem cell transplantation, such as low dose radiation, cyclophosphamide, pentostatin, and sirolimus, work by suppressing the recipient's immune system to enhance donor stem cell acceptance. Low dose radiation and cyclophosphamide reduce bone marrow activity and immune response, lowering the risk of rejection and graft-versus-host disease (GVHD). Pentostatin depletes lymphocytes by inhibiting adenosine deaminase, while sirolimus prevents T-cell activation and proliferation. These mechanisms are vital for increasing the success of engraftment and minimizing complications in stem cell transplantation patients.

Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease.