What side effects are associated with this type of intervention?

Common treatments for Sickle Cell Disease, such as Total Marrow and Lymphoid Irradiation (TMLI) and Alemtuzumab, have several known side effects. TMLI can cause fatigue, nausea, and increased risk of infections due to bone marrow suppression. Alemtuzumab may lead to infusion reactions, increased susceptibility to infections, and potential autoimmune complications. Both treatments can also contribute to graft-versus-host disease (GVHD) when used in stem cell transplantation.

What prior FDA approvals exist?

The FDA has approved several treatments for Sickle Cell Disease, including hydroxyurea, which reduces the frequency of pain crises, and L-glutamine, which helps reduce complications. More recently, voxelotor and crizanlizumab have been approved; voxelotor improves hemoglobin levels, while crizanlizumab reduces the frequency of vaso-occlusive crises. While TMLI and Alemtuzumab are being studied as conditioning regimens for stem cell transplantation, the FDA has not yet approved these specific therapies for SCD. However, hematopoietic stem cell transplantation remains a potential curative option for SCD, with ongoing research into optimizing conditioning regimens and reducing complications like graft-versus-host disease.

What other types of research exist?

Promising novel alternatives for Sickle Cell Disease treatment in 2024 include: 1) Gene therapy approaches such as CRISPR-Cas9 and lentiviral vector-based therapies, which aim to correct the genetic defect causing SCD. 2) Voxelotor, a hemoglobin S polymerization inhibitor that improves hemoglobin levels and reduces hemolysis. 3) L-glutamine, which reduces oxidative stress and the frequency of vaso-occlusive crises. 4) Crizanlizumab, a monoclonal antibody targeting P-selectin, which reduces the frequency of pain crises by preventing the adhesion of sickled cells to blood vessel walls.

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Radiation

TMLI + Alemtuzumab for Sickle Cell Disease

Phase 1

Recruiting

Led By Joseph Rosenthal

Research Sponsored by City of Hope Medical Center

Eligibility Criteria Checklist

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

Must have

Age: 2-40 years

Creatinine clearance (CrCl) of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 30 days prior to day 1 of protocol)

Must not have

DONOR: Prior radiation therapy

Prior allogeneic or autologous stem cell transplant

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of a special type of radiation and a drug to prepare patients with sickle cell disease for a procedure that replaces their bone marrow. The treatment helps clear out the old bone marrow and prevents complications, making it easier for new cells to grow. The goal is to ensure the new cells are accepted by the body and reduce the risk of rejection and other issues. The drug has been used successfully in treating certain types of blood cancers.

Who is the study for?

This trial is for people aged 2-40 with sickle cell disease who've had severe pain crises or other complications despite treatment, and have a related donor matched on at least 8/10 HLA markers. Participants must be in relatively good health with proper organ function and not pregnant, breastfeeding, or have any active infections or malignancies.

What is being tested?

The trial tests TMLI and alemtuzumab as a conditioning regimen before stem cell transplantation in sickle cell patients. The goal is to prepare the body for new blood cells, reduce rejection risk, minimize radiation damage to organs, and lower GVHD chances after transplant.

What are the potential side effects?

Potential side effects include immune system reactions due to alemtuzumab that may affect organ function; risks associated with radiation therapy like fatigue and skin changes; plus typical transplant-related complications such as infection risk increase.

Eligibility Criteria

Inclusion Criteria

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

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I am between 2 and 40 years old.

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My kidney function, measured by creatinine clearance, is good.

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I have a donor who matches at least 8 out of 10 of my HLA markers.

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I have sickle cell disease with a history of stroke or high risk of stroke.

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I am a woman who can have children and my pregnancy test is negative.

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I've had severe pain crises yearly despite treatment.

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I am 60 years old or younger.

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I have a donor who matches at least 8 out of 10 of my HLA markers.

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I have bone damage in two or more joints despite receiving care.

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I have sickle cell disease and am at high risk for serious health problems.

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I am 60 years old or younger.

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My kidney function, measured by creatinine clearance, is good.

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I've had 8 or more blood transfusions yearly for over a year to prevent complications.

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I have had regular blood transfusions (8 or more per year) for over a year to prevent complications.

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I've had severe pain crises yearly despite treatment in the last 2 years.

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My blood clotting time is within the target range for my anticoagulant therapy.

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My blood clotting time is within the normal range and I'm not on blood thinners.

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I have had a stroke or lasting neurological issues.

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I have bone damage in two or more joints despite receiving care.

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I can take care of myself but might not be able to do heavy physical work.

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I've had one or more acute chest syndrome episodes in the last 2 years despite treatment.

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I have had one or more episodes of acute chest syndrome in the last 2 years despite treatment.

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My blood clotting time is within the target range for my anticoagulant therapy.

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I have had repeated priapism treated by a doctor.

Exclusion Criteria

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

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I have previously undergone radiation therapy.

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I have had a stem cell transplant before.

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I am not currently on any experimental treatments or undergoing chemotherapy or radiation.

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I, as a donor, cannot undergo certain medical procedures due to health reasons.

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I am not pregnant or breastfeeding.

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I am currently taking antibiotics for an infection.

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I do not have any active cancer except for non-melanoma skin cancers.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 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

Feasibility

Incidence of adverse events

Secondary study objectives

Disease-free Survival (DFS)

Event-free survival (EFS)

Overall survival (OS)

+3 more

Other study objectives

Bone marrow environment inflation - levels of inflammatory cytokines

Bone Marrow

Immune cell reconstitution

+2 more

Side effects data

From 2010 Phase 2 trial • 21 Patients • NCT00060424

48%

Neutropenia

10%

Death following disease progression post transplant

10%

Thrombocytopenia

10%

Hyperbilirubinemia

10%

Hypoxia

Typhlitis & Bowel Perforation

Death following progression of GVHD

Cardiac Arrhythmia and Seizure

Death: Sepsis/Renal failure/ with history of GVHD

Severe abnormal pain due to gut GVH

Acute Pulmonary Embolism

Perforated sigmoid diverticulitis

Minimal hydronephosis

Cholecystectomy

Hypotension

Increased creatinine

Neurotoxicity

Renal failure

Tumor lysis syndrome

100%

80%

60%

40%

20%

Study treatment Arm

Treatment (Enzyme Inhibitor, Transplant, GVHD Prophylaxis)

Awards & Highlights

No Placebo-Only Group

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

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (TMLI, alemtuzumab)Experimental Treatment4 Interventions

Patients receive alemtuzumab IV over 4 hours QD on days -7 to -3. Patients undergo TMLI BID on day -2. Patients also undergo HCT on day 0 and receive sirolimus on day -1 and day 0.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Intensity-Modulated Radiation Therapy

2010

Completed Phase 3

~2160

Alemtuzumab

2004

Completed Phase 4

~1880

Hematopoietic Cell Transplantation

2006

Completed Phase 2

~360

Sirolimus

2013

Completed Phase 4

~2750

0 / 31Eligibility 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

Hydroxyurea is a cornerstone treatment for Sickle Cell Disease (SCD) that works by increasing fetal hemoglobin production, which reduces the sickling of red blood cells and decreases vaso-occlusive crises. Red blood cell transfusions help by diluting the sickled cells with normal red blood cells, thereby reducing the risk of complications like stroke and severe pain episodes. Total Marrow and Lymphoid Irradiation (TMLI) and Alemtuzumab are investigational therapies used as conditioning regimens for stem cell transplantation. TMLI targets the bone marrow and lymphoid tissues to make space for new stem cells, while Alemtuzumab, a monoclonal antibody, reduces the risk of graft-versus-host disease by depleting immune cells that might attack the transplanted cells. These treatments are crucial for SCD patients as they aim to reduce the frequency and severity of painful crises, improve quality of life, and potentially offer a curative option through stem cell transplantation.

A reanalysis of pain crises data from the pivotal l-glutamine in sickle cell disease trial.Advances in the management of sickle cell disease.