TMLI + Alemtuzumab for Sickle Cell Disease

Recruiting at 1 trial location

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Active malignancy, Active infection, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 38

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for patients with sickle cell disease, a condition that causes pain and other serious health issues. Researchers aim to determine if total marrow and lymphoid irradiation (TMLI, a type of targeted radiation) combined with alemtuzumab (a drug that may stop certain harmful cells) can safely prepare the body for a stem cell transplant. The goal is to reduce complications and improve transplant success. The trial seeks participants with sickle cell disease who experience frequent severe pain crises, strokes, or other significant health problems related to the condition. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that patients receiving other investigational agents, or concurrent biological, chemotherapy, or radiation therapy are excluded, which might imply some restrictions. It's best to discuss your specific medications with the trial team.

What prior data suggests that this conditioning regimen is safe for patients with sickle cell disease?

Research has shown that alemtuzumab, one of the treatments under consideration, can cause serious side effects. These include immune system issues, infusion reactions, and even stroke. Typically, it is administered to patients who have not responded to other treatments, highlighting the importance of understanding the associated risks.

Conversely, studies on total marrow and lymphoid irradiation (TMLI) have shown promising results. TMLI can deliver higher doses of radiation without increasing harmful effects, potentially making it a safer option for preparing patients for a stem cell transplant. This approach targets necessary areas while sparing important organs from damage.

Although the safety of these treatments remains under study, each has distinct risks and benefits. Participants should carefully weigh these factors and discuss them with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TMLI combined with alemtuzumab for treating sickle cell disease because it offers a different approach from standard treatments like hydroxyurea and blood transfusions. TMLI, or Total Marrow and Lymphoid Irradiation, targets the bone marrow with radiation, potentially creating a more conducive environment for a successful stem cell transplant. Alemtuzumab, an antibody therapy, is used to suppress the immune system, which helps reduce the risk of transplant rejection. This combination could improve transplant success rates and offer a new hope for those who haven't had success with conventional therapies.

What evidence suggests that TMLI and alemtuzumab might be an effective treatment for sickle cell disease?

Research shows that alemtuzumab, one of the treatments in this trial, effectively prepares patients with sickle cell disease for stem cell transplants. It increases the likelihood that the new stem cells will successfully settle in the body. Notably, no deaths or cases of graft-versus-host disease (where donor cells attack the patient's body) have occurred in patients using alemtuzumab with total body irradiation. Total marrow and lymphoid irradiation (TMLI), another treatment in this trial, is associated with good survival rates for patients undergoing stem cell transplants. It protects organs from damage and is considered safe and effective for high-risk patients. Together, these treatments offer hope for better outcomes for those with sickle cell disease receiving transplants. ^{4 6 7 8 9}

Who Is on the Research Team?

Anna Pawlowska, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

Assent, when appropriate, will be obtained per institutional guidelines

If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be require.

Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy

Exclusion Criteria

DONOR: Lactating female or, if of child-bearing potential, is unwilling to implement adequate birth control

I have previously undergone radiation therapy.

I am a donor without increased risk from donation procedures.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive alemtuzumab intravenously over 4 hours once daily on days -7 to -3, undergo TMLI twice daily on day -2, and receive sirolimus on day -1 and day 0.

1 week

Daily visits for 7 days

Hematopoietic Cell Transplantation (HCT)

Participants undergo hematopoietic cell transplantation on day 0.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of immune reconstitution and quality of life.

Up to 2 years

Visits on days 30, 100, 180, and at 1 year post-HCT

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• TMLI

Trial Overview 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.

How Is the Trial Designed?

Group I: Treatment (TMLI, alemtuzumab) Experimental Treatment 4 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.

TMLI is already approved in United States for the following indications:

Approved in United States as TMLI for:

• Conditioning regimen for hematopoietic stem cell transplantation in sickle cell disease

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Alemtuzumab, when used in reduced-intensity conditioning for allogeneic stem cell transplantation, significantly reduces the incidence of graft-versus-host disease (GvHD) and treatment-related mortality (TRM), improving patient outcomes in hematological diseases.

However, while it effectively prevents GvHD, alemtuzumab can lead to increased disease relapse and slower immune recovery, necessitating careful monitoring for opportunistic infections and managing the risk of disease recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in allogeneic hematopoetic stem cell transplantation. Poiré, X., van Besien, K.[2021]

In a study of 206 pediatric and young adult patients undergoing reduced-intensity conditioning hematopoietic cell transplantation (HCT), 97% successfully engrafted, indicating high efficacy of the treatment.

Mixed chimerism occurred in 46% of patients, with lower risks observed in those with marrow failure and higher risks in patients receiving cord blood grafts, suggesting that the underlying diagnosis and graft source significantly influence outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen. Marsh, RA., Rao, MB., Gefen, A., et al.[2022]

Alemtuzumab, a monoclonal antibody targeting CD52, shows significant efficacy in treating aggressive T-cell malignancies, achieving a 76% overall response rate in T-PLL patients and a 100% response in CTCL patients, with responses lasting up to 4 years.

While treatment was generally well tolerated, with the main side effects being first-dose reactions and infections due to prolonged lymphopenia, alemtuzumab may also enhance outcomes when combined with high-dose therapy and stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in T-cell malignancies. Dearden, CE., Matutes, E., Catovsky, D.[2019]

Alemtuzumab, a monoclonal antibody targeting CD52, shows significant efficacy in treating B-cell chronic lymphocytic leukaemia (B-CLL), with overall response rates of 21-59% in relapsed patients and over 80% when combined with fludarabine.

The treatment is generally safe, with manageable side effects such as flu-like symptoms and cytopenias, and requires anti-infective prophylaxis due to the risk of infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab. Frampton, JE., Wagstaff, AJ.[2018]

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]

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]

In a study of 38 children with sickle cell disease who underwent matched related donor hematopoietic stem cell transplant using alemtuzumab, all patients successfully engrafted, demonstrating the treatment's efficacy in facilitating successful transplants.

The use of alemtuzumab resulted in very low rates of acute and chronic graft-versus-host disease (GVHD), with a 5-year event-free survival rate of 94.7%, indicating its potential as a safer alternative to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matched related hematopoietic cell transplant for sickle cell disease with alemtuzumab: the Texas Children's Hospital experience. John, TD., Friend, B., Yassine, K., et al.[2022]

In a phase 2 trial involving 25 patients with T-cell large granular lymphocytic leukaemia (T-LGL), 56% of participants achieved a hematological response after treatment with alemtuzumab, indicating its potential efficacy as a therapy for this condition.

While alemtuzumab showed promise in improving blood cell counts, it was associated with significant side effects, including infusion reactions and severe lymphopenia in 88% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study. Dumitriu, B., Ito, S., Feng, X., et al.[2019]

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. 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. •.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0966327425000073

Comparison of outcomes following subcutaneous or ... Subcutaneous administration of alemtuzumab for children undergoing transplant for sickle cell disease is safe and effective. Introduction. Alemtuzumab is a ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06358638

NCT06358638 | Sickle Cell Disease Transplant Using a ... This is a phase 2 study given that the studied nonmyeloablative conditioning backbone (alemtuzumab, 300 cGY TBI, sirolimus) has been previously used effectively ...

5. researchgate.net researchgate.net/publication/281621630_Non-Myeloablative_Stem_Cell_Transplant_with_AlemtuzumabLow_Dose_Irradiation_to_Cure_and_Improve_the_Quality_of_Life_of_Adults_with_Sickle_Cell_Disease

Non-Myeloablative Stem Cell Transplant with ... These results underscore the successful use of a chemotherapy-free regimen in MRD HSCT for high-risk adult SCD patients and demonstrate a high ...

6. lemtrada.com lemtrada.com/about/safety-side-effects

Safety & Side Effects: LEMTRADA® (alemtuzumab) LEMTRADA can cause serious side effects including autoimmune problems, infusion reactions, stroke, tears in your arteries that supply blood to your brain.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/24797180/

Reduced toxicity, myeloablative conditioning with BU, ... We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, ...

8. go.drugbank.com go.drugbank.com/drugs/DB00087

Alemtuzumab: Uses, Interactions, Mechanism of Action Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated ...

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2001/alemmil050701LB.htm

Campath (ALEMTUZUMAB) Package Insert Safety data, except where indicated, are based on 149 patients with B-CLL enrolled in studies of Campath as a single agent administered at a ...