TMLI + Alemtuzumab for Sickle Cell Disease

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Anna Pawlowska, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Active malignancy, Active infection, others

No Placebo Group

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

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.

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 data supports the effectiveness of the drug Alemtuzumab for treating sickle cell disease?

Alemtuzumab, when used in combination with hematopoietic stem cell transplantation, has shown promise in treating sickle cell disease by achieving successful donor-recipient engraftment and preventing sickling crises in patients. Additionally, Alemtuzumab is effective in reducing complications like graft-versus-host disease in other hematological conditions, suggesting potential benefits for sickle cell disease treatment. ^{1 2 3 4 5}

Is the combination of TMLI and Alemtuzumab generally safe for humans?

Alemtuzumab has been used in various treatments and is generally considered safe with predictable and manageable side effects, such as flu-like symptoms after the first dose, which can be minimized with medication. In studies involving hematopoietic cell transplantation, Alemtuzumab has shown low rates of graft-versus-host disease and treatment-related mortality, indicating a favorable safety profile. ^{1 2 5 6 7}

How is the TMLI + Alemtuzumab treatment different from other treatments for sickle cell disease?

The TMLI + Alemtuzumab treatment is unique because it combines targeted radiation (TMLI) with a monoclonal antibody (Alemtuzumab) to prepare the body for a stem cell transplant, potentially reducing complications like graft-versus-host disease (GVHD) and improving transplant success in sickle cell disease. ^{1 2 4 5 8}

Research Team

Anna Pawlowska, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Alemtuzumab (Monoclonal Antibodies)
• TMLI (Radiation)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

Robert Stone

City of Hope Medical Center

Chief Executive Officer since 2014

Juris Doctorate from the University of Chicago, Bachelor's degree in Political Science from the University of Redlands

Sumanta (Monty) Pal

City of Hope Medical Center

Chief Medical Officer since 2023

MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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 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]

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]

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]

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 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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Alemtuzumab in allogeneic hematopoetic stem cell transplantation. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Alemtuzumab in T-cell malignancies. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Alemtuzumab clearance, lymphocyte count, and T-cell chimerism after hematopoietic stem cell transplant in sickle cell disease. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Alemtuzumab. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Matched related hematopoietic cell transplant for sickle cell disease with alemtuzumab: the Texas Children's Hospital experience. [2022]

7. United States 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study. [2019]