Alemtuzumab Dosing for Bone Marrow Transplant

Overseen By Richard Cooper

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Disqualifiers: Anaphylaxis to alemtuzumab, Dialysis, Cancer, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 days

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Alemtuzumab is an antibody that reduces the strength of the immune system that is given in preparation for allogeneic hematopoietic cell transplant (HCT). In this research study the investigators want to find out if they can adjust the dose of alemtuzumab used as part of allogeneic HCT to target the level of Day 0 (the planned day of graft infusion) to an optimal therapeutic window of 0.15-0.9 ug/mL.

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the drug Alemtuzumab for bone marrow transplant?

Research shows that Alemtuzumab can help reduce the risk of acute graft-versus-host disease (a condition where the donor's immune cells attack the recipient's body) after bone marrow transplants. It has been effective in achieving rapid engraftment (when the transplanted cells start to grow and make healthy blood cells) and maintaining high survival rates in patients. ^{1 2 3 4 5}

What safety data exists for Alemtuzumab in bone marrow transplant patients?

Alemtuzumab, also known as Campath, has been used in bone marrow transplants but can cause delayed immune recovery, viral reactivations, and leukemia relapse. Some patients have experienced serious side effects like acute kidney failure and blood clotting issues, although these are rare. ^{1 4 5 6 7}

How is the drug alemtuzumab unique in bone marrow transplant treatment?

Alemtuzumab is unique in bone marrow transplant treatment because it is used in very low doses to reduce the risk of graft-versus-host disease (GVHD) while allowing for rapid engraftment of neutrophils and platelets. Its dosing is tailored to achieve specific serum concentrations that minimize immune system complications, making it different from standard treatments that may not have such precise dosing strategies. ^{1 2 3 4 8}

Research Team

Parinda Mehta, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

This trial is for patients aged 6 weeks to 30 years who need a bone marrow transplant due to non-malignant diseases and are getting an alemtuzumab-based treatment. Initially, only those with a perfect donor match or receiving selected stem cells can join. After review, others may be eligible. Exclusions include life expectancy under 4 weeks, previous alemtuzumab use without clearance, dialysis or plasmapheresis at the start of treatment, cancer diagnosis, severe skin conditions preventing subcutaneous dosing, and history of allergy to alemtuzumab.

Inclusion Criteria

I am between 6 weeks and 30 years old.

I have a perfect match donor for my stem cell transplant.

I am getting a stem cell transplant with alemtuzumab for a non-cancerous disease.

Exclusion Criteria

I have not signed and cannot sign the informed consent form.

Life expectancy less than 4 weeks

I cannot receive injections due to severe skin conditions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive alemtuzumab subcutaneously over days -14, -13, and -12 in preparation for allogeneic hematopoietic cell transplant

3 days

3 visits (in-person)

Transplantation

Day 0 is the planned day of graft infusion for allogeneic hematopoietic cell transplant

1 day

1 visit (in-person)

Follow-up

Participants are monitored for alemtuzumab levels, acute GVHD, mixed chimerism, and immune recovery

100 days

Treatment Details

Interventions

• Alemtuzumab

Trial Overview The study tests if adjusting the dose of Alemtuzumab can achieve optimal levels in the blood on Day 0 (day of graft infusion) for better outcomes in allogeneic hematopoietic cell transplantation (HCT). The goal is to maintain drug levels between 0.2-0.6 ug/mL.

Participant Groups

Group I: Alemtuzumab Experimental Treatment 1 Intervention

Patients will be given 10 mg/m2 alemtuzumab divided over days -14, -13, and -12. The first dose should be limited to no more than 3 mg per the manufacturer's recommendation. If the calculated daily dose is greater than 3 mg, the first dose (day -14) should be limited to 3 mg and the remainder of the dosing should be divided over days -13 and -12. Alemtuzumab will be drawn into a sterile syringe and given to patients subcutaneously.

Alemtuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Campath for:

• Chronic lymphocytic leukemia
• Multiple sclerosis

Approved in European Union as Lemtrada for:

• Multiple sclerosis

Approved in European Union as Campath for:

• Chronic lymphocytic leukemia

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Findings from Research

In a study of 37 high-risk leukemia patients undergoing transplantation, a low dose of 10-20 mg of alemtuzumab was used, resulting in rapid neutrophil and platelet engraftment with minimal severe acute graft-versus-host disease (GvHD) cases.

After a median follow-up of 371 days, 70% of patients were alive and in complete remission, indicating that this dosing strategy is effective and safe for patients undergoing allogeneic transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and clinical activity of very low-dose alemtuzumab in transplantation for acute leukemia. Spyridonidis, A., Liga, M., Triantafyllou, E., et al.[2021]

A study involving 29 pediatric and young adult patients showed that individualized dosing of alemtuzumab, based on body weight or surface area, can optimize drug levels for better outcomes in hematopoietic cell transplantation (HCT).

The research identified a specific therapeutic range for alemtuzumab (0.15-0.6 μg/mL) that is associated with improved HCT results, highlighting the importance of precise dosing to achieve effective lymphodepletion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Model-informed precision dosing for alemtuzumab in paediatric and young adult patients undergoing allogeneic haematopoietic cell transplantation. Dong, M., Emoto, C., Fukuda, T., et al.[2022]

In a study of 12 patients with aggressive CD52-positive hematologic malignancies, low-dose alemtuzumab (10 mg daily) combined with cyclophosphamide and total body irradiation effectively prevented grade III/IV acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, with no cases reported.

All patients experienced rapid engraftment, achieving significant donor chimerism by 3 months post-transplant, and at a median follow-up of 14.7 months, seven patients were alive and five were disease-free.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose alemtuzumab (Campath) in myeloablative allogeneic stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host-disease with unique pharmacokinetics. Khouri, IF., Albitar, M., Saliba, RM., et al.[2017]

A population pharmacokinetic model for alemtuzumab was developed using data from 206 pediatric patients, revealing that body weight significantly affects the drug's clearance and distribution, which can lead to variable drug exposure.

The study suggests that the current standard dosing method may not be optimal for all children, and individualized dosing based on this model could improve treatment outcomes and reduce toxicity associated with alemtuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. Admiraal, R., Jol-van der Zijde, CM., Furtado Silva, JM., et al.[2023]

In a study of 11 kidney transplant recipients, alemtuzumab induction led to a high patient and graft survival rate of 91% at one year, indicating its efficacy as an induction agent in renal transplantation.

The use of alemtuzumab was found to be safe, with no serious adverse events such as hyperlipidemia or new-onset diabetes, and no cases of acute rejection were observed, even among recipients of extended criteria donor kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab induction in deceased donor kidney transplantation. Shin, M., Song, SH., Kim, JM., et al.[2017]

Alemtuzumab (Campath 1H), a monoclonal antibody targeting CD52 on B and T cells, is increasingly used as a conditioning agent for bone marrow transplantation, but it can have serious side effects.

In a case study of a 37-year-old woman, acute renal failure and disseminated intravascular coagulation (DIC) occurred after receiving Campath, leading to the abortion of her transplant and ongoing dialysis, highlighting the need for caution and further investigation into its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. Osborne, WL., Lennard, AL.[2017]

In a study of 10 kidney transplant recipients treated with alemtuzumab, long-term immunosuppressive therapy was found to influence the balance of T-regulatory and Th17 cells, which are important for immune response regulation.

The research demonstrated that T-regulatory cells can effectively suppress Th17 cell activity, suggesting a potential mechanism for managing immune responses in patients undergoing long-term immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Th17 cells in alemtuzumab-treated patients: the effect of long-term maintenance immunosuppressive therapy. Hester, J., Mills, N., Shankar, S., et al.[2022]

In a study of 53 children undergoing hematopoietic stem cell transplantation, high exposure to alemtuzumab was linked to delayed T-cell reconstitution and an increased risk of graft failure, highlighting the need for careful dosing.

The developed pharmacokinetics model allows for individualized dosing of alemtuzumab, aiming to optimize T-cell recovery and minimize graft failure in pediatric patients with nonmalignant diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of alemtuzumab in pediatric allogeneic HSCT for nonmalignant diseases: the ARTIC study. Achini-Gutzwiller, FR., Schilham, MW., von Asmuth, EGJ., et al.[2023]

References

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

Pharmacokinetics and clinical activity of very low-dose alemtuzumab in transplantation for acute leukemia. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Model-informed precision dosing for alemtuzumab in paediatric and young adult patients undergoing allogeneic haematopoietic cell transplantation. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Low-dose alemtuzumab (Campath) in myeloablative allogeneic stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host-disease with unique pharmacokinetics. [2017]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. [2023]

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

Alemtuzumab induction in deceased donor kidney transplantation. [2017]

6. Italy pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. [2017]

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

Th17 cells in alemtuzumab-treated patients: the effect of long-term maintenance immunosuppressive therapy. [2022]

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

Exposure-response analysis of alemtuzumab in pediatric allogeneic HSCT for nonmalignant diseases: the ARTIC study. [2023]