Haploidentical Transplant for Chronic Granulomatous Disease

Overseen By Elizabeth M Kang, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Anti-TNF, Anti-interleukin, Anti-integrin

Disqualifiers: Severe colitis, Heart failure, Psychiatric disorders, others

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

Compensation: Varies

Number of Visits: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety of using a partially matched bone marrow donor for individuals with chronic granulomatous disease (CGD), a condition that causes severe infections and inflammation. The study will also evaluate the effectiveness of certain medications, including Alemtuzumab (an immunosuppressive drug), Busulfan (a chemotherapy drug), Cyclophosphamide (a chemotherapy drug), Sirolimus (an immunosuppressant), and Total Body Irradiation (a form of radiation therapy), in helping the body accept the transplanted cells. Participants aged 4-65 with CGD, who face significant health issues like life-threatening infections and lack a perfectly matched donor, are sought for this trial. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants a chance to be among the first to receive this innovative approach.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking certain medications for severe colitis, like prednisone or biologics, you may be excluded from the trial. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, since the trial involves chemotherapy and other treatments, it's possible that some medications might need to be adjusted. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the treatment for chronic granulomatous disease (CGD) using alemtuzumab, busulfan, and total body irradiation has promising safety results from earlier studies. Alemtuzumab has been used successfully, with studies showing high survival rates and good outcomes for CGD patients. One study found that survival improved when alemtuzumab levels were carefully managed.

Busulfan, another component of the treatment, is used with precise dosing to improve results in stem cell transplants for CGD. Research indicates that closely monitored busulfan doses are generally safe.

Total body irradiation is also part of the treatment plan. It has been linked to resolving chronic infections and enhancing quality of life for CGD patients. Overall survival rates have been positive, especially for those without existing infections.

These findings suggest that the treatment is generally well-tolerated when administered with proper care. However, this trial is in an early phase, so the treatment's safety is still under close study. This phase typically involves smaller groups to gather initial safety information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the treatment for Chronic Granulomatous Disease (CGD) using a haploidentical transplant because it offers a new approach compared to traditional bone marrow transplants. Unlike standard treatments, which often require a perfect donor match and use immunosuppressive drugs, this method allows for a partial donor match, making it easier to find suitable donors. Additionally, the combination of Alemtuzumab, Busulfan, and Total Body Irradiation in the treatment plan aims to more effectively prepare the patient’s body to accept the transplant, potentially improving the success rate and reducing complications. This innovative approach could significantly expand treatment options for patients with CGD.

What evidence suggests that this treatment might be an effective treatment for CGD?

Research has shown that alemtuzumab, which participants in this trial will receive, can lower the risk of acute graft-versus-host disease, facilitating the body's acceptance of new cells. Busulfan, also included in this trial's treatment regimen, has improved outcomes for patients with chronic granulomatous disease (CGD) by ensuring a better match between donor and recipient. Total body irradiation, another component of the treatment, has increased the success rate of stem cell transplants in CGD, resulting in fewer infections and an improved quality of life. Together, these treatments aim to make mismatched donor transplants safer and more effective for CGD patients. ^{1 3 6 7 8}

Who Is on the Research Team?

Elizabeth M Kang, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

This trial is for people aged 4-65 with Chronic Granulomatous Disease (CGD) who need a stem cell transplant but don't have a perfect donor match. They must be HIV negative, understand and agree to the study's requirements, and stay near the NIH for three months post-transplant with a companion.

Inclusion Criteria

I have had severe infections or ongoing inflammation that makes me a candidate for a transplant.

I can stay near the NIH for 3 months post-transplant and have someone to stay with me.

I am 65 years old or older.

Exclusion Criteria

Brain CT or MRI findings suggestive of neurologic disorders other than infection

Left ventricular ejection fraction < 40%

I need ongoing treatment with specific medications for my colitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for medical history, physical exam, and tests

Pre-Transplant Preparation

Participants receive drugs, chemotherapy, and radiation to prepare for the transplant

2 weeks

Inpatient hospital stay

Transplantation

Participants receive the donated cells through their catheter

1 day

Inpatient hospital stay

Post-Transplant Hospitalization

Participants stay in the hospital for recovery and monitoring post-transplant

6 weeks

Inpatient hospital stay

Initial Follow-up

Participants have frequent visits for monitoring and care post-transplant

100 days

2 visits per week

Long-term Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 to 6 months

Extended Follow-up

Annual visits for continued monitoring

3 years

Once a year

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Busulfan
• Cyclophosphamide
• Sirolimus
• Total Body Irradiation

Trial Overview The trial tests if using partially matched related bone marrow donors is safe for CGD patients. It involves pre- and post-transplant drugs like Alemtuzumab, Busulfan, Cyclophosphamide, Sirolimus, and Total Body Irradiation to help the body accept the new cells.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 6 Interventions

This is a single arm open-label pilot study.

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?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

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 single-center study involving four patients with chronic granulomatous disease (CGD) showed that a reduced-intensity conditioning regimen (RIC) using alemtuzumab and other agents led to early immune recovery and a low rate of infections post-transplant.

The study reported a 75% disease-free survival rate at a median follow-up of five years, suggesting that this RIC approach is a viable alternative for CGD patients who cannot tolerate traditional busulfan-based conditioning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single-center experience using alemtuzumab, fludarabine, melphalan, and thiotepa as conditioning for transplantation in pediatric patients with chronic granulomatous disease. Bhatt, ST., Schulz, G., Hente, M., et al.[2020]

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 72 patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), both in vitro T-cell depletion (TCD) methods (like CD34 selection) and in vivo TCD using alemtuzumab showed similar effectiveness in terms of overall survival and relapse rates.

While in vivo TCD led to more significant early lymphocyte suppression and a higher incidence of CMV reactivations, it did not increase the risk of treatment-related mortality, indicating that both TCD approaches are viable options for improving HSCT outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT. Marek, A., Stern, M., Chalandon, Y., et al.[2021]

In a study involving 10 patients with chronic granulomatous disease, a reduced intensity conditioning regimen for allogeneic hematopoietic stem-cell transplantation showed promising results, with 8 out of 10 patients alive and well after a median follow-up of at least 2 years.

The use of donor lymphocyte infusion in three patients who developed mixed donor chimerism suggests a potential strategy to enhance treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Experience of Donor Lymphocyte Infusion after Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease. Rostami, T., Kiumarsi, A.[2020]

A reduced-intensity conditioning regimen for allogeneic hematopoietic stem-cell transplantation in patients with chronic granulomatous disease resulted in a high overall survival rate of 93% and event-free survival of 89% after a median follow-up of 21 months, indicating its efficacy in high-risk patients.

The regimen demonstrated a low incidence of serious complications, with only 5% experiencing graft failure and 4% developing severe acute graft-versus-host disease, suggesting it is a safe option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Güngör, T., Teira, P., Slatter, M., et al.[2022]

Transplantation of G-CSF-primed unmanipulated bone marrow from haploidentical donors shows promising results in patients with hematologic malignancies, indicating a potential new treatment option.

This approach could make haploidentical transplantation more accessible in various transplant centers, expanding treatment opportunities for patients who need bone marrow transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haplo-BMT: which approach? Velardi, A.[2021]

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]

Alemtuzumab, when used in vivo after reduced-intensity conditioning for allografts, leads to durable engraftment and significantly reduces graft-versus-host disease (GVHD), but it also causes impaired immune recovery and increased risk of infections.

In vitro use of alemtuzumab showed similar benefits for engraftment and GVHD reduction without severely affecting immune recovery, and reducing the dose from 20 mg to 10 mg improved outcomes, suggesting that dose optimization is crucial for better clinical results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab (Campath-1H) in allogeneic stem cell transplantation: where do we go from here? Chakrabarti, S., Hale, G., Waldmann, H.[2017]

A 22-year-old male with chronic granulomatous disease successfully underwent an allogeneic hematopoietic stem cell transplant, which is notable as he was older than most patients typically treated for this condition.

The patient achieved engraftment by day 13 post-transplant and remains healthy 12 months later, with no serious complications or signs of graft-versus-host disease, indicating the procedure's efficacy and safety in this case.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplant for high-risk adult patients with chronic granulomatous disease: first case report from Iran. Ramzi, M., Rezvani, A., Haghighinejad, H.[2019]

In a study of 42 pediatric patients undergoing haploidentical hematopoietic cell transplantation, the use of αβ(+) T-cell-depleted grafts led to successful neutrophil engraftment in all patients within a median of 10 days, indicating effective transplantation.

The approach significantly reduced transplant-related mortality to 2.6% and showed promising 2-year event-free survival rates of 88% for non-malignant diseases and 50% for hematologic malignancies, suggesting it is a viable option for patients without suitable donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ(+) cells by add-back after a reduced intensity preparative regimen containing low-dose TBI. Im, HJ., Koh, KN., Suh, JK., et al.[2018]

In a study of 18 patients with steroid-refractory acute graft-versus-host disease (aGVHD), alemtuzumab treatment resulted in an 83% response rate, with 33% achieving complete response by day 28.

While alemtuzumab was generally well tolerated, it did lead to significant infections in 14 patients, including cytomegalovirus reactivation, and some cases of severe neutropenia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Gómez-Almaguer, D., Ruiz-Argüelles, GJ., del Carmen Tarín-Arzaga, L., et al.[2022]

In a Phase I/II study involving 41 patients with relapsed refractory cancer, haploidentical transplantation using 100 cGy of total body irradiation (TBI) and CD3+ cell infusion showed promising safety and efficacy, with 14 responses observed, including 5 durable complete responses in acute myelogenous leukemia (AML) patients.

The treatment demonstrated effectiveness through mechanisms such as graft-versus-tumor (GVT) activity and breaking host tolerance to tumors, indicating that this nonimmunosuppressive approach could be a viable option for patients with refractory AML and lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonengraftment haploidentical cellular immunotherapy for refractory malignancies: tumor responses without chimerism. Colvin, GA., Berz, D., Ramanathan, M., et al.[2022]

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Alemtuzumab and CXCL9 levels predict likelihood of ... The overall survival was higher in patients with day 0 alemtuzumab levels >0.32 μg/mL at 1 year (Figure 5A). However, survival in that group ...

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Stem Cell Transplant + Drug Therapy for Chronic ... ... alemtuzumab and busulfan, is a curative treatment for Chronic Granulomatous Disease. Studies have reported successful outcomes with high survival rates and ...