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

4 Participants Needed

Trial Summary

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.

What data supports the idea that Haploidentical Transplant for Chronic Granulomatous Disease is an effective treatment?

The available research shows that Haploidentical Transplant for Chronic Granulomatous Disease can be effective. In one study, a reduced-intensity conditioning regimen led to a 75% disease-free survival rate at a median of five years after transplant. Another study reported that 8 out of 10 patients were alive and well after at least two years of follow-up. These results suggest that this treatment can lead to positive outcomes for many patients. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment for chronic granulomatous disease?

Research shows that using a combination of drugs like alemtuzumab and busulfan in stem cell transplants can be effective for chronic granulomatous disease, with studies reporting successful outcomes and survival rates. For example, one study reported a 75% disease-free survival rate at five years, and another case showed a patient doing well one year after transplant. ^{1 2 3 4 5}

What safety data exists for Haploidentical Transplant for Chronic Granulomatous Disease using Alemtuzumab and other treatments?

Alemtuzumab (Campath) is used in hematopoietic cell transplantation to prevent graft-versus-host disease (GVHD) and graft failure. Safety concerns include delayed immune reconstitution, viral reactivations, and leukemia relapse. Studies show that alemtuzumab can reduce GVHD but may impair immune recovery and increase infection risk. Lower doses of alemtuzumab have been associated with reduced GVHD and better outcomes. In treating steroid-refractory acute GVHD, alemtuzumab showed promising response rates but was associated with infections and cytomegalovirus reactivation. Overall, alemtuzumab is well-tolerated but requires careful dosing to balance efficacy and safety. ^{5 6 7 8 9}

Is alemtuzumab generally safe for use in humans?

Alemtuzumab has been used in various transplant settings and is generally well-tolerated, but it can cause delayed immune recovery, leading to increased risk of infections and viral reactivations. It has shown promising response rates in treating certain conditions, but careful dosing is important to minimize side effects. ^{5 6 7 8 9}

Is the treatment Alemtuzumab, Busulfan, Total Body Irradiation promising for Haploidentical Transplant in Chronic Granulomatous Disease?

Yes, the treatment shows promise as it helps in reducing graft failure and transplant-related mortality, and supports successful engraftment in patients who lack a suitable donor. ^{5 10 11 12 13}

How is the haploidentical transplant treatment for Chronic Granulomatous Disease unique?

This treatment is unique because it uses a combination of alemtuzumab, busulfan, and total body irradiation to prepare the body for a haploidentical transplant, which involves using a partially matched donor. This approach aims to reduce the risk of graft failure and transplant-related complications, making it a novel option for patients who lack a fully matched donor. ^{5 10 11 12 13}

What is the purpose of this trial?

Background: CGD causes infections and inflammation. The only cure currently is a bone marrow transplant. Most often a perfectly matched bone marrow donor is used. Researchers want to see if they can lower the risks of using a mismatched donor. Objectives: To see if it is safe to use a related bone marrow donor who is only a partial match to a person with CGD. To see how well drugs given to a person before and after transplant help the body accept the transplant. Eligibility: People ages 4-65 with CGD for whom stem cell transplant may be a cure and who do not have a perfectly matched donor, related or unrelated. Design: Participants will be screened with: Medical history Physical exam Blood tests Participants will be admitted to the hospital about 2 weeks before the transplant. They will have blood, urine, breathing, and heart tests. They may have CT and/or MRI scans. They will have a needle inserted into their hipbone to remove marrow. They will have dental, neurologic, and psychologic tests. They will have a central catheter placed: A line will be placed into a vein in their upper chest. They will get drugs, chemotherapy, and radiation to prepare for the transplant. Participants will receive the donated cells through their catheter. The cells will be from one of their relatives. Participants will stay in the hospital about 6 weeks after the transplant. After they leave the hospital, participants will have to stay in the area with visits about 2 times a week for approximately 100 days post transplant. Then visits will be every 3 to 6 months for 2 years. Then visits will be once a year.

Research Team

Elizabeth M Kang, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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 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 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]

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 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 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]

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]

References

1. United States 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. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

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

3. England 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. [2022]

4. Turkey pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplant for high-risk adult patients with chronic granulomatous disease: first case report from Iran. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Alemtuzumab (Campath-1H) in allogeneic stem cell transplantation: where do we go from here? [2017]

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

Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. [2022]

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

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

9. England pubmed.ncbi.nlm.nih.gov

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

10. England 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. [2018]

11. England pubmed.ncbi.nlm.nih.gov

The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT. [2021]

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

Nonengraftment haploidentical cellular immunotherapy for refractory malignancies: tumor responses without chimerism. [2022]

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

Haplo-BMT: which approach? [2021]