Stem Cell Transplant + Drug Therapy for Chronic Granulomatous Disease

Overseen By Sandra M Maxwell, R.N.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

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

Disqualifiers: Heart failure, Lung disease, Psychiatric disorder, others

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

Compensation: Varies

Number of Visits: 3

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to improve the success of stem cell transplants for individuals with chronic granulomatous disease (CGD), a condition that weakens the immune system and increases the likelihood of frequent infections. Researchers seek to determine if a new combination of drug treatments, including Alemtuzumab (an immunosuppressive drug), Busulfan (a chemotherapy drug), Cyclophosphamide (a chemotherapy drug), and Emapalumab-Izsg (an immunotherapy drug), can enhance the effectiveness of stem cell transplants. Participants will receive a series of medications and radiation before receiving donor stem cells through a catheter. This trial may suit those with CGD who experience complications like ongoing inflammation or infections despite preventive treatment. Participants must stay near the hospital for follow-up care after the transplant. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol 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 to get specific guidance based on your situation.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatments in this clinical trial have varying safety levels. Here's a simple breakdown:

Alemtuzumab has undergone extensive study. It can increase the risk of infections and other complications, including a higher chance of death from infections. However, it has been used successfully for other conditions, so its risks are known and manageable.

Busulfan is often used in stem cell transplants and is carefully monitored to achieve the best results. It is administered in precise doses to minimize side effects, but it can temporarily impair the body's ability to produce enough blood cells.

Emapalumab generally has a good safety record, with most people tolerating it well. However, serious side effects like infections can still occur. It is approved for another condition, so doctors understand its effects on the body.

Tocilizumab is another drug used in this trial. While it can lead to serious infections, its safety has been well-documented in various conditions. It is commonly used in medical settings, which helps doctors manage any side effects.

Total Body Irradiation is part of the treatment plan for this trial. Although it can cause side effects, it is a standard component of many stem cell transplant procedures and effectively prepares the body to accept new cells.

Overall, while these treatments have risks, they are well-studied, and doctors know how to manage their side effects. Participants will be closely monitored to ensure safety throughout the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for Chronic Granulomatous Disease (CGD) because it combines stem cell transplants with innovative drug therapies that enhance the immune system in unique ways. Unlike traditional treatments that focus mainly on antibiotics and antifungals to manage infections, this approach uses Alemtuzumab, Busulfan, and Cyclophosphamide to prepare the body for a stem cell transplant, potentially offering a long-term solution. Additionally, Emapalumab-Izsg targets specific immune pathways to reduce inflammation, which is not a focus of current standard therapies. This combination not only aims to replace defective immune cells but also modulates the immune response, offering a comprehensive approach to tackling CGD.

What evidence suggests that this trial's treatments could be effective for chronic granulomatous disease?

Research has shown that stem cell transplants can effectively cure chronic granulomatous disease (CGD), but they don't always succeed on their own. In this trial, participants in different arms will receive various treatment combinations to improve success rates.

In Arm 1, participants will receive alemtuzumab and busulfan, which have shown promise in reducing complications like acute GVHD (graft-versus-host disease) and improving transplant outcomes.

In Arm 2, participants will receive emapalumab, which has been effective in controlling severe immune responses in other conditions, potentially aiding successful transplants.

Both arms will include tocilizumab to manage inflammation, helping stabilize patients during treatment. Together, these treatments aim to increase the chances of a successful stem cell transplant for those with CGD. ^{1 2 3 6 7}

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 have complications from the disease or a specific level of oxidase production. They must not be HIV positive, pregnant, or breastfeeding and should agree to use contraception. Participants need an HLA-matched stem cell donor and must stay close to the NIH post-transplant.

Inclusion Criteria

Stated willingness to comply with all study procedures and is available for protocol visits for the duration of the study when possible.

I have been diagnosed with Chronic Granulomatous Disease (CGD).

I have a donor match for my transplant.

Exclusion Criteria

I do not have an active TB infection.

Ejection fraction of less than 30% by echocardiography.

My lung function tests show severe limitations.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Conditioning and Transplantation

Participants receive conditioning regimen including Alemtuzumab, Busulfan, and TBI, followed by donor stem cell transplantation

10-21 days

In-hospital stay

Post-Transplant Recovery

Participants remain in the hospital for recovery and monitoring after receiving donor stem cells

6 weeks

In-hospital stay

Initial Follow-up

Participants visit the clinic for monitoring and assessment of engraftment and infection rates

3 months

2-3 visits per week (in-person)

Long-term Follow-up

Participants are monitored for overall survival, engraftment stability, and absence of GvHD

5 years

Periodic visits

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Busulfan
• Cyclophosphamide
• Emapalumab-Izsg
• Tociluzumab
• Total Body Irradiation

Trial Overview The study tests if a combination of drugs including Busulfan, Sirolimus, Cyclophosphamide, Alemtuzumab plus cytokine antagonists Emapalumab-Izsg and Tocilizumab can improve stem cell transplant success in CGD patients. It includes pre-transplant medication, total body irradiation, and follow-up for five years.

How Is the Trial Designed?

Group I: Arm 2 / Group 2 High Risk. Experimental Treatment 7 Interventions

Group 2 (High risk group will receive tociluzumab at day -24, a repeat dose at day -19, Alemtuzumab at day -9,-8,-7,-6,-5; Busulfan at day -4 and -3, Emapalumab at Day -1, matched donor PBSC infusion, and post transplant cyclophosphamide at Day +3 and +4

Group II: Arm 1 / Group 1 Standard Risk Active Control 7 Interventions

Group 1 (Standard group) will receive tociluzumab at Day -10, Alemtuzumab on Day -9,-8,-7,-6,-5; Busulfan on Day -4, and -3, TBI, matched donor PBSC infusion, and Post transplant Cyclophosphamide.

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

A patient with chronic granulomatous disease (CGD) successfully underwent hematopoietic stem cell transplantation (HSCT) using a targeted busulfan and fludarabine conditioning regimen, which minimized toxicity and improved outcomes.

The conditioning involved precise dosing of busulfan and fludarabine, leading to successful engraftment without severe transplantation-related complications, suggesting this approach may enhance HSCT safety and efficacy for CGD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted busulfan and fludarabine-based conditioning for bone marrow transplantation in chronic granulomatous disease. Ju, HY., Kang, HJ., Hong, CR., et al.[2020]

Rituximab (RTX) showed a high overall response rate of 61.3% in patients with refractory granulomatosis with polyangiitis (GPA), with complete remission achieved in 9.3% of cases, indicating its efficacy in treating this condition.

Granulomatous manifestations, particularly orbital masses, were more resistant to RTX treatment compared to vasculitic manifestations, with a significant difference in response rates (89.2% for renal disease vs. 44.4% for orbital masses), highlighting the need for tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Holle, JU., Dubrau, C., Herlyn, K., et al.[2022]

Chronic granulomatous disease (CGD) is a rare immunodeficiency that leads to difficulty in fighting certain infections and causes inflammation, but new antibiotics and antifungals are improving survival rates into adulthood.

Allogeneic hematopoietic stem cell transplantation is currently the only proven cure for CGD, while gene-replacement therapy is still experimental but has shown some promise in treating severe infections in patients without suitable donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modern management of chronic granulomatous disease. Seger, RA.[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 51 patients with minor relapsing Wegener's granulomatosis, the combination of methotrexate (MTX) and leflunomide (LEF) successfully controlled the disease in 84% of patients, with 28 achieving complete remission (BVAS=0).

Despite some adverse effects leading to treatment discontinuation in 18 patients, MTX+LEF remains a viable option for maintaining remission in patients who do not require cyclophosphamide, highlighting its efficacy when tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate plus leflunomide for the treatment of relapsingWegener's granulomatosis. A retrospective uncontrolled study. Bremer, JP., Ullrich, S., Laudien, M., et al.[2018]

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]

Cyclosporine (CsA) is primarily associated with nephrotoxicity, along with other side effects like hypertension and gum overgrowth, necessitating careful monitoring and management to minimize these risks.

Azathioprine (AZA) can lead to dose-related bone marrow suppression, particularly leukopenia, which requires regular blood count monitoring and dosage adjustments to prevent serious complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications associated with immunosuppressive therapy and their management. Min, DI., Monaco, AP.[2013]

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]

Rituximab (RTX) was found to be effective in inducing remission in patients with eosinophilic granulomatosis with polyangiitis (EGPA), including those who had previously not responded to cyclophosphamide (CYC), with comparable remission rates between RTX and CYC treatments.

Both RTX and CYC treatments led to significant reductions in disease markers like eosinophils and C-reactive protein, but RTX was associated with a decline in serum immunoglobulin levels, indicating a need for monitoring for potential hypogammaglobulinemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab as Induction Therapy in Eosinophilic Granulomatosis with Polyangiitis Refractory to Conventional Immunosuppressive Treatment: A 36-Month Follow-Up Analysis. Thiel, J., Troilo, A., Salzer, U., et al.[2018]

Mepolizumab, an IL-5 inhibitor, has shown high efficacy in treating eosinophilic granulomatosis with polyangiitis (EGPA) that is resistant to standard therapies, particularly in cases with lung lesions and otitis media.

The report highlights two specific cases where mepolizumab effectively managed severe symptoms and organ lesions in EGPA patients who had not responded to multiple immunosuppressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two cases of refractory eosinophilic granulomatosis with polyangiitis wherein mepolizumab was effective against pulmonary and ear lesions. Ushio, Y., Wakiya, R., Kato, M., 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]

Children with Chronic Granulomatous Disease (CGD) experience a significantly lower quality of life compared to healthy children, as shown by parent and self-reported scores from the Pediatric Quality of Life Inventory.

After undergoing hematopoietic stem cell transplant (HSCT), children with CGD reported quality of life scores comparable to those of healthy children, indicating that HSCT can effectively improve emotional well-being and overall quality of life in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health related quality of life and emotional health in children with chronic granulomatous disease: a comparison of those managed conservatively with those that have undergone haematopoietic stem cell transplant. Cole, T., McKendrick, F., Titman, P., et al.[2021]

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