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?

Background: Chronic granulomatous disease (CGD) affects the immune system. People with CGD are more likely to get infections. Drugs can help control infections, but these treatments can cause side effects including kidney failure and deafness. Stem cell transplants can cure CGD, but these don t always work. Objective: To find out if a different drug treatment can improve the success rates of stem cell transplants in people with CGD. Eligibility: People aged 4-65 years with CGD. Design: Participants will undergo screening. They will have a physical exam. They will have blood and urine tests and tests of their heart function and breathing. They will have imaging scans. They will have a bone marrow biopsy; a needle will be inserted into their hip to draw a sample of tissue from the bone. A tube called a catheter will be placed into a vein in the participant s chest. This catheter will remain in place for the transplant and recovery period. Blood for tests can be drawn from the catheter, and medications and the stem cells can be administered through it. Participants will be in the hospital for either 10 or 21 days to receive 3 or 4 drugs before the transplant. They will get 2 doses of total body radiation on the same day. Participants will receive donor stem cells through the catheter. They will remain in the hospital for 6 weeks afterward. Participants will visit the clinic 2 to 3 times per week for 3 months after discharge. Follow-up visits will continue for 5 years.

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.

What safety data exists for the drugs used in stem cell transplant and drug therapy for chronic granulomatous disease?

The safety of cyclophosphamide, one of the drugs used in this treatment, has been studied in other conditions. It is known to cause side effects like bone marrow suppression, which can lead to a low white blood cell count, increasing the risk of infections. Careful monitoring and dosage adjustments are important to manage these risks. ^{1 2 3 4 5}

How is the Stem Cell Transplant + Drug Therapy for Chronic Granulomatous Disease unique?

This treatment is unique because it combines stem cell transplantation with a specific set of drugs, including Alemtuzumab, Busulfan, Cyclophosphamide, and Emapalumab-Izsg, along with Total Body Irradiation, to potentially improve outcomes for patients with Chronic Granulomatous Disease. This combination aims to enhance the effectiveness of the transplant and reduce the risk of complications compared to traditional conditioning regimens. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment for Chronic Granulomatous Disease?

Research shows that allogeneic hematopoietic stem cell transplantation, which includes drugs like alemtuzumab and busulfan, is a curative treatment for Chronic Granulomatous Disease. Studies have reported successful outcomes with high survival rates and low incidence of infections in patients who underwent this treatment. ^{6 7 8 11 12}

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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

Modern management of chronic granulomatous disease. [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. 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]

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

Complications associated with immunosuppressive therapy and their management. [2013]

7. United States 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. [2018]

8. Italy pubmed.ncbi.nlm.nih.gov

Methotrexate plus leflunomide for the treatment of relapsingWegener's granulomatosis. A retrospective uncontrolled study. [2018]

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

Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Two cases of refractory eosinophilic granulomatosis with polyangiitis wherein mepolizumab was effective against pulmonary and ear lesions. [2021]

11. Netherlands 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. [2021]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Targeted busulfan and fludarabine-based conditioning for bone marrow transplantation in chronic granulomatous disease. [2020]