Stem Cell Transplant for Job Syndrome

Not currently recruiting at 1 trial location

Overseen By Corina E Gonzalez, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Disqualifiers: HIV, Hepatitis B, Psychiatric disorder, Pregnancy, 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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of stem cell transplants for individuals with DOCK8 deficiency, a genetic disorder that weakens the immune system, leading to severe infections or certain cancers. The study compares stem cell transplants from various donors, such as matched siblings or parents. It is ideal for those with confirmed DOCK8 deficiency who have experienced life-threatening infections or virus-related cancers and have a suitable stem cell donor. Participants will undergo chemotherapy, including drugs like Busulfan, Cyclophosphamide, and Fludarabine, and possibly Total Body Irradiation before receiving the transplant. They will then be monitored for several months to assess success and side effects. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, since the trial involves chemotherapy and a stem cell transplant, it's important to discuss your current medications with the trial team to ensure there are no interactions.

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

A previous study showed that a reduced-intensity hematopoietic stem cell transplant (a type of bone marrow transplant) is linked to strong survival rates, with lower immediate risks of death. Recipients of this transplant often live longer and experience fewer early complications. However, risks associated with stem cell transplants remain.

Regarding chemotherapy drugs, studies indicate that busulfan and cyclophosphamide are generally well-tolerated, though they can cause side effects. Busulfan has been linked to a 67% survival rate over five years at certain exposure levels, but excessive exposure can lead to complications. Cyclophosphamide may help reduce the risk of graft-versus-host disease, where donor cells attack the recipient's body.

Total Body Irradiation (a type of radiation therapy) has shown low rates of serious side effects over nearly 20 years, though some individuals might develop cataracts or other issues over time.

These treatments have been used for other conditions, and their past use provides insight into their safety. However, as with any medical treatment, risks exist, and discussing these with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the stem cell transplant approach for Job Syndrome because it uses a combination of treatments like Busulfan, Cyclophosphamide, Fludarabine, and Total Body Irradiation (TBI) to prepare the body for reduced-intensity hematopoietic stem cell transplantation. Unlike traditional treatments that might focus on managing symptoms, this method aims to address the underlying immune dysfunction by introducing healthy stem cells. By using donors with a 9/10 or 10/10 HLA match, this approach potentially offers a more personalized and effective treatment, improving the immune system's function in a way that current therapies might not. Researchers hope this could lead to better long-term outcomes for patients with Job Syndrome.

What evidence suggests that this trial's treatments could be effective for DOCK8 deficiency?

Research has shown that stem cell transplants can effectively treat DOCK8 deficiency, a condition that severely weakens the immune system. This trial compares different donor matching strategies for stem cell transplants. Studies have found that replacing damaged blood and immune cells with healthy ones through hematopoietic stem cell transplants can help patients live longer and experience fewer infections. Successful transplants have used donors such as matched siblings or unrelated individuals. In this trial, chemotherapy drugs like busulfan and fludarabine prepare the body for the transplant by weakening the immune system to prevent rejection. Cyclophosphamide also lowers the risk of graft-versus-host disease, where the new cells might attack the patient's body. Overall, stem cell transplants offer hope for fixing immune system problems caused by DOCK8 deficiency. ^{1 2 6 7 8}

Who Is on the Research Team?

Corina E Gonzalez, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for individuals aged 4-35 with confirmed DOCK8 deficiency, who've had life-threatening infections or viral-related cancers and have a suitable stem cell donor. Donors must be healthy, matched to the recipient, and aged 2-60. Participants need functioning hearts (with specific ejection fraction criteria), adequate kidney function, normal liver tests, and must not be pregnant or breastfeeding.

Inclusion Criteria

I have a donor who is a perfect or near-perfect match, or a half-matched related donor.

My cancer is in remission, or I have a virus-related cancer.

My child doesn't need extra oxygen and can breathe and play without getting too tired or short of breath.

Exclusion Criteria

I have cancer in another part of my body not related to blood, except if it's virus-caused.

I am using effective birth control or abstaining from sex for 1 year post-transplant.

My cancer has spread to my brain, except if it's caused by a virus where the transplant might help.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-transplant Conditioning

Recipients receive chemotherapy and radiation to suppress the immune system and prepare for the transplant

6 days

Inpatient stay

Transplant

Donor hematopoietic stem cells are infused

1 day

Inpatient stay

Post-transplant Immunosuppression

Recipients receive immunosuppressive therapy to prevent graft-versus-host disease

180 days

Regular visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Periodic visits

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan (Busulfex)
• Cyclophosphamide
• Fludarabine
• Reduced-intensity hematopoietic stem cell
• Total Body Irradiation (TBI)

Trial Overview The study tests whether bone marrow cells from different donors can treat DOCK8 deficiency. Recipients will undergo chemotherapy with busulfan and fludarabine (or cyclophosphamide added for certain matches) plus radiation in some cases to prepare for transplant. Post-transplant care includes more chemo and drugs to prevent graft versus host disease.

How Is the Trial Designed?

Group I: Group D Experimental Treatment 1 Intervention

Family Interview (closed)Participation in research interview

Group II: Group C Experimental Treatment 3 Interventions

Donor (closed)

Group III: Group A Active Control 3 Interventions

10/10 HLA Matched Related or Unrelated Donor Transplant

Group IV: Group B Active Control 5 Interventions

9/10 HLA Matched Related or Unrelated Donor Transplant

Group V: Group E Active Control 1 Intervention

Patient and caregiver psychosocial and QOL assessments during HSCTParticipation in interview and questionnaires

Busulfan (Busulfex) is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Busulfex for:

• Chronic myelogenous leukemia
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myelogenous leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study comparing two treatment regimens for children undergoing hematopoietic cell transplantation, the combination of fludarabine and busulfan (FluBu) showed similar survival rates to busulfan and cyclophosphamide (BuCy), with 2-year survival rates of 82% for FluBu and 78% for BuCy.

The FluBu regimen was associated with significantly lower toxicity, including reduced rates of lung injury, veno-occlusive disease, and infections, as well as a shorter duration of neutropenia, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Bartelink, IH., van Reij, EM., Gerhardt, CE., et al.[2014]

The studies compared the efficacy of busulfan versus total body irradiation (TBI) as preparative treatments for hematopoietic transplantation in patients with acute myeloid leukemia (AML).

The findings from these comparisons could provide insights into the optimal conditioning regimens for improving treatment outcomes in AML patients undergoing transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Busulfan or TBI: answer to an age-old question. Champlin, RE.[2021]

In a study of 42 patients undergoing allogeneic hematopoietic stem cell transplantation, the combination of busulfan and fludarabine (BuFlu) resulted in significantly lower rates of mucositis compared to the traditional busulfan and cyclophosphamide (BuCy) regimen.

Both BuFlu and BuCy showed similar efficacy in terms of engraftment time, relapse risk, event-free survival, and overall survival, suggesting that BuFlu is a viable alternative to BuCy for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. Lee, JH., Choi, J., Kwon, KA., et al.[2021]

In a study of 77 patients undergoing haploidentical stem cell transplantation for hematologic malignancies, the conditioning regimen with busulfan plus cyclophosphamide (BU+CY) resulted in a significantly better 3-year overall survival rate of 56.4% compared to 31.6% for total body irradiation plus cyclophosphamide (TBI+CY).

The BU+CY regimen also demonstrated a lower short-term relapse rate (2.56% at 1 year) compared to TBI+CY (26.67%), while both regimens had similar rates of acute graft-versus-host disease (GVHD), but TBI+CY was associated with a higher incidence of chronic GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of BU and CY versus TBI and CY as conditioning regimens on the efficacy of haploidentical stem cell transplantation in patients with hematologic malignancy]. Shao, Q., Han, D., Liu, D., et al.[2014]

In a study comparing total body irradiation (TBI) and busulfan in mice undergoing bone marrow transplantation, both treatments caused late effects such as tissue damage and mortality starting around 80 weeks post-transplant.

While both TBI and busulfan effectively engrafted bone marrow, TBI was associated with severe nephrotoxicity and anemia, highlighting that their long-term impacts on organ systems and stem cells differ significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late tissue-specific toxicity of total body irradiation and busulfan in a murine bone marrow transplant model. Down, JD., Berman, AJ., Warhol, M., et al.[2019]

In a study of 146 adults with acute lymphoblastic leukemia undergoing transplantation, both conditioning regimens (Cyclophosphamide/Total Body Irradiation vs. Fludarabine/Busulfan/Low-dose TBI) showed similar overall and progression-free survival rates, indicating comparable efficacy.

However, the Fludarabine/Busulfan/Low-dose TBI regimen resulted in a significantly lower relapse rate (18.5% vs. 31.5% for Cy/TBI), suggesting it may be a safer option, especially for patients with poorer performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, busulfan, and low-dose TBI conditioning versus cyclophosphamide and TBI in allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. Speziali, C., Daly, A., Abuhaleeqa, M., et al.[2020]

In a meta-analysis of 15 randomized controlled trials involving 10,160 pediatric patients, total body irradiation plus cyclophosphamide (TBI/CY) was found to be more effective than busulfan plus cyclophosphamide (BU/CY) in reducing transplant failure rates and improving long-term disease-free survival rates.

The TBI/CY regimen also demonstrated a lower incidence of adverse reactions compared to the BU/CY regimen, indicating it may be a safer option for pediatric hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. Wang, X., Mu, D., Geng, A., et al.[2023]

Both total body irradiation (TBI) and busulfan effectively reduce the survival of colony-forming units (CFUs) in bone marrow preparation for transplantation, but busulfan may be more favorable for donor marrow engraftment based on lower extrapolated CFUs survival rates.

While both treatments resulted in over 80% complete engraftment in mice, busulfan was associated with severe pulmonary vascular injury in some cases, indicating potential safety concerns despite its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recipient preparation for bone marrow transplantation. I. Efficacy of total-body irradiation and busulfan. Mauch, P., Down, JD., Warhol, M., et al.[2019]

In a phase I study involving 28 patients with blood cancers, the maximum tolerated dose of etoposide was found to be 60 mg/kg when combined with total body irradiation (TBI) and cyclophosphamide, but only 30 mg/kg when combined with busulfan, indicating a higher tolerance with TBI.

Despite significant toxicities, including mucosal and hepatic complications, the treatment showed promising outcomes with 11 patients surviving and 10 in complete remission at a median follow-up of 9 months, suggesting that etoposide-containing regimens merit further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation. Spitzer, TR., Cottler-Fox, M., Torrisi, J., et al.[2013]

In a study of 1,118 patients with acute lymphoblastic leukemia undergoing hematopoietic cell transplantation, those receiving busulfan (Bu) had lower treatment-related mortality (19%) compared to those receiving total body irradiation (TBI) (25%), indicating a potential safety advantage for Bu.

Despite a higher risk of relapse in the Bu group (37% vs. 28% for TBI), overall survival and disease-free survival rates were similar between the two groups, suggesting that Bu-containing regimens can be effective alternatives to TBI in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia. Kebriaei, P., Anasetti, C., Zhang, MJ., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11922810/

Hyper IgE Syndromes: Understanding, Management, and ... Animal studies on HIES have displayed promising outcomes, indicating the viability and effectiveness of gene therapy in rectifying immunological ...

2. malacards.org malacards.org/card/hyper_ige_recurrent_infection_syndrome_1

Hyper Ige Recurrent Infection Syndrome 1 This primary immune deficiency syndrome is characterized by elevated serum IgE levels, eczema, recurrent skin and respiratory infections, and various nonimmune ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2473952925003441

Allogeneic hematopoietic stem cell transplantation for ... Conditioning regimens were predominantly treosulfan-based (59%; with thiotepa, 34%); other patients received busulfan-based (24%) or melphalan- ...

4. nature.com nature.com/articles/s41409-025-02705-z

Outcome after Treosulfan-based conditioning in a real- ... The estimated 2-year RFS, OS, CIR and NRM rates were 63%, 68%, 18% and 22% (Fig. 1). Engraftment data, day +100 mortality and GvHD incidence are ...

5. malacards.org malacards.org/card/hyper_ige_syndrome_1_autosomal_dominant_with_recurrent_infections

Hyper-Ige Syndrome 1, Autosomal Dominant, with ... A very rare primary immunodeficiency disorder characterized by the clinical triad of high serum IgE (>2000 IU/ml), recurring staphylococcal skin abscesses, and ...

6. nature.com nature.com/articles/s41409-022-01641-6

Impact of busulfan pharmacokinetics on outcome in adult ... Secondary endpoints were the relation of long-term outcomes to Bu-PK, namely chronic GvHD, NRM, relapse, GvHD-free-relapse-free survival, ...

7. researchgate.net researchgate.net/publication/373908574_Hyper_IgE_Syndromes

Hyper IgE Syndromes The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10500467/

Association between busulfan exposure and survival in ... Key Points. •. Busulfan exposure is associated with OS; 5-year survival with an exposure of ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40%.