Stem Cell Transplant for Job Syndrome

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

128 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment for Job Syndrome?

Research on similar treatments for leukemia shows that using busulfan and fludarabine, along with total body irradiation, can lead to similar survival outcomes compared to other standard treatments, despite differences in relapse rates. This suggests that the combination of these drugs and therapies might be effective in other conditions like Job Syndrome. ^{1 2 3 4 5}

Is stem cell transplant with these treatments generally safe for humans?

Research shows that using fludarabine with busulfan in stem cell transplants can lead to fewer side effects compared to using busulfan with cyclophosphamide. Common side effects include lung injury, liver issues, and infections, but these are less frequent with fludarabine. Total body irradiation and busulfan can cause severe lung damage at high doses, but they are generally used safely at controlled levels. ^{1 6 7 8 9}

How is the stem cell transplant treatment for Job Syndrome unique?

This treatment for Job Syndrome is unique because it combines reduced-intensity hematopoietic stem cell transplantation with a specific regimen of drugs and total body irradiation, which is typically used in treating leukemia and other blood disorders. This approach aims to prepare the body for stem cell engraftment while minimizing damage to healthy tissues, potentially offering a novel option for a condition with limited standard treatments. ^{1 3 5 8 10}

What is the purpose of this trial?

Background: -DOCK8 deficiency is a genetic disorder that affects the immune system and can lead to severe recurrent infections and possible death from infections or certain types of cancers, including blood cancers. A stem cell transplant is a life-saving treatment for this condition. In this study we are evaluating the efficacy and safety of transplant from different donor sources for DOCK8 deficiency. The donors that we are using are matched siblings, matched unrelated donors, and half-matched donors, so called haploidentical related donors, such as mothers or fathers or half-matched siblings. Objectives: -To determine whether transplant of bone marrow cells from different types of donors corrects DOCK8 deficiency. Eligibility: * Donors: Healthy individuals between 2 and 60 years of age who are matched with a recipient. * Recipient: Individuals between 4 and 35 years of age who have confirmed DOCK8 deficiency, have suffered at least one life-threatening infections, or have had certain viral related cancers of cancer and have a stem cell donor. Design: * All participants will be screened with bloodwork, a physical examination and medical history. * DONORS: --Donors who have donate bone marrow cells or blood stem cells will have a sample of blood/bone marrow stored to be compared with the recipients sample after transplant. * RECIPIENTS: * Recipients receiving 10/10 matched related or unrelated donors will receive 4 days of chemotherapy with busulfan and fludarabine to suppress their immune system and prepare them for the transplant. Donors receiving 9/10 matched related or unrelated donors as well as haploidentical related donors will receive 5 days chemotherapy with cyclophosphamide, fludarabine, and busulfan. They will also receive one dose of radiation to suppress their immune system and prepare them for the transplant. * After the initial chemotherapy and radiation (if indicated), recipients will receive the donated stem cells as a single infusion. * After the stem cell transplant, recipients will receive two days of a chemotherapy called cyclophosphamide on day's + 3 and + 4 followed by two drugs tacrolimus and mycophenolate to prevent graft versus host disease where the donor cells attack the patient's body. All patients will remain in the hospital for at least approximately 1 month, and will be followed with regular visits for up to 3 years with periodic visits thereafter to evaluate the success of the transplant and any side effects.

Research Team

Corina E Gonzalez, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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 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 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]

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 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]

References

1. England 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. [2023]

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

Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia. [2019]

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

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

4. United States 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. [2020]

5. China 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]. [2014]

6. Korea (South) 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. [2021]

7. United States 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. [2014]

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

Recipient preparation for bone marrow transplantation. I. Efficacy of total-body irradiation and busulfan. [2019]

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

Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation. [2013]

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

Late tissue-specific toxicity of total body irradiation and busulfan in a murine bone marrow transplant model. [2019]