Stem Cell Transplant for Job Syndrome

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Corina E Gonzalez, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

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

No Placebo Group

Prior Safety Data

Trial Summary

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.

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}

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.

Trial 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) (Chemotherapy)
• Cyclophosphamide (Chemotherapy)
• Fludarabine (Chemotherapy)
• Reduced-intensity hematopoietic stem cell (Stem Cell Transplant)
• Total Body Irradiation (TBI) (Radiation Therapy)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, MD

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Cancer Institute (NCI) Lead Sponsor

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] To observe the therapeutic effect and the incidence of adverse reactions of total body irradiation plus cyclophosphamide (TBI/CY) and busulfan plus cyclophosphamide (BU/CY) in the treatment of pediatric hematopoietic stem cell transplantation.

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

Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia. [2019] Total body irradiation (TBI) has been included in standard conditioning for acute lymphoblastic leukemia (ALL) before hematopoietic cell transplantation (HCT). Non-TBI regimens have incorporated busulfan (Bu) to decrease toxicity. This retrospective study analyzed TBI and Bu on outcomes of ALL patients 18-60 years old, in first or second complete remission (CR), undergoing HLA-compatible sibling, related, or unrelated donor HCT, who reported to the Center for International Blood and Marrow Transplant Research from 2005 to 2014. TBI plus etoposide (25%) or cyclophosphamide (75%) was used in 819 patients, and intravenous Bu plus fludarabine (41%), clofarabine (30%), cyclophosphamide (15%), or melphalan (13%) was used in 299 patients. Bu-containing regimens were analyzed together, since no significant differences for patient outcomes were noted between them. Bu patients were older, with better performance status; took longer to achieve first CR and receive HCT; were treated more recently; and were more likely to receive peripheral blood grafts, antithymocyte globulin, or tyrosine kinase inhibitors. With median follow-up of 3.6 years for Bu and 5.3 years for TBI, adjusted 3-year outcomes showed treatment-related mortality Bu 19% versus TBI 25% (P = .04); relapse Bu 37% versus TBI 28% (P = .007); disease-free survival (DFS) Bu 45% versus TBI 48% (P = .35); and overall survival (OS) Bu 57% versus TBI 53% (P = .35). In multivariate analysis, Bu patients had higher risk of relapse (relative risk, 1.46; 95% confidence interval, 1.15 to 1.85; P = .002) compared with TBI patients. Despite the higher relapse, Bu-containing conditioning led to similar OS and DFS following HCT for ALL.

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

Busulfan or TBI: answer to an age-old question. [2021] In this issue of Blood, authors of 2 articles have compared busulfan with total body irradiation (TBI) in preparative regimens for hematopoietic transplantation as treatment of acute myeloid leukemia (AML).

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] The optimal conditioning regimen for adults undergoing transplantation for acute lymphoblastic leukemia (ALL) remains undetermined. Cyclophosphamide and total body irradiation (Cy/TBI) has emerged as a standard myeloablative regimen but is associated with significant toxicity. We compared outcomes between patients undergoing transplant for ALL at centers using Cy/TBI as standard of care and another center using fludarabine, busulfan, and low-dose TBI (400 cGy) in combination with anti-thymocyte globulin as its standard. Among 146 patients (74 Cy/TBI and 72 Flu/Bu/TBI) there were no significant differences in overall or progression-free survival between groups. Non-relapse mortality was similar (12% vs. 16.7% for Cy/TBI and Flu/Bu/TBI, respectively, p = .62) despite the Flu/Bu/TBI group having significantly worse performance status. Flu/Bu/TBI resulted in significantly lower cumulative incidence of relapse compared with Cy/TBI (2-year point estimate 18.5% vs. 31.5%, p = .05). These results demonstrate similar outcomes for patients receiving Flu/Bu/TBI versus Cy/TBI. Flu/Bu/TBI may allow the possibility of providing myeloablative conditioning to patients with poor performance status.

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] To investigate the therapeutic effects of the conditioning regimen with busulfan plus cyclophosphamide (BU+CY) or total body irradiation plus cyclophosphamide (TBI+CY) on haploidentical stem cell transplantation (HSCT) in hematologic malignancy.

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] A combination of busulfan (Bu) and cyclophosphamide (Cy) has been used as a standard myeloablative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). Recent studies postulate that fludarabine (Flu) is a less toxic substitute for Cy.

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] Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a myeloid malignancy, or a lymphoid malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu + Bu at a target dose of 80-95 mg·h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg·h/L + Cy. In the latter group, Mel was added for patients with myeloid malignancy (n = 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P = not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P = .007), veno-occlusive disease (3% versus 28%; P = .003), chronic graft-versus-host disease (9% versus 26%; P = .047), adenovirus infection (3% versus 32%; P = .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P = .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P

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

Recipient preparation for bone marrow transplantation. I. Efficacy of total-body irradiation and busulfan. [2019] The efficacy of total body irradiation and busulfan were studied in recipient preparation for bone marrow transplantation. Male C57BL/6 (B6) mice were prepared for BMT with fractionated TBI or busulfan given in 4 equal doses over 3 days. Both TBI and busulfan are potent stem-cell killers. Both agents resulted in an exponential decrease in CFUs survival with increasing dose down to a 1 x 10(-4) CFUs survival. There appeared to be no break in the curve for either agent. Extrapolated fractional CFUs survival, as related to equivalent donor marrow engraftment or to equivalent 30-day survival without marrow transplantation, appeared lower for TBI as compared to busulfan. This may be due to the effect of busulfan and TBI on different stem-cell populations. Erythroid engraftment was tested after transplanting H-2 compatible LP marrow cells into treated B6 recipients. Greater than 80% of animals demonstrated complete engraftment with 3.4 mg busulfan or 1640 cGy TBI. At these 2 doses, the rate of recovery of donor marrow cellularity and CFUs content in treated recipients were identical for both preparative agents such that a selective effect on the host hematopoietic microenvironment harmful to engraftment was not seen. Complete engraftment in 100% of busulfan-prepared animals could not be achieved as such doses resulted in severe and fatal pulmonary vascular injury at 7-12 weeks posttransplant.

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] In a phase I study 28 patients with lymphohematopoietic malignancies were treated with escalating doses of etoposide combined with cyclophosphamide 120 mg/kg and either fractionated total body irradiation (TBI) 1320 cGy in 11 fractions (n = 17) or busulfan 16 mg/kg (n = 11). Twenty transplants were allogeneic, seven autologous and one syngeneic. The maximally tolerated dose of etoposide in combination with TBI and cyclophosphamide was 60 mg/kg; at etoposide doses of 65 mg/kg three patients developed life-threatening or fatal mucosal toxicity. In combination with busulfan, the maximally tolerated dose of etoposide was 30 mg/kg. At an etoposide dose of 40 mg/kg two patients developed life-threatening or fatal toxicity (one mucosal, one hepatic). Mucositis requiring narcotic analgesics, hepatotoxicity, hematologic toxicity and interstitial pneumonitis were otherwise similar in TBI and busulfan-treated patients. Skin toxicity was observed significantly more often in the busulfan group. Five deaths occurred before day +30, two in the TBI group and three in the busulfan group. Eleven patients are surviving, ten in continuous complete remission, at a median of 9 (range 3-23) months following transplantation. Etoposide in combination with TBI and cyclophosphamide or busulfan and cyclophosphamide is associated with significant but acceptable toxicities. The maximally tolerated dose of etoposide is higher when combined with TBI than with busulfan. Promising response rates in this high risk group of hematologic malignancies warrant further evaluation of these etoposide containing conditioning regimens.

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] Total body irradiation (TBI) and busulfan were compared for late effects in a murine model of bone marrow transplantation (BMT). Male C57BL/6 mice were given fractionated TBI or busulfan given in 4 equal daily doses followed by infusion of 10(7) syngeneic bone marrow cells. Total doses of 16.4 Gy TBI and 3.4 mg busulfan were chosen for their equivalence in inducing near complete engraftment of allogeneic marrow from donor mice of the LP strain. The two treatment groups had a late wave of mortality starting at about 80 weeks after transplantation. Specific tissue damage was manifested in bone marrow stem cells, splenic T-cell precursors, hair greying and cataract formation for both TBI and busulfan but to varying degrees. Severe nephrotoxicity and anemia were observed only after TBI. Although both busulfan and TBI kill early marrow stem cells and are effective preparative agents in bone marrow transplantation, their effects on other stem cell and organ systems are not similar. In addition, many of the injuries seen are late to occur. The delayed expression of injury deserves careful long-term evaluation of BMT recipients before the therapeutic potential of effective preparative regimens can be fully appreciated.