Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 Deficiency
- Conditions
- DOCK8 Deficiency
- Interventions
- Drug: Fludarabine(Fludara, Berlex Laboratories)Procedure: Reduced-intensity hematopoietic stem cellProcedure: Donor peripheral blood stem cell mobiliation and collectionDrug: Cyclophosphamide(CTX, Cytoxan)Procedure: Bone Marrow Harvest ProcedureProcedure: Total Body Irradiation (TBI)
- Registration Number
- NCT01176006
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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....
- Detailed Description
Background
Mutations in the Dedicator of Cytokinesis-8 (DOCK8) gene are responsible for an immunodeficiency disease characterized by: severe cutaneous and sinopulmonary infections with bacterial organisms; extensive cutaneous viral infections with Herpes simplex, Herpes zoster, Molluscum contagiosum, and Human Papilloma Virus; a marked elevation in serum IgE levels and eosinophilia; homozygous or compound heterozygous mutations in the dedicator of cytokinesis 8 (DOCK8) gene. Patients with DOCK8 deficiency die from severe infections, squamous cell carcinomas, or hematological malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially life-saving treatment for immunodeficiency diseases such as DOCK8 deficiency. In this study, we will evaluate the efficacy and safety of allogeneic HSCT for DOCK8 deficiency. We are particularly interested in determining whether allogeneic HSCT using different donor sources and conditioning regimens reverses the lethal disease phenotype in DOCK8 deficiency by reconstituting normal host defense. The development of lethal squamous cell carcinomas and lymphomas arising from the immunodeficiency in DOCK8 deficiency supports therapeutic intervention before overt malignancy arises.
Objective
To determine whether allogeneic HSCT reconstitutes T-lymphocyte and B-lymphocyte cells and myeloid cells with normal donor cells at one-year post-transplant and reverses the clinical phenotype of severe recurrent infections in subjects with DOCK8 deficiency.
Eligibility
Subjects 4-35 years old with DOCK8 deficiency who have suffered one or more life-threatening infections, or who have developed lymphoma or squamous cell carcinoma, and have a 10/10 matched related donor, a 10/10 matched unrelated donor, a 9/10 matched related donor a 9/10 matched unrelated donor, or a haploidentical related donor.
Design
Subjects with a 10/10 matched related or unrelated donor will receive a pre-transplant conditioning regimen consisting of fludarabine 40 mg/m2/day on days -6, -5, -4, and -3, and busulfan IV (dose based on pharmacokinetic levels) every day for 4 days on days -6, -5, -4, and -3. Donor hematopoietic stem cells will be infused on day 0.
Subjects with a 9/10 matched related, 9/10 matched unrelated, or a haploidentical related donor will receive a pre-transplant conditioning regimen consisting of cyclophosphamide 14.5 mg/kg on days -6 and -5, fludarabine 30 mg/m2/day on days -6, -5, -4, -3 and -2, busulfan IV (dose based on pharmacokinetic levels) once daily for three days on -4, -3 and -2, and 200 cGy TBI on day -1. Donor hematopoietic stem cells will be infused on day 0. Post-transplant immunosuppression for graft-versus-host-disease (GVHD) prophylaxis for recipients of 9/10 matched related or unrelated donors will consist of cyclophosphamide 50 mg/kg IV once daily for two days on day s +3 and +4, along with mycophenolate mofetil from day +5 to day +35 and tacrolimus from day +5 to day 180. If there is no evidence of graft-versus-host disease, tacrolimus will be stopped at approximately day+180.
All subjects will receive post-transplant immunosuppression for graft-versus-host-disease (GVHD) prophylaxis for recipients of 10/10 matched related and unrelated donors will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to day +35 and tacrolimus from day +5 to approximately day 180. If there is no evidence of graft-versus-host disease, tacrolimus will be stopped at approximately day +180.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 128
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group A Fludarabine(Fludara, Berlex Laboratories) 10/10 HLA Matched Related or Unrelated Donor Transplant Group B Reduced-intensity hematopoietic stem cell 9/10 HLA Matched Related or Unrelated Donor Transplant Group B Fludarabine(Fludara, Berlex Laboratories) 9/10 HLA Matched Related or Unrelated Donor Transplant Group B Cyclophosphamide(CTX, Cytoxan) 9/10 HLA Matched Related or Unrelated Donor Transplant Group B Total Body Irradiation (TBI) 9/10 HLA Matched Related or Unrelated Donor Transplant Group B Busulfan (Busulfex) 9/10 HLA Matched Related or Unrelated Donor Transplant Group C Reduced-intensity hematopoietic stem cell Donor (closed) Group C Donor peripheral blood stem cell mobiliation and collection Donor (closed) Group C Bone Marrow Harvest Procedure Donor (closed) Group D Reduced-intensity hematopoietic stem cell Family Interview (closed)Participation in research interview
- Primary Outcome Measures
Name Time Method Feasibility 1 year post transplant Number of severe recurrent infections in patients with DOCK8 post transplant compared to number of severe recurrent infections in patients with DOCK8 pre transplant
- Secondary Outcome Measures
Name Time Method Toxicity 180 days post transplant To determine whether post-transplant cyclophosphamide results in a lower incidence of grade III-IV acute and chronic GVHD compared to standard methotrexate and tacrolimus in 10/10 matched related and unrelated donor recipients.
Safety Overall and disease free survival To determine the safety of this allogeneic transplant regimen in DOCK8 deficiency by assessing transplant related toxicity, the incidence of acute and chronic graft-versus-host disease, immune reconstitution, overall survival, and disease-free survival
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States