Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 Deficiency
- DOCK8 deficiency is a genetic disorder that affects the immune system and can lead to severe recurrent infections and possible death from blood poisoning or certain types of cancers, including blood cancers. Stem cell transplants from matching or closely related donors (allogenic stem cell transplants) may be a life-saving treatment for this condition. However, stem cell transplants can have serious complications, because they tend to be performed with very high doses of chemotherapy and/or radiation. Reduced-intensity stem cell transplants use smaller doses of radiation and chemotherapy to weaken but not completely eliminate the recipient's stem cells and immunity. Researchers are exploring whether reduced-intensity stem cell transplants in people with DOCK8 deficiency may decrease the chance of graft rejection and the overall side effects of the transplant.
- To evaluate the safety and effectiveness of reduced-intensity allogeneic stem cell transplant as a treatment for DOCK8 deficiency.
- Donors: Healthy individuals between 4 and 60 years of age who are matched with a recipient.
- Recipient: Individuals between 10 and 60 years of age who have DOCK8 deficiency, have suffered two or more life-threatening infections, have either low white blood cell levels or have had certain types of cancer (lymphoma or squamous cell carcinoma), and have a stem cell donor.
- All participants will be screened with a physical examination and medical history.
- Donors will receive injections of filgrastim to release stem cells into the blood. After 5 days of filgrastim injections, donors will have apheresis to donate stem cells and white blood cells that are present in the blood.
- Donors who are not eligible to receive filgrastim will provide the stem cells through bone marrow donation.
- From 7 days before the stem cell transplant, recipients will be admitted to the inpatient unit of the National Institutes of Health Clinical Center and will receive regular doses of cyclophosphamide, fludarabine, and radiation to suppress their immune system and prepare them for the transplant.
- From 3 days before the stem cell transplant, recipients will receive the drugs tacrolimus and sirolimus to help prevent complications from the transplant.
- After the initial chemotherapy and radiation, recipients will receive the donated stem cells as a single infusion. Recipients may also receive white blood cells from their stem cell donor to encourage acceptance of the stem cells.
- After the stem cell and white blood cell transplant, recipients will remain in inpatient care for up to 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.
Procedure: Allogeneic HSC transplant
Procedure: Total Body Irradiation (TBI)
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pilot Study of Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplant of DOCK8 Deficiency|
- To determine whether reduced-intensity allogeneic (HSCT) reconstitutes T-lymphocyte, B-lymphocyte, and NK cell populations with normal donor cells and reverses the clinical phenotype of severe recurrent in patients with DOCK8. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- To determine the safety of this allogeneic transplant regimen in DOCK8 by assessing transplant related toxicity, the incidence of acute and chronic GVHD, immune reconstitution, overall survival, and disease-free survival. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
|Study Start Date:||July 2010|
Mutations in the dedicator of cytokinesis-8 (DOCK8) gene are responsible for a newly described immunodeficiency disease characterized by a constellation of signs: severe cutaneous and sinopulmonary infections with bacterial organisms; severe cutaneous viral infections with Herpes simplex, Herpes zoster, Molluscum contagiosum, and Human Papilloma Virus; a marked elevation in serum IgE levels and eosinophilia; and homozygous or compound heterozygous mutations in the dedicator of cytokinesis 8 (DOCK8) gene. Patients with this syndrome die from bacterial sepsis, squamous cell carcinomas, or hematological malignancies. Hematopoietic stem cell transplantation (HSCT) represents a potentially life-saving treatment for immunodeficiency diseases, such as DOCK8 deficiency. In this pilot study we propose to evaluate the efficacy and safety of allogeneic HSCT for DOCK8 deficiency. We are particularly interested in determining whether allogeneic HSCT 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 malignancy arises.
- To determine whether allogeneic HSCT reconstitutes T-lymphocyte and B-lymphocyte cells and myeloid cells with normal donor cells at Day +100 and reverses the clinical phenotype of severe recurrent infections in patients with DOCK8 deficiency.
- 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
Patients 10-60 years old with DOCK8 deficiency who have suffered two 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, or a 9/10 matched unrelated donor (HLA -A, -B, -C, DRB1, and DQ by high resolution typing identified through the National Marrow Donor Program), or a haploidentical donor
DOCK8 deficiency patients with a 10/10 matched related or 10/10 matched unrelated donor will receive a pre-transplant conditioning regimen consisting of fludarabine 40 mg/m2/day on days -6, -5, -4, and -3, Busulfex 3.2 mg/kg IV every day for four days on -6, -5, -4, and -3, and HT on day 0. Patients with DOCK8 deficiency and a 9/10 matched unrelated donor will receive a pre transplant conditioning regimen consisting of fludarabine 40mg/m2/day on days -6, -5, -4, and -3, and HSCT on day 0. Patients with a haploidentical donor will receive a reduced intensity- conditioning regimen with cyclophosphamide 14.5 mg/kg on days -6 and -5, fludarabine 30mg/m2 on days -6 to -2, and 200 cGy TBI on day -1. Donor bone marrow cells will be infused on day 0. Post-transplant immunosuppression for graftversus- host-disease (GVHD) prophylaxis will consist of methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 and tacrolimus daily from day -3 until day +180. If there is no evidence of graftversus- host disease and patients have achieved full donor chimerism, Tacrolimus will be tapered off after day +180. Post- transplant immunosupression for graft-versus-host-disease prophylaxis for recipents of haploidentical donors will consist of cyclophosphamide 50 mg/kg on days +3 and +4, along with sirolimus from day +5 to day 180, and tacrolimus from day +5 to day 180, providing that there is no GVHD.
|Contact: Kristen Cole, R.N.||Not Listedfirstname.lastname@example.org|
|Contact: Dennis D Hickstein, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937|
|Principal Investigator:||Dennis D Hickstein, M.D.||National Cancer Institute (NCI)|