Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 Deficiency

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    90
  • sponsor
    National Cancer Institute (NCI)
Updated on 15 September 2021

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 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 5 and 40 years of age who have DOCK8 deficiency, have suffered one or more 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 a physical examination and medical history.
  • DONORS:
  • Donors will donate bone marrow cells or blood stem cells. If donating blood stem cells, 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 provide the stem cells through bone marrow donation will have their bone marrow cells harvested in the operating room.
  • RECIPIENTS:
  • Recipients receiving 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 haploidentical related donors will receive two doses of chemotherapy with cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and one dose of radiation to suppress their immune system and prepare them for 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 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 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.

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.

Objectives

-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 patients with DOCK8 deficiency.

Eligibility

Patients 5-35 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

  • DOCK8 deficiency patients with 10/10 matched related donors and unrelated donors 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. The busulfan dosing will be adjusted based upon a test dose of busulfan given prior to the start of the conditioning regimen. Donor hematopoietic stem cells will be infused on day 0.
  • 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.
  • DOCK8 deficiency patients with 9/10 matched related or 9/10 matched unrelated donors 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. The busulfan dosing will be adjusted based upon a test dose of busulfan given prior to the start of the conditioning regimen. 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.

DOCK8 deficiency patients with a haploidentical related donor will receive a pre-transplant conditioning regimen consisting of cyclophosphamide 14.5 mg/kg on days -6 and -5, busulfan IV (dose based on pharmacokinetic levels) once daily for 3 days on days -4, -3,and -2, fludarabine 30 mg/m2 on days -6, -5, -4, -3, and -2, and 200 cGy TBI on day -1. The busulfan dosing will be adjusted based upon a test dose of busulfan given prior to the start of the conditioning regimen. Donor hematopoietic stem cells will be infused on day 0. Post-transplant immunosuppression for GVHD prophylaxis 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.

Details
Condition DOCK8 Deficiency
Treatment Total Body Irradiation (TBI), Reduced-intensity hematopoietic stem cell, Fludarabine(Fludara, Berlex Laboratories), Cyclophosphamide(CTX, Cytoxan), Busulfan (Busulfex), Donor peripheral blood stem cell mobiliation and collection, Bone Marrow Harvest Procedure
Clinical Study IdentifierNCT01176006
SponsorNational Cancer Institute (NCI)
Last Modified on15 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Parent/caregiver of a patient(s) who received a transplant for DOCK8 deficiency on this study
Transplant recipient greater than or equal to 18 who has undergone a transplant for DOCK8 deficiency on this study
Note: If a transplant recipient has completed follow-up or has come off study
for any reason, re-enrollment will be permitted to complete the interview
Must be able to give consent and sign the informed consent document
Able to understand the English language

Exclusion Criteria

History of severe cutaneous viral infections with herpes simplex, herpes zoster, or molluscum contagiosum
HIV infection
Chronic active hepatitis B. Donor may be hepatitis core antibody positive
Other medical contraindications to stem cell donation (i.e. severe atherosclerosis, autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident)
History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-bycase basis. The risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient
Donors must not be pregnant. Pregnancy is an absolute contraindication under this protocol. The effects of cytokine administration on a fetus are unknown. Donors of childbearing potential must use an effective method of contraception. Effective forms of contraception include one or more of the following: intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partner s vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or abstinence
Other medical conditions that in the opinion of the PI constitute exclusion as a donor
Mutation of DOCK8 on both alleles
EXCLUSION CRITERIA - MATCHED UNRELATED DONOR
Failure to qualify as an NMDP donor
EXCLUSION CRITERIA - HAPLOIDENTICAL RELATED DONOR
HIV infection
Chronic active hepatitis B. Donor may be hepatitis core antibody positive
History of psychiatric disorder which in the opinion of the PI may compromise compliance with transplant protocol, or which does not allow for appropriate informed
Other medical contraindications that in the opinion of the PI constitute exclusion as a donor. History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-bycase basis. The risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient
Donors must not be pregnant. Pregnancy is an absolute contraindication under this protocol. The effects of cytokine administration on a fetus are unknown. Donors of childbearing potential must use an effective method of contraception. Effective forms of contraception include one or more of the following: intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partner s vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or abstinence
Mutation of DOCK8 on both alleles in a sibling donor
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