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Clinical Trial
. 2025 Jan;155(1):176-187.
doi: 10.1016/j.jaci.2024.08.021. Epub 2024 Sep 2.

Hematopoietic cell transplantation for DOCK8 deficiency: Results from a prospective clinical trial

Alexandra F Freeman  1 , Corina E Gonzalez  2 , Bonnie Yates  3 , Kristen Cole  4 , Lauren Little  3 , Erin Flannelly  5 , Seth M Steinberg  6 , George Mo  3 , Nicole Piette  7 , Thomas E Hughes  7 , Jennifer Cuellar-Rodriguez  1 , Juan Gea-Banacloche  1 , Theo Heller  8 , Dima A Hammoud  9 , Steve M Holland  1 , Heidi H Kong  10 , Fernanda D Young  11 , Huie Jing  1 , Basak Kayaoglu  1 , Helen C Su  1 , Sung-Yun Pai  5 , Dennis D Hickstein  5 , Nirali N Shah  3
Affiliations
Clinical Trial

Hematopoietic cell transplantation for DOCK8 deficiency: Results from a prospective clinical trial

Alexandra F Freeman et al. J Allergy Clin Immunol. 2025 Jan.

Abstract

Background: DOCK8 deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency.

Objectives: To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1 year post HCT.

Methods: We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5, 2010, to December 30, 2022. Donor sources included fully matched related and unrelated donors and haploidentical donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor with methotrexate or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil. The trial was later amended to study PT/Cy in all patients. (Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 [NCT01176006].) RESULTS: Thirty-six subjects, both children and adults (median age 16.4 years), underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day +30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received matched unrelated donor and haploidentical transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis.

Conclusions: A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well tolerated, leading to the reversal of the clinical immunophenotype.

Keywords: DOCK8 deficiency; hematopoietic cell transplantation; immunophenotype reversal.

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Conflict of interest statement

Disclosure statement This work was supported in part by the Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research; the Warren Grant Magnuson Clinical Center (ZIA BC 011823 to N. Shah, ZID BC 012026 to S.-Y. Pai); National Institute of Allergy and Infectious Diseases (1ZIAAI001193 to H. Su); National Institute of Diabetes, Digestive, and Kidney Diseases; and National Institute of Arthritis and Musculoskeletal and Skin Diseases. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

References

    1. Aydin SE, Freeman AF, Al-Herz W, Al Mousa HA, Arnaout RK, Aydin RC, et al. Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency. J Allergy Clin Immunol Pract. 2019;7:848–55. - PMC - PubMed
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    1. Pillay BA, Avery DT, Smart JM, Cole T, Choo S, Chan D, et al. Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients. JCI Insight. 2019;5:1–22. - PMC - PubMed
    1. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361:2046–55. - PMC - PubMed

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