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The following is a summary of “Hematopoietic Cell Transplantation for DOCK8 Deficiency: Results from a Prospective Clinical Trial,” published in the September 2024 issue of Allergy and Immunology by Freeman et al.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a severe primary immunodeficiency disorder for which allogeneic hematopoietic cell transplantation (HCT) remains the only definitive cure. This study aimed to assess the effectiveness of a busulfan-based conditioning regimen in achieving reliable engraftment, high levels of donor chimerism, and acceptable toxicity profiles in patients with DOCK8 deficiency. Additionally, researchers sought to determine the ability of HCT to reverse the clinical manifestations of the disease and correct underlying immunologic abnormalities within one year post-transplantation.

Investigators conducted a prospective clinical trial involving patients with DOCK8 deficiency who underwent HCT between October 5th, 2010, and December 30th, 2022. The study recruited 36 subjects, including both children and adults, with a median age of 16.4 years. Donor sources included fully matched related (MRD), matched unrelated (MUD), and haploidentical (Haplo) donors. The conditioning regimen was designed to be reduced-toxicity myeloablative and did not include serotherapy. Graft-versus-host disease (GVHD) prophylaxis initially comprised a calcineurin inhibitor (CNI) with methotrexate (MTX) or post-HCT cyclophosphamide (PT/Cy), followed by tacrolimus and mycophenolate mofetil (MMF). The study was later amended to standardize the use of PT/Cy in all patients.

The results demonstrated that 92% of patients (33 out of 36) achieved full donor chimerism (≥98%) in whole blood by day +30 post-transplantation. With a median follow-up of 7.4 years, 80.6% of the patients (29 out of 36) were alive, with no evidence of new complications related to DOCK8 deficiency. PT/Cy was particularly effective in reducing the risk of acute GVHD in patients who received MUD or Haplo transplants, although it was associated with transient delays in immune reconstitution and instances of hemorrhagic cystitis (HC).

In conclusion, the busulfan-based HCT regimen, combined with PT/Cy for GVHD prophylaxis and utilizing a broad range of donor types, proved to be well-tolerated and effective. The regimen successfully reversed the clinical immunophenotype of DOCK8 deficiency in the majority of patients, demonstrating the potential for long-term disease remission and improved survival outcomes.

Source: sciencedirect.com/science/article/abs/pii/S0091674924009047