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

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.

Figure 1.. Immune Reconstitution after HCT for DOCK8 Deficiency (To be printed in color)

A) CD3⁺ cells; B) CD4⁺ cells; C) CD8⁺ cells; G) CD19⁺ and L) NK cells during the first year post-HCT showed a transient delay in count recovery exerted by PT-Cy. D) Recent thymic emigrants; E) Naïve CD4⁺ cells; F) Naïve CD8⁺ cells; H) Memory B cells and I) Switched memory B cells gradually recovered to normal values in most patients over a 3-year period. J) Progressive decline in IgE levels over time, and K) Normalization of IgM levels. Asterisks mark significant differences when pre-transplant (pre-tx) levels are compared with timepoint data by Wilcoxon matched pairs signed rank test (*=p< 0.05; **=p< 0.01; ***=p<0.001). Dotted lines mark the lower range of normal for individuals ≥12 years old for T-cell subsets and NK cells and ≥16 years old for B-cell subsets^–.

Figure 2.. Kaplan-Meier estimated probabilities of survival post-HCT (To be printed in color)

(A) Overall survival for the entire cohort of DOCK8 deficient patients undergoing HCT was 80.6%. and was not influenced by donor age (B), HCT-CI (C), GVHD prophylaxis(D) or donor type (E). Severe GVHD event free survival post-HCT was 69.4% at 6 months and beyond (F). Abbreviations: HCT-CI: Hematopoietic cell transplantation-comorbidity index; MRD: matched related donor; MUD: matched unrelated donor; Haplo: haploidentical related donor; CNI: calcineurin inhibitor; MTX: methotrexate; PT/Cy: post-HCT cyclophosphamide; GVHD: graft-versus-host disease; SGEFS: severe GVHD event free survival.

Figure 3.. Engraftment and Selected Complications 2A.

Neutrophil engraftment, stratified by donor source and GVHD prophylaxis. 2B. Platelet engraftment, stratified by donor source and GVHD prophylaxis. 2C. Incidence of ≥ grade 2 hemorrhagic cystitis. 2D. Incidence of viral infections, stratified by donor source and GVHD prophylaxis. Abbreviations: CNI: calcineurin inhibitor; GVHD: graft-versus-host disease; HC: hemorrhagic cystitis; Haplo: haploidentical related donor; MRD: matched related donor; MUD: matched unrelated donor; MTX: methotrexate; PT/Cy: post-HCT cyclophosphamide. (*=p< 0.05; **=p< 0.01; ***=p<0.001)

Figure 4.. Reversal of clinical phenotype of DOCK8-deficient patients by 1 year after allogeneic HCT. (To be printed in color)

MCV: Molluscum Contagiosum virus; HS: Herpes Simplex virus; VZV: Varicella Zoster virus; HPV: Human Papilloma virus; CMV: Cytomegalovirus; EBV: Epstein Barr virus; PNA: pneumonia; AS: acute sinusitis; AOM: acute otitis media. Asterisks mark significant differences between a given clinical manifestation before and 1-year after HCT (*=p< 0.05; **=p< 0.01; ***=p<0.001, by the Sign test)

Figure 5.. Resolution of eczema and viral skin infections post-HCT. (To be printed in color)

Verrucae pre-HCT A) and 9 months post-HCT B); molluscum contagiosum pre-HCT C) and one-year post-HCT D); severe eczema with ulcers pre-HCT E) and 1-year post-HCT F).

Figure 6.. Magnetic resonance angiography showing improvement of cerebral vasculopathy in a patient with DOCK8 deficiency post-HCT.

A) Patent basilar artery 3-years before HCT; B) high grade stenosis at pre-HCT evaluation (arrow) and C) improvement with filling irregularities 7-years post-HCT. D) patent middle cerebral artery 3-years before HCT; E) diffuse narrowing of right middle cerebral artery (arrow) with diminished filling of its branches (circle) at pre-HCT evaluation; and F) improvement with filling irregularities 7-years post-HCT.