Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity

Abstract

BackgroundWe herein report the first case of X-linked agammaglobulinemia (XLA) that underwent allogeneic stem cell transplantation using reduced intensity conditioning (RIC). We chronologically observed the reconstitution of humoral immunity in this case.Case presentationThe patient was a 28-year-old Japanese male with XLA who previously had life-threatening infectious episodes and was referred for the possible indication of allogeneic stem cell transplantation. After a thorough discussion within specialists from different backgrounds, we decided to perform allogeneic peripheral stem cell transplantation from his HLA-identical elder brother. Due to the non-malignant nature of XLA, we selected RIC consisting of fludarabine, cyclophosphamide, anti-thymocyte globulin, and 3 Gy of total body irradiation. Neutrophil engraftment was achieved on day 11 with complete donor chimerism. No major complications, except for stage 1 skin graft-versus-host disease, were observed. The patient was discharged on day 75 and has been followed as an outpatient without any infectious episodes for more than 500 days.ConclusionsRegarding immune reconstitution, CD19+ cells, IgA, and IgM, which were undetectable before allogeneic stem cell transplantation (allo-SCT), started to increase in number 10 days after allo-SCT and continued to increase for more than 1 year. Anti-B antibodies appeared as early as day 10. Total IgG levels decreased after the discontinuation of IgG replacement and spontaneously recovered after day 350. However, most anti-viral IgG titers, except EB virus-virus capsid antigen IgG, disappeared after the discontinuation of IgG replacement. A seasonal vaccination to influenza was performed on day 148, with neither anti-influenza type A nor type B being positive after the vaccination. The transient transfer of allergic immunity to orchard grass was observed. Similar Bruton’s tyrosine kinase (BTK) expression levels in monocytes and B-cells were observed between the patient and healthy control. B-cells in the peripheral blood (PB) of the patient on day 279 showed sufficient proliferation after a CD40L and IL-21 or CD40L and CpG stimulation. Effective immunoglobulin production and class switching were also observed after a CD40L and IL-21 or CpG stimulation. Signal joint kappa-deleting recombination excision circles (sjKRECs) became positive 16 days post-SCT, increased to 6300 copies/μg DNA at 42 days, and were maintained at a high level thereafter. The recovery of T-cell receptor excision circles (TRECs) was slow, but became detectable 1 year post-hematopoietic stem cell transplantation (HSCT).

Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India

“…HSCT was performed in four patients at a single center with expertise in transplant facility ( 48 , 49 ). There have been rare reports of successful HSCT in patients with XLA ( 50 , 51 ). All 4 children in the present series underwent successful HSCT and are off IVIg.…”

Functional Antibody Responses Following Allogeneic Stem Cell Transplantation for TP53 Mutant pre-B-ALL in a Patient With X-Linked Agammaglobulinemia

“…An early series of 6 patients failed to demonstrate engraftment in the absence of myeloablative conditioning (10). Table 2 summarizes 3 subsequent allograft cases, including the patient in this manuscript, in which conditioning resulted in high levels of sustained donor engraftment, restoration of B-cell numbers and detectable antibody levels (11, 12). In Case 1, total Ig levels post-transplant were reported to be normal, as were responses to vaccination, but no details were given for IgA and IgM levels (11).…”

“…In Case 1, total Ig levels post-transplant were reported to be normal, as were responses to vaccination, but no details were given for IgA and IgM levels (11). In Case 2 antibody levels were restored, but remained below the range of healthy controls, and an antibody response to vaccination was demonstrated (12). Case 2 had received a mild conditioning regime, which is a potentially lower-risk strategy than the standard conditioning in the other 2 cases.…”

“…Initial attempts of alloSCT without conditioning resulted in failed engraftment in 6 XLA patients (10). Since then, two XLA patients were treated with allograft with conditioning: full myeloablation in a 13 yr-old XLA with acute myeloid leukemia (11), and reduced conditioning in 28 yr-old XLA with recurrent serious infections in spite of IgRT (12). Both cases demonstrated alloSCT provided at least partial reconstitution of antibody levels and responses.…”

From clinical observations and molecular dissection to novel therapeutic strategies for primary immunodeficiency disorders

“…One, a 13‐year‐old male with known XLA and newly diagnosed acute myeloid leukemia, was transplanted following myelo‐ablative conditioning (Abu‐Arja et al, ). The other, a 28‐year‐old male with XLA and recurrent life‐threatening infections, received a matched sibling transplant following reduced intensity conditioning (Ikegame et al, ). Both XLA patients had an excellent immune recovery and no longer require immunoglobulin replacement.…”