Successful hematopoietic cell transplantation in a patient with X‐linked agammaglobulinemia and acute myeloid leukemia

Abu‐Arja, Rolla; Chernin, Leah; Abusin, Ghada; Auletta, Jeffery J.; Cabral, Linda; Egler, Rachel A.; Ochs, Hans D.; Torgerson, Troy R.; López-Guisa, Jesús M.; Hostoffer, Robert; Tcheurekdjian, Haig; Cooke, Kenneth R.

doi:10.1002/pbc.25554

Cited by 25 publications

(16 citation statements)

References 20 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Patients with X-linked agammaglobulinemia (XLA) have failure of B-cell development with lack of immunoglobulin (Ig) production. While immunoglobulin replacement therapy (IgRT) is beneficial, XLA patients remain at risk for infections, structural lung damage, and rarely, neoplasia. Allogeneic stem cell transplantation (alloSCT) may offer a potential cure, but is associated with significant life-threatening complications. Here, we present a 25-year old XLA patient who developed pre-B acute lymphocytic leukemia (ALL) with somatic TP53 mutation, and treatment for this high-risk malignancy involved full myeloablative conditioning and a HLA-matched sibling alloSCT. Full donor chimerism was achieved for CD3+ and CD3- cell fractions. The patient remains in morphological and flow cytometric remission 14 months post-transplant, with late-onset oral GvHD requiring low dose prednisolone and cyclosporin. Following IgRT discontinuation at 4 months post-transplantation, humoral immunity was established within 14 months as reflected by normal numbers of total B cells, memory B cells, serum IgG, IgM, and IgA, and production of specific IgG responses to Prevenar-13 vaccination. This is only the second reported case of an XLA patient with pre-B-ALL, and the most detailed report of engraftment following alloSCT in XLA. Together with the two previous XLA cases treated with alloSCT, our report provides evidence for the potential for successful humoral reconstitution with alloSCT in patients with B-cell intrinsic antibody deficiency. These observations may be relevant given IgRT, while beneficial, remains an imperfect solution to long-term infectious complications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…In contrast to xid , stable donor engraftment was not achieved in human cases, and resulted in no harm, but to no benefit. Abu-Arja et al recently reported successful allo-SCT in a patient with XLA and AML, in which they used a myeloablative conditioning regimen because it is the standard treatment for AML [ 7 ]. They suggested the use of a RIC regimen in the case of allo-SCT for XLA.…”

Section: Case Presentationmentioning

confidence: 99%

“…They did not use a preconditioning regimen based on findings obtained in XLA model mice, in which no stable donor engraftment was achieved, resulting in no harm, but no benefit [ 6 ]. Allo-SCT was recently performed on a patient with XLA coincidentally complicated with acute myeloid leukemia (AML), in which a myeloablative conditioning regimen was used because it is the standard treatment for AML [ 7 ]. Since XLA itself is a non-malignant disorder, reduced intensity conditioning (RIC) may be suitable for cases of allo-SCT for XLA in order to minimize transplantation-associated toxicity [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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).

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“…More recently, two XLA patients were successfully transplanted with matched donor hematopoietic stem cells. 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, ).…”

Section: Introductionmentioning

confidence: 99%

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

Ochs

Petroni²

2017

American J of Med Genetics Pt A

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The field of primary immunodeficiency diseases (PID) is rapidly expanding with more than 300 genetically defined disorders that have been clinically described and molecularly analyzed. The molecular dissection of these entities has led to the discovery of new immunologic pathways and to novel and effective disease-specific therapies. This review provides a summary of these primary immune defects categorized by clinical phenotype and molecular similarity as defined by the International Union of Immunologic Societies (IUIS) Expert Committee for PID. In this synopsis, we discuss the molecular basis of various categories of PIDs including, but not limited to, severe combined immunodeficiencies, primary antibody deficiencies, immune dysregulation syndromes, as well as defects of the innate immune system such as phagocytic abnormalities, autoinflammatory fever syndromes, and complement deficiencies. We have attempted to focus on current strategies to prevent complications, ameliorate symptoms, or cure these disorders by promptly using antimicrobial therapies, immunoglobulin replacement, and hematopoietic stem cell transplantation. In addition, we will explore novel therapies such as molecularly targeted immunosuppression with monoclonal antibodies and specific immunomodulatory agents. Finally, we address experimental therapies targeting specific molecular defects, including gene therapy and gene editing.

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Successful hematopoietic cell transplantation in a patient with X‐linked agammaglobulinemia and acute myeloid leukemia

Cited by 25 publications

References 20 publications

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

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

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

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

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