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Treatment of severe forms of LPS-responsive beige-like anchor protein deficiency with allogeneic hematopoietic stem cell transplantation

2017; Elsevier BV; Volume: 141; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2017.04.023

1097-6825

Markus G. Seidel, K. Böhm, Figen Doğu, Austen Worth, Adrian J. Thrasher, Benoît Florkin, Aydan İkincioğulları, Anke Peters, Shahrzad Bakhtiar, Marie Meeths, Polina Stepensky, Isabelle Meyts, Svetlana O. Sharapova, Laura Gámez‐Díaz, Lennart Hammarström, Stephan Ehl, Bodo Grimbacher, Andrew R. Gennery,

Cystic Fibrosis Research Advances

LPS-responsive beige-like anchor protein (LRBA) deficiency is a severe primary immunodeficiency with a variable clinical phenotype, including features overlapping with common variable immunodeficiency, autoimmune lymphoproliferative syndrome, and immune dysregulation polyendocrinopathy enteropathy X-linked syndrome and an association with lymphoma.1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google Scholar, 2Alkhairy O.K. Abolhassani H. Rezaei N. Fang M. Andersen K.K. Chavoshzadeh Z. et al.Spectrum of phenotypes associated with mutations in LRBA.J Clin Immunol. 2016; 36: 33-45Crossref PubMed Scopus (151) Google Scholar, 3Charbonnier L.M. Janssen E. Chou J. Ohsumi T.K. Keles S. Hsu J.T. et al.Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA.J Allergy Clin Immunol. 2015; 135: 217-227Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar Despite accumulating experience, the procedure of allogeneic hematopoietic stem cell transplantation (HSCT) to treat primary multiorgan autoimmunity disorders and combined immunodeficiencies with immune dysregulation, such as LRBA deficiency, is not routine. First, the indication and optimal time point are undetermined. Second, the outcome of HSCT in patients with syndromes with predominant autoimmunity is unclear, given that target antigens of autoimmune reactions remain unchanged, and both autoimmunity and inflammation can persist because of disease-causing factors extrinsic to the hematopoietic and immune system. For instance, LRBA is a ubiquitously expressed protein functioning in autophagy and intracellular vesicle trafficking, facilitating cell-surface translocation of cytotoxic T lymphocyte–associated antigen 4 (CTLA4).4Lo B. Zhang K. Lu W. Zheng L. Zhang Q. Kanellopoulou C. et al.Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.Science. 2015; 349: 436-440Crossref PubMed Scopus (448) Google Scholar, 5Lopez-Herrera G. Tampella G. Pan-Hammarstrom Q. Herholz P. Trujillo-Vargas C.M. Phadwal K. et al.Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.Am J Hum Genet. 2012; 90: 986-1001Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar Its relevance in tissues other than immune cells is unknown. Augmentation of regulatory T-cell function in LRBA-deficient patients manifesting with chronic enteropathy by regular CTLA4-Ig infusions potentially induces remission.4Lo B. Zhang K. Lu W. Zheng L. Zhang Q. Kanellopoulou C. et al.Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.Science. 2015; 349: 436-440Crossref PubMed Scopus (448) Google Scholar However, not all symptoms respond equally, and patients remain dependent on CTLA4 substitution. Furthermore, the additional use of steroids, sirolimus, hydroxychloroquine, and other immunosuppressants might not prevent the long-term deterioration of patients with this potentially fatal disease. Finally, CTLA4-Ig is not available in many countries because of limited resources. Although HSCT has proved helpful in single patients,1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google Scholar, 6Seidel M.G. Hirschmugl T. Gamez-Diaz L. Schwinger W. Serwas N. Deutschmann A. et al.Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency.J Allergy Clin Immunol. 2015; 135: 1384-1390.e8Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 7Tesi B. Priftakis P. Lindgren F. Chiang S.C. Kartalis N. Lofstedt A. et al.Successful hematopoietic stem cell transplantation in a patient with lps-responsive beige-like anchor (LRBA) gene mutation.J Clin Immunol. 2016; 36: 480-489Crossref PubMed Scopus (31) Google Scholar, 8Sari S. Dogu F. Hwa V. Haskologlu S. Dauber A. Rosenfeld R. et al.A successful HSCT in a girl with novel LRBA mutation with refractory celiac disease.J Clin Immunol. 2016; 36: 8-11Crossref PubMed Scopus (28) Google Scholar, 9Bakhtiar S. Gamez-Diaz L. Jarisch A. Soerensen J. Grimbacher B. Belohradsky B. et al.Treatment of infantile inflammatory bowel disease and autoimmunity by allogeneic stem cell transplantation in LPS-responsive beige-like anchor deficiency.Front Immunol. 2017; 8: 52Crossref PubMed Scopus (24) Google Scholar early reports of HSCT in cases of LRBA deficiency indicated a higher transplant-related mortality than in other inborn errors (2 of first 4 patients); it is unclear whether disease status at the time of HSCT or other disease- or transplant-related factors were involved. To better understand the role of HSCT as a potentially curative treatment for LRBA deficiency, we performed an international European Group for Blood and Marrow Transplantation– and European Society for Immunodeficiencies–wide survey in 2016 to collect information about the HSCT experience. Data were obtained in accordance with the Declaration of Helsinki and an institutional review board review (IRB00002556, 29-142ex16/17) by means of retrospective chart review by local physicians. From a cohort of 72 patients with LRBA deficiency, 12 underwent HSCT between 2005 and 2016 (Table I).1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google Scholar, 6Seidel M.G. Hirschmugl T. Gamez-Diaz L. Schwinger W. Serwas N. Deutschmann A. et al.Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency.J Allergy Clin Immunol. 2015; 135: 1384-1390.e8Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 7Tesi B. Priftakis P. Lindgren F. Chiang S.C. Kartalis N. Lofstedt A. et al.Successful hematopoietic stem cell transplantation in a patient with lps-responsive beige-like anchor (LRBA) gene mutation.J Clin Immunol. 2016; 36: 480-489Crossref PubMed Scopus (31) Google Scholar, 8Sari S. Dogu F. Hwa V. Haskologlu S. Dauber A. Rosenfeld R. et al.A successful HSCT in a girl with novel LRBA mutation with refractory celiac disease.J Clin Immunol. 2016; 36: 8-11Crossref PubMed Scopus (28) Google Scholar, 9Bakhtiar S. Gamez-Diaz L. Jarisch A. Soerensen J. Grimbacher B. Belohradsky B. et al.Treatment of infantile inflammatory bowel disease and autoimmunity by allogeneic stem cell transplantation in LPS-responsive beige-like anchor deficiency.Front Immunol. 2017; 8: 52Crossref PubMed Scopus (24) Google Scholar Indications for transplantation included refractory immune cytopenias, gastrointestinal problems, parenchymal lung disease, failure to thrive, severe neurological or infectious complications, or “severe course of the disease” (Fig 1, A, and Table I). Overall survival of patients undergoing transplantation was 67% (8/12 patients); all deaths were due to transplant-related mortality (pre-existing infections, graft failure, multiorgan failure, and thrombotic microangiopathy) and occurred within 3 months of HSCT (Fig 1, Table I, and see Fig E1 in this article's Online Repository at www.jacionline.org). Eleven donors were HLA-matched unrelated (n = 4) or family (n = 7) donors. One of the deceased patients was the only subject of the cohort with a mismatched (haploidentical family) donor. Surviving patients had mostly favorable degrees of remission (complete, 4; good partial, 2 [some mild or moderate potentially LRBA-related symptoms not requiring immunosuppressive therapy]; and partial, 2 [amelioration of disease but need of immunosuppression for potentially LRBA-related symptoms]) with a median follow-up of 26 months (range, 4-142 months; Fig 1 and Table I). HSCT course and recurrence or persistence of symptoms were apparently not dependent on the donor's LRBA status or on the type/intensity of conditioning. All survivors in complete or good partial remission showed full donor chimerism (>95% donor white blood cells [WBCs]). Two patients with partial remission (requiring immunosuppressive treatment) showed decreasing donor WBC chimerism of less than 90%. Patient 3 had 89% donor WBCs and 88% donor T cells on day +240, further decreasing to 83% and 84%, respectively, on day +720, and was treated with sirolimus and romiplostim for moderate immune thrombocytopenia and autoimmune hemolytic anemia that developed on days +90 and +270, respectively. Patient 9, with only 7% WBC and 23% T-cell chimerism on day +578, was successfully treated with abatacept after attempts with steroids and rituximab for autoimmune hemolytic anemia (see details in Table I). Both patients are clinically stable under the current treatment and did not have other autoimmune symptoms previously showed because of LRBA deficiency (Fig 1, A, and Table I). Thus the best results of HSCT for LRBA deficiency were associated with full donor chimerism. Donor source, transplantation regimen, graft-versus-host disease incidence, and disease response are listed in Fig 1 and Table I. Strikingly, LRBA-related symptoms resolved or decreased significantly in number and intensity, and performance scores increased in all HSCT survivors (Fig 1, A-C). Consequently, the need for immunosuppressive treatment decreased, and most patients were off immunoglobulin replacement after HSCT (Fig 1, D and E). Unfortunately, there are no up-to-date follow-up and survival data of patients not undergoing transplantation beyond previous publications of large cohort studies that reported at least 6 deceased of 58 patients not undergoing transplantation but many patients with new diagnoses and family members.1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google Scholar, 2Alkhairy O.K. Abolhassani H. Rezaei N. Fang M. Andersen K.K. Chavoshzadeh Z. et al.Spectrum of phenotypes associated with mutations in LRBA.J Clin Immunol. 2016; 36: 33-45Crossref PubMed Scopus (151) Google Scholar, 5Lopez-Herrera G. Tampella G. Pan-Hammarstrom Q. Herholz P. Trujillo-Vargas C.M. Phadwal K. et al.Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.Am J Hum Genet. 2012; 90: 986-1001Abstract Full Text Full Text PDF PubMed Scopus (361) Google ScholarTable IClinical characteristics and laboratory parameters of 12 LRBA-deficient patients who underwent allogeneic HSCTCharacteristics123456789101112Mutationc.7162delAc.5505delTc.675G>Ac.1420G>A; c.2834_2837delTCTTc.7162delAc.2004+2A>Gc.3647_3651delCTAA;c.7937T>GExon 1-30 deletionc.2978C>Gc.4522 C>Tc.7937T>Gc.2762G>CAge at onset (y)7133230,141314Previous publicationTesi et al7Tesi B. Priftakis P. Lindgren F. Chiang S.C. Kartalis N. Lofstedt A. et al.Successful hematopoietic stem cell transplantation in a patient with lps-responsive beige-like anchor (LRBA) gene mutation.J Clin Immunol. 2016; 36: 480-489Crossref PubMed Scopus (31) Google ScholarSari et al8Sari S. Dogu F. Hwa V. Haskologlu S. Dauber A. Rosenfeld R. et al.A successful HSCT in a girl with novel LRBA mutation with refractory celiac disease.J Clin Immunol. 2016; 36: 8-11Crossref PubMed Scopus (28) Google Scholar∗Manuscripts (single patient reports) in preparation (personal communication).Gámez-Díaz et al1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google ScholarGámez-Díazet al1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google Scholar and Seidel et al6Seidel M.G. Hirschmugl T. Gamez-Diaz L. Schwinger W. Serwas N. Deutschmann A. et al.Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency.J Allergy Clin Immunol. 2015; 135: 1384-1390.e8Abstract Full Text Full Text PDF PubMed Scopus (56) Google ScholarGámez-Díazet al1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google ScholarBakhtiar et al9Bakhtiar S. Gamez-Diaz L. Jarisch A. Soerensen J. Grimbacher B. Belohradsky B. et al.Treatment of infantile inflammatory bowel disease and autoimmunity by allogeneic stem cell transplantation in LPS-responsive beige-like anchor deficiency.Front Immunol. 2017; 8: 52Crossref PubMed Scopus (24) Google ScholarGámez-Díaz et al1Gámez-Díaz L. August D. Stepensky P. Revel-Vilk S. Seidel M.G. Noriko M. et al.The extended phenotype of LRBA deficiency.Front Immunol. 2016; 137: 223-230Scopus (194) Google Scholar∗Manuscripts (single patient reports) in preparation (personal communication).∗Manuscripts (single patient reports) in preparation (personal communication).∗Manuscripts (single patient reports) in preparation (personal communication).∗Manuscripts (single patient reports) in preparation (personal communication).LRBA-directed treatment before SCT SteroidsXXXXXXXXXXXX RituximabXXXXXX AbataceptX SirolimusXXXXX HydroxychloroquineXX MMFXXXX AzathioprineXXXX Other ISCSA/FKCSA/FK, infliximabCSA/FK, basiliximabMTX, CSA/FKCSA/FKNot specified IVIGXXXXXXXXXXX SCIGXXXXSCT conditioning and course Indication for SCTSevere CVID-related clinical problems, ADEMSevere clinical course unresponsive to treatmentSevere clinical course unresponsive to treatmentChronic interstitial lung disease, chronic inflammatory bowel diseaseRefractory pancytopenia and lymphoproliferationRecurrent respiratory infections and insufficiency, pancytopenia, lymphoproliferationEnteropathy, autoimmunitySteroid refractory lymphocytic interstitial pneumoniaSevere clinical course, enteropathy, infections, failure to thriveRefractory CNS lymphoproliferationLymphoproliferationSevere humoral immunodeficiency, intestinal problems, autoimmunity Age at HSCT (y)13127111061110316910 Year of SCT201320142015201520052013201020122015201520162009 Donor type (and LRBA status)MFD (het)MSD (ND)MSD (het)MUD (ND)MFD (het)MMFD (het)MSD (het)MUD (ND)MFD (WT)MUD (ND)MSD (het)MUD (ND) Fludarabin and serotherapyXXXXXXXXXXXX TreosulfanXXXX BusulfanXXX ThiotepaXXX MelphalanXXXXX aGvHD1° (skin)1°-2° (skin) cGvHDLimited: eye, gut Peri-SCT infectionsAspergillosis and CMV (pre-SCT)AdVAdV, CMV Post-SCT complications/TRM and cause of deathInvasive aspergillosisPost-SCT autoimmune hepatitis, successfully treated with AZT and resolvedRespiratory failure, lung fibrosis, granuloma, adenovirus pneumonia, graft rejectionTMA, AdV viremia, pneumonitisPost-SCT AIHAStill requires hematopoietic growth factor support, might need SC boostPoor engraftment, CMV pneumonitis, Enterobacter and Acinetobacter sepsisOutcome Overall survivalXXXXXXXX FU (mo)362527(3)142(3)75(2)2294(2) Donor chimerism (% WBC unless otherwise stated)‡Time point after HSCT.>95 T, B, myeloid(+3 y)98(+2 y)83 WBC, 84 CD3+ (+2 y†Decreasing donor chimerism in patient 3 from 95% to 99% donor WBCs with 91% donor T cells (days +30 and +60) to 89% WBCs and 88% CD3+ cells (day +240) and further decreasing to 83% WBC and 84% T-cell chimerism 2 years after HSCT and in patient 9 from 100% donor WBCs on days +30 and +60 to 93% on day +82, which further decreased to 15% WBCs and 31% CD3+ cells on day +430 and down to 7% donor-derived WBCs and 23% CD3+ T cells day +578 at the latest follow-up (as shown).)100 (d+100)100 (+3 y)NA100(+3 y)100 (d+30)7 WBC, 23 CD3+(d+578†Decreasing donor chimerism in patient 3 from 95% to 99% donor WBCs with 91% donor T cells (days +30 and +60) to 89% WBCs and 88% CD3+ cells (day +240) and further decreasing to 83% WBC and 84% T-cell chimerism 2 years after HSCT and in patient 9 from 100% donor WBCs on days +30 and +60 to 93% on day +82, which further decreased to 15% WBCs and 31% CD3+ cells on day +430 and down to 7% donor-derived WBCs and 23% CD3+ T cells day +578 at the latest follow-up (as shown).)97 WBC, 44 CD3+ (d+180)100 (d+120)0 (d+30) Remission statusGPR (mild thrombocytopenia and thyroid disease)CRPR (moderate cITP and AIHA)died3 mo after SCT (TRM)GPR(mild cITP, vitiligo)Died3 mo after SCT (TRM)CRdied2 mo after SCT (TRM)PR(AIHA; irreversible IDDM after pancreatitis)CRGPR (thrombocytopenia, neutropenia, flares of arthritis)Died2 mo after SCT (TRM) Current treatmentNoneNoneTRA, sirolimus, IVIGNATRA (recently discontinued)NANoneNAAbatacept IVIGNoneTRA, GCSFNAADEM, Acute disseminated encephalomyelitis; AdV, adenovirus; aGvHD, acute graft-versus-host disease; AIHA, autoimmune hemolytic anemia; AZT, azathioprine; cGvHD, chronic graft-versus-host disease; cITP, chronic immune thrombocytopenia; CMV, cytomegalovirus; CNS, central nervous system; CR, complete remission; CSA, cyclosporine A; CVID, common variable immunodeficiency; FK, tacrolimus/FK506; FU, follow-up; GCSF, granulocyte colony stimulating factor; GPR, good partial remission (mild residual symptoms, potentially LRBA related, but without requirement of immunosuppressive treatment); het, heterozygous; IDDM, insulin-dependent diabetes mellitus (in this case as sequelae after pancreatitis); IS, immunosuppressive drugs; IVIG, regular intravenous immunoglobulin replacement therapy; MFD, matched family donor; MMF, mycophenolate mofetil; MMFD, mismatched family donor; MSD, matched sibling donor; MTX, methotrexate; MUD, matched unrelated donor; ND, no data or not determined; PR, partial remission (moderate residual symptoms, potentially LRBA related, with requirement of immunosuppressive treatment); SC boost, stem cell boost; SCT, stem cell transplantation; SCIG, regular subcutaneous immunoglobulin replacement therapy; steroids, glucocorticoids; T and B, T and B lymphocytes; TMA, thrombotic microangiopathy; TRA, thrombopoietin receptor agonist treatment; TRM, transplant-related mortality; WT, wild-type.∗ Manuscripts (single patient reports) in preparation (personal communication).† Decreasing donor chimerism in patient 3 from 95% to 99% donor WBCs with 91% donor T cells (days +30 and +60) to 89% WBCs and 88% CD3+ cells (day +240) and further decreasing to 83% WBC and 84% T-cell chimerism 2 years after HSCT and in patient 9 from 100% donor WBCs on days +30 and +60 to 93% on day +82, which further decreased to 15% WBCs and 31% CD3+ cells on day +430 and down to 7% donor-derived WBCs and 23% CD3+ T cells day +578 at the latest follow-up (as shown).‡ Time point after HSCT. Open table in a new tab ADEM, Acute disseminated encephalomyelitis; AdV, adenovirus; aGvHD, acute graft-versus-host disease; AIHA, autoimmune hemolytic anemia; AZT, azathioprine; cGvHD, chronic graft-versus-host disease; cITP, chronic immune thrombocytopenia; CMV, cytomegalovirus; CNS, central nervous system; CR, complete remission; CSA, cyclosporine A; CVID, common variable immunodeficiency; FK, tacrolimus/FK506; FU, follow-up; GCSF, granulocyte colony stimulating factor; GPR, good partial remission (mild residual symptoms, potentially LRBA related, but without requirement of immunosuppressive treatment); het, heterozygous; IDDM, insulin-dependent diabetes mellitus (in this case as sequelae after pancreatitis); IS, immunosuppressive drugs; IVIG, regular intravenous immunoglobulin replacement therapy; MFD, matched family donor; MMF, mycophenolate mofetil; MMFD, mismatched family donor; MSD, matched sibling donor; MTX, methotrexate; MUD, matched unrelated donor; ND, no data or not determined; PR, partial remission (moderate residual symptoms, potentially LRBA related, with requirement of immunosuppressive treatment); SC boost, stem cell boost; SCT, stem cell transplantation; SCIG, regular subcutaneous immunoglobulin replacement therapy; steroids, glucocorticoids; T and B, T and B lymphocytes; TMA, thrombotic microangiopathy; TRA, thrombopoietin receptor agonist treatment; TRM, transplant-related mortality; WT, wild-type. Although the number of patients surveyed was too small to routinely recommend HSCT for LRBA deficiency based on the evidence collected, these data support the feasibility and curative potential of HSCT and allow us to state 3 important points. First, remissions without further need for immunosuppression are achievable and occurred in 6 of the 8 surviving patients. No relapse occurred in patients with full donor chimerism. Importantly, although the treatment-requiring autoimmune cytopenias in patients 3 and 9 observed after HSCT were possibly caused by LRBA deficiency because of waning donor chimerism, they could also be attributed to graft failure, after HSCT immune dysregulation or marrow dysfunction, as suspected in the growth factor–responsive thrombocytopenia and neutropenia of patient 11, because such sequelae can occur similarly in HSCT recipients with other underlying diseases. With a median follow-up of 2 years, 6 of 8 patients did not need further pharmacologic immunosuppression or immunoglobulin replacement therapy, indicating curability. Only 1 patient in this cohort received abatacept as bridging treatment to HSCT. It is unclear whether response to abatacept would have changed the HSCT indication. However, despite the overall satisfying responses to abatacept (reported in 10 patients in the cohort of 72 patients), the long-term dependency on this treatment with its associated potential risks remains. The risk of LRBA-related lymphoma or immunosuppression-associated malignancy would be anticipated to be substantially reduced or abolished in HSCT survivors, as well as the future risk of infections, compared with patients undergoing continuous treatment with CTLA4-Ig, sirolimus, or other immunosuppression. Thus, based on the present results, we would proceed to HSCT if a suitable donor was present. The optimal time point remains to be determined, but it can be expected that long-term organ damage will have a negative effect on HSCT results. Second, among the small cohort of 12 LRBA-deficient patients who underwent transplantation from heterozygous LRBA mutation carriers (n = 6) or LRBA wild-type (n = 1) or unrelated donors (n = 5), no correlation between residual or recurring LRBA-related symptoms and donor LRBA status was detected, arguing against a dose effect of LRBA.2Alkhairy O.K. Abolhassani H. Rezaei N. Fang M. Andersen K.K. Chavoshzadeh Z. et al.Spectrum of phenotypes associated with mutations in LRBA.J Clin Immunol. 2016; 36: 33-45Crossref PubMed Scopus (151) Google Scholar, 6Seidel M.G. Hirschmugl T. Gamez-Diaz L. Schwinger W. Serwas N. Deutschmann A. et al.Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency.J Allergy Clin Immunol. 2015; 135: 1384-1390.e8Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Lastly, these data indicate that any alluded LRBA-dependent effects outside the (transplanted) hematopoietic/immune tissues play no or only an inferior role with regard to outcome and remission. Together, accepting the limitation that the retrospective case series lacked a matched control group, our findings strongly support the use of early HSCT in patients with severe presentations of LRBA deficiency. We thank the European Group for Blood and Marrow Transplantation and European Society for Immunodeficiencies for providing platforms for data accrual and Sara Crockett for scientific editing. Dr Sharapova thanks E. Haapaniemi, Karolinska Institutet, Huddinge, Sweden, for help with the genetic analyses.