Regardless of their age, adult patients with Wiskott-Aldrich syndrome should be considered for hematopoietic stem cell transplantation if clinically indicated

Anantharachagan, A

Burns, SO

Laurence, A

Loh, SY

Lwin, Y

Martinez-Calle, N

Morris, EC

Tadros, S

Tholouli, E

Vaitla, P

English

UCL Discovery

Case reportAllogeneic hematopoietic stem celltransplantation outcome in oldest knownsurviving patients with Wiskott-AldrichsyndromeAriharan Anantharachagan, MBChB,MRCP, MsC,FRCPath,a,b Sook Yin Loh, MBBCh,MRCP,a Siobhan O. Burns, MB PhD,c,dArian Laurence, PhD, MRCP, FRCPath,c,d,e Susan Tadros, MBBS, BSc, MRCP, FRCPath,d Eleni Tholouli, MD, PhD,fYadanar Lwin, MBBS, MMed (Infn, Imm), FRACP, FRCPA,g Nicolas Martinez-Calle, MD, PhD,gP. Vaitla, MBBS, MRCP, FRCPath,h and Emma C. Morris, PhD, FMedScic,d,e Preston, London, Manchester, and Nottingham,United KingdomAbbreviations usedCMV: CytomegalovirusFTT: Fludarabine, treosulfan, and thiotepaGVHD: Graft-versus-host diseaseHSCT: Hematopoietic stem cell transplantationIRT: Immunoglobulin replacement therapyMUD: Matched unrelated donorRhD: Rhesus factor and D-antigenWAS: Wiskott-Aldrich syndromeWASP: Wiskott-Aldrich syndrome proteinRegardless of their age, adult patients with Wiskott-Aldrichsyndrome should be considered for hematopoietic stem celltransplantation if clinically indicated. (J Allergy Clin ImmunolGlobal 2024;3:100191.)Key words: Wiskott-Aldrich syndrome, WAS, hematopoietic stemcell transplantation, HSCT, adultWiskott-Aldrich syndrome (WAS) is a rare, X-linked combinedimmune deficiency caused by mutations in the WAS gene.1 Itsclinical features include eczema, thrombocytopenia, life-threatening infections, autoimmunity, and malignancy.1,2 TheFrom athe Department of Allergy and Clinical Immunology and bthe Department ofImmunology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston; ctheUniversity College London Institute of Immunity and Transplantation; dthe Depart-ment of Immunology, The Royal Free London NHS Foundation Trust; ethe Depart-ment of Clinical Haematology, University College London NHS Foundation Trust;fthe Manchester University NHS Foundation Trust, Department of Haematology;and gthe Department of Haematology and hthe Department of Immunology Notting-ham University Hospitals, NHS Trust.Informed consent was obtained from the patients. They understood that the informationwill be published without their names attached and that every attempt will be made toensure anonymity although complete anonymity cannot be guaranteed and that it couldbe possible for somebody to identify them. They also understood that the informationmight be published in a journal that is read worldwide or an online journal thatalthough aimed mainly at health care professionals, might be seen by others such asjournalists and that their information might be presented as a poster or placed on awebsite.Received for publication June 6, 2023; revised September 1, 2023; accepted for publica-tion September 8, 2023.Available online November 22, 2023.Corresponding author: Ariharan Anantharachagan, MBChB, MRCP, MsC, FRCPath,Department of Allergy & Clinical Immunology, Lancashire Teaching HospitalsNHS Foundation Trust, Royal Preston Hospital, Sharoe Green Ln, Fulwood, Preston,PR2 9HT, United Kingdom. E-mail: Ariharan.anantharachagan@lthtr.nhs.uk. Or:EmmaMorris, PhD, FMedSci,UCL Institue of Immunity andTransplantation, The PearsBuilding, Pond Street, London, NW3 2PP, United Kingdom. E-mail: e.morris@ucl.ac.uk.The CrossMark symbol notifies online readers when updates have been made to thearticle such as errata or minor corrections2772-8293 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academy ofAllergy, Asthma & Immunology. This is an open access article under the CC BY li-cense (http://creativecommons.org/licenses/by/4.0/).https://doi.org/10.1016/j.jacig.2023.100191median survival of patients who lack the Wiskott-Aldrich syn-drome protein (WASP) expression and have not undergone he-matopoietic stem cell transplantation (HSCT) is less than 20years.3 Until recently, the potentially curative treatments, alloge-neic HSCT and gene therapy, have been reserved for childrenowing to the risks of higher transplant-related morbidity and mor-tality in adults with significantWAS-related complications beforeHSCT.1Here, we present the 2 oldest patients with WAS reported todate who have undergone HSCT. Both patients received fludar-abine, treosulfan, and thiotepa (FTT)-conditioned matchedunrelated donor (MUD) allografts (9 of 10 and 10 of 10HLA-matched, respectively). They underwent in vivo T-celldepletion with alemtuzumab. Cyclosporine and mycophenolatemofetil were used for graft-versus-host disease (GVHD) prophy-laxis and letermovir was used for cytomegalovirus (CMV)prophylaxis.PATIENT 1A 44-year-old male was clinically diagnosed withWAS shortlyafter birth. He had 2 affected brothers, and his mother was aknown WAS gene carrier. One of his brothers died at age 4 yearsfollowing an intracranial haemorrhage, and the other died at age44 years with complications of large vessel vasculitis. Subsequentgenetic testing identified hemizygosity for the c.257G>A(p.Arg86Pro), a known pathogenic variant in theWAS gene asso-ciated with reduced WASP expression (4.5%) by flow cytometryof peripheral blood.1J ALLERGY CLIN IMMUNOL GLOBALFEBRUARY 20242 ANANTHARACHAGAN ET ALDuring childhood he had mild eczema, profound thrombocy-topenia (platelet count < 103 109/L), and recurrent sinusitis. Byadulthood he had recurrent sinusitis and ear infections, with occa-sional chest infections. At age 36 years he developed a subduralhaematoma that required surgical evacuation with blood productsupport. He commenced IRTat age 38 years following pneumoniaand documentation of failed test vaccinations. Before startingIRT, his total IgG and IgA levels were normal, with a reducedIgM level (0.29 g/L). Chest imaging demonstrated moderatebronchiectasis. He had no history of autoimmunity or lymphopro-liferation. He was 42 years old when referred for consideration ofHSCT shortly after the death of his older brother owing to com-plications of a large vessel vasculitis. His WAS score (definedin Albert et al4) before HSCTwas 4.He underwent HSCT at age 43 years (FTT alemtuzumab [60mg], 10 of 10 MUD allograft, CMV 1/1, Toxoplasma –/–,hepatitis B virus –/–, and blood group A Rhesus factor andD-antigen [RhD]-positive/blood group O RhD-positive). Atlast follow-up, 18 months after HSCT, he had trilineage100% donor chimerism and was no longer undergoing systemicimmune suppression and IRT, with only minimal skin GVHD.His full blood count and white cell differential, including plate-lets, were normal. His times to platelet engraftment >20 3 109/L and >50 3 109/L were 7 and 34 days, respectively. His timesto neutrophil engraftment >0.5 3 109/L and >1.0 3 109/L were14 and 16 days, respectively. His early post-HSCT complica-tions included adenoviremia requiring cidofovir, BK viruria,chronic renal impairment, and acute GVHD of the skin (grade2). At last follow-up, his renal function was normal. He devel-oped mild coronavirus disease 2019 (COVID-19) at 12.5months after HSCT and was treated with nirmatrelvir with rito-navir (Paxlovid) with complete resolution of symptoms. IRTwas stopped at 10 months after HSCT with no subsequent bac-terial infections to date. Administration of cyclosporine wasstopped at 13 months after HSCT. Test vaccination responses(14 months after HSCT) to 1 dose of Prevenar 13 (Pneumo-coccal 13-valent conjugate vaccine [diphtheria CRM197 Pro-tein] vaccine) and Menitorix (Haemophilus influenzae type b[Hib]/ Meningococcal C [MenC] vaccine) identified protectiveantibodies to 2 of 9 pneumococcal serotypes present in Preve-nar 13 (normal response is >_0.35 mg/mL to >_50% serotypestested) and adequate antibodies to Haemophilus influenzaetype B (>_0.15 mg/L) at 0.22 mg/L.PATIENT 2A 41-year-old male presented with a purpuric rash andthrombocytopenia at age 3 months. There was a positive familyhistory, with 2 maternal uncles having died of WAS-relatedcomplications at a young age. Genetic testing identified hemi-zygosity for C.763delC (p.Gln255ArgfsX6) , a pathogenic variantin theWAS gene, and hisWASP expression by flow cytometry waslow (10.4%), which is consistent withWAS. In early childhood hedeveloped moderate eczema and had recurrent ear, nose, andthroat infections. Thrombocytopenia resulted in several major ep-istaxes and 2 instances of hemarthroses of the right kneefollowing an osteochondral fracture. In adulthood he developedmild bronchiectasis and inflammatory arthropathy, and he hadrecalcitrant human papillomavirus warts affecting his hands. Heremained stable with conservative management (co-trimoxazole,aciclovir, IRT, and tranexamic acid) for several years.At age 38 years he was diagnosed with diffuse large B-celllymphoma (Epstein-Barr early RNA–negative) and received 6cycles of rituximab, cyclophosphamide, hydroxydaunorubicin,oncovin, and prednisone chemotherapy with additional romiplos-tim for platelet support, achieving complete remission accordingto positron emission tomography–computed tomography.Following chemotherapy, he was assessed for HSCT.He underwent HSCT at age 39 years (FTT alemtuzumab [60mg], 9 of 10 [A mismatch] MUD allograft, CMV 1/1, Toxo-plasma –/–, and blood group A RhD-positive/blood group ABRhD-negative). At 18 months follow-up, he had trilineage100% donor chimerism but continued receiving cyclosporinefor chronic GVHD of the gut. His full blood count and whitecell differential, including platelets, were normal. His times toplatelet engraftment >20 3 109/L and >50 3 109/L were 12and 16 days, respectively. His times to neutrophil engraftment>0.5 3 109/L and >1.0 3 109/L were 13 and 22 days, respec-tively. His early post-HSCT course was complicated by 4 ep-isodes of herpes simplex virus 2 requiring aciclovir, foscarnet,and topical cidofovir; grade 2 acute GVHD of the skin andgut; and adenoviremia requiring cidofovir. At 6 months afterHSCT he developed Lhermitte sign (an electric shock–likesensation on neck flexion) and clinical features of a progres-sive axonal neuropathy (distal muscle wasting and weakness).Electromyography confirmed axonal neuropathy. Magneticresonance imaging and cerebrospinal fluid examination havenot identified an underlying cause. At last follow-up, the pa-tient’s Lhermitte sign was resolving. He developed asymp-tomatic COVID-19 at 8 months after HSCT, which wastreated with sotrovimab, and a further episode 8 months later,which improved after 3 days of remdesivir. Assessment of testvaccine responses are pending after cessation of cyclosporineand IRT.Recent data have demonstrated that good outcomes can beachieved for adults who undergo HSCT for combined immunedeficiencies.5,6 The aforementioned cases show that HSCT isfeasible in older patients with WAS and should be consideredfor those for whom a donor is available. In these 2 patients, longerfollow-up is required to provide evidence of definitive improve-ment in quality of life and disease-free survival.DISCLOSURE STATEMENTSupported by the National Institute for Health Research Uni-versity College London Hospitals Biomedical Research Centre(to E.C.M.).Disclosure of potential conflict of interest: A. Ananthar-achagan has received honoraria from Takeda (for chairing awebinar and advisory board work) and support for attending aconference. S. Tadros has received support from CSL Behringfor attending a conference. E. Morris has received salarysupport from the University College London Hospitals Na-tional Institute for Health Research Biomedical ResearchCentre and support from GSK, AstraZeneca, GE Healthcare,and Orchard Therapeutics; in addition, she is an Orchard Ther-apeutics Limited data and safety and monitoring board mem-ber for the X-Linked Chronic Granulomatous Disease PhaseI trial, a panel member on the Wellcome Trust Career Devel-opment Panel, and a scientific founder of Quell TherapeuticsLimited. The rest of the authors declare that they have no rele-vant conflicts of interests.J ALLERGY CLIN IMMUNOL GLOBALVOLUME 3, NUMBER 1ANANTHARACHAGAN ET AL 3REFERENCES1. Albert MH, Slatter MA, Gennery AR, G€ung€or T, Bakunina K, Markovitch B, et al.Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMTInborn Errors Working Party analysis. Blood 2022;139:2066-79.2. Pai S-Y, Nortarangelo LD. Hematopoietic cell transplantation for Wiskott-Aldrichsyndrome: advances in biology and future directions for treatment. Immunol AllergyClin North Am 2010;30:179-94.3. Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, et al. Clinical course of patientswith WASP gene mutations. Blood 2004;103:456-64.4. Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiologyand treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol 2011;18:42-8.5. Albert MH, Sirait T, Eikema DJ, Bakunina K, Wehr C, Suarez F, et al. Hematopoi-etic stem cell transplantation for adolescents and adults with inborn errors of immu-nity: an EBMT IEWP study. Blood 2022;140:1635-49.6. Cheminant M, Fox TA, Alligon M, Bouaziz O, Neven B, Moshous D, et al. Alloge-neic stem cell transplantation compared to conservative management in adults withinborn errors of immunity. Blood 2023;141:60-71.

Allogeneic hematopoietic stem cell transplantation outcome in oldest known surviving patients with Wiskott-Aldrich syndrome

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Allogeneic hematopoietic stem cell transplantation outcome in oldest known surviving patients with Wiskott-Aldrich syndrome

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