Lymphoproliferative disease in patients with Wiskott-Aldrich syndrome: Analysis of the French Registry of Primary Immunodeficiencies

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 6; pp. 2311 - 2315.e7
• Main Authors: Cheminant, Morgane, Mahlaoui, Nizar, Desconclois, Céline, Canioni, Danielle, Ysebaert, Loïc, Dupré, Loïc, Vasconcelos, Zilton, Malphettes, Marion, Moshous, Despina, Neven, Bénédicte, Rohrlich, Pierre-Simon, Bernard, Marc, Bertrand, Yves, Fischer, Alain, Suarez, Felipe
• Format: Journal Article
• Language: English
• Published: St. Louis Elsevier Inc 01.06.2019; Elsevier Limited; Elsevier
• Subjects: Age; Amino acids; Azathioprine; Biopsy; Bone marrow; CD8 antigen; Clinical trials; Clonal deletion; Contingency; France / epidemiology; Gastrointestinal tract; Graft-versus-host reaction; Human health and pathology; Humans; Immunohistochemistry; Immunoproliferative diseases; Infections; Infectious diseases; Insertion; Knee; Life Sciences; Lungs; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoproliferative Disorders / epidemiology; Lymphoproliferative Disorders / genetics; Lymphoproliferative Disorders / therapy; Middle Aged; Monoclonal antibodies; Mud; Mutation; Nervous system; Patients; Point mutation; Primary immunodeficiencies; Registries; Sarcoma; Statistical analysis; Stem Cell; Targeted cancer therapy; Transplantation; Transplants & implants; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome / epidemiology; Wiskott-Aldrich Syndrome / genetics; Wiskott-Aldrich Syndrome / therapy; Wiskott-Aldrich Syndrome Protein / genetics
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2019.01.046

[...]in half of the patients, the discordant WASP expression between T lymphocytes and large tumor B cells, suggests that revertant T cells cannot, at least in some cases, prevent the occurrence of LPD.7 Intensive immunochemotherapy was well tolerated, and patients who reach a CR might have a long-term survival. AlloSCT seems justified when feasible in young patients but should be weighed against transplantation risks in older patients.9 Prospective studies are unrealistic for such a rare disease, but collaborative observational trials would be helpful to set optimized therapeutic approach.Methods Description of the French National Reference Center for Primary Immune Deficiencies (CEREDIH) Registry The French National Reference Center for Primary Immune Deficiencies (CEREDIH) is a national network of academic centers in metropolitan France. WAS/XLT clinical manifestations Score WAS mutation type WASP expression by IHC Age at onset of LPD (y) Extranodal manifestations Histologic subtype AlloSCT Overall outcome, age at last follow-up (cause of death) 1 KS 5 Nonsense Negative 4 CNS, lung B-cell PTLD-like, EBV+ No Died, 5 y (progressive LPD) 2 AIHA 5 NA Discordant (positive LT, negative LB) 22 CNS DLBCL non GCB type, EBV− MUD Died, 23 y (sepsis) 3 AI pancytopenia 5 Missplicing Negative 22 Bone (knee) DLBCL GCB type, EBV− MUD A/W, 24 y 4 Infections 3 Missplicing Discordant (positive LT, negative LB) 24 Lung, bone DLBCL non-GCB type, EBV− No Died, 25 y (progressive LPD) 5 KS, AIHA 5 Deletion Negative 2 CNS B-cell PTLD-like, EBV+ Haplo A/W, 12 y 6 Life-threatening infections 4 Missplicing Negative 6 CNS, lung B-cell PTLD-like, EBV+ No Died, 8 y (progressive LPD) 7 Life-threatening infections 4 NA NA 14 CNS Unclassified B-cell LPD No Died, 15 y (progressive LPD) 8 AIHA 5 NA Negative 4 Digestive tract B-cell PTLD-like, EBV+ MUD Died, 12 y (chronic GVHD) 9 Life-threatening infections 4 Insertion Discordant (positive LT, negative LB) 50 CNS B-cell PTLD-like, EBV+ No A/W, 55 y 10 Thrombocytopenia 1 Missplicing Positive CD8+ T cells (see Fig E1) 50 Bone marrow DLBCL non-GCB type, EBV+ No A/W, 53 y 11 SRT 5-SRT Insertion Discordant (positive LT, negative LB) 22 No DLBCL GCB type, EBV− MMUD Alive, 23 y (GVHD) 12 Infections 3 Missplicing Discordant (positive LT, negative LB) 43 No Lymphoplasmacytic lymphoma, EBV+ No A/W, 44 y 13 Thrombocytopenia 1 Missense Negative 27 No DLBCL, non-GCB type, EBV+ No A/W, 44 y Table I WAS gene mutation types, clinical manifestations of WAS/XLT syndrome, LPD characteristics, and outcomes in patients with WAS/XLT Score No. of patients (n = 13) Clinical manifestations Median age at LPD (y) Treatment received before LPD 5 6 AIHA (n = 4) Kaposi sarcoma (n = 2) SRT (n = 1) 13 CYC–MTX–TPO agonist Rituximab–azathioprine Docetaxel–CTC 4 3 Life-threatening infections (n = 3) 14 — 3 2 Infections (n = 2) 34 — 2 0 — — — 1 2 Microthombocytopenia 39 — Table E1 Clinical manifestations of patients with WAS/XLT with LPDs ranked according to their severity score Patient no. WAS mutation Type Expected WASP expression WASP expression by IHC 1 Exon 7 c.607C>T Nonsense (p.Gln203 Stop Q203X) Reduced and truncated Negative 2 NA NA NA Discordant (positive LT, negative LB) 3 Intron 8 c.777+5 G>C Missplicing (deletion exon 8) Negative Negative 4 Intron 8 c.777+1 G>A Missplicing (deletion exon 8) Negative Discordant (positive LT, negative LB) 5 Exon 4 c.395_400 del6 Deletion in frame (p.Asp132_Glu133) Unknown Negative 6 Intron 2 c.274−1 G>A Missplicing (deletion exon 3) Negative Negative 7 NA NA NA NA 8 NA NA NA Negative 9 Exon 10 c.1001dupG Insertion frameshift (stop amino acid 335) Reduced and truncated Discordant (positive LT, negative LB) 10 Exon 11 c.1453 G>A Missplicing (deletion exon 11) Reduced and truncated Positive CD8+ T cells (see Fig E1) 11 Exon 11 c.1447dupT Insertion frameshift (stop amino acid 494) Reduced and truncated Discordant (positive LT, negative LB) 12 Intron 6 c.559+5 G>A Missplicing (fs stop amino acid 190/normal) Reduced Discordant (positive LT, negative LB) 13 Exon 2 c.223G>A Missense Heterogeneous (normal to negative) Negative Table E2 WAS gene mutations and WASP protein expression by immunohistochemistry on lymphoma biopsy specimens among the patients with WAS/XLT who had an LPD No LPD LPD Total No alloSCT 135 8 143 AlloSCT 87 5 92 Total 222 13 235 Table E3 Contingency table of patients with WAS/XLT with versus without LPDs according to hematopoietic alloSCT