Details

Autor(en) / Beteiligte

• Ege, Markus J.
• Schuetz, Catharina
• Jacobsen, Eva-Maria
• Müller-Langer, Susanna M.
• Furlan, Ingrid
• Sirin, Mehtap
• Pannicke, Ulrich
• Schwarz, Klaus
• Debatin, Klaus-Michael
• Hönig, Manfred
• Schulz, Ansgar
• Friedrich, Wilhelm

Titel

Late thymic deficiency after HLA-haploidentical hematopoietic stem cell transplantation for severe combined immunodeficiency

Ist Teil von

• Journal of allergy and clinical immunology, 2019-04, Vol.143 (4), p.1623-1626.e13

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• For prevention of graft versus host disease (GvHD), we used T-cell–depleted marrow (n = 60) or purified CD34+ peripheral blood stem cells (n = 69) (Table I). Naomi Taylor and Richard O'Reilly provided helpful comments.Methods This study was approved by the Ethical Review Board of the University Hospital of Ulm (250/16).Evaluation of immune reconstitution Lymphocyte and T-cell subsets were determined by flow cytometry. T-cell receptor repertoire differentiating 24 Vß T-cell receptors was assessed by flow cytometry using the Vß T-cell repertoire kit (Beckman-Coulter, Marburg, Germany).Statistical methods Groups of patients were compared by Fisher exact test for frequencies and by Wilcoxon test for continuous variables. Characteristic No conditioning (n = 41) Conditioning (n = 88) P value Baseline characteristics Female sex 9 (22) 29 (33) .221 B+ SCID variant 31 (82) 42 (54) .004 Omenn syndrome 1 (2) 7 (8) .434 Maternofetal transfusion 19 (49) 39 (44) .701 Pulmonary infection at diagnosis 19 (48) 40 (46) 1 Abnormal liver function 8 (20) 11 (12) .299 Transplant characteristics Transplantation after 1995 12 (29) 56 (64) <.001 Donor Mother 23 (56) 60 (68) .236 Father 18 (44) 27 (31) .167 Peripheral blood stem cells∗ 13 (32) 56 (64) .001 Immune reconstitution B cells of donor origin 5 of 25 (20%) 52 of 59 (88%) <.001 IVIG independence† 6 of 25 (24%) 49 of 56 (88%) <.001 Any myeloid engraftment‖ 1 of 25 (4%) 47 of 59 (80%) <.001 Full myeloid engraftment 1 of 25 (4%) 38 of 59 (64%) <.001 Early posttransplant events Acute GvHD ≥ grade 2 6 (16) 28 (34) .051 GvHD de novo‡ 0 (0) 9 (10) .057 Chronic GvHD 3 (9) 17 (22) .115 Veno-occlusive disease or capillary leak 0 (0) 15 (17) .003 Early fatalities 12 (29) 20 (23) .512 Late posttransplant events Late fatalities 3 of 21 1 of 59 Pulmonary complications 8 of 21 3 of 59 .008 Recurrent infections 5 of 21 2 of 59 Chronic lung disease 3 of 21 1 of 59 CD8+ T-cell proliferative disorders 2 of 21 — Autoimmunity — 4/59 Tumors — (3§+1)/59 Growth retardation (<fifth percentile) 2§/21 (7§+1)/59 Table I Details of patients and transplantation outcomes Characteristic Graft failure (n = 13) Other reasons (n = 5) Time between first and second HSCT (y), median (range) 0.4 (0.2-3.2) 5.5 (0.6-11.5) No conditioning at first HSCT 10 4 Repeat without conditioning 3 Repeat with conditioning 7 4 Conditioning at first HSCT 3 1 Repeat with conditioning 3 1 Haploidentical donor at second HSCT, n (%) 13 (100) 4 (80) Survival > 2 y, n (%) 10 (77) 3 (60) Table E1 Details of patients receiving a repeat HSCT Characteristic No conditioning (n = 41) Conditioning∗ (n = 88) P value Diagnosis within 90 d 20 (49) 45 (51) .851 Family history of SCID 20 (49) 42 (48) 1 CMV infection at diagnosis 7 (17) 9 (10) .389 BCG infection at diagnosis 6 (15) 13 (15) 1 Table E2 Additional characteristics of patients with SCID undergoing HSCT (1982-2013) Molecular characterization All patients (n = 129) Unconditioned patients (n = 41) Conditioned patients (n = 88) B− NK+ DCLRE1C deficiency 17 5 12 RAG1/2 deficiencies 20 2 18 Undefined 6 0 6 B+ NK− IL2R deficiency 44 20 24 JAK3 deficiency 9 5 4 Undefined 5 1 4 B+ NK+ CD3 deficiency 2 0 2 ZAP70 deficiency 3 1 2 IL7R deficiency 4 0 4 Undefined 5 3 2 ADA deficiency 6 0 6 AK2 deficiency 7 3 4 LIG4 deficiency 1 1 0 Table E3 SCID variants according to molecular characterization Characteristic Without conditioning (n = 41) With conditioning (n = 88) P value Days until HSCT, median (range) 162 (18-494) 169.5 (24-750) .682 Early fatalities, n (%) 12 (29) 20 (23) .512 Causes of death, n (%) Graft failure 3 (7) 0 (0) .031 GvHD 3 (7) 11 (12) .546 Any infections 11 (27) 16 (18) .352 Liver failure 1 (2) 2 (2) 1 Lymphoproliferative syndrome 2 (5) 2 (2) .591 Immune reconstitution (2 y), n (%) CD3+ T-cell counts > 1000/μL 25 (100) 60 (100) 1 CD4+ T-cell counts > 500/μL 23 (96) 58 (97) 1 CD8+ T-cell counts > 300/μL 24 (100) 58 (98) 1 Table E4 Details of HSCT and early outcome as a function of conditioning Characteristic Events/individuals per group Unadjusted models Mutually adjusted model Present Absent P value HR (95% CI) P value HR (95% CI) P value Diagnosis within 90 d 3/38 7/32 .025 0.23 (0.06-0.92) .038 Female sex 4/26 6/44 .471 1.62 (0.43-6.05) .475 Family history of SCID 4/36 6/34 .149 0.4 (0.11-1.45) .162 B+ vs B− SCID 7/40 2/25 .808 1.22 (0.24-6.14) .809 Omenn syndrome 0/4 10/66 .657 NA Maternofetal transfusion 6/36 4/33 .153 2.73 (0.65-11.37) .169 Pulmonary infection at diagnosis 8/27 2/41 .001 8.67 (1.83-41.02) .006 6.66 (1.39-31.9) .018 CMV infection at diagnosis 1/5 9/65 .426 2.29 (0.28-18.67) .439 BCG infection at diagnosis 0/5 10/65 .399 NA Liver problems 3/11 7/59 .004 6.84 (1.53-30.61) .012 Transplantation after 1995 4/45 6/25 .835 1.16 (0.28-4.86) .835 Peripheral blood stem cells 6/47 4/23 .156 3.09 (0.6-15.79) .176 Secondary transplantation 1/9 9/61 .642 0.61 (0.07-5.02) .645 No myeloablative conditioning 9/19 1/51 .002 14.07 (1.73-114.08) .013 11.95 (1.46-97.94) .021 Acute GvHD 3/16 7/54 .391 1.82 (0.45-7.33) .398 Chronic GvHD 0/8 10/62 .26 NA VOD or capillary leak 0/12 10/58 .192 NA Table E5 Evaluation of factors associated with a decline in naive T-cell counts (<100/μL) following HSCT Complication All patients (n = 80) Without conditioning (n = 21) With conditioning (n = 59) Late deaths 4 3 1 Adenoviral infection, chronic GvHD (age 5 y) 1 Varicella pneumonia (age 11 y) 1 Degenerative CNS disease of unknown cause (age 20 y) 1 Accident (age 5 y) 1 Organ failure following chronic GvHD 2 2 Renal (kidney transplant, age 15 y) 1 Pulmonary (lung transplant, age 7 y) 1 CD8+ T-cell proliferative disorders 2 2 Tumors 4 4 Thyroid carcinoma (age 6 y) 1 1∗ Rhabdomyosarcoma (age 6 y) 1 1∗ Hemangiopericytoma (age 13 y) 1 1 Hepatocellular carcinoma (age 25 y) following liver cirrhosis 1 1∗ Pulmonary complications 11 8 3 Recurrent infections 7 5 2 Chronic lung disease 4 3 1 Autoimmunity 4 4 AIHA and/or ITP 2 2 Resolved 1 1 IDDM 2 2 Extensive verrucosis (HPV) 8 5 3 Resolved 2 1 1 Lymphedema (lower extremities) 3 2 1 Psychomotor retardation 5 5 CNS CMV infection 2 2 Gliosis 1 1 ADA deficiency 2 2 Growth retardation (<fifth percentile) 10 2∗ 7∗ + 1 Table E6 Late complications in unconditioned and conditioned patients with SCID after haploidentical HSCT