AĞIR KOMBİNE İMMÜN YETMEZLİK DIŞINDAKİ PRİMER İMMÜN YETMEZLİK HASTALARININ HEMATOPOİETİK KÖK HÜCRE NAKLİ SONRASI KLİNİK ÖZELLİKLERİNİN, LABARATUVAR BULGULARININ VE İMMÜN REKONSTİTÜSYONLARININ DEĞERLENDİRİLMESİ

Abstract

ÖZEREN, Z., Evaluation of Clinical Features, Laboratory Findings, and Immune Reconstitution of Patients with Primary Immunodeficiencies Other than Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation. Hacettepe University Faculty of Medicine Department of Pediatrics. Thesis in Pediatrics. Ankara, 2024. Primary immune deficiencies (PID) are a group of genetic disorders that result in disruptions in the immune system's development and function. Although the number of identified diseases increases every year, 485 types have currently been described. Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many PID patients. This study examined pre-transplant comorbidities, transplant characteristics, transplant complications, and immune reconstitution features in non-severe combined immunodeficiency (SCID) PID patients. These characteristics were compared across PID subgroups, aiming to identify factors that may influence immune reconstitution and survival. For this purpose, the files of 104 patients who underwent HSCT for non-SCID PID between January 2004 and July 2023 at the Hacettepe University Faculty of Medicine Pediatric Bone Marrow Transplantation Unit were retrospectively reviewed. Sixty patients (57%) were male, and 44 (42%) were female. The median age at diagnosis was 2.2 years, the median age at transplantation was 5.8 years, and the median time from diagnosis to transplantation was 1.1 years. Based on the PID subgroups: 44 patients (42.3%) had immune dysregulation, 33 patients (31.7%) had CID, 16 patients (15.4%) had phagocytic system defects, 10 patients (9.6%) had syndromic CID, and one patient (1.0%) had an autoinflammatory disease. The time from diagnosis to transplantation was longest in the phagocytic system defect group (median 2.4 years) and shortest in the immune dysregulation group (median 0.8 years) (p=0.036). Engraftment occurred in 98 patients (94.2%), while engraftment failure was observed in six patients (5.8%). No significant difference in engraftment rates was found between PID subgroups (p>0.05). The engraftment rate was higher in patients who received a myeloablative regimen (100%) compared to those who received a reduced-intensity conditioning (RIC) regimen (90.7%) (p=0.038). Neutrophil engraftment occurred later in patients who received a myeloablative regimen (median 16 days) compared to those who received a RIC regimen (median 14 days), and later in patients who received bone marrow + cord blood (median 18 days) compared to bone marrow (median 15 days) and peripheral blood stem cells (median 12 days) (p<0.05). The complete chimerism rate at one month was higher in the syndromic CID group (100%), while the mixed chimerism rate was higher in the phagocytic system defect group (41.7%) (p=0.046). The complete chimerism rate at both one month and the last follow-up was higher in patients who received a myeloablative regimen (90.2% and 92.3%, respectively) compared to those who received RIC (73.0% and 75.0%, respectively) (p<0.05). Immune reconstitution occurred in the following order: CD8+>CD16/56+>CD4+>CD19+, from the earliest to the latest. Patients under the age of six showed earlier reconstitution of MLS, CD8+, CD4+, and CD19+ (p<0.05). Patients who received a busulfan-based regimen showed earlier reconstitution of MLS, CD8+, and CD19+ compared to those who received treosulfan and melphalan-based regimens (p<0.05). Patients who received more nucleated cells showed faster MLS reconstitution (p=0.004). Delayed reconstitution of MLS, CD8+, and CD4+ was observed in patients who received serotherapy (p<0.05). Patients who developed acute GVHD showed delayed reconstitution of MLS, CD16/56+, and CD19+ (p<0.05). Patients with delayed MLS reconstitution had a higher rate of pulmonary complications (p<0.05). The median follow-up period after HSCT was 5.8 years, and overall survival was 78.8%. No significant difference in survival was observed between PID subgroups (p>0.05). According to univariate Cox regression analysis, significant risk factors for survival included acute GVHD, veno-occlusive disease, hemorrhagic cystitis, pulmonary complications, infections, CD8+<200/uL at month three, and MLS<1000/uL at month six (p<0.05). In multivariate analysis, MLS<1000/uL at month six was found to be an independent risk factor for survival (p<0.05). In conclusion, immune reconstitution plays a critical role in survival. The significantly increased mortality risk in patients with MLS<1000/uL at month six suggests that this parameter may be an important prognostic indicator. Monitoring immune reconstitution and managing complications that may arise through early intervention is crucial for improving patient outcomes.