Genetic and clinical profiles of chronic lymphocytic leukemia in Thailand: Nationwide insights from the thai lymphoma study group

Abstract Introduction: Genomic studies have illuminated the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL) offering critical insights into disease prognosis and therapeutic outcomes. Over the past decade, next-generation sequencing (NGS) has enabled the identification of recurrent somatic mutations that inform risk stratification and guide treatment decisions in CLL. This study aimed to characterize the clinical and genetic landscape of patients with CLL in Thailand and compare these features with those reported in Western cohorts, as CLL is much less common in Asian populations than in Western populations. Methods: Patients with newly diagnosed CLL prospectively enrolled across 12 academic centers participating in the Thai Lymphoma Study Group (TLSG) between May 2018 and October 2023. Diagnosis was made in accordance with iwCLL guidelines. Deletion of TP53 and ATM were assessed using fluorescence in situ hybridization (FISH). Targeted NGS was performed to detect somatic mutations in key 26 CLL-associated genes. The variable region of the immunoglobulin heavy chain (IGHV) mutational status was determined by NGS using IGH sequencing. Results: A total of 235 patients were included in the study. The median age at diagnosis was 66 years (interquartile range, 58–72 years), and 65.5% were male. Among 196 patients tested for gene mutations, 91 patients (46.4%) harbored at least one mutation. The most frequently mutated gene was MYD88, detected in 35 patients (17.9%), followed by TP53 in 24 (12.2%), SF3B1 in 18 (9.2%), ARID1A in 8 (4.1%), and ATM in 6 (3.1%). Mutations in BCL2 and BRAF were each found in 5 patients (2.6%). Less common mutations included XPO1, CREBBP, and CD79B in 2 patients each (1.0%), and EZH2, KMT2D, PIM1, and B2M in 1 patient each (0.5%). Among 119 patients with available IGHV data, 86 (72.3%) had mutated IGHV, while 33 (27.7%) were unmutated. TP53 deletion, assessed by FISH, was detected in 15 of 213 patients (7.0%), and ATM deletion in 15 of 205 patients (7.3%). The presence of a MYD88 mutation was associated with a favorable prognosis, demonstrating a reduced risk of relapse (hazard ratio [HR] 0.30, 95% CI 0.09–0.98, p= 0.047). In contrast, relapse risk was significantly higher among patients among SF3B1mutations (HR 2.94, 95% CI 1.35–6.43, p = 0.007, TP53mutations (HR 3.41, 95% CI 1.77–6.57, p < 0.001), unmutated IGHV (HR 3.71, 95% CI 1.78–7.74, p < 0.001), TP53 deletion (HR 5.37 95% CI 2.43-11.87, p < 0.001) and ATM deletion (HR 7.09, 95% CI 3.23-15.58 p < 0.001). In multivariate analysis,SF3B1 mutations(adjusted HR 2.66, 95% CI 1.08–6.53, p = 0.033), unmutated IGHV (aHR 2.89, 95% CI 1.27–6.58, p = 0.012), and ATMaberrations(mutation and/or deletion) (aHR 3.13, 95% CI 1.01–9.66, p = 0.047) were independent predictors of relapse in CLL. There is a strong association between MYD88 mutation and IGHV status, with nearly all MYD88-mutated patients carrying mutated IGHV and only one harboring unmutated IGHV. In contrast, TP53 and ATM mutations were significantly associated with unmutated IGHV (p = 0.006 and p = 0.004, respectively). A stratified analysis of specific genomic aberrations revealed that both the combination of an ATM mutation and deletion (HR=4.62, 95% CI 1.09−19.63, p=0.038) and the ATM mutation alone (HR=8.07, 95% CI 3.06−21.25, p<0.001) were significantly associated with an increased risk of relapse. Similarly, patients harboring both TP53 mutation and deletion exhibited markedly increased relapse risk (HR 7.10, 95% CI 3.01–16.74, p < 0.001). Compared with Western cohorts, our patients had a younger median age at diagnosis (66 vs. 70 years). The prevalence of TP53 and SF3B1 mutation were comparable between cohorts, whereas MYD88 mutations were more frequent in the Thai cohort (17.9% vs. 2.5-3%). Similarly, cases with mutated IGHV were more frequent in our cohort (72.3%) compared with Western studies (60%). Conclusion: Our study delineates the genetic landscape of CLL in Thailand and underscores the prognostic relevance of specific genomic alterations. MYD88 mutations, which were strongly associated with mutated IGHV, conferred a favorable prognosis, whereas SF3B1 and ATM aberrations significantly increased the risk of relapse. The coexistence of both mutation and deletion in TP53 or ATM further amplified this prognostic impact. These findings underscore the distinct clinical and genetic characteristics of CLL in Asian populations compared to Western cohorts.