Clinical and Genetic Landscape of Peripheral T-Cell Lymphomas in Chinese Population: A Retrospective Study
Authors: Wang Lingling , Yang Lei , Guan Fangshu , Chen Jing , Cheng Yuexin , Miao Yuqing , He Jingsong , Cai Zhen , Huang He , Zhao Yi 
Published: December 2024

Introduction: There are limited studies on mutation profiling for Peripheral T-cell lymphomas (PTCL) in the Chinese population.

Methods: We analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients admitted to the Bone Marrow Transplantation Center of the First Affiliated Hospital of Zhejiang University School of Medicine from July 2020 to November 2023. Formalin-fixed, paraffin-embedded tissue slices (FFPE) were used to extract genomic DNA at diagnosis and all patients went through next-generation sequencing (NGS). All cases were treated with ﬁrst-line therapy and were evaluated with PET-CT or CT. Patients who did not achieve partial remission (PR) were switched to second-line therapy or entered clinical trials.

Results: Among 66 patients with PTCL, 40 were male and 26 were female. The median age was 62.5 (25-81) years. There were 4 kinds of histologic types, 33 (50%) were Angioimmunoblastic T-cell Lymphoma (AITL), 1 (1.5%) was Anaplastic Lymphoma Kinase negative anaplastic large cell lymphoma (ALK-ALCL), 5 (7.6%) were extranodal natural killer TCL nasal type (ENKTL) and 27 (40.9%) were Peripheral T-cell Lymphoma, Not Otherwise Specified (PTCL-NOS). The median follow-up was 16 (2-33) months, of which 16 (24.2%) died and 50 (75.8%) survived. The median overall survival (OS) was 28 months. At least 1 mutation was detected in 60 (90.9%) patients, with a median mutation number of 3 (0-7), and 32 (48.5%) cases with more than 4 mutations. The top five genes in terms of mutation rate were TET2 (53%), RHOA (33%), DNMT3A (26%), IDH2 (18%), and TP53 (14%), followed by STAT3 (11%), KMT2D (8%), FAS (6%), FAT1 (6%), KRAS (6%), MTOR (6%), ATM (5%), CD28 (5%), and NOTCH1 (5%). Nine patients were positive for TP53, of which 2 were AITL, 6 were PTCL-NOS, 1 was ENKTL, and not detected in ALK-ALCL. Five patients were positive for KMT2D, of which 2 were AITL, 3 were PTCL-NOS and were not detected in ENKTL and ALK-ALCL. All five KMT2D-positive patients were positive for serum EBV-DNA. The frequency of mutant genes related to epigenetics was highest at 45.78%, whereas the proportion of DNA methylation was 37.85%. IPI≥2, PIT≥2, and failure to achieve PR were risk factors for inferior OS (p=0.018, P&lt;0.001, and P=0.001, respectively). Univariate analysis suggested that gender, age, ECOG score, LDH value, EBV-DNA, bone marrow invasion, B-symptoms, Ann Arbor stage, number of mutated genes, histologic subtype, use of Azacitidine, HSCT, TET2, RHOA, DNMT3A, and IDH2 had no impact on OS and progression-free survival (PFS) (P&gt;0.05). IPI≥2 and PIT≥2 were factors for inferior OS (HR, 0.779; 95% CI, 0.340-1.783; P=0.026 and HR, 0.594; 95% CI, 0.265-1.329; P=0.004, respectively). Failure to achieve PR were factors for inferior OS and PFS (HR, 0.049; 95% CI, 0.006-0.372; P=0.004 and HR, 0.002; 95% CI, 0.003-0.166; P&lt;0.001, respectively). Multivariate analyses suggested that IPI≥2 (HR, 10.962; 95% CI, 1.118-107.528; P=0.04), PIT &gt;2 (HR, 13.664; 95% CI, 2.303-81.072; P=0.004), treatment efficacy (HR, 0.007; 95% CI, 0.00-0.180; P=0.003) and KMT2D mutation (HR, 10.097; 95% CI, 1.000-101.953; P=0.048) were independent prognostic factors impacting OS. Treatment efficacy (HR, 0.015; 95% CI, 0.002-0.120; P&lt;0.001) and TP53 (HR, 3.523; 95% CI, 1.262-9.835; P=0.016) were independent prognostic factors influencing PFS.

Conclusion: Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses. TP53 and KMT2D mutations are associated with a worse prognosis in PTCL.