Survival Outcomes and Genetic Assessment in Patients with Dual Diagnoses of B-Cell and T-Cell Lymphomas

Background: Epidemiological studies have found that patients with lymphoma have a significantly higher risk of second malignancies compared to the general population, either solid tumors or other hematological neoplasms. The study utilizing Surveillance, Epidemiology, and End Results (SEER) database revealed increased bidirectional risk between B-cell lymphomas and T-cell lymphomas, which was nearly five-fold higher than the risk in the general population (Chihara et al. Blood, 2021), however, etiology remains unknown. We thus conducted a retrospective analysis of a large single-institution cohort of patients with dual diagnosis of B-cell and T-cell lymphoma to explore shared genetic aberrations in two different lymphomas and evaluated impact of two different lymphomas on survival outcomes.

Methods: We screened database of patients with lymphoma at MD Anderson Cancer Center from 6/2013 to 1/2024. Patients with dual diagnoses of B-cell and T-cell lymphoma from separate biopsy specimens during or before the screening period were included in the study cohort. Patients with composite lymphoma of B-cell and T-cell lymphoma from same biopsy specimen were excluded. Next-generation sequencing (NGS) using tissue biopsy specimens was conducted with the EndLymphoma panel that covers a combination of coding sequence, limited exons and selected mutation hotspots from 162 cancer risk genes. Variant allele frequencies were utilized to predict the potential origin of the genetic variant as “probable germline” or “probable somatic.” The ClinVar and COSMIC databases were used for annotation of the clinical significance of germline genetic variants. Overall survival (OS) was calculated after diagnosis of the first lymphoma.

Results: The total number of screened patients was 16,144. Among these, 89 patients (0.5%) had dual diagnoses of T-cell and B-cell lymphomas and were included in the study cohort. This cohort had 51 males (57%), 64 Whites (72%), 11 African Americans (12%), 6 Asians (7%) and 11 patients (12%) with Hispanic ethnicity. Median ages at the time of first and second lymphoma diagnosis were 62.5 years and 67 years, respectively. With a median follow-up time of 4.5 years (range: 0.1 to 34 years) from the first lymphoma diagnosis, the median OS of the total cohort was eight years. The most common combinations of B-cell and T-cell lymphoma diagnoses in the cohort were Large B-cell Lymphoma (LBCL) and Peripheral T-cell lymphoma (PTCL) (17% of patients; median OS 2.4 years), LBCL and Cutaneous T-cell lymphoma (CTCL) (8%; median OS 16 years), CLL/SLL and CTCL (8%; median OS not reached), Hodgkin lymphoma (HL) and CTCL (8%; median OS not reached), LBCL and anaplastic large cell lymphoma (7%; median OS 14 years), follicular lymphoma (FL) and CTCL (6%; median OS not reached) and HL and PTCL (6%; median OS 2 years). The other combinations were found in ≤ 5% of patients.

Results were available from NGS-based gene panel testing of tissue biopsies from 9 patients. There were 52 genetic variants of potential germline origin, of which 33 were annotated as benign or likely benign in the ClinVar and/or COSMIC databases. The remaining 19 genetic variants were of unknown significance and were found in 14 different genes. These included three variants in PRDM1, two variants in S1PR1, TENT5C and ZFAT and one variant each in DIS3, H1-2, LTB, NOTCH1, RBMX, SF3A1, SP140, SPEN, TRAF2 and ZRSR2. There were 25 genetic variants of potential somatic origin, of which 12 (48%) were in TET2, likely representing low-level clonal hematopoiesis in the 7 patients in which these were found. The other genes with variants of potential somatic origin in more than one patient were TP53 (in 2 patients) and ZRSR2 (in 2 patients).

Conclusions: Previous epidemiological research has established an overall increased risk of second malignancies in patients with lymphoma, including increased bidirectional risk for B-cell and T-cell lymphomas. We characterized the common combinations of dual diagnoses of B-cell and T-cell lymphomas within an extensive single-institution database and determined their OS. NGS-based gene panel testing revealed several genetic variants which will serve as a resource for future investigations of the contribution of heritable risk factors for dual diagnoses of B-cell and T-cell lymphomas.