Outcomes of patients with dual primary T-cell and B-cell lymphoid malignancies

Abstract Background Patients with T-cell lymphomas and other mature T-cell malignancies are at increased risk of developing subsequent B-cell malignancies and vice versa. This elevated bidirectional risk, although previously reported, is poorly understood. Little is known about the natural history and clinical outcomes of patients who develop both primary B-cell and T-cell lymphoid malignancies. Even less is known about the predisposing risk factors and whether they are intrinsic to the patient or treatment history. A deeper understanding of this sequence may yield better insights into the process of lymphomagenesis. Methods This is an ongoing retrospective study conducted across multiple academic centers of patients with dual primary B-cell and T-cell neoplasms. Inclusion criteria include patients over the age of 18 with a diagnosis of a mature T-cell neoplasm and a mature B-cell neoplasm, Hodgkin lymphoma, or post-transplant lymphoproliferative disorder (PTLD) as defined by the revised 2016 WHO classification of lymphoid neoplasms. The primary objectives are to assess the clinical characteristics of patients with dual primary T-cell and B-cell neoplasms and describe clinical outcomes. Continuous variables are summarized as a median and categorical variables are reported as a frequency (%). Results At the time of this interim analysis, 40 patients from 4 academic centers were identified with dual B- and T-cell lymphoid malignancies confirmed on biopsy. Of these patients, 60% (24/40) were male and 40% (16/40) female. The median age at first primary lymphoid malignancy diagnosis was 64 years (range 32-87) and second primary lymphoid malignancy was 66.5 years (range 32-88) with a median latency between diagnoses of 2.2 years (range 0-16.6). The most frequently occurring first primary lymphoid malignancy subtypes included diffuse large B-cell lymphoma (DLBCL; 17.5%; 7/40), angioimmunoblastic T-cell lymphoma (AITL; 17.5%; 7/40) and mycosis fungoides (MF; 17.5%; 7/40). The most frequently occurring second primary lymphoid malignancy subtypes included DLBCL (22.5%; 9/40) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS; 15%; 6/40). Autoimmune comorbid conditions including rheumatoid arthritis, sarcoidosis and autoimmune thyroiditis were observed in 20% (8/40) of patients, while a history of either HBV and HCV was noted in 12.5% (5/40) of patients. EBV positive tumors by IHC +/- associated viremia were identified at diagnosis of one lymphoid malignancy in 27.5% (11/40) of patients and in both lymphoid malignancies in 12.5% (5/40) of patients. A family history of autoimmune disease was observed in 7.5% (3/40) of patients and 10% (4/40) of patients had a family history of blood cancer. The incidence of solid malignancies, excluding non-melanoma skin cancer, was 17.5% (7/40) and the incidence of myeloid malignancies beyond dual primary lymphoid malignancies was 5% (2/40). Mutational data was available in 23 patients and mutations associated with clonal hematopoiesis were detected at variant allele frequencies above 5% in TET2 (20%; 8/40), DNMT3A (10%; 4/40), TP53 (7.5%; 3/40) and ASXL1 (2.5%; 1/40). In our cohort, 45% (18/40) of patients received systemic chemotherapy prior to diagnosis of the second lymphoid malignancy. One patient received a CD19-directed CAR-T prior to the development of a second lymphoid malignancy (T-cell LGL), which was determined to be unrelated to CAR-T after transgene testing. Median overall survival (OS) from diagnosis of first primary lymphoid malignancy was not reached at the time of analysis; follow-up time ranged from 4 months to 24 years. Conclusions This multicenter real-world study suggests autoimmune conditions occur relatively frequently in patients with dual B- and T-cell lymphoid malignancies and further investigation into immune dysregulation and elevated bidirectional risk of lymphoid malignancies is warranted. Furthermore, we observed the occurrence of mutations associated with clonal hematopoiesis, particularly TET2, in our cohort. These data are also consistent with prior observations showing that histologies such as DLBCL, AITL, and PTCL, NOS are more often associated with dual primary lymphoid malignancies. In our cohort, we did not observe an association with CAR-T therapy and the development of second T-cell lymphoid malignancies. Accrual of additional patients with dual lymphoid malignancies is in process and will be important to expand on these observations.