Real world population-based outcome analysis of small lymphocytic lymphoma (SLL) in British Columbia (BC)

Abstract Background: Small lymphocytic lymphoma (SLL) primarily involves lymph nodes (LNs) and is considered biologically identical to its peripheral blood (PB)/bone marrow counterpart, chronic lymphocytic leukemia (CLL). Although CLL/SLL are effectively considered the same disease, little is known about the epidemiology and natural history of SLL and patients (pts) with SLL are often excluded from clinical trials. The objective herein was to evaluate clinical characteristics, treatment (tx) patterns, and survival in a large population-based cohort of SLL pts distinct from CLL. Methods: Adults ≥18 years (y) newly diagnosed with SLL from 1989-2024 in BC, Canada, were identified using provincial databases. SLL was defined as requiring the presence of enlarged LNs with <5x10^9/L PB clonal B lymphocytes, or <10x10^9/L PB lymphocytes when clonal B-cell count was unknown, confirmed by histopathologic LN/tissue evaluation where possible. Pts with concurrent Richter transformation (RT) were excluded. Time-to-event analyses were conducted for overall survival (OS), treatment-free survival (TFS, time from diagnosis to first tx or death/last follow-up [f/u]), and, for those who were treated, time from first to second-line tx (TTNT). Subgroups were compared using the log-rank test. Time to development of CLL was also assessed, defined as time from SLL diagnosis to PB clonal B lymphocytes >5x10^9/L or PB lymphocyte count ≥10x10^9/L when clonal B-cell count was unknown. Results: 676 pts were identified. Median age was 68y (range 25-97y), with 419 (62%) ≥65y and 404 (60%) male. At diagnosis, the majority had Ann Arbor stage 3-4 (89%), no B symptoms (82%), and ECOG performance status 0-1 (85%). Median PB lymphocytes were 3x10^9/L (range 0-10) and 30% had bulk ≥5cm. Among the 228 pts with FISH performed prior to any tx, prevalence of FISH abnormalities were: 63 (28%) del13q; 76 (33%) trisomy 12; 28 (12%) del11q; 20 (9%) del17p, and 85 (37%) had none of these 4 abnormalities. Among the 104 pts with IGHV mutation testing performed, 34 (33%) were mutated, 64 (62%) unmutated, and 6 (5%) indeterminate. At a median f/u of 12.4y (range 0.5-31.6y), median OS was 9.2y with 5- and 10-y OS 70% and 49%, respectively. OS was significantly worse for males (P=.005), those with B symptoms (P=.004), bulk ≥5cm (P<.001), elevated LDH (P<.001) or del17p (P=.002). Over the f/u period, 473 pts (70%) received tx with median 1 line (range 0-13). Median TFS was 1.6y with 5- and 10-y TFS 27% and 14%, respectively. TFS was significantly worse for those with stage 3-4, B symptoms, bulk ≥5cm, ECOG 2-4, or elevated LDH (all P<.001). First-line tx included: 150 (32%) purine analog (PA) + rituximab (R); 23 (5%) PA alone; 97 (20%) alkylating chemotherapy + R; 88 (19%) alkylating chemotherapy alone; 67 (14%) BTK inhibitor; 17 (4%) BCL2 inhibitor ± anti-CD20 monoclonal antibody; 31 (6%) other, including localized radiation/surgery. After first-line treatment, median TTNT was 3.8y (range 0.1-23.4y), which was not statistically different for those with del17p (P=.283). 45 pts (7%) developed RT at a median of 3.5y from diagnosis (range 0.2-18.8y), including 26 (58%) DLBCL, 8 (18%) Hodgkin lymphoma, and 11 (24%) unspecified. During the f/u period, 175 pts (26%) developed into CLL at a median of 3.5y from diagnosis (range 0.1-19.8y). When evaluating only those who developed CLL while on watchful waiting (natural history cohort, n=88), CLL developed at a median of 2.6y from diagnosis (range 0.1-18.7y). Treatment was more frequent in those who developed CLL (P=0.04), more often with PAs and targeted agents. Conclusion: In this large real-world cohort of SLL pts spanning three decades, median OS was 9.2y with worse OS for those with del17p and high-risk features typical of lymphoma including bulk, B symptoms, and elevated LDH. Median TFS was notably short at 1.6y, likely reflecting the classic symptomatic presentation of SLL prompting treatment, in contrast to the often incidental diagnosis of CLL. Treatment patterns differed among those who developed CLL versus those who did not. These results highlight both overlapping and distinct clinical trajectories in SLL and reinforce the need for dedicated SLL research, including disease biology which may be distinct from CLL, to better inform risk stratification and guide optimal treatment strategies.

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