Introduction:

Expression of FMC7, an epitope of CD20, can be detected in several CD5+ lymphoproliferative disorders (LPDs) leading to diagnostic uncertainty. When FMC7 is present, the pathologic diagnosis commonly rendered is CD5+ LPD and includes a broad differential of indolent lymphomas. These FMC7+ LPDs have historically been associated with worse clinical outcomes (Jang et al, 2013), enrichment of trisomy 12, and complex cytogenetics (Reddy et al, 2012). Importantly, these outcomes of FMC7+ LPDs are noted in the setting of chemoimmunotherapy. Over the past decade patients (pts) with CD5+/FMC7+ LPDs are commonly managed as atypical CLL/SLL (aCLL/SLL) and treated with targeted agents. There is limited data on treatment outcomes for CD5+/FMC7+ LPDs, treated with upfront BTKi as compared to classic CLL/SLL pts. Thus, we performed a retrospective study evaluating outcomes in CD5+/FMC7+ LPDs compared to CLL/SLL treated with frontline BTKi.

Methods:

We conducted a single center retrospective study evaluating characteristics and outcomes of consecutively diagnosed CD5+/FMC7+ pts compared to classic CLL/SLL pts between 2015-2024. Mantle cell lymphoma diagnoses were excluded. Pts included in the analysis were treated with frontline BTKi monotherapy and had aCLL/SLL immunophenotype by flow cytometry defined by at least expression of CD5 and FMC7 and without BCL1 overexpression or classic CLL/SLL without FMC7 expression. We compared baseline characteristics by Pearson's chi-squared test for categorical and Wilcoxon rank-sum test for continuous variables. Due to limited sample size and data availability, we utilized propensity score weighting by age at diagnosis and sex to balance the groups and compare the time-to-first treatment (TTFT), progression-free survival (PFS), and overall survival (OS) using the Kaplan-Meier (KM) method and Cox regression. Log-rank test was used to compare the KM curves. The median follow-up time was estimated by reverse KM method. Hazard Ratios (HR) were obtained from Cox regression.

Results:

We identified 111 CLL/SLL pts and 54 aCLL/SLL pts treated with upfront BTKi. Positive FMC7 expression for aCLL/SLL pts ranged from dim, small subset, partial, heterogeneous, variable, and positive. The median follow-up time was 107.8 months. The median age at diagnosis was 62.7 years (range 34-87 years) for CLL/SLL pts and 68.9 years (range 41-91years) for aCLL/SLL pts, which was significantly different between the groups, p= 0.001. Out of a total of 165 pts, 160 were evaluable for del13q, trisomy 12 and del11q, while 161 were evaluable for del17p. There was no significant difference in the rates of del11q, del13q or del17p between the groups. The aCLL/SLL group had a higher rate of trisomy 12 detected (21.3% vs 53.8%; p < 0.001). No difference in NOTCH1 (N=129), TP53 (N=127), and SF3B1 (N=127) mutations was identified. No difference in immunoglobulin heavy chain gene (IGHV) mutation status (N=126) or complex karyotype (N=91) was identified either. The TTFT was not different between the groups: median TTFT was 38.5 months for CLL/SLL pts vs 38.4 months for aCLL/SLL pts (HR 0.93; 95% CI: 0.64 to 1.34; p = 0.69). On PFS analysis, a significant difference was detected with a median PFS of 88.9 months for CLL/SLL pts and 47.3 months for aCLL/SLL pts (HR 2.07; 95% CI 1.21 to 3.55, p = 0.008). There was no statistically significant difference in OS (HR 1.88; 95% CI 0.70 to 5.07, p = 0.210).

Conclusions:

We present outcomes in classic CLL/SLL and aCLL/SLL FMC7+ pts treated with upfront BTKi. Our results corroborate previously reported findings of increased rates of trisomy 12 in aCLL/SLL pts. When analyzing treatment outcomes with frontline BTKi monotherapy we found a significant difference in PFS with no difference in TTFT and OS. The difference in PFS is of interest because even in the era of targeted therapies such as BTKi, we found that pts with aCLL/SLL had worse outcomes despite no differences in classic high-risk cytogenetics or mutations signifying a higher risk disease phenotype. However, the OS was still comparable between the groups, signifying advances in CLL/SLL care and treatment options in later-line use. These results are believed to be the first to evaluate this group of pts treated with frontline BTKI and suggest further research focused on FMC7+ LPDs is warranted. Given our study's retrospective nature, the results should be interpreted with caution.

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2025
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