Background Previous work has linked the inferior prognosis of patients with newly diagnosed large B cell lymphoma (LBCL) of activated B cell (ABC) cell of origin (COO) by gene expression profiling (GEP) with both double expressor (DE) features (PMID 23449635) and MCD genetic subtype (PMID 32289277 and 34739844). However, it is unknown whether these findings apply to LBCL tumors diagnosed in routine clinical practice, for which COO is typically assigned by immunohistochemistry (IHC) and genetic subtype based upon targeted next generation sequencing (NGS) panels.

Methods We retrospectively compiled patients with newly diagnosed LBCL from multiple data sets (PMID 32780847, 30523716, and Hematological Oncology, 43: e180_70094). Inclusion criteria were cases with non-GCB COO by Hans algorithm, treatment with R-CHOP, known DE status (cutoffs MYC IHC ≥40% and BCL2 IHC ≥50%), known MYC rearrangement (MYC-R) status, calculable International Prognostic Index (IPI) score of <3 vs ≥3, available NGS data, and >12 months of follow-up without evidence of disease progression. MCD-like subtype by LymphPlex (PMID 37032379) and MYD88 subtype (PMID 34378195) were assigned based upon available variant data.

Results Of 689 total cases, 218 met inclusion criteria and were analyzed. Baseline characteristics included IPI score ≥3 46%, MYC-R 6%, DE 43%, TP53 mutation 24%, any MYD88 mutation 31%, MYD88 L265P mutation 22%, PIM1 mutation 33%, ETV6 mutation 14% (tested in 83 cases), TBL1XR1 mutation 16% (tested in 83 cases), MCD-like subtype 16%, and MYD88 subtype 22%.

Of note, for 138 cases for which COO was also reported by Lymph2Cx, 72% were assigned ABC, 9% GCB, and 19% unclassified.

DE was associated with the presence of MYC-R (p=0.046), MCD-like subtype (p=0.09), and MYD88 subtype (p=0.02), but no other baseline characteristic. As was the case for DE, neither MCD-like nor MYD88 subtype were associated with IPI score. Neither MCD-like nor MYD88 subtype was associated with MYC-R, and MYD88 subtype was not associated with TP53 mutation (noting cases with TP53 mutation were assigned to an independent cohort by LymphPlex).

For the entire cohort, with a median length of follow-up was 70 months (range 37-123 months across cohorts), the 3-year progression-free survival (3yPFS) was 65% (95% confidence interval [CI] 58-71%) and estimated 3-year overall survival (3yOS) was 71% (95% CI 64-77%). Inferior 3y PFS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.008), DE (p=0.002), TP53 mutation (p=0.07), MYD88 mutation (p=0.02), and MYD88 L265P mutation (p=0.004) by univariate analysis (UVA) with significance level p<0.10; however, only IPI score ≥3 (hazard ratio [HR] 2.2, 95% CI 1.4-3.5, p=0.001) and DE (HR 1.9, 95% CI 1.2-3.0, p=0.007) remained significant on multivariate analysis (MVA) with significance level p<0.05. On UVA, inferior 3yOS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.001), and DE (p<0.001), with all remaining significant on MVA: IPI score ≥3 (HR 3.1, 95% CI 1.8-5.4, p<0.001), DE (HR 2.3, 95% CI 1.4-3.9, p=0.002), and MYC-R (HR 2.3, 95% CI 1.1-5.0, p=0.03). For patients with vs without DE, 3yPFS was 53% (95% CI 42-62%) vs 74% (95% CI 65-81%) (p=0.001) and 3yOS 57% (95% CI 47-67%) vs 81% (95% CI 77-87%) (p<0.001).

Finally, one cohort (PMID 30523716) reported genetic classification by LymphGen, in which 16% of cases were classified as MCD genetic subtype. Subgroup analysis of this cohort (n=122) revealed an association between DE and MCD genetic subtype by LymphGen (p<0.001). Additionally, MCD genetic subtype by LymphGen was associated with inferior 3yPFS on UVA (p=0.06), but not MVA (HR 1.4, 95% CI 0.7-2.7, p=0.32) when incorporating IPI score and DE, both of which remained significant. MCD genetic subtype by LymphGen was not significantly associated with 3yOS on UVA (p=0.20).

Conclusions DE is a biomarker of inferior 3yPFS and 3yOS independent of IPI score or genomic features analyzed in this multi-national cohort of newly diagnosed non-GCB LBCL patients. MCD genetic subtype as well as genetic subtypes approximating MCD are associated with DE but are not independently prognostic in this patient population. These findings have implications for non-GCB LBCL patients diagnosed in routine clinical practice, and support further exploration of common molecular features that predict for chemoresistance, as well as evaluation of the efficacy of targeted therapies, in newly diagnosed non-GCB DE LBCL patients.

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2025
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