Somatic mutations and clinical outcomes in primary central nervous system lymphoma among hispanic and non-hispanic patients: A study from the University of California hematologic malignancies consortium (UCHMC)

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma characterized by frequent MYD88 L265P activating mutations, alterations in CD79B, CARD11and PIM1 as well as biallelic CDKN2A loss, all contributing to dysregulated NF-κB and B-cell receptor signaling. Recent studies have expanded our understanding of the molecular landscape of PCNSL, yet the influence of ethnicity on mutation patterns remains poorly understood. In this study we investigate genetic and survival differences in PCNSL across ethnic groups to better understand potential biologic contributors to outcome disparities. Methods: We conducted a multi-institutional retrospective study of patients aged ≥18 years with a diagnosis of PCNSL between January 2011 and December 2020. Patients were treated at UCSF Fresno, UC Davis, UC Irvine, UC San Diego, and the University of Oklahoma. Next-generation sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue. DNA sequencing included targeted panels of 301 genes or 434 genes, while RNA sequencing included targeted panels of 1,408 or 1,600 genes. All sequencing was performed using the Illumina NextSeq 550 or Novaseq 6000 platforms. Treatment response was assessed by MRI and evaluated according to the International Primary CNS Lymphoma Collaborative Group response criteria. Comparisons of patient characteristics and mutation frequencies between Hispanic and non-Hispanic patients were conducted using Fisher's exact test or the Chi-square test, as appropriate. Time-to-event outcomes were evaluated using the Kaplan-Meier method and compared by log-rank test. Univariate survival analyses were performed using Cox proportional hazards models. Results: Among 99 patients, median age was 62 years; 47% were male and 28% identified as Hispanic. HIV was present in 11%, deep brain involvement in 52%, and 64% had non-germinal center subtype per Hans criteria. There were no statistically significant differences between Hispanic (H) and non-Hispanic (NH) patients in age, performance status, HIV status, deep brain involvement, or CSF involvement. Systemic chemotherapy was used as initial treatment in 91% of patients. 86% received high dose methotrexate (MTX) based therapy. 52% received high dose MTX, rituximab, and temozolomide. 16% received high dose MTX alone. Rates of systemic chemotherapy were similar between H and NH patients (89% vs. 90%, p=0.447). Autologous stem cell transplantation consolidation was performed in 10 patients, all of whom were NH. A complete or unconfirmed complete response was achieved in 52% (52 of 99 patients). Two-year progression-free survival (PFS) and overall survival (OS) for all patients were 42% and 55%, respectively. Molecular data were available for 71 patients (H = 25, NH = 46), revealing 278 somatic alterations. The most frequent mutations were MYD88 (61.1%), CD79B (36.1%), PIM1 (31.9%), TP53 (27.8%), TET2 (22.2%), KMT2D (20.8%), ETV6 (19.4%), IRF4 (16.7%), CARD11 (13.9%), and DNMT3A (12.5%). EZH2, APC, PRDM1, and CDKN2A were each detected in 9.7% of patients. Compared with NH patients, H patients had significantly lower frequencies of MYD88 (40% vs. 72%, p=0.009), TP53 (12% vs. 37%, p=0.026), and IRF4 mutations (4% vs. 24%, p=0.046). Two-year PFS was significantly lower in patients with CARD11 mutations (p=0.0037), trended lower with KMT2D mutations (p=0.053), and was significantly lower in patients lacking TP53, ETV6, and BTG1 mutations compared to those harboring at least one (p=0.0015). Two-year OS was lower in patients with IRF4 (p=0.042) and KMT2D (p=0.06) mutations. Two-year PFS did not differ significantly between H and NH patients (38% vs. 43%, p=0.2), nor did 2-year OS (63% vs. 52%, p=0.94). On univariate analysis, age was not associated with differences in PFS or OS. However, ECOG performance status ≤2, negative CSF cytology, and treatment with multi-agent chemotherapy (vs. high-dose methotrexate alone) were associated with improved 2-year OS. Conclusions: We identified highly recurrent genetic alterations in PCNSL, with MYD88, TP53, and IRF4 mutations observed less frequently in Hispanic patients. These findings support ethnic variability in the molecular landscape of PCNSL. Despite these genetic differences, Hispanic patients had comparable 2-year PFS and OS. However, the interpretation of these results is limited by the retrospective design and modest sample size.