THE INCIDENCE, CLINICAL APPLICATION AND PROGNOSTIC SIGNIFICANCE OF MYD88 AND CXCR4 MUTATION IN CHINESE PATIENTS WITH LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTRöM MACROGLOBULINEMIA

Abstract

Introduction: Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, B-cell lymphoma with highly prevalent somatic mutations including MYD88, and CXCR4. The mutation rates of LPL/WM in China and the direct comparison among different deletion means are still not clear. Methods: 387 patients with LPL/WM were included in this study. Tumor cells were collected from 357 un-sorted BM 28 PB and 2 lymph nodes (FFPE). MYD88L265P mutation were detected by Sanger sequencing (FGS), NGS, allele-specific quantitative polymerase chain reaction (ASPCR), and droplet digital polymerase chain reaction (ddPCR). CXCR4 mutation were detected by Sanger sequencing, NGS, and ASPCR. Results: 386 patients were assessed for MYD88L265P mutation, of whom 263 were tested by FGS, 235 by NGS, 311 for AS-PCR, 118 for ddPCR. The MYD88L265P mutation was found in 88.6% of the patients. ASPCR and ddPCR had the highest sensitivity of 97.1% and 96.8%. FGS and NGS failed to detected the mutation in low tumor load. A high false-negative rate (FNR) for MYD88 by FGS and NGS was observed in patients with tumor load less than 10% (FNR: 35.5% and 20%). There was no significant difference in the MYD88 mutation rate detected by ddPCR and ASPCR among patients with different tumor load groups (p = 0.794). MYD88 mutation was detected in a high incidence of 88.5% in less than 1% infiltrated WM tumor cells specimens by ddPCR and ASPCR. CXCR4 mutation testing was performed in 358 patients of LPL/WM, comprising 301 with FGS, 236 with NGS, and 311 with ASPCR. Overall, 31.2% patients were identified as having the CXCR4 mutation. NGS exhibited the highest sensitivity among the three detection means. MYD88 wild-type patients had a significantly lower Hb levels (median 79 g/L vs. 90 g/L, p = 0.015), lower proportion of males (54.5% vs. 51.8%, p = 0.012) and a significantly higher proportion elevated β2-MG (84.2% vs. 65.6%, p = 0.021), and LDH (30.2% vs. 11.9%, p = 0.001). However, there were no significant differences in either PFS or OS between MYD88L265P wild-type and MYD88L265P mutation group (p = 0.35, p = 0.42). Patients with CXCR4 mutation tended to be older (median 64 vs. 60, p < 0.001) and displayed lower hemoglobin level (median 81 g/L vs. 93 g/L, p = 0.008), higher serum IgM level (median 36.1 g/L vs. 31.6 g/L, p < 0.001), and higher baseline BM involvement (by FCM, median 15.1% vs. 7.1%, p < 0.001) compared with CXCR4 wild-type patients. Notably, CXCR4 mutation group had significantly worse survival compared with the wild-type group (p = 0.03, p = 0.02). The research was funded by: National Nature Science Foundation of China (81970187, 82170193, 81920108006, and 81900203) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2022-I2M-1-022, 2021-I2M-C&T-B-081) Keywords: diagnostic and prognostic biomarkers, indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.