CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in primary central nervous system lymphoma

Abstract

Background: Rituximab, high-dose methotrexate (HD-MTX), procarbazine and vincristine (R-MPV), has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), but predictive factors for response to R-MPV have not yet been investigated. Herein, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV.

Methods: We investigated the long-term clinical course and status of MYD88 and CD79B genes in 85 patients with PCNSL treated with R-MPV or HD-MTX treatment, and the correlation of these genetic mutations with prognosis.

Results: R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). While MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (p < 0.05). However, the association of CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations.

Conclusions: In conclusion, CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in PCNSL. The rapid identification of MYD88 L265P and CD79B Y196 mutations can be helpful not only for the accurate molecular diagnosis of PCNSL but also for the prediction of response to R-MPV.

Keywords: CD79B; MYD88; R-MPV; primary central nervous system lymphoma; rapid molecular diagnosis.

FIGURE 1

Summary of clinical course and molecular characteristics of the rituximab, high‐dose methotrexate (HD‐MTX), procarbazine and vincristine (R‐MPV) cohort. (A) Kaplan–Meier curve showing progression‐free survival (PFS: upper) and overall survival (OS: lower) of patients undergoing R‐MPV (pink line) and HD‐MTX (blue line) regimens. (B) Diagram showing initial response to R‐MPV (complete response [CR], partial response [PR], or progressive disease [PD]), histological molecular subgroup (germinal center B‐cell‐like [GCB] or non‐GCB type), CD79B Y196 and MYD88 L265P status, and PFS (months) and OS (months) in each case. MYD88 L265P and CD79B Y196 mutations were identified by droplet digital PCR (ddPCR).

FIGURE 2

Correlation of MYD88 L265P and CD79B Y196 mutations with survival. (A) Kaplan–Meier curve showing progression‐free survival (PFS; left) and overall survival (OS; right). The pink line shows survival of patients with MYD88 L265P mutations and the blue line shows patients with wild‐type MYD88. The solid line indicates survival of patients treated with R‐MPV and the dotted line indicates patients treated with HD‐MTX. (B) Kaplan–Meier curve showing PFS (left) and OS (right). The pink line shows survival of patients with CD79B Y196 mutations and the blue line shows patients with wild‐type CD79B. The solid line indicates survival of patients treated with R‐MPV and the dotted line shows patients treated with HD‐MTX.

FIGURE 3

Genotyping of MYD88 L265P and CD79B Y196 mutations using i‐densy and droplet digital PCR (ddPCR). Genotyping of MYD88 L265P and CD79B Y196 mutations of four consecutive biopsies by i‐densy (left) and ddPCR (right). The fluorescence peak of MYD88 L265P mutation was confirmed at 67°C and that of CD79B Y196 mutation was found at 57°C (black inverted triangle; left). The fluorescence peak of wild‐type MYD88 or those of wild‐type CD79B were found at 56°C or 60°C, respectively. Two‐dimensional cluster (right) plot of droplet fluorescence of MYD88 L265P and wild‐type MYD88 dots and those of CD79B Y196 and wild‐type CD79B dots. FAM‐positive and HEX‐negative droplets (blue) include MYD88 L265P or CD79B Y196. HEX‐positive and FAM‐negative droplets (green) include wild‐type MYD88 or wild‐type CD79B. Cases 1 and 3 exhibited MYD88 L265P mutation (+) and CD79B Y196 mutation (−). Case 2 exhibited MYD88 L265P mutation (−) and CD79B Y196 mutation (−). Case 4 exhibited MYD88 L265P mutation (+) and CD79B Y196 mutation (+).