A Genetic Predictive Model for Precision Treatment of Diffuse Large B-cell Lymphoma with Early Progression

Abstract Background: Early progression after standard immunochemotherapyleads to a very dismal outcome and necessitates alternative treatmentforpatients with diffuse large B-cell lymphoma (DLBCL). This study aimed todevelop a genetic predictive model for early progression and evaluate its potentialin advancing alternative treatment.Methods:Thirty-two hotspot driver genes were examined in 145 DLBCL patients and 5DLBCL cell linesusing next-generation sequencing. The association of clinical features, cell-of-origin, double expression, positive p53 protein, and gene alterations with early progression was analyzed, and the genetic predictive model was developed based on the related independent variables and assessed by the area under receiver operating characteristic.The potential of novel treatment based on the modeling was investigated ininvitro DLBCL cell lines and invivo xenograft mouse models.Results:The frequency of CD79B(42.86% vs 9.38%, p = 0.000)and PIM1 mutations (38.78% vs 17.71%, p = 0.005) showed asignificant increase in patients with early progression. CD79B and PIM1 mutations were associated with complex genetic events,double expression, non-GCB subtype, advance stageand unfavorable prognosis. Apowerful genetic predictive model (AUROC=0.771, 95% CI: 0.689-0.853)incorporatinglactate dehydrogenase levels(OR = 2.990, p = 0.018), CD79B mutations (OR = 5.970, p = 0.001), and PIM1 mutations (OR = 3.021, p=0.026)was created andverified in the other cohort. This modeling outperformed the prediction accuracy of conventional International Prognostic Index, and new molecular subtypes of MCD and Cluster 5. CD79B and PIM1 mutations indicateda better response to inhibitorsof BTK (ibrutinib) and pan-PIM kinase(AZD 1208) through repressingactivated oncogenic signaling. Since the two inhibitorsfailed to decrease BCL2level,BCL2 inhibitor (venetoclax) was added and demonstrated to enhancetheirapoptosis-inducing activityin mutant cells with double expression.Conclusions: Thegenetic predictive model provides a robust tool to identify early progression and determine precision treatment.These findings warrant the development of optimal alternative treatment in clinical trials.