Abstract
The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1high) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R+) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1high observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R+ DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
Highlights
The XPO1 inhibitor selinexor was recently approved in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL
Deng et al J Hematol Oncol (2020) 13:148 inhibitor selinexor has received FDA approval recently to treat refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) after at least 2 lines of systemic therapy, showing an overall response rate of 28% in the SADAL trial [3]. It remains largely unknown whether and how XPO1 interplays with other adverse predictors in DLBCL, how to predict selinexor effectiveness, and what combination therapy is optimal in R/R DLBCL patients
We evaluated the prognostic significance of XPO1 expression in 544 well-characterized DLBCL cases, and investigated the therapeutic effect of selinexor in 30 DLBCL cell lines with variable genetic background
Summary
Manman Deng1,2†, Mingzhi Zhang3†, Zijun Y. Xu‐Monette2† , Lan V. Pham4†, Alexandar Tzankov5, Carlo Visco6, Xiaosheng Fang2, Govind Bhagat7, Feng Zhu2, Karen Dybkaer8, April Chiu9, Wayne Tam10, Youli Zu11, Eric D. Hsi12, William W. L. Choi13, Jooryung Huh14, Maurilio Ponzoni15, Andrés J. M. Ferreri16, Michael B. Møller16, Benjamin M. Parsons17, J. Han van Krieken18, Miguel A. Piris19, Jane N. Winter20, Fredrick Hagemeister21, Lapo Alinari22, Yong Li23, Michael Andreeff24, Bing Xu1,25* and Ken H. Young2,26*
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