CD47 Expression Defines Efficacy of Rituximab with CHOP in Non-Germinal Center B-cell (Non-GCB) Diffuse Large B-cell Lymphoma Patients (DLBCL), but Not in GCB DLBCL

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Addition of rituximab (R) to "CHOP" (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improved outcome for diffuse large B-cell lymphoma (DLBCL) patients. Approximately 40% of patients who receive R-CHOP still succumb to disease due to intrinsic resistance or relapse. A potential negative regulator of DLBCL treatment outcome is the CD47 "don't eat me" immune checkpoint. To delineate the impact of CD47, we used a clinically and molecularly well-annotated cohort of 939 DLBCL patients, comprising both germinal center B-cell (GCB) and non-GCB DLBCL subtypes, treated with either CHOP or R-CHOP. High (above median) CD47 mRNA expression correlated with a detrimental effect on overall survival (OS) when DLBCL patients received R-CHOP therapy (P = 0.001), but not CHOP therapy (P = 0.645). Accordingly, patients with low CD47 expression benefited most from the addition of rituximab to CHOP [HR, 0.32; confidence interval (CI), 0.21-0.50; P <0.001]. This negative impact of high CD47 expression on OS after R-CHOP treatment was only evident in cancers of non-GCB origin (HR, 2.09; CI, 1.26-3.47; P = 0.004) and not in the GCB subtype (HR, 1.16; CI, 0.68-1.99; P = 0.58). This differential impact of CD47 in non-GCB and GCB was confirmed in vitro, as macrophage-mediated phagocytosis stimulated by rituximab was augmented by CD47-blocking antibody only in non-GCB cell lines. Thus, high expression of CD47 mRNA limited the benefit of addition of rituximab to CHOP in non-GCB patients, and CD47-blockade only augmented rituximab-mediated phagocytosis in non-GCB cell lines. Patients with non-GCB DLBCL may benefit from CD47-targeted therapy in addition to rituximab.

Originele taal-2English
Pagina's (van-tot)1663-1671
Aantal pagina's9
TijdschriftCancer immunology research
Volume7
Nummer van het tijdschrift10
Vroegere onlinedatum13-aug-2019
DOI's
StatusPublished - okt-2019

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