Key Points Activation of BCR and canonical NF-κB signaling in the lymph node correlates with survival in MCL. Mutations and polymorphisms in BCR and NF-κB pathways may confer cell autonomous signaling and affect response to ibrutinib.

We examined whether draft 2020 United States Preventive Services Task Force (USPSTF) lung-cancer screening recommendations “partially ameliorate racial disparities in screening eligibility” compared to 2013 guidelines, as claimed. Using data from the 2015 National Health Interview Survey, USPSTF-2020 increased eligibility by similar proportions for minorities (97.1%) and Whites (78.3%). Contrary to the intent of USPSTF-2020, the relative disparity (differences in percentages of model-estimated gainable life-years from National Lung Screening Trial-like screening by eligible Whites vs minorities) actually increased from USPSTF-2013 to USPSTF-2020 (African Americans: 48.3%–33.4%=15.0% to 64.5%–48.5%=16.0%; Asian Americans: 48.3%–35.6%=12.7% to 64.5%–45.2%=19.3%; Hispanic Americans: 48.3%–24.8%=23.5% to 64.5%–37.0%=27.5%). However, augmenting USPSTF-2020 with high-benefit individuals selected by the Life-Years From Screening with Computed Tomography (LYFS-CT) model nearly eliminated disparities for African Americans (76.8%–75.5%=1.2%), and improved screening efficiency for Asian/Hispanic Americans, although disparities were reduced only slightly (Hispanic Americans) or unchanged (Asian Americans). Draft USPSTF-2020 guidelines increased the number of eligible minorities versus USPSTF-2013 but may inadvertently increase racial/ethnic disparities. LYFS-CT could reduce disparities in screening eligibility by identifying ineligible people with high predicted benefit, regardless of race/ethnicity.

Purpose Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAbs) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in pre-clinical studies in vitro ibrutinib was reported to decrease CD20 expression and inhibits cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox. Experimental Design Patients received single agent ibrutinib (420mg daily) on an investigator-initiated phase 2 trial. Serial blood samples were collected pre-treatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs. Results We demonstrate that CD20 expression on ibrutinib was rapidly and persistently down-regulated (median reduction 74%, day 28, P<0.001) compared to baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and down-regulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pre-treatment cells (median reduction 75%, P<0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. Additionally, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy. Conclusions Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal anti-tumor effects of such combinations requires further investigation.