Citations

AbstractPurpose:CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied.Experimental Design:We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT.Results:In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model.Conclusions:Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.

Obinutuzumab is used for the treatment of chronic lymphocytic leukemia. So far there are no data of using this for retreatment in patients who have received it previously. We introduced obinutuzumab for the retreatment in a chronic lymphocytic leukemia patient, who had first achieved partial remission with it and eventually relapsed over a course of 2.5 years. After retreatment with single-agent obinutuzumab, the patient achieved a partial remission again within one cycle and continues to maintain the response status. This case is a platform for considering obinutuzumab as a viable option for retreatment of chronic lymphocytic leukemia patients who have received it before, similar to the pattern of use for other anti-CD20 monoclonal antibodies in this disease, including rituximab.

448 Background: Cholangiocarcinoma (CCA) is a rare, lethal cancer with five-year survival of less than 10%. Although incidence rates have been increasing in the United States, ethnic variations in survival have not been investigated. We examined multi-ethnic variation in overall survival (OS) and CCA-specific survival (CSS) using data from the population-based Surveillance Epidemiology and End Results (SEER) program in the four year periods before and after introduction of gemcitabine/cisplatin as treatment for CCA. Methods: The study included data from 9,975 CCA cases reported in SEER between 2006 and 2013. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated to examine overall and cholangiocarcinoma-specific survival by ethnicity, age, gender and in the pre- and post- gemcitabine/cisplatin era (2006-2009 vs. 2010-2013). Results: Compared to non-Hispanic Whites, Hispanics had poorer 3-year OS (HR = 1.18, 95% CI = 1.10-1.26) and 3-year CCA-specific survival (HR = 1.25, 95% CI = 1.16-1.35). Similarly, non-Hispanic Blacks had 3-year OS (HR = 1.22, 95% CI = 1.12-1.30) and 3-year CCA-specific survival (HR = 1.24, 95% CI = 1.13-1.37). Males and older patients also were found to have shorter survival compared to females and younger patients. Also noted was an increase in CCA incidence rate over time (2006-2013) of 5.93%. Among those < 50 versus ≥50 years old, a 23% higher rate of incidence in those < 50 was noted. Overall survival and CSS were both significantly improved for patients post-advent of Gemcitabine/Cisplatin. Statistically significant improvement in CSS pre- and post-advent of Gemcitabine/Cisplatin was noted in non-hispanic whites (p < 0.001) and Hispanics (p = 0.02). Conclusions: Hispanics and non-Hispanic Blacks have worse survival after diagnosis with CCA. Further studies are needed to determine the determinants of poor survival among these groups toward targeted intervention. Significant improvements in OS and CSS have been seen after the advent of Gemcitabine/Cisplatin. The incidence of CCA is rising faster in young persons, under the age of 50, compared with older patients.

e18061 Background: Despite a favorable genetic profile, African-Americans (AAs) with mm have poorer outcomes secondary to inferior treatment. NCI-CCs provide the highest-quality of care and attendance has been associated with better outcomes in many cancers. AAs have greater access to NCI-CCs proximally; however, they attend these facilities at lower rates than their white peers. The impact of attendance at NCI-CCs on mediating racial disparities in mm outcomes has not been reported on to date. Methods: We reviewed cases of mm the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2000-2011 who were enrolled in Medicare Part A and B > 1 year prior to diagnosis, excluding cases enrolled prior to age 65 and those where mm diagnosis occurred post-mortem. Any center designated a NCI-clinical or -comprehensive center in 2002, 2005, or 2010 was considered a NCI-CC; attendance was defined as 2 or more claims on separate dates (MEDPAR and Outpatient files) from a NCI-CC in the 12 months following mm diagnosis. Logistic regression was performed to determine if race was associated with attendance, Cox regression to determine the association of attendance with survival. Results: 21,843 cases were analyzed; the median age was 77 years; 80% were white, 15% AA/Black. Overall NCI-CC attendance was low, only 11% of the population. Compared to white patients, black patients had a 13% decreased odds (aOR 0.87, 95% CI 0.75-0.99) of NCI-CC attendance after controlling for age, gender, socioeconomic status, geographic, and overall health variables. Attendance was associated with a 28% decrease risk for death (aHR 0.72, 95% CI 0.68-0.76), but had little impact on black-white outcome disparities. Black patients had a 9% increase in risk (aHR 1.09, 95% CI 1.04-1.13) after controlling for NCI-CC attendance. Conclusions: Black patients with mm have lower NCI-CC attendance. This may be related to referral bias and/or patient declining referral. NCI-CC attendance was associated with superior outcomes; however, controlling for attendance did not mediate black-white outcome disparities suggesting that racial treatment disparities pervade beyond access to NCI-CCs.