Citations

SummaryIbrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B‐cell malignancies. In ibrutinib clinical studies, low‐grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any‐grade bleeding were similar for single‐agent ibrutinib and ibrutinib combinations (39% and 40%). Low‐grade bleeding was more common in ibrutinib‐treated than comparator‐treated patients (35% and 15%), and early low‐grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person‐months). MH led to treatment discontinuation in 1% of all ibrutinib‐treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure‐adjusted relative risk for MH in both the total ibrutinib‐treated population (1.9; 95% confidence interval, 1.2–3.0) and RCT comparator‐treated patients (2.4; 95% confidence interval, 1.0–5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B‐cell malignancies.

74 Background: U.S. National Antiemetic Guidelines recommend upfront triple prophylaxis (NK1 receptor antagonist (RA) + 5HT3 RA + dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC), including carboplatin AUC ≥ 4 per 2017 guidelines. While existing data show gaps in guideline compliance, variation between individual physicians is less studied, and a realistic target compliance rate remains unknown. Methods: In a large electronic health record database (IBM Explorys), we identified HEC courses of therapy initiated from 2012 to 2017. Guideline compliance was defined as triple prophylaxis at chemotherapy initiation. Patient courses for ≥ 7 day cycles of cisplatin or anthracycline + cyclophosphamide (AC), or carboplatin (≥ 14 day cycles as a proxy for AUC ≥ 4) were ascribed to oncologists based on encounter frequency. We then ranked physicians treating ≥ 5 HEC courses and evaluated guideline compliance and individual physician variation. Results: In total, 10,074 HEC courses were identified and attributed to 451 unique physicians. Overall antiemetic guideline compliance with cisplatin and AC averaged 68% and 81% respectively. When ranked by compliance, the top 20% of physicians were 2.5 - 1.5 times as compliant as the bottom 20% (cisplatin 100% vs 40%; AC 100% vs 67%). For cisplatin, 32% of physicians had > 90% compliance; the remaining 68% were evenly distributed from 0 - 90%. For AC, 56% of physicians had > 90% compliance, and another 14% had 80 - 90%; the remaining 30% were evenly distributed. For carboplatin, 62% of physicians had ≤ 10% compliance, and another 17% had 11 - 20%; however, the majority of these data preceded guideline inclusion of carboplatin AUC ≥ 4 as HEC. Rates were independent of course volume per physician. Conclusions: Considerable physician-level variation exists in triple antiemetic prophylaxis guideline adherence for HEC. Hundreds of physicians had > 90% compliance with guidelines, suggesting 90% is a realistic target. However, the majority exhibited substantial gaps in NK1 RA use in HEC, placing patients unnecessarily at risk for CINV. Interventions are needed to bolster triple antiemetic prophylaxis in HEC, perhaps especially for carboplatin.

112 Background: Reducing hospitalizations for chemotherapy-related toxicities represents an opportunity to improve both the quality and cost of cancer treatment. Nausea and vomiting (NV) account for almost 10% of “avoidable” toxicity-related post-chemotherapy hospitalizations (2016 Medicare data). We sought to evaluate the event cost of NV-related hospitalizations among patients with cancer from a US payer perspective. Methods: From a large US claims database (Truven MarketScan), we identified hospitalizations with NV as the primary diagnosis and cancer as a secondary diagnosis (01/2011-06/2017). This method increases specificity for NV as the principal hospitalization factor, while underreporting the prevalence of NV as a contributory factor. To determine event costs, we evaluated hospital and other reimbursement during the hospitalization. To explore subgroup differences, we stratified results by tumor type, payer type, admission route, receipt of highly emetogenic chemotherapy (HEC; 2017 definition includes carboplatin AUC ≥4) and antiemetic prophylaxis. We adjusted all costs to 2017 US dollars. Results: Among 918,192 hospitalizations involving cancer, we identified 80,995 with both NV and a cancer diagnosis code. Of these, 5,293 had NV as the primary diagnosis and 62 lacked cost data. Patients (mean age = 57.7±16.2) were 67% female. Median hospital length of stay was 4 days and mean cost per hospitalization was $15,085. Non-Medicare admissions (82%) had a higher mean cost vs. Medicare ($15,737 vs. $12,111, p < 0.01). We found < $1,000 difference between the highest and lowest cost per hospitalization among the 6 most common tumor types. We found the 65% of patients with a chemotherapy claim ≤30 days prior to hospitalization had costs of $13,882 per event. Among the 45% of chemotherapies that were HEC, > 50% lacked an NK1 receptor antagonist as prophylaxis. Conclusions: The average cost of NV-related hospitalizations among patients with cancer exceeds $15,000 per event, highlighting the need to effectively address this symptom. Roughly half the hospitalizations involved HEC, with over half of those patients not receiving guideline-based antiemetic prophylaxis.

Abstract A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend &lt; 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p‐values for case–case and case–control comparisons for risk factors in relation to levels of grade and quartiles (Q1–Q4) of KI67 were estimated using polytomous logistic regression models. Case–case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs. 1 = 1.68 (1.31, 2.16)] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1 = 0.27 (0.16, 0.44)] tumors. In case–control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs. 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs. 0.88 (0.66, 1.16) for grade 1] and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs. 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors.

Objective Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions These data suggest several plausible genetic links between DLBCL and SLE.

Investigating the most likely causal variants identified by fine‐mapping analyses may improve the power to detect gene–environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine‐scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER–) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene–environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR‐rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67–0.88, pint = 1.8 × 10−4). The interaction with the strongest statistical evidence was found between 5q14‐rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16–1.59, pint = 1.9 × 10−5) in relation to ER– disease risk. The remaining two gene–environment interactions were also identified in relation to ER– breast cancer risk and were found between 3p21‐rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12–1.43, pint =1.8 × 10−4) and between 8q23‐rs13267382 and age at first full‐term pregnancy (ORint = 0.89, 95% CI: 0.83–0.95, pint = 5.2 × 10−4). While these results do not suggest any strong gene–environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.