Key Points Ibrutinib increases the incidence of AF in patients with hematologic malignancies treated on or off a clinical trial. Patients with a history of AF and those with a high FHS-AF risk score are at highest risk for developing AF while on ibrutinib.

No abstract

Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 10% of all new cancer diagnoses. Angiogenesis is a tightly regulated process that is mediated by a group of angiogenic factors such as vascular endothelial growth factor and its receptors. Given the widespread use of antiangiogenic agents in CRC, there has been considerable interest in the development of methods to identify novel markers that can predict outcome in the treatment of this disease with angiogenesis inhibitors. Multiple biomarkers are in various phases of development and include tissue, serum, and imaging biomarkers. The complexity of the angiogenesis pathway and the overlap between the various angiogenic factors present a significant challenge to biomarker discovery. In our review, we discuss the angiogenesis pathway and the most promising evolving concepts in biomarker discovery, as well as highlight the landmark studies that identify subgroups of patients with CRC who may preferentially benefit from angiogenesis inhibitors.

No abstract

Introduction: Since a link between solar radiation, vitamin D production, and decreased colon cancer mortality was established in 1980, there has been increasing interest in vitamin D and cancer, suggesting that higher vitamin D levels improve overall survival, specifically in breast and colorectal cancer (Maalmi H et al, Eur J Canc, May-2014, PMID 24582912), but also in follicular lymphoma (Kelly JL, J Clin Onc, 1-May-2015, PMID 25823738). In myeloma, largest published series is from the Mayo Clinic reporting on 148 newly diagnosed MM patients for which no survival association was found, but there were associations between low 25-OH-Vit D (<20 ng/mL) and higher serum CRP, serum creatinine, and ISS stage (Ng AC, Am J. Heme, Jul-2009, PMID 19415724); we wanted to expand on their trailblazing analysis. Cytogenetically high risk myeloma characterized by the amplification of 1q21 is associated with increased serum levels of soluble IL-6 receptor (sIL-6r) (Stephens OW, Blood, 2012, PMID 22072558) which may be associated with other markers of inflammation, e.g. CRP, creatinine, and b2microglobulin. Methods: The Buckeye Myeloma Registry (OSU 10115) opened in 2011 to enroll any patient with a plasma cell dyscrasia. Serum total 25-OH-Vitamin D was measured at the time of the initial clinic visit to the myeloma group at Ohio State. Results: Of a total of 843 patients, 115 (13.6%), 53 (6.3%) with SMM, and 675 (80.1%) with MM. In the 675 MM patients, the median age was 64 y.o. (range 28-95), 14.5% African-American and the remainder Caucasian, with 28.6% ISS stage 1, 48.7% ISS stage 2, 21.9% ISS stage 3, and 24.5% unknown. At diagnosis for the MM patients, 67% presented with lytic bone disease. Out of 675 MM patients, there were 52 (7.7%) patients with < 10 ng/mL 25-OH-Vit D, 394 (51%) with low vit D (10-30 ng/mL), and 229 (39%) for 25-OH-Vit D 30-100 ng/mL. There was no correlation between 25-OH-Vit D and BMI or creatinine, but there was a strong correlation with race (r=0.18, p<0.000026). Among the MM patients, log-rank [Mantel-Cox] analysis of overall survival with serum 25-OH-Vit D including all groups demonstrated no significant differences (p=0.9725) with only 101 events. There was no correlation between 25-OH-Vit D and the presence on CD138-selected FISH of 1q21 amplification (p=0.196), 17p (p53) deletion (p=0.68), or 13q deletion (p=0.812). Conclusion: The majority of myeloma patients are vitamin D deficient, but this was not associated with worsened overall survival or with high risk cytogenetics. Cox proportional hazards analyses of survival adjusted for significant univariate covariates will be presented at the meeting. Correlations with presence or absence of diffuse lytic bone disease, severity of renal insufficiency, and race will also be presented at the meeting. Disclosures No relevant conflicts of interest to declare.

Key Clinical Message Significant elevations in alpha‐fetoprotein should raise suspicion for hepatocellular carcinoma as malignancies with metastasis to the liver can elevate the alpha‐fetoprotein level but typically <300 ng/mL. Diagnosis should be confirmed with typical characteristics of hepatocellular carcinoma on imaging and or liver biopsy to confirm diagnosis.

BACKGROUND: Ibrutinib is an irreversible inhibitor of Burton's tyrosine kinase (BTK) in the B-cell receptor (BCR) signaling cascade and is a practice changing treatment for chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits Interleukin-2 Inducible Kinase (ITK) in T-cells and has demonstrated immunomodulatory effects. Recently, cases of opportunistic infections (OI) have been reported during ibrutinib treatment including pneumocystis jirovecii pneumonia (PJP), cryptococcus, and fusarium. To date there are no reports on OI in large unselected cohorts of patients taking ibrutinib. We conducted a single-institution retrospective study to determine the incidence and type of OI during ibrutinib treatment as well as outcomes and characteristics associated with risk. METHODS: We reviewed medical records of all patients treated with ibrutinib at the Ohio State University between June 1st 2010 and March 31st 2016. Patients who received ibrutinib for graft versus host disease were excluded. All charts were initially reviewed by one of the investigators and patients with OI were independently reviewed by a second investigator. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All OI occurring after the first dose of ibrutinib were recorded. Onset of OI was considered as the time of first presentation for a complaint related to OI. Time to OI was calculated from the date of starting ibrutinib until the onset of OI or censored at the last assessment date, discontinuation of ibrutinib, or death prior to OI as competing risks. The cumulative incidence of OI was estimated and the Fine and Gray regression models were used to examine the association between patient characteristics and risk of OI. Covariates with significance level of p&lt;0.20 from univariable analyses were further evaluated in a multivariable analysis using a stepwise selection procedure, retaining those with p&lt;0.05 in the final model. RESULTS: The cohort included 566 patients. Median age was 65 (range 23-89) and 70.1% (397/566) were men. The majority of patients had CLL (73.7%, 417/566). Other diagnoses included mantle cell lymphoma (9.9%, 56/566), indolent B-cell malignancies (8.1%, 46/566; 11 Waldenström's Macroglobulinemia, 13 Hairy Cell Leukemia, 15 Follicular Lymphoma, 6 Marginal Zone Lymphoma, and 1 Prolymphocytic Leukemia), and aggressive lymphoma (8.3%, 47/566; 35 diffuse large B-cell or transformed lymphoma and 12 Richter's syndrome). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/566) of patients were treatment naïve. Ibrutinib was prescribed on clinical trial for 80.9% (458/566) of patients with the rest receiving it as standard of care. A second agent was given with ibrutinib in 30.9% (175/566) of cases and was most often a monoclonal antibody (81.7%, 143/175). Use of antiviral prophylaxis was common (78.6%, 445/566) with fewer patients receiving PJP (44.9%, 254/566) or fungal (11.5%, 65/566) prophylaxis. The most utilized prophylactic antifungal agent was fluconazole (70.8%, 46/65). Total ibrutinib exposure for the cohort was 1,225 person-years with a median exposure of 1.98 (range 0.008-6.40) years. Median duration of follow-up was 2.69 (range 0.03-6.40) years. Twenty-three of 566 (4.1%) patients developed an OI at a median of 0.39 (range 0.03-4.33) years after starting ibrutinib. The cumulative incidence of OI was 2.3% (95% CI: 1.3-3.8%) at 0.5 years and increased to 4.7% (95% CI: 3.0-7.0-%) at 5 years. Types of OI and outcomes are detailed in Table 1. Median survival of the entire cohort was not reached. Among 23 OI patients, the median survival after infection was 1.39 years. Univariable analysis revealed ≥3 prior treatments (HR 2.61), diabetes (HR 3.03), pulmonary disease (HR 2.81), chronic kidney disease (HR 2.56), and liver disease (HR 6.42) were associated with an increased risk for OI (p&lt;0.05). In a multivariable analysis ≥3 prior treatments (HR 2.87, 95% CI: 1.12-7.35; p=0.028), diabetes (HR 3.63, 95% CI: 1.50-8.77; p=0.004), and liver disease (HR 7.53, 95% CI: 2.14-26.49; p=0.002) retained independent association with OI development. CONCLUSIONS: The cumulative incidence of OI during ibrutinib treatment was low (4.7% at 5 years) and the most common type was invasive fungal (61%) with no PJP cases. Three or greater prior treatments, diabetes, and liver disease were independently associated with risk for OI. Disclosures Byrd: Janssen: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

No abstract