Citations

Abstract Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy is standard of care for patients with newly diagnosed DLBCL. A majority of patients respond to R-CHOP, however ∼9% will have primary refractory disease and outcomes in these patients are extremely poor. While there is some knowledge of the pharmacogenomic (PGx) determinants of individual agents within R-CHOP, little is known about the PGx determinants of combination therapy. Our study aims to elucidate germline PGx determinants of drug bioavailability and undesirable side chain reactions in DLBCL patients treated with R-CHOP having potential to influence refractory disease. Methods: Newly diagnosed, DLBCL patients treated with R-CHOP between 2002 and 2012 with germline DNA and genotyping data were selected from the Molecular Epidemiology Resource within the Iowa/Mayo Lymphoma SPORE. Refractory disease was defined as either i) a best response of stable or progressive disease or ii) progressive disease by the end of the planned number of cycles of R-CHOP. PGx candidates within known pharmacokinetics and pharmacodynamics (PD) pathways for 11 genes (1,040 single nucleotide polymorphisms (SNPs)) were selected for study (CPT 2012;92(4):414-7). Odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate the association of SNPs with refractory disease, controlling for age, gender, and age-adjusted International Prognostic Index. Results: The median age at diagnosis of 424 of DLBCL patients treated with R-CHOP was 62 years (range 18-92); 45.7% were female; and 58.4% had Ann Arbor Stage III-IV. By the end of initial therapy 40 patients had primary refractory disease. Of the 1,040 SNPs evaluated, 120 (12%) were significantly associated with refractory disease at the 5% significance threshold suggesting novel associations with drug metabolism. The top SNP from each PGx candidate gene are shown in Table, with ALDH5A1 and CYP2B6 showing the most significant associations. Conclusions: While needing replication, we identified associations within two PGx candidate genes that are potentially functionally related to cyclophosphamide PD: alleles within CYP2B6 may have relevance in R-CHOP outcomes due to potential competition with other drug metabolizing enzymes shared with prednisone and vincristine biotransformation in the liver, and alleles withinALDH5A1 may impact a deactivating side chain reaction in B lymphocytes. Table: R-CHOP PGx candidates with known side chain reactionsPGx candidaten SNPsTop SNPChrOR* (95% CI)P-valueMAFABCB1365rs3480093571.86 (1.14 – 3.04)1.32E-020.29ADH1A32rs122996841.66 (0.60 - 4.53)3.27E-010.038ALDH3A116rs2228100171.26 (0.71 - 2.22)4.28E-010.24ALDH5A1192rs946103466.30 (2.43 - 16.4)1.55E-040.030CBR110rs2835266212.10 (0.90 - 4.89)8.76E-020.052CBR356rs45527331212.12 (0.91 - 4.98)8.29E-020.050CYP2B6107rs1038376192.38 (1.44 - 3.94)7.74E-040.27CYP3A421rs2898858372.32 (0.80 - 6.78)1.23E-010.028CYP3A531rs778032871.69 (0.68 - 4.16)2.57E-010.054SLC22A16193rs11217403561.80 (1.06 - 3.03)2.78E-020.21SOD116rs1041740211.35 (0.83 - 2.19)2.26E-010.32Chr=chromosome, MAF=minor allele frequency, *Adjusted for age, sex, and age-adjusted International Prognostic Index Citation Format: Matthew K. Breitenstein, Susan L. Slager, Anne J. Novak, Matthew J. Maurer, Carrie A. Thompson, Umar Farooq, Brian K. Link, Thomas M. Habermann, Curtis L. Olswold, Andrew L. Feldman, Grzegorz S. Nowakowski, Stephen M. Ansell, Thomas E. Witzig, Richard M. Weinshilboum, Liewei Wang, James R. Cerhan. Pharmacogenomic of refractory response to R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL) patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B143.

Abstract Background: Activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor receptor (MET) pathway promotes tumor growth, invasion and dissemination. Emibetuzumab is a humanized IgG4 monoclonal antibody that binds to and inhibits ligand-dependent and ligand-independent activation of MET. In the first-in-human dose escalation study NCT0128756, emibetuzumab demonstrated favorable tolerability when administered up to 2000mg Q2W IV in unselected patients. The study was expanded to evaluate emibetuzumab in expansion cohorts for patients with tumors positive for MET expression. Methods: Patients with locally advanced or metastatic castration-resistant prostate cancer (CRPC) with bone metastasis, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) received 2000 mg emibetuzumab Q2W IV on a 28-day cycle. RCC, NSCLC, and HCC patients were required to have measurable disease as defined by RECIST v1.1 and have MET positive tumors (≥50% of cells to be ≥2+ for MET expression) as determined by a MET IHC assay (Ventana). The objectives were to evaluate the safety and activity of emibetuzumab in patients with MET positive tumors. Additional objectives included pharmacokinetics (PK) and pharmacodynamics (PD). Results: A total of 62 patients received emibetuzumab across the 4 cohorts: CRPC n = 15, RCC n = 19, NSCLC n = 19,and HCC n = 9, with a median of prior systemic oncology therapies of 6, 3, 5, and 3, respectively. Common possibly related treatment-emergent adverse events included fatigue (29% all grades, 3% Gr3/4), nausea (13% all grades, no Gr3/4), edema of limbs (8% all grades, 2% Gr3/4), and anorexia (8%, no Gr3/4) and were similar among cohorts. No evidence of clinical activity was observed in CRPC patients. For RCC, NSCLC, and HCC patients with MET positive tumors, an overall disease control rate (DCR = partial response [PR] + stable disease [SD]) of 32% (15/47) was observed. In the individual cohorts, DCR was 26% (5/19) in RCC, 26% (5/19) in NSCLC, and 56% (5/9) in HCC. The median duration of disease stabilization in the 3 cohorts was: 4.2 months (range 1.6-24.6) in RCC, 3.9 months (range 2.5-6.4) in NSCLC, and 3.7 months (range 1.2-6.6) in HCC. One PR was observed in an HCC patient with MET amplification. After a single dose of 2000 mg emibetuzumab, PK parameters were similar among these cohorts and also comparable to patients treated at this dose during dose escalation. Conclusions: In cohorts enriched for tumor MET expression, limited single-agent activity of emibetuzumab was observed indicating that MET positivity by IHC (Ventana assay) at the cut-point employed here might not be a sufficient predictive biomarker to select patients receiving benefit from emibetuzumab monotherapy for the tumor types studied. Further evaluation of biomarkers/assays to identify patients who may benefit from treatment with emibetuzumab may be warranted. Citation Format: Michaela S. Banck, Rashmi Chugh, Ronald B. Natale, Alain Algazi, Bradley C. Carthon, Lee S. Rosen, Michael E. Menefee, Andrew Xiuxuan Zhu, Takami Sato, Brian Moser, P. Kellie Turner, Jay Tuttle, Xuejing Aimee Wang, Volker Wacheck, Frederick E. Millard. Phase 1 results of emibetuzumab (LY2875358), a bivalent MET antibody, in patients with advanced castration-resistant prostate cancer, and MET positive renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A55.

Abstract Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259–70. ©2016 AACR.

OBJECTIVE Successful stereotactic radiosurgery (SRS) for the treatment of arteriovenous malformations (AVMs) results in nidus obliteration without new neurological deficits related to either intracranial hemorrhage (ICH) or radiation-induced complications (RICs). In this study the authors compared 5 AVM grading scales (Spetzler-Martin grading scale, radiosurgery-based AVM score [RBAS], Heidelberg score, Virginia Radiosurgery AVM Scale [VRAS], and proton radiosurgery AVM scale [PRAS]) at predicting outcomes after SRS. METHODS The study group consisted of 381 patients with sporadic AVMs who underwent Gamma Knife SRS between January 1990 and December 2009; none of the patients underwent prior radiation therapy. The primary end point was AVM obliteration without a decline in modified Rankin Scale (mRS) score (excellent outcome). Comparison of the area under the receiver operating characteristic curve (AUC) and accuracy was performed between the AVM grading scales and the best linear regression model (generalized linear model, elastic net [GLMnet]). RESULTS The median radiological follow-up after initial SRS was 77 months; the median clinical follow-up was 93 months. AVM obliteration was documented in 297 patients (78.0%). Obliteration was 59% at 4 years and 85% at 8 years. Fifty-five patients (14.4%) had a decline in mRS score secondary to RICs (n = 29, 7.6%) or ICH (n = 26, 6.8%). The mRS score declined by 10% at 4 years and 15% at 8 years. Overall, 274 patients (71.9%) had excellent outcomes. There was no difference between the AUC for the GLMnet (0.69 [95% CI 0.64–0.75]), RBAS (0.68 [95% CI 0.62–0.74]), or PRAS (0.69 [95% CI 0.62–0.74]). Pairwise comparison for accuracy showed no difference between the GLMnet and the RBAS (p = 0.08) or PRAS (p = 0.16), but it did show a significant difference between the GLMnet and the Spetzler-Martin grading system (p < 0.001), Heidelberg score (p < 0.001), and the VRAS (p < 0.001). The RBAS and the PRAS were more accurate when compared with the Spetzler-Martin grading scale (p = 0.03 and p = 0.01), Heidelberg score (p = 0.02 and p = 0.02), and VRAS (p = 0.03 and p = 0.02). CONCLUSIONS SRS provides AVM obliteration without functional decline in the majority of treated patients. AVM grading scales having continuous scores (RBAS and PRAS) outperformed integer-based grading systems in the prediction of AVM obliteration without mRS score decline after SRS.

Monocyte‐derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell‐cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte‐derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk‐stratification of CLL patients for TTT. As an elevated AMC at diagnosis is associated with accelerated disease progression, and monocyte‐derived cells in the CLL microenvironment promote CLL cell survival and proliferation, these findings suggest that monocytes and monocyte‐derived cells are rational therapeutic targets in CLL. Am. J. Hematol. 91:687–691, 2016. © 2016 Wiley Periodicals, Inc.

Abstract BACKGROUND We assessed the impact of clinical decision support (CDS) rules within the electronic health record for ionized calcium (iCa), serum magnesium (Mg), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in intensive care unit (ICU) inpatients at a large academic center. METHODS A repeat order for measurement of iCa or Mg placed within 24 (iCa) or 48 (Mg) h of a previously nonactionable result, or additional orders for NT-proBNP beyond 1 within a single hospitalization, triggered a CDS pop-up alert showing the prior result and offering the opportunity to cancel the order or to place the order after entering an indication for repeat testing. The number of tests performed for each of these analytes and incidence of adverse clinical outcomes potentially associated with hypocalcemia or hypomagnesemia were compared between the 90-day period before CDS implementation and two 90-day periods immediately following. RESULTS iCa test volumes decreased by 48%, Mg by 39%, and NT-proBNP by 28% in the 90-day period immediately following implementation and remained decreased by 54%, 49%, and 22%, respectively, during the following 90-day period (all P values &lt;0.0002). Adverse clinical outcomes potentially associated with hypocalcemia or hypomagnesemia did not increase (all P-values &gt;0.17). CONCLUSIONS Implementation of CDS dramatically decreased repeat testing of iCa, Mg, and NT-proBNP without adversely impacting clinical outcomes in the ICU. Expansion of the rules from the ICU units to include the entire hospitalized patient population and expansion to additional analytes is expected to lead to further reductions in testing.

ObjectiveThe aim of our study was to study the impact of glycoprotein IIb/IIIa inhibitors (GPI) on in‐hospital outcomes.BackgroundThere is paucity of data regarding the impact of GPI on the outcomes following peripheral endovascular interventions.MethodsThe study cohort was derived from Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) database between the years 2006 and 2011. Peripheral endovascular interventions and GPI utilization were identified using appropriate ICD‐9 Diagnostic and procedural codes. Two‐level hierarchical multivariate mixed models were created. The study outcomes were: primary (in‐hospital mortality and amputation studied separately) and secondary (composite of in‐hospital mortality and postprocedural complications). Hospitalization costs were also assessed.ResultsGPI utilization (OR, 95% CI, P‐value) was independently predictive of lower amputation rates (0.36, 0.27–0.49, <0.001). There was no significant difference in terms of in‐hospital mortality (0.59, 0.31–1.14, P 0.117), although GPI use predicted worse secondary outcomes (1.23, 1.03–1.47, 0.023). Following propensity matching, the amputation rate was lower (3.2% vs. 8%, P < 0.001), while hospitalization costs were higher in the cohort that received GPI ($21,091 ± 404 vs. 19,407 ± 133, P < 0.001).ConclusionsMultivariate analysis revealed GPI use in peripheral endovascular interventions to be suggestive of an increase in composite end‐point of in‐hospital mortality and postprocedural complications, no impact on in‐hospital mortality alone, significantly lower rate of amputation, and increase in hospitalization costs. © 2016 Wiley Periodicals, Inc.

About 85% of patients with essential thrombocythemia (ET) harbor one of three driver mutations: JAK2, calreticulin (CALR), and MPL; the remaining ( ∼15%) are wild type for all three mutations and are referred to as being “triple negative.” Furthermore, CALR mutations in ET are structurally classified as type 1/type 1‐like or type 2/type 2‐like variants. The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis‐free (MFFS), thrombosis‐free, and leukemia‐free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple‐negative. Among the 109 CALR‐mutated cases, 52% were classified as type 1/type 1‐like and 48% as type 2/type 2‐like. In univariate analysis, triple‐negative patients displayed the best and MPL mutated the worst OS (P = 0.007); however, the difference in OS was no longer apparent on multivariable analysis that included age and sex as covariates (P = 0.5). LFS was also similar among the different mutational groups (P = 0.6) whereas MFFS was significantly shorter in MPL‐mutated patients on both univariate and multivariable analyses (age‐adjusted P = 0.02; HR 7.9, 95% CI 2.0–31.5). Also in multivariable analysis that included thrombosis history, age, and cardiovascular risk factors, the presence of JAK2 or MPL mutations was independently associated with higher risk of thrombosis (P = 0.02; HR 1.9, 95% CI 1.1–3.4). In conclusion, driver mutational status in ET does not appear to influence overall or LFS, even after CALR variant stratification. However, the presence of MPL mutations might be associated with a higher risk of fibrotic transformation and the presence of JAK2/MPL mutations with higher risk of thrombosis. Am. J. Hematol. 91:503–506, 2016. © 2016 Wiley Periodicals, Inc.

Refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS‐T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS‐T. We analyzed clinical and laboratory variables in 82 patients and applied a 27‐gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2 V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis ( n = 82), anemia ( P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2–4.6] and abnormal karyotype ( P =.01) [HR 6.1, 95% CI 2.7‐13.8] were independently prognostic for inferior survival. In patients with NGS information ( n = 48), univariate analysis showed association between poor survival and presence of SETBP1 ( P = 0.04) or ASXL1 ( P = 0.08) mutations whereas the absence of these mutations ( ASXL1 wt/ SETBP1 wt) was favorable ( P = 0.04); the number of concurrent mutations did not provide additional prognostication ( P = 0.3). We developed a HR‐weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively ( P = 0.01). In summary, we confirm the unique mutational landscape in RARS‐T and provide a novel mutation‐enhanced prognostic model. Am. J. Hematol. 91:492–498, 2016. © 2016 Wiley Periodicals, Inc.