Kuter, David J.

Abstract BACKGROUND: Previous work has demonstrated that smokers have higher white blood cell counts than nonsmokers, but the effect of biochemically-confirmed smoking cessation on peripheral leukocyte counts has not been demonstrated in a large prospective study. METHODS: Subjects were healthy smokers enrolled in a trial of sustained-release bupropion for relapse prevention after smoking cessation. White blood cell (WBC) counts and absolute neutrophil counts (ANC) were measured at baseline, week 7 and week 52. Smoking status was assessed at weeks 7 and 52 by self-report and biochemically confirmed with expired air carbon monoxide levels. Multivariate analyses compared changes in WBC count and ANC between smokers who did and did not stop smoking, adjusting for treatment group, age, sex, and body mass index. RESULTS: Of 784 smokers enrolled, 461 had biochemically-confirmed tobacco abstinence after 7 weeks of bupropion; 429 were randomly assigned to receive continued bupropion or placebo until week 52. At baseline, the mean WBC count was 8.4 x 109/L (SD ±2.3) and the mean ANC was 5.3 x 109/L (SD ±1.9). The baseline WBC count and ANC were higher in smokers with greater tobacco exposure, measured by daily cigarette consumption and serum cotinine level. Between baseline and week 7, there was a significantly larger decrease in WBC count in continuously abstinent subjects compared with continuing smokers (adjusted p =.031). At 52 weeks, biochemically-confirmed continuously abstinent subjects, as compared with continuing smokers, had a greater decline from baseline in WBC count (1.2 x 109/L versus 0.1 x 109/L, p<0.001) and ANC (0.1 x 109/L versus 0.2 x 109/L, p<0.001). CONCLUSION: The WBC count and ANC of healthy smokers increase with increasing tobacco exposure. Biochemically-confirmed tobacco abstinence leads to a rapid and sustained decrease in WBC count and ANC, possibly reflecting a decrease in an underlying state of tobacco-induced inflammation.

Introduction : Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare hereditary multisystem vascular disease of disordered angiogenesis. Pathologic elevations in vascular endothelial growth factor (VEGF) result in fragile, abnormal vessels in nasal and gastrointestinal (GI) mucosa causing recurrent epistaxis, chronic GI bleeding, and anemia that is often transfusion-dependent. Bevacizumab is a monoclonal IgG1 antibody that neutralizes circulating VEGF and is a potential targeted anti-angiogenic treatment in HHT, which has no FDA-approved therapy. Data for use of intravenous (IV) bevacizumab in HHT is currently limited to case reports and small single-center retrospective case series. The International HHT Intravenous Bevacizumab Investigative Team study of Bleeding (InHIBIT-Bleed) is an international collaboration of HHT Centers seeking to more definitively describe the safety and effectiveness of systemic bevacizumab to treat chronic bleeding and anemia in HHT. Methods : The following data was retrospectively collected at each participating center for all HHT patients treated for at least 3 months with off-label systemic bevacizumab for chronic bleeding: demographics, baseline HHT characteristics, epistaxis severity score (ESS, a validated 10-point scale to evaluate epistaxis in HHT), bevacizumab dosing, treatment-emergent adverse events (TEAEs), hemoglobin (Hgb), red blood cell (RBC) transfusions, and IV iron infusions. Hgb and ESS at baseline were compared with post-bevacizumab values at 3, 6, 9, and 12 months with the paired t-test. RBC transfusion and iron infusion requirements before and after bevacizumab treatment were compared with the Wilcoxon signed rank test. Results : 140 HHT patients were treated with IV bevacizumab for chronic bleeding for a median of 23 (range, 3-96) months with a median of 12 (range, 2-74) total infusions. Bevacizumab was dosed at 5 mg/kg every 2 weeks for the first 2 months, then monthly for 4 months; following this, maintenance dosing practices varied depending on center. Baseline patient characteristics are given in Table 1. After bevacizumab initiation, patients with baseline anemia (Hgb<11, N=104) had an increase in mean Hgb from 8.6 g/dL to 11.9 g/dL at 3 months (P<0.0001) up to 12.5 g/dL at 12 months (P<0.0001) (Table 2, Figure 1). For patients with epistaxis as an indication for treatment (N=119), mean ESS dropped from 6.8 at baseline to ≤3.5 on treatment (P<0.0001) (Table 2, Figure 2). In patients requiring RBC transfusion prior to bevacizumab (N=81), transfusion requirements decreased from a median of 8 units in the 6 months before treatment to a median of 0 units in the first 6 months after treatment (P<0.0001); similarly, in patients requiring iron infusion prior to bevacizumab (N=99), requirements decreased from a median of 4 infusions to 2 infusions (P<0.0001) (Table 2). RBC transfusion and iron infusion requirements continued to improve with ongoing bevacizumab treatment (Table 2) and improvement occurred regardless of baseline bleeding severity; Figure 3 illustrates the dramatic reduction in RBC transfusion and iron infusion requirements in a severe patient sub-cohort. Overall, compared with pretreatment, RBC transfusion and iron infusion requirements decreased by 86% and 66%, respectively, on bevacizumab. On subgroup analysis by underlying mutation (ENG vs. ACVRL1), there were no significant differences in baseline parameters or bevacizumab response. Bevacizumab was well-tolerated; TEAEs felt to be likely or possibly related to bevacizumab occurred in 36% of patients (Table 3), with new or worsened hypertension (16%) and fatigue (9%) most common. No patient developed venous thromboembolism on bevacizumab. Only 5 patients (4%) discontinued bevacizumab for TEAEs and only 3 patients (2%) discontinued bevacizumab for lack of effectiveness. Conclusions : We present results of IV bevacizumab treatment of chronic bleeding and anemia in a large cohort of 140 HHT patients, demonstrating that bevacizumab was highly effective, with an improvement in mean Hgb of 3.9 g/dL, dramatic reduction in ESS, and decrease in RBC transfusion and iron infusion requirements by 86% and 66%, respectively. Effectiveness was maintained over time. Safety analysis included a total of 194 patient-years of IV bevacizumab administration to HHT patients and had low TEAE rates with only 4% discontinuing treatment due to TEAEs. Disclosures Al-Samkari: Agios: Consultancy, Research Funding; Moderna: Consultancy; Dova: Consultancy, Research Funding. Kuter:Caremark: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Agios: Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kezar: Research Funding; Shire: Consultancy, Honoraria; Kezar: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; UCB: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Momenta: Consultancy, Honoraria. OffLabel Disclosure: The presentation will discuss off-label use of systemic bevacizumab for the treatment of chronic bleeding and anemia in hereditary hemorrhagic telangiectasia.

Introduction Romiplostim is a fusion protein agonist of the thrombopoietin receptor, approved by the US FDA for the treatment of immune thrombocytopenia (ITP) after failure of glucocorticoid therapy. This agent has been examined in other settings, including its use in the management of the thrombocytopenic surgical patient (Marshall et al., Transfusion 2015) and its use for the treatment of refractory aplastic anemia (Gill et al., Br J Haematol 2016). Thrombocytopenia is a complication of chemotherapy in cancer patients that may lead to treatment delays, dose reductions, and discontinuation of therapy (Kuter DJ, Oncology 2015). This study is a retrospective, single-center review of cancer patients who either developed thrombocytopenia as a result of chemotherapy or who had an underlying pre-existing thrombocytopenic disorder (such as ITP or chronic liver disease) who were supported with romiplostim during all or part of their chemotherapy. Methods We performed a retrospective review of patients with solid tumor malignancies who received at least two sequential weekly doses of romiplostim concurrently with chemotherapy. We collected patient demographics, dates and doses of romiplostim administration with corresponding platelet (Plt) counts, and outcomes of therapy, including ability of the treating oncologist to administer chemotherapy before initiating and during use of romiplostim as measured by number of treatment cycles administered, number and duration of delays in therapy, and number and extent of clinically necessary dose reductions. Results Review of pharmaceutical dispensation records from at our institution from January 1, 2010 through April 1, 2016 revealed 19 patients concurrently treated with romiplostim and chemotherapy, with 15 meeting our inclusion criteria (Table 1). At initiation of romiplostim, 40% of patients had a Plt count ≥75 x 109/L and 26.7% of patients had a Plt count ≥100 x 109/L, with a median Plt count of 72 x 109/L (range, 21-145 x 109/L). Patients were treated with weekly injections of romiplostim, with platelet count measured at the time of drug administration; the most common starting dose was 3 mcg/kg. The average duration of romiplostim therapy required to achieve a platelet count ≥75 x 109/L was 13.6 days, and the average time to achieve a platelet count ≥100 x 109/L was 21.1 days. During treatment with romiplostim, 85.3% and 73.2% of all platelet counts measured were ≥75 x 109/L and ≥100 x 109/L, respectively (Figure 1). All patients were able to receive two or more cycles (range, 2-18) of chemotherapy while on romiplostim. Twelve patients (80%) had delays in receiving antineoplastic therapy attributed to thrombocytopenia prior to initiation of romiplostim, with an average per-patient cumulative delay time of 4.7 weeks; 5 patients (33.3%) concurrently treated with romiplostim and chemotherapy had such delays (p=0.010 by Pearson's chi-squared test), with an average per-patient cumulative delay time of 1 week. Eleven patients (73.3%) required at least 1 dose-reduction in chemotherapy attributed to thrombocytopenia prior to initiation of romiplostim; 4 patients (26.7%) required at least 1 such dose-reduction while receiving romiplostim (p=0.011 by Pearson's chi-squared test). Three patients required platelet transfusion and 10 patients required red blood cell (RBC) transfusion while receiving romiplostim, though 8 of the patients received RBC transfusions only for chemotherapy-associated anemia or fatigue. While receiving romiplostim, no patient suffered a thrombotic event, and 3 patients suffered from bleeding (1 patient developed grade 1 mucosal bleeding and 2 patients developed grade 3 gastrointestinal bleeding). Conclusion In patients with solid tumor malignancies with chemotherapy-associated thrombocytopenia or who have co-existing thrombocytopenic disorders (such as ITP or chronic liver disease), this study provides evidence that romiplostim is safe and increases the platelet count sufficiently in a majority of patients to allow subsequent chemotherapy to be given at full dose and on schedule. Table 1 Patient Characteristics. Table 1. Patient Characteristics. Fgure 1 Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Fgure 1. Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Disclosures Kuter: Protalex: Research Funding; ONO: Consultancy; Pfizer: Consultancy; 3SBios: Consultancy; Eisai: Consultancy; GlaxoSmithKline: Consultancy; Bristol-Myers Squibb: Research Funding; Genzyme: Consultancy; Shire: Consultancy; Amgen: Consultancy, Paid expert testimony; Shionogi: Consultancy; Rigel: Consultancy, Research Funding; Syntimmune: Consultancy; MedImmune: Consultancy; CRICO: Other: Paid expert testimony.

Abstract Pyruvate kinase deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.

SummaryThrombocytopenic patients requiring invasive surgery have few options to improve their platelet count preoperatively. This is a single‐centre, retrospective review of thrombocytopenic patients receiving the thrombopoietin receptor agonist romiplostim perioperatively to allow for surgical interventions. Patient characteristics, romiplostim use, and surgical and safety outcomes (bleeding, thrombosis, transfusions) were collected and analysed. Forty‐seven patients underwent 51 surgical procedures (ranging from total hip arthroplasty to open cardiac surgery) with romiplostim support. Thrombocytopenia aetiologies included immune thrombocytopenia, chronic liver disease, haematological malignancy, drug‐related thrombocytopenia, and hereditary thrombocytopenia. Median (range) platelet counts improved, from 47 × 109/l (9–120 × 109/l) at romiplostim initiation to 164 × 109/l (28–603 × 109/l) at the time of surgery (P < 0·0001). A dose of 3 μg/kg per week for 2 doses increased the platelet count to >100 × 109/l in 79% of patients within 14 days. In 96% of cases, surgery proceeded on schedule without delay or cancellation. Four patients had bleeding events unrelated to thrombocytopenia and 1 patient developed deep venous thrombosis. Six patients required red cell transfusion and 3 patients required platelet transfusion perioperatively. In conclusion, romiplostim was effective in increasing platelet counts to allow surgery to proceed safely and on schedule. Bleeding and thromboembolic events were within acceptable limits for this surgical population.