Albitar, Hasan Ahmad Hasan

Background. Immune checkpoint inhibitors (ICI) have changed the landscape in the treatment of a number of cancers. Immune-related adverse events (irAEs) have emerged as a serious clinical problem with the use of ICI. Methods. All oncology patients diagnosed with pulmonary complications secondary to ICI at Mayo Clinic Rochester from January 1, 2012 to December 31, 2018 were reviewed. Demographics, comorbidities, smoking, and oncologic history were analyzed. Results. A total of 10 patients developed pulmonary complications secondary to ICI. Seven patients were men (70%), and the median age at diagnosis was 61.5 (IQR 55.8-69.3) years. All patients had stage IV disease. Melanoma was the most common malignancy. Seven (70%) patients had a positive smoking history, and 6 (60%) were obese (BMI>30). Most cases were grade 2 pneumonitis (70%). One patient with grade 4 pneumonitis required endotracheal intubation and a prolonged course of systemic corticosteroids (>30 days). Eight (80%) patients received prior radiation therapy. The median time from initiation of ICI to pneumonitis diagnosis was 3.5 months. Conclusion. Melanoma was the most common malignancy, the majority of patients had grade 2 pneumonitis and required treatment with steroids, and all patients affected by ICI-related pneumonitis had stage IV malignancy. Potential risk factors included smoking history, prior radiotherapy, obesity, and advance stage at the time of ICI initiation. Extrapulmonary irAEs are common in patients with pneumonitis.

Purpose of review The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides a comprehensive review and guidance for clinicians managing patients with chronic obstructive pulmonary disease (COPD). However, adherence to GOLD guidelines has been suboptimal over the years. The current review summarizes the current body of literature addressing the multitude of reasons for the lack of adherence to GOLD guidelines in clinical practice. Recent findings There continue to be several reasons for suboptimal adoption of GOLD guidelines in clinical practice. A primary and recurrent theme appears to be both delayed as well as missed diagnosis of COPD. There are several reasons for this including lack of awareness about current COPD guidelines, lack of availability as well as utilization of office spirometry and improper symptom assessment. Other issues include improper selection of proper pharmacotherapy options, misdiagnosis/mislabeling of COPD phenotypes, lack of smoking cessation counselling as well as enrollment in pulmonary rehabilitation. Potential solutions include adoption of clinical decision support systems, self-care models and careful phenotyping of COPD patients. Summary There are currently several barriers for the adoption of GOLD guidelines into routine clinical practice. These barriers are all amenable to systematic solutions that will increase adherence to current GOLD guidelines.

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.