Abstract 15395: Immune Checkpoint Inhibitors for Cancer Are Associated With Increased Venous Thromboembolism Events

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jingyi Gong ◽  
Zsofia Drobni ◽  
Raza Alvi ◽  
Sean Murphy ◽  
Sarah Hartmann ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Immune Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Massachusetts General Hospital ◽  
Control Period ◽  
Fold Increase ◽  
Vein Thrombosis ◽  
Increased Risk

Introduction: Immune checkpoint inhibitors (ICI) lead to immune activation, increased inflammation and cancer cell death. Both immune activation and inflammation are critical pathobiological drivers for venous thromboembolism (VTE). There are no robust data testing the effect of ICIs on the risk of developing VTE. Methods: This is a retrospective study of 2854 patients who received ICIs at Massachusetts General Hospital, Boston, MA. VTE events, defined as a composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were identified by individual chart review and were blindly adjudicated using standard criteria. A case-crossover design was applied with an “at-risk period” defined as the two-year period after and the “control period” as the two years prior to treatment. Incidence rate ratio (IRR) was calculated using Poisson’s regression. Results: Immune checkpoint inhibitor use increased VTE risk by 1.84-fold from 4.85 per 100-person years to 8.91 per 100 person-years (IRR 1.84, 95% confidence interval: 1.54 - 2.19, p <0.001). Of the individual components, there was a 2.44-fold increase in DVT risk (2.30 to 5.58 per 100 person-years) and 1.68-fold increase in PE risk (2.96 to 5.00 per 100 person-years). Comparing patients with and without a VTE event, those with a VTE event after ICI initiation had a higher rate of prior VTE, lung cancer, urothelial cancer, and a higher platelet count and white blood cell count at baseline. At 6 months post ICI initiation, 165 (8.6%) patients had a VTE event and of these patients 136 (7.1%) had no prior VTE. Conclusions: Patients with cancer treated with ICIs are at increased risk of developing VTE. Whether prophylaxis for VTE among patients starting an ICI reduces this risk is unclear.

scholarly journals Risk of Venous Thromboembolism in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3223-3223
Author(s):  
Doaa Attia ◽  
Wei Wei ◽  
Nathan A Pennell ◽  
Keith R. McCrae ◽  
Alok A Khorana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Venous Thromboembolism ◽  
Incidence Rate ◽  
Immune Checkpoint ◽  
Cumulative Incidence ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Rank Test ◽  
Cumulative Incidence Rate ◽  
Vein Thrombosis

Abstract Background: Thromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Cancer immunotherapy is linked to several inflammatory immune mediated adverse events. Inflammation plays a key role in thrombosis but the association between immunotherapy and venous thromboembolism (VTE) has not been thoroughly investigated. Here, we report the incidence of thromboembolism in patients with lung cancer treated with immune checkpoint inhibitors (ICIs). Methods: A single institution retrospective cohort of 514 adult patients with lung cancer who received ICIs (pembrolizumab, nivolumab, atezolizumab, ipilumab, avelumab) between 2013 and 2017 was included. Diagnosis of VTE (deep vein thrombosis and/or pulmonary embolism, and visceral vein thrombosis "VVT") was confirmed by imaging. Overall survival (OS) was estimated by Kaplan-Meier and compared using log rank test. Cumulative incidence rate of VTE was estimated and compared using Gray's method. Results: Of 514 patients (pts), 58.75% were males, 83.27% were white with a median age of 67 (range 22-91). Nivolumab was most commonly used (52.14%), followed by Pembrolizumab (30.16%), Atezolizumab (10.89%), combination of ipilimumab plus nivolumab (6.61), ipilimumab (2.33%), Avelumab (1.17%). 88.52% had stage 4 disease at treatment initiation. VTE events occurred in 62 pts (12%) (3.5% DVT, 4.47% PE, 2.72% both, 0.97 VVT, 0.19 VVT + PE, 0.19% VVT+DVT+PE). The cumulative incidence rate of VTE of all pts at 6-month and 1-year post IO was 7.6% (95% CI:5.3-9.9%) and 11.6% (95% CI:8.7-14.6%) respectively. The rate of survival without VTE at 6 months after IO treatment was 91% (95% CI: 89-94%). None of the following factors (age, gender, race, cancer staging, IO type or line) were significantly associated with time-to-VTE (TTVTE) survival post treatment (P &gt;0.05). Median OS of all pts was 12.6 months (95% CI: 11.0-16.7 months), with 2-year OS rate of 35% (95% CI: 31-41%). Conclusion: ICIs in lung cancer are associated with higher VTE risk within six months and a year of initiation of treatment. Further studies are needed to investigate the risk factors for ICIs-associated VTE. Disclosures Pennell: Astrazeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; G1 therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Mirati Therapeutics, Inc.: Consultancy, Honoraria; Viosera Therapeutics: Consultancy, Honoraria; Eli Lilly: Consultancy, Honoraria; BMS: Consultancy, Honoraria. McCrae: Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria; Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy. Khorana: Pfizer: Consultancy, Honoraria; Anthos: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Bayer: Consultancy, Honoraria.

scholarly journals From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2278
Author(s):  
Afshin Derakhshani ◽  
Zeinab Rostami ◽  
Hossein Safarpour ◽  
Mahdi Abdoli Shadbad ◽  
Niloufar Sadat Nourbakhsh ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Development ◽  
Immune Checkpoints ◽  
Single Cell Sequencing ◽  
Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

Host metabolic factors and prognosis in patients treated with immune checkpoint inhibitors for advanced malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14162-e14162
Author(s):  
Federica Biello ◽  
Marco Audisio ◽  
Silvia Genestroni ◽  
Gloria Borra ◽  
Francesca D'Avanzo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Fold Increase ◽  
Advanced Melanoma ◽  
Host Metabolism ◽  
Increase In Risk

e14162 Background: It is well established that an altered host metabolism has an impact on cancer outcome, possibly mediated by several mechanisms, including hyperglicaemia, hyperinsulinemia and presence of chronic inflammation. The aim of our analysis was to evaluate the correlation between host metabolism and clinical outcome in patients with advanced melanoma, kidney and non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (anti-CTLA4, anti PD1 and anti PDL1). Methods: The relationship between presence of type 2 diabetes mellitus (DMII) at baseline and outcome was assessed in 187 patients treated with immune checkpoint inhibitors in two cancer centers. Progression Free Survival (PFS) and Overall Survival (OS) were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to age, gender, BMI (normal < 25 kg/m2, overweight 25-30 kg/m2, obese > 30 kg/m2), type of cancer and line of treatment. Results: One-hundred-sixty-eight patients were available for our analysis. Twenty-eight patients (17%) were diabetic at baseline. Median age was 65 (range 25-80); 83 patients were males (49%); 82 (48%) had advanced melanoma, 83 (49%) NSCLC and 3 (3%) kidney cancer. One-hundred-two (60%) patients had BMI < 25, 51 (30%) were overweight and 16 (10%) were obese. The first line of treatment was immunotherapy in 83 (49%) patients. By univariable analysis median PFS was 4.2 months in non diabetics vs 6.4 in diabetics patients (HR 0.95; 95%CI 0.58-1.58); median OS was 6.17 and 9.1 months, respectively (HR 1.00; 95%CI 0.58-1.75). At multivariable analysis, taking into account DMII, BMI, sex, age, line of treatment and type of cancer, we found that BMI ≤25 was associated with a two fold increase in risk of progression (PD) or death (p = 0.005), whereas patients who received immunotherapy as second or subsequent line had a two fold increase in risk of PD or death (p = 0.003). Conclusions: The results of our analysis show that in patients with advanced cancer treated with immune checkpoint inhibitors, the presence of DMII does not adversely affect the clinical outcome. Conversely, lower BMI was associated with a significantly worse PFS and OS, independently from type of cancer, age and gender. As expected, patients who received immunotherapy in later lines of treatment had a significantly shorter survival.

Multidisciplinary team management for high grade immune-related adverse events (irAEs): A single center experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15076-e15076
Author(s):  
PRABHSIMRANJOT SINGH ◽  
Osama Abu-Shawer ◽  
Amanda Brito ◽  
Eric Yenulevich ◽  
Shilpa Grover ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Massachusetts General Hospital ◽  
Average Length ◽  
Immunosuppressive Agents ◽  
Future Research ◽  
Inpatient Service ◽  
High Grade

e15076 Background: Immune checkpoint inhibitors (ICIs) are increasingly used in the management of cancer. High grade irAEs are uncommon but can be severe and require hospital admission. There is an urgent need for early identification and triage of patients with irAEs in order to improve their management and outcomes. Methods: We established Immunotherapy toxicity (ITOX) team as the first in nation inpatient service at DFCI and Brigham and Women's Hospital (BWH) along with our partners at Massachusetts General Hospital (MGH) that is specifically devoted to mitigating irAEs. The ITOX service is consistent of 2 PAs and a medical oncology attending with an expertise in immunotherapy. The service utilizes algorithms that are modified from the ASCO and NCCN guidelines by our medical subspecialty experts at BWH. The service uses a multi-disciplinary approach with around the hour consulting service from experts in the field including GI, pulmonary, endocrinology and others. We leveraged EPIC to triage patients who are admitted to BWH and have ever received or currently on immune checkpoint inhibitors (ICIs). The daily list generated by EPIC is then curated manually by a PA to identify patients with potential irAEs. Results: A total of 138 patients with high grade irAEs were admitted to BWH between June 2018 and June 2019. Seventy percent of the 201 irAEs- related admissions were to ITOX service (70% accuracy in triaging). Most common irAEs was colitis (31%), pneumonitis (28%) and hepatitis (13%) which is consistent with the most common reported irAEs due to ICIs. Eighty five percent of the patients had grade 3 irAEs and 15% were admitted with life threatening grade 4 adverse events. About half of the patient had received ICI monotherapy; 33% received combination of ICI and non-ICI (chemotherapy or targeted therapy) and 17% received combination of ICIs. Most patients responded to steroids and only 9% had steroid-refractory irAEs requiring other immunosuppressive agents. The average length of stay for irAEs-related admission was 11 days with readmission rate of 26% within a year. Over 50 patients consented for tissue and blood biospecimen collection at the time of toxicity. Conclusions: We demonstrated the feasibility of empowering EMR to accurately triage patients with suspected irAEs to the ITOX service that is supported by institution developed guidelines and specialists. Our model is adaptable in major academic centers and can have major impact on quality improvement and future research studies that can be conducted in this unique setting.

scholarly journals Antibiotics Treatment and Immune-checkpoint Inhibitors Efficacy: A Systematic Review and Meta-analysis

2020 ◽  
Author(s):  
Jie Hao ◽  
Yang Zhao ◽  
Jiangyi He ◽  
Yunlong Wang ◽  
Yan Dong
Keyword(s):  
Prognostic Factor ◽  
Advanced Cancer ◽  
Immune Checkpoint ◽  
Fixed Effects ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Time Interval ◽  
Prognostic Information ◽  
Increased Risk

Abstract Background: Immune-checkpoint inhibitors (ICIs) have been approved as 1st line therapy and benefit patients with advanced cancer. However, still many patients fail to achieve the significant efficacy, a predictor for precise patient selection is needed. The aim of our study is to determine whether the administration of antibiotics before or at the beginning of ICIs treatment is a prognostic factor of progression-free survival (PFS) and overall survival (OS) in patients with advanced cancer.Methods: A systematic search in PubMed, Embase, Cochrane and Web of Science databases was conducted using the search terms antibiotic, PD-1, PD-L1, CTLA-4, combined with cancer, tumor, neoplasm, or carcinoma. Data extraction was performed independently. Hazard ratio (HR) for PFS and OS of antibiotics (+) group vs antibiotics (-) group were pooled according to random or fixed-effects models. HRs with 95% confidence intervals (CIs) for PFS and OS were pooled to obtain prognostic information and aggregate values.Results: Nine studies including 1163 patients were included in this meta-analysis. By PFS analysis, antibiotics administration was associated with a significantly increased risk of disease progression (HR, 1.76; 95% CI, 1.37-2.26; P< 0.01). By OS analysis, antibiotics uptake also showed an HR in favor of death (HR, 1.7; 95% CI, 1.40-2.07; P< 0.01).Conclusions: Based on the existing evidence, antibiotics administration is a prognostic factor for reduced PFS and OS in patients receiving ICIs treatment. The time interval between antibiotics administration and ICIs treatment should be considered.

scholarly journals Risk of tuberculosis in patients with cancer treated with immune checkpoint inhibitors: a nationwide observational study

2021 ◽  
Vol 9 (9) ◽  
pp. e002960
Author(s):  
Seongman Bae ◽  
Ye-Jee Kim ◽  
Min-ju Kim ◽  
Jwa Hoon Kim ◽  
Sung-Cheol Yun ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Exposure Group ◽  
Patients With Cancer ◽  
Increased Risk ◽  
Insurance Claims Data ◽  
Health Insurance Claims Data

BackgroundWhile some recent studies have reported the development of tuberculosis (TB) in patients exposed to immune checkpoint inhibitors (ICIs), there is limited evidence to date. Therefore, we evaluated the risk of TB in patients with cancer exposed to ICIs using the National Health Insurance claims data in South Korea.MethodsPatients with diagnostic codes for non-small cell lung cancer, urothelial carcinoma or melanoma between August 2017 and June 2019 were identified. The incidence rate and standardized incidence ratio (SIR) of TB were calculated for both the ICI exposure and non-exposure groups. The risk of TB according to ICI exposure was assessed using a multivariable Cox regression model.ResultsDuring the study period, 141 550 patients with cancer and 916 new TB cases were identified. Among the 5037 patients exposed to ICIs, 20 were diagnosed with TB at a median of 2.2 months after the ICI was initiated. The crude incidence rate of TB per 100,000 person-years was 675.8 (95% CI 412.8 to 1043.8) for the ICI exposure group and 599.1 (95% CI 560.5 to 639.6) for the non-exposure group. The SIR for TB was 8.1 (95% CI 8.0 to 8.2) in the ICI exposure group. After adjusting for potential confounding factors, ICI treatment was not significantly associated with an increased risk of TB (HR: 0.73; 95% CI 0.47 to 1.14).ConclusionsWhile the incidence of TB in cancer patients exposed to ICIs was eightfold higher than in the general population, the risk of patients with cancer developing TB did not significantly differ according to ICI exposure.

Hyperprogressive disease in patients with recurrent high grade gliomas treated with immune checkpoint inhibitors or other therapies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13575-e13575
Author(s):  
Laura Donovan ◽  
Samuel Gedailovich ◽  
Adela Joanta-Gomez ◽  
Jessica Schulte ◽  
Teri Nguyen Kreisl ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Fold Increase ◽  
Tumor Growth Rate ◽  
Control Group ◽  
High Grade ◽  
Advanced Cancer Patients ◽  
High Grade Gliomas ◽  
Hyperprogressive Disease

e13575 Background: Hyperprogressive disease (HPD) has been described in solid tumor patients treated with immune checkpoint inhibitors (ICI). HPD is defined as a ≥2-fold increase in tumor growth rate (TGR) following initiation of ICI. HPD has not been explored in patients with high grade gliomas (HGG) on ICI or standard cytotoxic regimens. In advanced cancer patients receiving ICI, MDM2/4 amplification or EGFR alterations, both found in HGG, correlated with HPD. We compared the rate of HPD in recurrent HGG patients receiving ICIs to those treated with non-immunotherapy agents. Methods: Patients with HGG on ICIs for 1st or 2nd recurrence were compared to a control group receiving other therapies at 1st recurrence. Patients with prior or concurrent bevacizumab or anti-VEGFR were excluded due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. Results: 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients treated with ICIs and 20/22 patients in the control group had complete imaging and were eligible for analysis. In the ICI group, 60% were men (15/25) and 88% (22/25) had a diagnosis of GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of GBM. 30% (6/20) were 65 years or older at diagnosis in the control group compared to 28% (7/25) in the ICI group. In total, 7/25 patients met criteria for HPD in the ICI group (28%) compared to 4/20 patients in the control group (20%). 10/25 patients (5/7 with HPD) in the ICI group and 8/20 patients (2/4 with HPD) in the control group had next generation sequencing of their tumors. EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in the HPD group (71% HPD vs. 33.3% no HPD). Conclusions: HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies. While the numbers are small, PTEN mutations may be associated with HPD in patients with HGG. In contrast to other solid tumors, EGFR alterations and MDM2/4 amplifications were not associated with HPD in HGG.

Liver injury by immune checkpoint inhibitors in patients with hepatocellular carcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 341-341 ◽  
Author(s):  
Nicola Personeni ◽  
Tiziana Pressiani ◽  
Antonio Capogreco ◽  
Arianna Dal Buono ◽  
Antonio D'Alessio ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Injury ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Subsequent Treatment ◽  
Drug Induced ◽  
Increased Risk ◽  
Grade 3

341 Background: In patients with hepatocellular carcinoma (HCC) and baseline liver dysfunction, hepatic immune-related adverse events (HIRAEs) during immunotherapy have not been adequately characterized and their impact on subsequent treatment outcomes is not known. Methods: 40 patients with advanced/unresectable HCC and Child Pugh score A have been enrolled in first and second-line clinical trials of anti-programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs). HCC etiologies were: hepatitis C (32.5%), hepatitis B (7.5%), alcohol abuse (27.5%), other (32.5%). 7 received anti-PD-1 mAbs alone and 33 received combined regimens that included anti-PD-1 mAbs plus either anti-cytotoxic T lymphocyte antigen 4 (30.4%) or tyrosine kinase inhibitors (TKIs) (54.5%), or both (15.1%). We reviewed their liver function tests and HIRAEs onset was related to time to treatment failure (TTF). Results: Overall, 12 patients (30%) developed grade ≥ 3 hepatitis according to Common Toxicity Criteria for Adverse Events v. 4.03, resulting in 4 cases of grade 2 drug-induced liver injury per DILI Working Group criteria. Time between therapy initiation and hepatitis onset was 1.4 months (0.4-2.8) and median peak aminotransferase (AT) level was 258 IU/L (85-869). Out of 6 permanent treatment discontinuations due to adverse events (AEs), 4 were linked to hepatitis. Higher AT median levels at baseline were significantly linked to grade ≥ 3 hepatitis compared with lower grades (95 IU/L vs. 36 IU/L, respectively; p = 0.008). Etiology, age, treatment did not predict HIRAEs onset. TTF in patients in patients with grade ≥ 3 hepatitis was shorter than in the whole cohort (1.4 vs. 3.8 months, p = 0.041), while overall survival did not differ (p = 0.125). Conclusions: We observed a 30% incidence of clinically significant HIRAEs. HIRAEs represent the most frequent AEs leading to treatment discontinuation in patients with HCC undergoing treatments with immune checkpoint inhibitors. Baseline AT levels may identify patients at increased risk of grade ≥ 3 hepatitis.

Neurotoxicity associated with immune checkpoint inhibitors: Systematic review and meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15096-e15096
Author(s):  
Muhammad Zain Farooq ◽  
Sheeba Habeeb Ba Aqeel ◽  
Prasanth Lingamaneni ◽  
Shristi Upadhyay Banskota ◽  
Rayli Pichardo ◽  
...  
Keyword(s):  
Systematic Review ◽  
Nervous System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Random Effect Model ◽  
Standard Of Care ◽  
Increased Risk ◽  
Statistical Heterogeneity

e15096 Background: Immune checkpoint inhibitors (ICI) are associated with multiple immune related adverse events (irAE). Moderate to severe neurotoxicity is reported in less than 1% of all patients treated with ICI. We performed a systematic review and meta-analysis to assess neurotoxicity associated with anti-PD-1/PD-L1 and anti-CTLA4 therapy. Methods: The Embase, Ovid, Pubmed and Scopus database were comprehensively searched by two independent reviewers, from inception to 2019, to include Phase II and III clinical trials reporting neurotoxicity with the combination of, or monotherapy with anti-PD-1/PD-L1 and/or anti-CTLA4 therapies. Our primary outcome was assessment of neurologic irAE of all grades. We divided neurotoxicity into two groups: peripheral nervous system (PNS) including peripheral neuropathy (PeN), fatigue, Guillain-Barre syndrome (GBS), myelitis; and central nervous system (CNS) including stroke, myasthenia gravis (MG), encephalopathy/encephalitis, altered mental status (AMS), decreased appetite and headache. Statistical heterogeneity was quantified using I2 statistics and publication bias was assessed with Eggers regression test. The estimates were reported as odds Ratio (OR) with 95% confidence intervals (CI) using random effect model. Results: A total of 2,876 full text articles retrieved in the initial database search were analyzed according to PRISMA guidelines. The final analysis included 39 trials, evaluating 10,595 patients in the control arm and 13,110 patients in the immunotherapy arm. All-grade neurotoxicity events with ICI were significantly lower compared to placebo or standard of care (OR 0.55, 95% CI 0.38-0.81, I2 96.82%, P < 0.001). Only significant CNS irAE observed was fatigue (OR 0.82, CI 0.71-0.96, I2 81.75%, P < 0.001). Other CNS irAE including AMS (OR 1.318, 95% CI 0.86-2.0, I2 0%, P = 0.442), encephalopathy/encephalitis (OR 1.36, 95% CI 0.38-4.96, I2 0%, P = 0.82) and seizures (OR 1.96, 95% CI 0.64-6.02, I2 0%, P = 0.56) had statistically non-significant increased risk in ICI group. Only one case of myelitis was reported in placebo group. The ICI arm had statistically significant lower rates of PeN (OR 0.28, CI 0.16-0.49, I2 87.31, P < 0.001). One trial reported 1 patient with MG and 5 trials reported 1 patient each of GBS in the ICI arm. Conclusions: Our meta-analysis concludes that use of ICI is associated with lower rate of neurotoxicity overall. Fatigue and PeN are lower with ICI compared to standard of care or placebo. Although, CNS irAE are increased with ICI, they do not reach statistical significance.

Coinheritance of the HR2 Haplotype in the Factor V Gene Confers an Increased Risk of Venous Thromboembolism to Carriers of Factor V R506Q (Factor V Leiden)

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3062-3066 ◽  
Author(s):  
E.M. Faioni ◽  
F. Franchi ◽  
P. Bucciarelli ◽  
M. Margaglione ◽  
V. De Stefano ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Family Members ◽  
Factor V Leiden ◽  
Protein S ◽  
Fold Increase ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Multicenter Cohort Study ◽  
Vein Thrombosis ◽  
Increased Risk

With the aim of establishing whether the HR2 haplotype in factor V affects the risk of venous thromboembolism, a retrospective multicenter cohort study was performed in 810 family members identified through 174 probands who suffered from at least 1 episode of deep vein thrombosis and/or pulmonary embolism and had an inherited defect associated with thrombophilia (antithrombin, protein C, or protein S deficiency; factor V R506Q or prothrombin G20210A). Fifty-eight percent (468/810) of the family members had an inherited defect and 10% (47/468) were symptomatic. The HR2 haplotype was found in association with factor V R506Q more frequently in family members with venous thromboembolism (18%) than in those without (8%). Double heterozygosity for factor V R506Q and HR2 conferred a 3- to 4-fold increase in the relative risk of venous thromboembolism compared with factor V R506Q alone. The median age at first event was lower when the 2 defects were associated (46v 52 years). No increase in risk of venous thromboembolism could be demonstrated when the HR2 haplotype was associated with inherited thrombophilic defects other than factor V R506Q. Because both factor V R506Q and the HR2 haplotype are very frequent, the effect of their coinheritance on the risk of venous thromboembolism might represent a clinically relevant issue, and screening for HR2 in carriers of factor V R506Q should be considered.

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