Venous thrombosis is an underappreciated adverse event associated with cancer immunotherapy. Roopkumar et al. describe the incidence of venous thrombosis in individuals with cancer receiving immunotherapy and suggest that elevated levels of myeloid-derived suppressor cells, interleukin-8, and soluble vascular cell adhesion molecule 1 before immunotherapy correlate with development of venous thrombosis.
Background Venous thromboembolism (VTE) is known to complicate several classes of anti-cancer therapies including chemotherapy and anti-angiogenic agents. Immunotherapy is a novel and growing approach to systemic treatment of cancer, but little is known about incidence or prevalence of VTE in cancer patients on immunotherapy. The objective of this study was to describe rates of VTE in cancer patients on various immunotherapy regimens. Methods We conducted a single institution, retrospective cohort study at Taussig Cancer Center of the Cleveland Clinic. The study was approved by the institutional review board. The study cohort was created using our center's pharmacy database of patients who received any of the six FDA approved immunotherapy agents (ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab or durvalumab) between July 2015 and December 2017. VTE events including deep venous thrombosis (DVT) and pulmonary embolism (PE) were identified by chart review. Overall survival (OS) was estimated by the Kaplan-Meier method and evaluated for association with VTE following immunotherapy using Cox proportional hazard regression with two-sided Wald test and adjustment for age at diagnosis and presence/absence of metastases. Patients receiving combination therapies were matched 1:3 to patients receiving monotherapy based on demographic and clinical attributes including: gender, race, ethnicity, primary cancer site, age at diagnosis, and stage. The incidence of VTE following immunotherapy was compared between single and combination therapy cohorts using the Pearson chi-squared test. Results The study population comprised 522 patients, of whom a small majority (n=307, 58.8%) were males with a median age at cancer diagnosis of 64 years (range 10 to 91 years). The vast majority of patients (n=463, 88.7%) had metastatic disease. Lung (n= 259, 49.6%) was the most common primary site of cancer. Nivolumab was the most commonly used single drug immunotherapy (n=273, 52.3%) and nivolumab + ipilimumab was the most common multidrug regimen (n=34, 6.5%). VTE occurred in 30.3% of patients (n=158), including DVT in 34.8% (n=55), PE in 34.2% (n=54), DVT+PE in 18.4% (n=29), visceral vein thrombosis in 8.9% (n=14), DVT +PE+ visceral vein in 2.5% (n=4). Using the matched subset of patients receiving single (n=129) and combination (n=43) immunotherapies, the rate of VTE in single vs. combination immunotherapy was 36% vs. 28% (p value = 0.45). VTE in patients on immunotherapy was associated with worse survival, but this association was not statistically significant when adjusting for age and metastases [HR = 1.215, (95%CI 0.94 to 1.55) p value = 0.121]. Conclusions VTE is common in cancer patients receiving immunotherapy either as single-agent or combination regimens, affecting nearly one-third of all patients and may potentially be associated with worsened survival. Further work is necessary to identify pathophysiology, risk factors and benefit of thromboprophylaxis in this setting. Figure. Figure. Disclosures Khorana: Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.
Introduction Thromboembolism (TE) is common in patients with non‐small cell lung cancer (NSCLC) and is associated with worse outcomes. Recent advances in the understanding of NSCLC have led to the identification of molecular subtypes such as anaplastic lymphocyte kinase (ALK) and epidermal growth factor receptor (EGFR) mutations. The association of these subtypes with risk of TE has not been fully explored. Methods We conducted a retrospective cohort study of consecutive NSCLC patients seen at the Cleveland Clinic from July 2002 through July 2017 for whom molecular classification and follow‐up were available. TE events included deep vein thrombosis (DVT), pulmonary embolism (PE), visceral vein thrombosis (VVT), and arterial events. TE‐free survival and overall survival rates for each of the molecular subtypes (wild‐type, ALK‐mutant, and EGFR‐mutant) were estimated by the Kaplan‐Meier method. Cox proportional hazard regression analysis was used to identify factors associated with the endpoints TE and overall survival. TE was analyzed as a conditional, time‐dependent covariate to assess its impact with respect to overall survival. Results The study population consisted of 461 patients. Approximately half were females (n = 263, 57%) and 58% (n = 270) were older than 65 years. TE occurred in 98 of 461 patients (21.3%) during a median follow‐up of 33.1 months. The highest cumulative rates of TE were observed in patients with ALK‐mutant NSCLC (N = 20/46, 43.5%) followed by patients with EGFR‐mutant cancers (N = 35/165, 21.2%) and wild‐type cancers (N = 43/250, 17.2%) P < .05. Cumulative incidence of TE at 6 months of follow‐up was 15.7% (95% confidence interval [CI]: 5.0%‐26.4%) for ALK‐mutant cancers, 8.8% (95% CI: 4.4%‐13.2%) for EGFR‐mutant cancers, and 9.2% (95% CI: 5.4%‐12.9%) for wild‐type cancers. Patients who experienced TE had worse overall survival (all patients: hazard ratio = 2.8 95% CI 2.1‐3.6, P < .001). Conclusions Patients with ALK‐mutant advanced lung adenocarcinoma have the highest rate of TE. TE is associated with worse survival across molecular subtypes. These findings should be taken into consideration in decision‐making regarding thromboprophylaxis.
Hospitalized patients with cancer are at an increased risk of developing venous thromboembolism (VTE). The recommendation for routine pharmacologic thromboprophylaxis in hospitalized patients with cancer to prevent VTE is based on extrapolation of results from noncancer cohorts. There are limited data to support the efficacy and safety of fixed-dose low-molecular-weight heparin (LMWH) regimens in high-risk hospitalized patients with cancer. We conducted a randomized, double-blinded, phase 2 trial in hospitalized patients with active cancer at high risk of developing VTE based on Padua risk score. Patients were randomly assigned to fixed-dose enoxaparin (40 mg daily) vs weight-adjusted enoxaparin (1 mg/kg daily) during hospitalization. The primary objectives were to evaluate the safety of dose-adjusted enoxaparin and evaluate the incidence of VTE with fixed-dose enoxaparin. Blinded clinical assessments were performed at day 14, and patients randomly assigned to fixed-dose enoxaparin subsequently underwent a bilateral lower extremity ultrasound. A total of 50 patients were enrolled and randomized. The median weight of patients enrolled in weight-adjusted enoxaparin arm was 76 kg (range, 60.9-124.5 kg). There were no major hemorrhages or symptomatic VTE in either arm. At time of completion of the blinded clinical assessment, there was only 1 incidentally identified pulmonary embolus that occurred in the weight-adjusted arm. In the group randomly assigned to fixed-dose enoxaparin who subsequently underwent surveillance ultrasound, the cumulative incidence of DVT was 22% (90% binomial confidence interval, 0%-51.3%). This phase 2 trial confirms a high incidence of asymptomatic VTE among high-risk hospitalized patients with cancer and that weight-adjusted LMWH thromboprophylaxis is feasible and well-tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02706249.
e14151 Background: ICIs have revolutionized outcomes in many advanced malignancies, however their use is associated with irAEs. Methods: An IRB-approved, retrospective chart review was done using the Cleveland Clinic pharmacy database. Patients were included who received six FDA approved (nivolumab, ipilimumab, pembrolizumab, atezolizumab, avelumab, or durvalumab) ICIs from July 2015 to December 2017. irAEs were identified from review of electronic medical records. Descriptive analysis was done to evaluate the incidence, pattern, and severity of irAEs. Results: A total of 1091 patients received ICI therapy, 651 (59.7%) were male, 958 (87.4%) white, 95 (8.7%) black. Lung cancer (540, 49.5%) comprised the majority of the cohort, followed by melanoma (152, 13.9%), and renal cell carcinoma (121, 11.1%). About 996 (91.3%) received treatment with only one ICI, 85 (7.8%) with 2 ICIs, and only 10 patients received 3 ICIs. A total of 487 (44.63%) patients encountered irAEs, 128 (11.73%) resulting in treatment cessation. Fatigue (152, 13.9%) was the most common, followed by dermatologic irAEs (131, 12%). Endocrine irAEs occurred in 108 (9.89%), GI toxicities, namely diarrhea and colitis, were seen in 92 (8.4%) and hepatotoxicity in 54 (4.94%). Other irAEs including rheumatologic, pneumonitis, renal, and neurological adverse effects were documented in 6.5%, 5.1%, 2.56%, and 2.01% respectively. Rare irAEs such as ocular toxicity, cardiac toxicity, and vasculitis were seen in 0.8%, 0.73%, and 0.54%, respectively. Compared with a pooled analysis from clinical trials (De Velasco G et al. Comprehensive Meta-analysis of Key irAEs from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients) dermatologic irAEs and fatigue were less frequent; diarrhea/colitis, pneumonitis and rheumatologic irAEs were more frequent. Conclusions: irAEs on ICI therapy are very common. Awareness of the relative frequencies of various irAEs, particularly severe and rare irAEs, in a real-world setting can help improve quality of care for cancer patients receiving ICI. [Table: see text]
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