Cancer-Associated Thrombosis: Management of a Patient With an Isolated Calf Deep Vein Thrombosis.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Venous thromboembolism occurs frequently in patients with cancer and is the second leading cause of death, after the cancer itself. There is a well-established consensus of the need for anticoagulation in patients with a proximal deep vein thrombosis or pulmonary embolism. But with improved imaging technology and widescale use of contrast imaging for cancer staging, many incidental pulmonary emboli are detected in patients with cancer. Furthermore, many isolated distal deep vein thromboses and subsegmental pulmonary emboli are identified. There have been questions if these small or asymptomatic thromboses require anticoagulation management similar to more proximal or symptomatic thromboses. In this Oncology Grand Rounds, we will review the existing evidence for these situations. We will also review management strategies for cancer-associated thrombosis, reflecting the evolving drugs and evidence over the past 20 years.

British Royalty and Aristocracy: Their skin maladies Part II. Queen Mary II's death from hemorrhagic smallpox.

In 1694, Queen Mary II (1662-1694) died at age 32 of hemorrhagic smallpox, a rare and fatal form of the viral infection. This contribution presents the clinical features of Queen Mary II's smallpox infection. It also reviews, from a modern-day perspective, the disseminated intravascular coagulopathy involved in the pathophysiology of hemorrhagic smallpox, which is characterized by thrombocytopenia, coagulation factor deficiency, and hypofibrinogenemia.

Thrombosis with thrombocytopenia syndrome: A database review of clinical trial and post-marketing experience with Ad26.COV2.S.

BACKGROUND: Thrombosis with thrombocytopenia syndrome (TTS) is a very rare disorder described after vaccination with adenoviral vector-based COVID-19 vaccines. Co-occurring thrombosis with thrombocytopenia reported after vaccination can be a proxy for identification of TTS. METHODS: Descriptive database review of all cases of co-occurring (within 42 days) thrombosis with thrombocytopenia in participants in Ad26.COV2.S clinical trials or recipients of Ad26.COV2.S in real-world clinical practice. Cases were retrieved from Janssens' clinical trial and Global Medical Safety databases. RESULTS: There were 34 cases of co-occurring thrombosis with thrombocytopenia in Ad26.COV2.S recipients (46 per 100,000 person-years) and 15 after placebo (75 per 100,000 person-years) in clinical trials. Among Ad26.COV2.S recipients, mean age at the time of the event was 63 years (range 25-85), 82 % were male, mean time-to-onset 112 days (range 8-339) post-last Ad26.COV2.S dose, 26 events occurred post-dose-1, and 7 within a 28-day risk window post-vaccination. Diagnostic certainty was evaluated using Brighton Collaboration, US Centers for Disease Control and Prevention, and European Medicines Agency Pharmacovigilance Risk Assessment Committee case definitions. One case met the highest level of diagnostic certainty for all 3 definitions. There were 355 spontaneous reports of co-occurring thrombosis with thrombocytopenia in the Global Medical Safety database, 47 % males, 85 % within 28-days after vaccination. Twenty-seven cases met the highest level of diagnostic certainty for all definitions, 21 female, 19 with cerebral venous sinus thrombosis, age-range 18-68 years. Time-to-onset was 7-14 days post-vaccination in 20 cases. There were 8 fatalities. CONCLUSION: TTS induced by Ad26.COV2.S is very rare. Most co-occurring thrombosis with thrombocytopenia does not constitute TTS.

Treatment of Cancer-Associated Thrombosis: Recent Advances, Unmet Needs, and Future Direction.

Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE.

A tumor-selective adenoviral vector platform induces transient antiphospholipid antibodies, without increased risk of thrombosis, in phase 1 clinical studies.

Tumor-selective viruses are a novel therapeutic approach for treating cancer. Tumor-Specific Immuno Gene Therapy (T-SIGn) vectors are tumor-selective adenoviral vectors designed to express immunomodulatory transgenes. Prolonged activated partial thromboplastin time (aPTT), associated with the presence of antiphospholipid antibodies (aPL), has been observed in patients with viral infections, and following administration of adenovirus-based medicines. aPL may be detected as lupus anticoagulant (LA), anti-cardiolipin (aCL) and/or anti-beta 2 glycoprotein antibodies (aß2GPI). No subtype alone is definitive for development of clinical sequalae, however, patients who are 'triple positive' have a greater thrombotic risk. Additionally, isolated aCL and aß2GPI IgM do not appear to add value in thrombotic association to aPL positivity, rather IgG subtypes must also be present to confer an increased risk. Here we report induction of prolonged aPTT and aPL in patients from eight Phase 1 studies who were treated with adenoviral vectors (n = 204). Prolonged aPTT (≥ Grade 2) was observed in 42% of patients, with a peak at 2-3 weeks post-treatment and resolution within ~ 2 months. Among patients with aPTT prolongation, LA, but not aCL IgG nor aß2GPI IgG, was observed. The transience of the prolongation and discordance between positive LA and negative aCL/aß2GPI IgG assays is not typical of a prothrombotic state. Among the patients with prolonged aPTT there was no evidence of an increased rate of thrombosis. These findings elucidate the relationship between viral exposure and aPL in the context of clinical trials. They suggest a framework in which hematologic changes can be monitored in patients receiving similar treatments.Clinical trial registration:NCT02028442, NCT02636036, NCT02028117, NCT03852511, NCT04053283, NCT05165433, NCT04830592, NCT05043714.

Open-label pilot study of romiplostim for thrombocytopenia after autologous hematopoietic cell transplantation.

There are no standard treatments to prevent or hasten the recovery from severe conditioning-regimen-induced thrombocytopenia occurring after autologous hematopoietic cell transplantation (auto-HCT). We conducted an open-label, single-arm pilot study of romiplostim, a thrombopoietin receptor agonist, to enhance platelet recovery in patients with multiple myeloma or lymphoma undergoing auto-HCT. All patients were treated weekly with romiplostim starting day +1 after auto-HCT until the platelet count was >50 × 109/L without transfusion. Compared with contemporary retrospective data from romiplostim-naïve patients (N = 853), romiplostim-treated patients (N = 59) had a similar median number of days of grade 4 thrombocytopenia or days requiring transfusions, time to platelet engraftment, and number of platelets transfusions during the auto-HCT. However, romiplostim-treated patients had enhanced platelet recovery to normal values beginning at approximately day +15. In matched cohort multivariable analyses, romiplostim treatment was associated with higher platelet counts by an average of 40 × 109/L (95% confidence interval (CI) (14, 67), P = .003) and 118 × 109/L (95% CI [84, 152], P<.001) at days +21 and +30, respectively, compared with those of no romiplostim. Only 1 adverse event was deemed possibly attributable to romiplostim: a low-risk pulmonary embolism in a patient with multiple myeloma. In conclusion, romiplostim showed promising activity and safety after auto-HCT, but the improvement in platelet counts occurred later than the goal of shortening the duration and depth of the platelet nadir. This trial was registered at www.clinicaltrials.gov (#NCT04478123).

Occult recurrent breast cancer masquerading as thrombotic thrombocytopenic purpura.

GATA3 immunohistochemistry stain of the bone marrow biopsy required to diagnose recurrent metastatic breast cancer.

Systematic literature review and meta-analysis on use of Thrombopoietic agents for chemotherapy-induced thrombocytopenia.

BACKGROUND: Currently, there are no approved options to prevent or treat chemotherapy-induced thrombocytopenia (CIT). We performed a systematic literature review and meta-analysis on use of thrombopoietic agents for CIT. PATIENTS AND METHODS: We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, EMBASE, ClinicalTrials.gov, and health technology assessments from January 1995 to March 2021 for studies evaluating thrombopoietic agents for CIT, including recombinant human thrombopoietin (rhTPO), megakaryocyte growth and development factor (MGDF), romiplostim, and eltrombopag. Random effects meta-analyses were conducted for efficacy and safety endpoints. RESULTS: We screened 1503 titles/abstracts, assessed 138 articles, and abstracted data from 39 publications (14 recombinant human thrombopoietin, 7 megakaryocyte growth and development factor, 9 romiplostim, 8 eltrombopag, and 1 romiplostim/eltrombopag). Random effects meta-analyses of data from multiple studies comparing thrombopoietic agents versus control (comparator, placebo, or no treatment) showed that thrombopoietic agents did not significantly improve chemotherapy dose delays and/or reductions (21.1% vs 40.4%, P = 0.364), grade 3/4 thrombocytopenia (39.3% vs 34.8%; P = 0.789), platelet transfusions (16.7% vs 31.7%, P = 0.111), grade ≥ 2 bleeding (6.7% vs 16.5%; P = 0.250), or thrombosis (7.6% vs 12.5%; P = 0.131). However, among individual studies comparing thrombopoietic agents with placebo or no treatment, thrombopoietic agents positively improved outcomes in some studies, including significantly increasing mean peak platelet counts (186 x 109/L with rhTPO vs 122 x 109/L with no treatment; P < 0.05) in one study and significantly increasing platelet count at nadir (56 x 109/L with rhTPO vs 28 x 109/L with not treatment; P < 0.05) in another study. Safety findings included thrombosis (n = 23 studies) and bleeding (n = 11), with no evidence of increased thrombosis risk with thrombopoietic agents. CONCLUSION: Our analyses generate the hypothesis that thrombopoietic agents may benefit patients with CIT. Further studies with well-characterized bleeding and platelet thresholds are warranted to explore the possible benefits of thrombopoietic agents for CIT.

Implementing a Clinical Decision Tool to Improve Oncologic Venous Thromboembolism Management.

Background: Cancer patients with venous thromboembolic (VTE) disease are complex, and many factors must be considered when initiating anticoagulation management. Clinical decision support systems can aid in decision-making by utilizing guidelines at the point of care. Objectives: The purpose of our project was to develop, implement, and evaluate an electronic clinical decision tool (CDT) utilizing evidence-based guidelines to aid in decision-making for adult oncologic patients who present with new VTE to symptom care clinics. Methods: We compared a pre-intervention group of patients who were prescribed anticoagulation (n = 98) with two post-intervention groups: CDT applied (n = 96) and not applied (n = 46). Outcomes included whether the CDT anticoagulation recommendations were followed and if the tool was perceived to be helpful or improve confidence in initiating management for new VTE by the SCC advanced practitioners and physicians. Results: There was no significant difference between the pre- and post-intervention groups in how many of the CDT anticoagulation recommendations were followed (68.8% pre-intervention, 60.8% post-intervention tool applied, and 63.5% post-intervention tool not applied; χ2 [2, N = 161] = .921, p = .631). However, the tool was found to be helpful and improved confidence of the providers in initiating management for new VTE (pre median = 3, interquartile range [IQR] = 2, 3.5; post median = 3, IQR 3, 4; p = .033). Conclusion: This CDT provided evidence-based anticoagulation recommendations for cancer-associated VTE and enhanced familiarity with the standard of care. Further development of the CDT will be required to account for situations that resulted in deviation from the recommendations.

Standardization of risk prediction model reporting in cancer-associated thrombosis: Communication from the ISTH SSC subcommittee on hemostasis and malignancy.

Since the development of the Khorana score to predict risk of cancer-associated venous thromboembolism (VTE), many modified and de novo risk prediction models (RPMs) have been proposed. Comparison of the prognostic performance across models requires comprehensive reporting and standardized methods for model development, validation and evaluation. To improve the standardization of RPM reporting, the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) tool was published in 2015. To better understand the quality of reporting and development of RPMs for cancer-associated VTE, we performed a literature search of published RPMs and assessed each model using the TRIPOD checklist. Our results yielded 29 RPMs for which 30 items were evaluated. There was a non-significant (p = 0.15) improvement in reporting of the 30 items in the post-TRIPOD era (81%) versus the pre-TRIPOD era (75%). Of seven items (title, sample size, missing data handling, baseline demographics, methods and results for model performance, and supplemental resources) with the lowest reporting in the pre-TRIPOD era (<70%), there was an average improvement of 22% in the post-TRIPOD era. Only two of the 22 studies published in the post-TRIPOD era acknowledged compliance with TRIPOD. Informed by the results of this assessment, the Scientific and Standardization Committee (SSC) Subcommittee on Hemostasis & Malignancy of the International Society on Thrombosis and Hemostasis (ISTH) advocates for standardization of four key elements of RPMs for cancer-associated VTE: (1) inclusion of the TRIPOD checklist, (2) clear definition of the derivation population, with justification of sample size, (3) clear definition of predictors, and (4) external validation prior to implementation.

Romiplostim for chemotherapy-induced thrombocytopenia: Efficacy and safety of extended use.

Background: Chemotherapy-induced thrombocytopenia (CIT) is common during treatment with antineoplastic therapies and may adversely impact chemotherapy dose intensity. There is no approved therapy for CIT. In our recent phase II randomized study, romiplostim led to correction of platelet counts in 85% of treated patients and allowed resumption of chemotherapy, with low rates of recurrent CIT in the first two cycles or 8 weeks of chemotherapy. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT. Objectives: To analyze efficacy and safety of romiplostim in the patients in the phase 2 study, who received romiplostim for ≥1 year. Patients/Methods: Twenty-one patients remained on romiplostim for ≥1 year. We analyzed the effect of romiplostim on platelet counts, absolute neutrophil counts, and hemoglobin, as well as impact on ongoing chemotherapy. We also tracked venous or arterial thrombotic events. Results: During the study period, romiplostim was effective in preventing reduction of chemotherapy dose intensity due to CIT. Fourteen of the 20 (70%) analyzable patients experienced no episode of CIT, 4 subjects experienced a single chemotherapy dose delay due CIT, and 2 patients required a chemotherapy dose reduction. Platelet counts were preserved throughout the duration of the extension analysis. One patient experienced a proximal deep vein thrombosis, and one patient experienced multiple tumor-related ischemic events. Conclusions: Long-term use of romiplostim for treatment of CIT was effective and safe, with no evidence of resistance or increased risk of thrombosis.

Chemotherapy-induced thrombocytopenia in pediatric oncology: Scope of the problem and opportunities for intervention.

BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is a known hematologic complication of oncology treatment. This single-institution study examines the degree with which CIT impacts specific pediatric solid tumor cohorts reflected by platelet transfusion burden and treatment modifications. PROCEDURE: Data regarding clinically relevant CIT were obtained via a retrospective chart review of pediatric solid tumor patients treated at Memorial Sloan Kettering Cancer Center from 2013 to 2020. Patients were stratified based on histologic diagnoses as well as chemotherapy regimen. CIT impact was assessed through platelet transfusion means, chemotherapy dose reductions, and treatment delays. RESULTS: A total of 150 patients were included with mean age 10.3 [0.2-21.0]. Patients receiving therapy for high-risk neuroblastoma and localized Ewing sarcoma, both of which included high-dose cyclophosphamide and doxorubicin, required the most platelet transfusions over the treatment course, with a mean of 13 and 9, respectively. Reduced relative dose intensity (RDI), due in part to CIT, was greatest for the patients receiving therapy for high-risk and intermediate-risk rhabdomyosarcoma. Fifty-six percent of high-risk patients experienced a reduced RDI during the final two cycles of treatment and 69% of intermediate-risk patients experienced one during the final four cycles of treatment. CONCLUSIONS: The impact of CIT varied by the administered chemotherapy regimens and dose intensity of chemotherapy agents. This study demonstrated that CIT causes both marked platelet transfusion burden as well as treatment reduction and delay within certain solid tumor cohorts. This can lend to future studies aimed at reducing the burden of CIT and targeting the most at-risk populations.

Rivaroxaban thromboprophylaxis for gastric/gastroesophageal junction tumors versus other tumors: A post hoc analysis of the randomized CASSINI trial.

BACKGROUND: Prophylactic anticoagulation with rivaroxaban significantly reduced the risk of cancer-associated thrombosis during the intervention period in the CASSINI trial. Direct oral anticoagulants may increase the risk of gastrointestinal (GI) tract bleeding in patients with an in situ GI tract cancer or lesion. OBJECTIVE: This post hoc analysis characterized the efficacy and safety of rivaroxaban in patients with and without gastric/gastroesophageal junction (G/GEJ) tumors. METHODS: Primary and secondary efficacy end points and adjudicated bleeding events, including bleeding sites, were analyzed for the intent-to-treat population by cancer type (G/GEJ vs non-G/GEJ) for the 180-day observation period. RESULTS: In patients with G/GEJ tumors, the rates for the primary efficacy end point were 3.4% for rivaroxaban versus 6.9% for placebo (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.11-1.80). In patients with non-G/GEJ tumors, the rivaroxaban group had a lower risk of the primary end point (6.6% vs 9.3%; HR, 0.70; 95% CI, 0.40-1.21). Rates of major bleeding in patients with G/GEJ tumors were 4.6% (4/88) versus 1.2% (1/85) for rivaroxaban and placebo; rates in patients with non-G/GEJ tumors were 1.3% (4/317) versus 0.9% (3/319), respectively. CONCLUSIONS: Excluding patients with G/GEJ tumors resulted in a definable population of cancer patients who achieved an improved benefit-risk balance from rivaroxaban prophylaxis.

Risk of venous thromboembolism in ovarian cancer patients receiving neoadjuvant chemotherapy.

PURPOSE: To determine the incidence of venous thromboembolism (VTE) and define clinical risk factors associated with the development of new-onset VTE in patients receiving neoadjuvant chemotherapy (NACT) for ovarian cancer (OC). METHODS: An institutional ovarian cancer database was used to identify all OC patients receiving NACT from 04/2015-09/2018. VTE events were recorded and included clinically diagnosed deep venous thrombosis (DVT) and/or pulmonary embolism (PE). The incidence of VTE events was categorized according to treatment phases (P): P0) First visit/prior to induction of NACT; P1) during NACT before interval debulking surgery (IDS); P2) intraoperative through day 28 post-IDS; P3) during adjuvant chemotherapy. RESULTS: A total of 290 patients were identified during the study period. Seventy-five (25.9%) developed a VTE at some point from time of presentation through the peri-operative period. Forty (13.8%) presented with VTE prior to initiation of NACT. An additional 27 (11.6%) developed a VTE during NACT (P1); 6 (3.9%) during the intraoperative and 28-day post-operative period (P2); and 2 (1.3%) during the adjuvant period (P3). The overall VTE rate was 25.9% (n = 75). FIGO stage IV disease was the only factor associated with increased risk for a new-onset VTE [Odds Ratio (OR): 3.9 (95% Confidence Interval [CI] = 1.2-13.6; p = 0.03]. CONCLUSIONS: Patients receiving NACT for advanced OC are at extremely high risk for developing thromboembolic events, either at initial presentation or during induction of NACT, a treatment phase that is traditionally without use of prophylactic anticoagulation. Since Khorana scoring is not predictive in this population, clinicians might need to consider increased screening or use of prophylactic anticoagulation in patients receiving NACT for OC, particularly in advanced metastatic disease.

Mechanisms of Ischemic Stroke in Patients with Cancer: A Prospective Study.

OBJECTIVE: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer. METHODS: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests. RESULTS: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005). INTERPRETATION: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.

Clinical challenges and promising therapies for chemotherapy-induced thrombocytopenia.

Introduction: Chemotherapy-induced thrombocytop enia (CIT) is a common complication of cancer treatment causing chemotherapy delays, dose reductions, and treatment discontinuation, negatively impacting treatment outcomes and putting patients at risk for bleeding complications. There is no FDA-approved agent available to manage CIT.Areas covered: This article covers the diagnosis, definitions, and clinical challenges of CIT, and then focuses on the therapeutics developed to manage CIT. The first-generation thrombopoietic agents (oprelvekin and recombinant human thrombopoietins) are reviewed for critical background and context, followed by a detailed discussion of the data for the thrombopoietin receptor agonists (TPO-RAs) to manage CIT. Efficacy of TPO-RAs in treatment and prevention of CIT, as well as safety concerns such as the risk of thromboembolic complications, are reviewed in detail. For this review, a PubMed/MEDLINE literature search was undertaken for relevant articles published from 1995-2021.Expert opinion: After over two decades of drug development for CIT, multiple clinical trials and observational studies have found TPO-RAs, in particular romiplostim, to be safe and effective agents to manage patients with CIT, although no agent is yet FDA-approved for this indication. Active management of CIT with TPO-RAs is likely to improve oncologic outcomes, although additional data are needed. Phase 3 trials are ongoing.

The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies.

OBJECTIVES: To estimate the risk of thrombocytopenia in various cancers and chemotherapy regimens. METHODS: Structured patient-level data from the Flatiron Health Electronic Health Record database were used to identify adult patients who received chemotherapy for a solid tumor or hematologic malignancy from 2012 to 2017. Three-month cumulative incidence of thrombocytopenia was assessed based on platelet counts, overall and by grade of thrombocytopenia. Co-occurrence of anemia, neutropenia, and leukopenia was evaluated. RESULTS: Of 15,521 patients with solid tumors, 13% had thrombocytopenia within 3 months (platelet count < 100 × 109 /L); 4% had grade 3 (25 to < 50 × 109 /L), and 2% grade 4 (<25 × 109 /L) thrombocytopenia. Of 2537 patients with hematologic malignancies, 28% had any thrombocytopenia, 16% with grade 3, and 12% with grade 4. Among patients with thrombocytopenia, it occurred without another cytopenia in 18% of solid tumors and 7% of hematologic malignancies. CONCLUSIONS: In a large, US-representative sample of patients undergoing chemotherapy in clinical practice, thrombocytopenia incidence varied across tumor and regimen types. Despite recommendations to alter chemotherapy to avoid severe thrombocytopenia, 4% of patients with solid tumors and 16% with hematologic malignancies experienced grade 3 thrombocytopenia. Prediction and prevention of thrombocytopenia may help oncologists avoid dose modifications and their adverse effects on survival.

Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors.

Venous thromboembolism (VTE) associated with cancer (CAT) is a well-described complication of cancer and a leading cause of death in patients with cancer. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14 000 solid tumor samples using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform to identify somatic alterations associated with VTE. End point was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis. Cause-specific Cox proportional hazards regression was used, adjusting for pertinent clinical covariates. Of 11 695 evaluable individuals, 72% had metastatic disease at time of analysis. Tumor-specific mutations in KRAS (hazard ratio [HR], 1.34; 95% confidence interval (CI), 1.09-1.64; adjusted P = .08), STK11 (HR, 2.12; 95% CI, 1.55-2.89; adjusted P < .001), KEAP1 (HR, 1.84; 95% CI, 1.21-2.79; adjusted P = .07), CTNNB1 (HR, 1.73; 95% CI, 1.15-2.60; adjusted P = .09), CDKN2B (HR, 1.45; 95% CI, 1.13-1.85; adjusted P = .07), and MET (HR, 1.83; 95% CI, 1.15-2.92; adjusted P = .09) were associated with a significantly increased risk of CAT independent of tumor type. Mutations in SETD2 were associated with a decreased risk of CAT (HR, 0.35; 95% CI, 0.16-0.79; adjusted P = .09). The presence of clonal hematopoiesis was not associated with an increased VTE rate. This is the first large-scale analysis to elucidate tumor-specific genomic events associated with CAT. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B, and MET were associated with an increased risk of VTE in patients with solid tumors. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types.