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Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays ('liquid biopsies') are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30-0.81); ctDNA- patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40-2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer.
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Objective: Romiplostim is used to treat chemotherapy-induced thrombocytopenia in a variety of tumor types; however, few studies have examined its use in breast and gynecologic cancers. We evaluated platelet response and durability of response to romiplostim in patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia. Methods: We retrospectively identified 33 patients with gynecologic or breast cancer who received romiplostim between 07/1/2021-07/31/2022 at an academic cancer center. Results: Thirty-three patients met inclusion criteria; 26 (79 %) had breast cancer, 4 (12 %) had ovarian cancer, and 3 (9 %) had endometrial cancer. Twenty patients (61 %) experienced treatment delays and 12 (36 %) required dose reductions prior to starting romiplostim for chemotherapy-induced thrombocytopenia, with some patients experiencing both. Eleven patients (33 %) did not undergo a dose reduction or delay prior to initiation of romiplostim. Median platelet count prior to romiplostim therapy was 53 k/mcL (range, 40.5-78.8). Median platelet count within 3 weeks following initiation of romiplostim was 147 k/mcL (range, 31-562). Twenty-one patients (64 %) achieved platelet correction within 3 weeks, of whom 10 (48 %) resumed anticancer therapy and maintained platelet levels above 100 k/mcL at 8 weeks. Twelve patients did not achieve platelet correction within 3 weeks of romiplostim initiation; 4 (33 %) required a treatment change secondary to persistent thrombocytopenia, 3 (25 %) required a treatment dose reduction, 3 (25 %) were deemed too ill to continue therapy, and 2 (17 %) required a treatment delay. Conclusions: Romiplostim facilitated the resumption of anticancer therapy in 64 % of patients with gynecologic or breast cancer complicated by chemotherapy-induced thrombocytopenia.
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Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.
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ABSTRACT: Venous thromboembolism (VTE) is a leading cause of preventable in-hospital mortality. Monitoring VTE cases is limited by the challenges of manual medical record review and diagnosis code interpretation. Natural language processing (NLP) can automate the process. Rule-based NLP methods are effective but time consuming. Machine learning (ML)-NLP methods present a promising solution. We conducted a systematic review and meta-analysis of studies published before May 2023 that use ML-NLP to identify VTE diagnoses in the electronic health records. Four reviewers screened all manuscripts, excluding studies that only used a rule-based method. A meta-analysis evaluated the pooled performance of each study's best performing model that evaluated for pulmonary embolism and/or deep vein thrombosis. Pooled sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with confidence interval (CI) were calculated by DerSimonian and Laird method using a random-effects model. Study quality was assessed using an adapted TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) tool. Thirteen studies were included in the systematic review and 8 had data available for meta-analysis. Pooled sensitivity was 0.931 (95% CI, 0.881-0.962), specificity 0.984 (95% CI, 0.967-0.992), PPV 0.910 (95% CI, 0.865-0.941) and NPV 0.985 (95% CI, 0.977-0.990). All studies met at least 13 of the 21 NLP-modified TRIPOD items, demonstrating fair quality. The highest performing models used vectorization rather than bag-of-words and deep-learning techniques such as convolutional neural networks. There was significant heterogeneity in the studies, and only 4 validated their model on an external data set. Further standardization of ML studies can help progress this novel technology toward real-world implementation.
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Aprendizado de Máquina , Processamento de Linguagem Natural , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Registros Eletrônicos de SaúdeRESUMO
ABSTRACT: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.
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Hematopoiese Clonal , Neoplasias Hematológicas , Humanos , Idoso , Hematopoese/genética , Mutação , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , GenótipoRESUMO
Venous thromboembolism (VTE) is a common and impactful complication of cancer. Several clinical prediction rules have been devised to estimate the risk of a thrombotic event in this patient population, however they are associated with limitations. We aimed to develop a predictive model of cancer-associated VTE using machine learning as a means to better integrate all available data, improve prediction accuracy and allow applicability regardless of timing for systemic therapy administration. A retrospective cohort was used to fit and validate the models, consisting of adult patients who had next generation sequencing performed on their solid tumor for the years 2014 to 2019. A deep learning survival model limited to demographic, cancer-specific, laboratory and pharmacological predictors was selected based on results from training data for 23,800 individuals and was evaluated on an internal validation set including 5,951 individuals, yielding a time-dependent concordance index of 0.72 (95% CI = 0.70-0.74) for the first 6 months of observation. Adapted models also performed well overall compared to the Khorana Score (KS) in two external cohorts of individuals starting systemic therapy; in an external validation set of 1,250 patients, the C-index was 0.71 (95% CI = 0.65-0.77) for the deep learning model vs 0.66 (95% CI = 0.59-0.72) for the KS and in a smaller external cohort of 358 patients the C-index was 0.59 (95% CI = 0.50-0.69) for the deep learning model vs 0.56 (95% CI = 0.48-0.64) for the KS. The proportions of patients accurately reclassified by the deep learning model were 25% and 26% respectively. In this large cohort of patients with a broad range of solid malignancies and at different phases of systemic therapy, the use of deep learning resulted in improved accuracy for VTE incidence predictions. Additional studies are needed to further assess the validity of this model.
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Background: Patients with cancer have an increased risk for arterial thromboembolism (ATE). Scant data exist about the impact of cancer-specific genomic alterations on the risk for ATE. Objectives: The aim of this study was to determine whether individual solid tumor somatic genomic alterations influence the incidence of ATE. Methods: A retrospective cohort study was conducted using tumor genetic alteration data from adults with solid cancers who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets testing between 2014 and 2016. The primary outcome, ATE, was defined as myocardial infarction, coronary revascularization, ischemic stroke, peripheral arterial occlusion, or limb revascularization and identified through systematic electronic medical record assessments. Patients were followed from date of tissue-matched blood control accession to first ATE event or death, for up to 1 year. Cause-specific Cox proportional hazards regression was used to determine HRs of ATE for individual genes adjusted for pertinent clinical covariates. Results: Among 11,871 eligible patients, 74% had metastatic disease, and there were 160 ATE events. A significantly increased risk for ATE independent of tumor type was noted for the KRAS oncogene (HR: 1.98; 95% CI: 1.34-2.94; multiplicity-adjusted P = 0.015) and the STK11 tumor suppressor gene (HR: 2.51; 95% CI: 1.44-4.38; multiplicity-adjusted P = 0.015). Conclusions: In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS and STK11 were associated with an increased risk for ATE independent of cancer type. Further investigation is needed to elucidate the mechanism by which these mutations contribute to ATE in this high-risk population.
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Cancer has long been known to incur an increased risk of venous thromboembolism (VTE). Multiple risk factors for cancer-associated thrombosis (CAT) have been identified, and several pathophysiological mechanisms elucidated. However, until recently there was scant data available about the influence of cancer-specific somatic genetic alterations on the risk of venous thromboembolism. In the last few years, several gene loci were found to modulate the risk of CAT, usually causing an increase in risk but sometimes found to have a protective effect. Notably, cancer-specific somatic genetic alterations in KRAS, IDH1, ALK and ROS1 have been found to alter the risk of CAT by independent groups. Work in this field is limited by the high-dimensionality and often sparse nature of genomic datasets. Also, early data suggest that for certain genes the effect on VTE risk can be tumor type-specific, which suggests that predictive models must factor such interactions in order to optimally leverage genetic information. Notably, individual gene effects appear to be often small and no one gene explains most of the variability of CAT risk. Ultimately, improved knowledge of the genetic determinants of CAT will help ameliorate risk stratification for this complication and hopefully provide mechanistic insights. Better risk stratification could lead to enhanced pharmacological VTE prophylaxis, while advancements in the understanding of the biology of CAT could conceivably lead to non-anticoagulant targeted therapies for thrombosis.
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Neoplasias , Trombose , Tromboembolia Venosa , Humanos , Neoplasias/complicações , Neoplasias/genética , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas p21(ras) , Receptores Proteína Tirosina Quinases , Medição de Risco , Fatores de Risco , Trombose/complicações , Tromboembolia Venosa/etiologiaRESUMO
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.
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Interventions for thrombotic and nonthrombotic venous disorders have increased with technical advances and more trained venous specialists. Antithrombotic therapy is essential to clinical and procedural success; however, postprocedural therapeutic regimens exhibit significant heterogeneity due to limited prospective randomized data and incomplete mechanistic understanding of the critical factors driving long-term patency. Postinterventional antithrombotic therapy for thrombotic venous disorders should adhere to existing venous thromboembolism management guidelines, which include 3-6 months of therapeutic anticoagulation at minimum and consideration of extended therapy in patients with higher risk of thrombosis because of procedural or patient factors. The added benefit of antiplatelet agents in the acute and intermediate period is unknown, having shown improved long-term stent patency in some retrospective studies. Dual- and/or triple-agent therapy should be limited based on individual risks of thrombosis and bleeding. The treatment of nonthrombotic disorders is more heterogeneous, though patients with limited flow, extensive stent material, or underlying prothrombotic states such as malignancy or chronic inflammation may benefit from single-agent or multiagent antithrombotic therapy. However, the agent, dose, and duration of therapy remain indeterminate. Future prospective studies are warranted to improve patient risk stratification and standardize postprocedural anti-thrombotic therapy in patients receiving venous interventions.
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Doenças Vasculares , Trombose Venosa , Fibrinolíticos/uso terapêutico , Humanos , Veia Ilíaca/patologia , Estudos Retrospectivos , Stents , Resultado do Tratamento , Grau de Desobstrução Vascular , Trombose Venosa/patologiaRESUMO
Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.
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Aberrações Cromossômicas , Evolução Clonal/genética , Hematopoiese Clonal/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Hematológicas/genética , Humanos , Pessoa de Meia-Idade , Mosaicismo , Neoplasias/genética , Medição de Risco , Seleção Genética , Adulto JovemRESUMO
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.
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Neoplasias/complicações , Tromboembolia Venosa/etiologia , Idoso , Predisposição Genética para Doença , Genômica , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Fatores de Risco , Tromboembolia Venosa/genéticaRESUMO
Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
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Hematopoiese Clonal/genética , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/efeitos da radiação , Criança , Pré-Escolar , Evolução Clonal , Hematopoiese Clonal/efeitos dos fármacos , Estudos de Coortes , Feminino , Aptidão Genética , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Seleção Genética , Adulto JovemAssuntos
Afibrinogenemia , Coagulação Intravascular Disseminada , Leucemia-Linfoma Linfoblástico de Células Precursoras , Afibrinogenemia/complicações , Afibrinogenemia/diagnóstico , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/etiologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
PURPOSE: Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS: We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/µL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/µL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS: The mean platelet count at enrollment was 62,000/µL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/µL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/µL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION: This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.
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Antineoplásicos/efeitos adversos , Plaquetas/efeitos dos fármacos , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Contagem de Plaquetas , Estudos Prospectivos , Proteínas Recombinantes de Fusão/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombopoetina/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Cancer can be associated with several distinct coagulation defects which can lead to bleeding complications. The primary hyperfibrinolytic syndrome associated with acute promyelocytic leukemia has been well recognized and is one of the most severe bleeding disorders. Acquired hemophilia, while rare and not only seen in the oncology setting, can be triggered by a malignancy and must be promptly recognized in order to prevent catastrophic hemorrhage. Other, less serious coagulopathic states have been linked to cancer, including acquired von Willebrand disease. Finally, several anti-neoplastic drugs can alter hemostasis and increase the risk of bleeding. A good understanding of this field can help mitigate the risk of complications in the cancer patient.
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Antineoplásicos/efeitos adversos , Transtornos da Coagulação Sanguínea/etiologia , Neoplasias/complicações , Antineoplásicos/uso terapêutico , Transtornos da Coagulação Sanguínea/induzido quimicamente , Hemorragia/induzido quimicamente , Hemorragia/etiologia , Hemostasia/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Low-molecular-weight heparin has been the preferred treatment of cancer-associated thrombosis (CAT); however, emerging data support the use of direct oral anticoagulants (DOACs). OBJECTIVES: The Memorial Sloan Kettering Cancer Center Clinical Pathway has served as the institutional guideline for the use of rivaroxaban to treat CAT since 2014. Key elements are to recommend against use of a DOAC in patients with active gastrointestinal (GI) or genitourinary tract lesions, and a prespecified dose reduction in the elderly (75+ years old). We present our institutional experience for treatment of CAT. METHODS: From January 2014 through September 2016, 1072 patients began rivaroxaban treatment for CAT; 91.9% had a solid tumor, 8.1% had hematologic malignancies, and 75% of patients with solid tumors had metastatic disease. All patients with CAT treated with rivaroxaban were included in this analysis, regardless of adherence to the Clinical Pathway. RESULTS: The 6-month cumulative incidence of recurrent venous thromboembolism and major bleeding were 4.2% (95% confidence interval [CI], 2.7%-5.7%) and 2.2% (95% CI, 1.1%-3.2%), respectively. The incidence of clinically relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days was 5.5% (95% CI, 3.7%-7.1%), and 73.3% of major bleeds occurred in the GI tract. The 6-month cumulative mortality rate was 22.2% (95% CI, 19.4%-24.9%). The elderly had similar rates of recurrent thrombosis and bleeding as those aged under 75 years. CONCLUSION: Our institutional experience suggests that in appropriately selected patients, rivaroxaban may be used for treatment of CAT with promising safety and efficacy.
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Acute promyelocytic leukemia (APL) is associated with a profound coagulopathy. Based on retrospective assessments, several potential risk factors for hemorrhagic morbidity and mortality have emerged. Several studies have shown elevated white blood cell (WBC) count at presentation to be a robust predictor of bleeding events. Other clinical and laboratory parameters have been evaluated with variable association with hemorrhagic morbidity or mortality. These include ECOG performance status, age, morphological subtype, platelet count, peripheral blood blast count, ethnicity, body mass index, prothrombin time, activated partial thromboplastin time, lactate dehydrogenase, d-dimers, creatinine and fibrinogen levels. Unfortunately, most of those assessments were based on a small patient sample and the results have been at times contradictory in terms of which parameters are independent predictors. More recently, two large retrospective studies have reported on the issue. They included data from several international trials of chemotherapy for APL, one on adults and the other focused on the pediatric population. Importantly, both analyses found that WBC count at presentation is the main predictor of early hemorrhagic death and early thrombo-hemorrhagic death, respectively. Much remains to be done if the rate of induction mortality in APL is going to be reduced significantly. One approach would be to incorporate the known risk factors for early hemorrhagic death into a risk stratification system and devise personalized transfusion interventions to meet an individual patient's risk, which could be evaluated in future randomized trials.