20457634, 2021, 21, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.4280 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Received: 8 December 2020 | Revised: 14 August 2021 | Accepted: 26 August 2021 DOI: 10.1002/cam4.4280 RESEARCH ARTICLE Incorporating genetic and clinical data into the prediction of thromboembolism risk in patients with lymphoma Mariana Bastos-­Oreiro1,2,3,4 | Javier Ortiz1 | Virginia Pradillo1 | Eduardo Salas5 | Carolina Marínez-­Laperche1,2 | Andrés Muñoz6 | Ismael Buño1,2 | José Luis Diéz-­Martin1,2 | Jose Manuel Soria | Cristina Pascual Izquierdo1,2 7 1 Hematology Department, Hospital General Universitario Gregorio Abstract Marañon, Madrid, Spain Background: The incorporation of genetic variables into risk scores for predict- 2 Gregorio Marañón Health Research ing venous thromboembolic events (VTE) could improve their capacity to identify Institute, Madrid, Spain 3 those patients for whom thromboprophylaxis would be most beneficial. Proof-­ Genomics Unit, Hospital General Universitario. Gregorio Marañón, of-­concept of this is provided by the TiC-­ONCO score for predicting the risk of Madrid, Spain VTE in patients with solid tumours. Our aim was to develop a similarly improved 4 Cell Biology Department, School of tool—­the TiC-­LYMPHO score—­for predicting VTE in patients with lymphoma. Medicine, Universidad Complutense de Methods: In a retrospective observational study of 208 patients with lymphoma, Madrid, Madrid, Spain 5 Gendiag, S.L. Scientific Department, 31 (14.9%) were found to have experienced an episode of VTE either at the time of Barcelona, Spain diagnosis or over the next 6 months. Clinical variables associated with VTE, de- 6 Oncology Department, Hospital termined via logistic regression analysis, plus the same genetic variables included General Universitario Gregorio in the TiC-­ONCO score, were used to build the TiC-­LYMPHO score algorithm. Marañón, Madrid, Spain 7 The sensitivity, specificity, predictive values and AUC of the TiC-­LYMPHO, the Hospital Universitario de la Santa Creu I Santa Pau, Barcelona, Spain Khorana and ThroLy scores were compared in the same population. Results: The TiC-­LYMPHO score showed a significantly higher AUC, sensi- Correspondence Mariana Bastos-­Oreiro, Hematology tivity and NPV (0.783, 95.35% and 97.98% respectively) than the other scores. Department, Hospital General The ThroLy score showed a significantly higher specificity (96.43% vs. 54.49%; Universitario Gregorio Marañon, p < 0.0001) and PPV (37.50% vs. 26.36%; p = 0.0147) than the TiC-­LYMPHO Dr Esquerdo 46, 28007, Madrid, Spain. Email: marianabeatriz.bastos@salud. score, whereas its AUC, sensitivity and NPV were significantly lower (0.579, madrid.org 19.35% and 86.48%, respectively). Conclusion: These results show that by incorporating genetic and clinical data into VTE risk assessment, the TiC-­LYMPHO score can categorize patients with lymphoma better in terms of their risk of VTE and allow individualized thrombo- prophylaxis to be prescribed. KEYWORDS genetic risk score, lymphoma complications, thromboembolism risk This project was approved by the Ethical committee of the Gregorio Marañón University Hospital, Madrid, Spain. This is an open access article under the terms of the Creat​ive Commo​ns Attri​bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Cancer Medicine. 2021;10:7585–7592.  wileyonlinelibrary.com/journal/cam4 | 7585 | 20457634, 2021, 21, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.4280 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 7586    BASTOS-­OREIRO et al. 1 | I N T RO DU CT ION analysis, NHLs were grouped according to their clinical aggressiveness into indolent and aggressive. Aggressive Venous thromboembolic events (VTE) are a frequent lymphomas included diffuse large cell lymphoma, mantle complication in patients suffering from haematologi- lymphoma, and plasmablastic lymphoma and T lympho- cal malignancies, particularly lymphoma.1,2 The inci- mas. Indolent lymphomas included follicular lymphoma, dence of such events is some 10%–­15%, depending on marginal lymphoma, lymphocytic lymphoma and lym- whether all lymphomas are included or only those pa- phoplasmacytic lymphoma. Among the aggressive ones, a tients treated by chemotherapy.1,3 In any event, they are distinction was made between diffuse large cell lymphoma a cause of increased morbidity and mortality4,5 and thus (DLBCL) due to its frequency. The same among the indo- represent an important economic cost to healthcare sys- lent, with follicular lymphoma (FL). Demographic, labo- tems.6 They can be prevented by thromboprophylaxis, ratory and clinical data were collected at diagnosis, and but this increases the risk of haemorrhage10,11 and in- further clinical data and any VTEs recorded over the next curs additional treatment costs.12 It is therefore import- 6 months. ant to be able to identify those patients who can most benefit from such treatment. Because the incidence of VTEs in cancer is high, it is 2.2 | Diagnosis of VTE important to evaluate the risk of their development at the time of diagnosis, and certainly before patients start che- Deep vein thrombosis in the lower limbs was diagnosed motherapy.6 The risk of VTE associated with lymphoma by ultrasound or ascending venography. Pulmonary em- has been assessed in multiple series of patients, focusing bolism was diagnosed by ventilation–­ perfusion lung on clinical variables.1,2,7 In the most consolidated models, scanning, pulmonary angiography or spiral computed to- such as the Khorana score,8 lymphomas are considered to mography. Intracranial venous thrombosis was diagnosed be a high risk factor for VTE. However, the usefulness of by magnetic resonance imaging. this score is limited; patients at high risk can still return an overall low-­middle score.9 Recently, a new and vali- dated score—­the ThroLy score—­was proposed by Antic 2.3 | Thromboembolism risk variables et al.13 for determining the risk of VTE in patients with lymphoma. However, this score too is based only on clini- Data were collected on clinical and laboratory variables cal and laboratory variables. It does not take into account known to be associated with VTE risk.16-­19 These included any genetic factors. Our group also recently proposed a lymphoma characteristics (histological type and subtype, new score, the TiC-­ONCO score, for determining the risk stage, risk score, bulky disease, mediastinal localization of VTE in patients with solid tumours. This combines and relapse/refractory disease), patient characteristics the clinical and genetic risk factors associated with VTE (age, sex, toxic habits, B symptoms, previous VTE, pres- and was found to be significantly better than the Khorana ence of a central venous catheter [port-­a-­cath in all cases score at identifying patients at high risk of VTE and who in our series], family history of thrombosis, ECOG per- would therefore benefit from personalized thrombopro- formance status, mobility and length of bed rest [days]) phylaxis.14 The present work describes a new score—­the and laboratory results (blood cell counts, lactate dehydro- TiC-­LYMPHO score, the algorithm of which was con- genase (LDH), fibrinogen value, activated partial throm- structed taking into account the same kind of data as used boplastin time (APTT), International Normalized Ratio in the TiC-­ONCO score—­for determining the risk of VTE (INR) and C-­reactive protein). None of the patient was on in patients with lymphoma. prophylaxis therapy. 2 | PAT I E N T S AN D M ET H ODS 2.4 | Sample genotyping 2.1 | Study population DNA was obtained from blood and bone marrow sam- ples and genotyped in TaqMan assays using the EP1 The study population of this observational, case–­control Fluidigm platform (an efficient endpoint PCR system study included all consecutive patients diagnosed with for high-­sample-­throughput SNP genotyping). Analyses non-­Hodgkin (NHL) or Hodgkin lymphoma (HL) (based were performed for F5 rs6025, F5 rs4524, F13 rs5985 and on the World Health Organization 2008 classifications15), SERPINA10 rs2232698, i.e., the genetic variables included presenting at the Gregorio Marañon University Hospital in the TiC-­ONCO score. Together these provide the ge- between January 2014 and December 2017. For the netic risk score (GRS) associated with VTE.14 | 20457634, 2021, 21, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.4280 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BASTOS-­OREIRO et al.    7587 F I G U R E 1 Cumulative incidence Time to VTE of VTE. At 6 months of follow-­up, the 25 incidence of VTE was 14.9% (those patients who died, relapsed or developed a second neoplasm were removed from the 20 analysis) Percentage VTE 15 10 5 0 0 10 20 30 40 50 Months since diagnosis 2.5 | Development of the risk model 2.7 | Statistical analysis We have counted with the previous experience in the Continuous variables were recorded as means and cat- generation of the clinical-­genetic VTE risk score, named egorical variables as proportions. Continuous variables TiC. TiC score for solid tumours included four genetic were compared using the Student t-­test or the Mann–­ variants: rs6025, rs4524, 3 rs5985 and SERPINA10 Whitney U test as required. Categorical variables were rs2232698. In TiC, as clinical variables, it includes compared using the χ2 or Fisher tests. The DeLong test BMI > 25; family history of VTE and two variables was used to examine the differences between the AUCs. linked to the tumour, the type of tumour and the TNM For cumulative incidence calculation, those patients who stage. For the generation of the score for patients suf- died, relapsed or developed a second neoplasm or develop fering from lymphomas, we have used the same genetic a VTE were censored for. All calculations were performed variants. We have analysed whether BMI > 25, family using MedCalc Statistical Software v.18.11.3 (MedCalc history of VTE and some characteristics of the tumours Software bvba; https://www.medca​lc.org; 2019). could be useful to elaborate a VTE risk score in a similar way as in solid tumours. A risk model for VTE was con- structed using the above genetic variables plus the clini- 3 | RESULTS cal variables found to be significantly associated with the appearance of a VTE (p ≤ 0.25). All these variables A total of 208 patients were diagnosed with lymphoma; were then subjected to multivariate logistic regression over the study period, 31 (14.97%) of these experienced a using an Akaike's Information Criterion based (AIC-­ VTE (Figure 1). based) backward selection process, and those still asso- Aggressive lymphoma (AL) (diffuse large cell lym- ciated with an increased risk of VTE were entered into phoma, Burkkit's lymphoma, peripheral T lymphoma the TiC-­LYMPHO score algorithm. and mantle B cell lymphoma) was diagnosed in 125 pa- tients (60%), Hodgkin lymphoma (HL) was diagnosed in 21 patients (10%) and indolent lymphoma (IL) (follic- 2.6 | Comparison with other risk scores ular B cell lymphoma and marginal B cell lymphoma) in 62 (30%). Sixty percent of the patients were in an The AUCs for the three scores were compared, along with advanced stage of disease (Ann Arbor III or IV), half the sensitivity, specificity and predictive values of each, of the patients had an extranodal localization (47%) taking into account their high risk cut-­offs, i.e., Khorana and 50% received a central catheter (51%). The most score ≥3,6 Thrombosis Lymphoma predictive score common chemotherapy regimen used was R-­ CHOP (ThroLy) >31,3 and that of the TiC-­LYMPHO as provided (Rituximab, cyclophosphamide, adramycin, vincris- by the Youden J index.20 tine and prednisone) or CHOP. CHOP was used in 119 | 20457634, 2021, 21, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.4280 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 7588    BASTOS-­OREIRO et al. patients (57%), mainly in those suffering from aggres- particular subject suffering from lymphoma is at high risk sive lymphomas (in 80% of such patients), followed by or at a low risk of developing a VTE in the 6 months after patients with indolent lymphoma (in 40% of these pa- the diagnosis. tients). Other treatments used for patients with AL were R-­EPOCH (Rituximab, Etoposide Phosphate, Prednisone, Vincristine Sulfate- ­Oncovin-­, Cyclophosphamide 3.2 | Comparison of the different scores and Doxorubicin Hydrochloride), CHOEP (Cyclosphosphamide, Doxorubicin Hydrochloride, Table 3 shows the discriminative and predictive capacity Etoposide, Vincristine and Prednisone), Burkimab of the different scores. The TiC-­LYMPHO score showed (Block A: Rituximab, Vincristine, Methotrewate, a better AUC than both the ThroLy and Khorana scores Iphosphamide, Dexamethason, Teniposide, Cytarabine; (0.783 vs. 0.579 and 0.502, respectively; p < 0.0001 for Block B, Rituximab, Vincristine, Methotrexate, both). The TiC-­LYMPHO score also showed higher sen- Cyclophosphamide, Dexamethasone, Doxorubicin, sitivity (93.55% vs. 19.35% and 6.45% for the ThroLy and Block C: Rituximab, Vindesine, Methotrexate, Khorana scores, respectively; p < 0.0001), the best nega- Dexamethasone, Etoposide and Cytarabine) and tive likelihood ratio (LHR-­) (0.12 vs. 0.47 and 0.86.1, re- HyperCVAD (Course A: Cyclophosphamide, Vincristine, spectively; p < 0.0001) and the best negative predictive Doxorrubicin, Dexametasone, Cytarabine, Mesna, value (NPV) (97.98% vs. 86.48%, and 84.41%, respectively; Methotrexate; Course B: Methotrexate, Leucovorin, p < 0.0001). The positive predictive value (PPV) shown by Sodium bicarbonate and Cytarabine). Other regimen the TiC-­LYMPHO score was significantly better than that for IL was R-­Bendamustine. Ninety percent of patients of the Khorana score (26.36% vs. 16.67%; p = 0.0161), but with HL received ABVD (Adriamycin, Bleomycin, lower than that of the ThroLy score (26.36% vs. 37.50%; Vinblastine and Dacarbazine), and 10% received p < 0.0001). Similarly, the LHR + shown by the TiC-­ BEACOOP (Bleomycin, Etoposide, Doxorubicin hydro- LYMPHO score was significantly better than that shown chloride, Cyclophosphamide, Vincristine, Procarbazine by Khorana score (2.06 vs. 1.39; p < 0.0001), but lower than and Prednisone). All patients with AL developed neu- that shown by the ThroLy score (2.06 vs. 3.29; p < 0.0001). tropenia during treatment. Finally, the specificity of the TiC-­LYMPHO score was sig- Table 1 shows the clinical characteristics of the patients nificantly lower than that of both the ThroLy and Khorana who experienced or did not experience a VTE. Univariate scores (54.49% vs. 96.43% and 94.01%; p < 0.0001). regression showed bed rest for >3 days, and having a cen- Treatment with semuloparin22 of all those patients tral venous catheter, a ThroLy score of ≥2, a family or per- with a TiC-­LYMPHO score indicating them to be at high sonal history of VTE, an advanced Ann Arbor stage (IV), a risk (63.64%) would have prevented 58% of the VTEs re- cancer histological type of aggressive DLBCL, non-­DLBCL corded. The treatment of all the patients with a Khorana or PCNSL and the presence of a mediastinal mass to be score indicating the same would have prevented 6.45%, more common in patients who experienced a VTE. These and the treatment of all those with a positive ThroLy score patients also showed a trend towards having B symptoms. would have prevented 9.68%. Patients who did not experience a VTE more commonly had an FL or an indolent LNH histological type. 4 | DISC USSION 3.1 | Variables included in the TiC-­ The present results show the TiC-­LYMPHO score to be LYMPHO algorithm better than the Khorana and ThroLy scores at identi- fying patients with lymphoma who are at high risk of After multivariate regression, the genetic variables in- VTE. The incidence of VTE in patients with solid ma- cluded in the TiC-­ ONCO score,14 plus the following lignancies and blood cancers is high.23 In patients with clinical variables, were included in the TiC-­ LYMPHO lymphoma, it is no less important to determine—­at the algorithm: the type of lymphoma according to the WHO time of diagnosis—­the risk of experiencing a VTE and classification,21 mediastinal involvement, Ann Arbor only then can adequate preventive steps be taken.4,24 stage, bed rest for >3 days, and a family or personal his- When the risk of VTE is not known, the use of prophy- tory of VTE. Table 2 shows the variables independently laxis in patients with lymphoma is often restricted due associated with the risk of VTE in the multivariate analy- to the fear of haemorrhage or of thrombopenia during sis. TiC-­LYMPHO algorithm can be used at the time of chemotherapy. This, however, may be overcautious diagnosis of the lymphoma. The use of this score consid- since thrombopenia at diagnosis is uncommon, even in ering the Jouden index J as a cut-­off will identify if any aggressive lymphomas,25,26 and chemotherapy does not | 20457634, 2021, 21, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.4280 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BASTOS-­OREIRO et al.    7589 TABLE 1 Clinical characteristics for lymphoma patients with or without VTE, expressed as N (%) VTE No VTE 31 (19.9) 177 (85.10) p value Age, years±SD 68.00 ± 16.64 60.24 ± 18.31 0.0173 Male N (%) 20 (64.52) 91 (51.41) 0.1779 BMI <1 8.5 2 (6.45) 4 (2.26) 0.2 18.5–­24.99 11 (35.48) 54 (30.50) 0.6 25–­29.99 11 (35.48) 58 (32.77) 0.8 >30 7 (22.58) 20 (11.30) 0.08 Unknown 0 (0) 41 (23.16) 0.0029 Ann Arbor I 3 (9.68) 9 (5.08) 0.4 II 5 (16.13) 20 (11.3) 0.4 III 6 (19.35) 15 (8.47) 0.06 IV 14 (45.16) 27 (15.25) 0.0001 Bed rest Yes 16 (51.61) 39 (22.03) 0.0006 No 15 (48.39) 138 (77.97) Central venous catheter Yes 22 (70.97) 87 (49.15) 0.02 No 9 (29.03) 90 (50.85) History of VTE Yes 9 (29.03) 16 (9.04) 0.002 No 22 (70.97) 161 (90.96) Histological type HL 5 (16.13) 17 (9.60) 0.3 FL 3 (9.68) 49 (27.68) 0.03 Indolent NHL 1 (3.23) 38 (21.47) 0.02 DLBCL 13 (41.94) 50 (28.25) 0.13 Aggressive, non DLBCL 7 (22.58) 22 (12.43) 0.13 Aggressive non DLBCL + non DLBCL (total) 20 (63.52) 72 (40.68) 0.04 PCNSL 2 (6.45) 1 (0.56) 0.01 B Symptoms Yes 17 (54.84) 64 (36.16) 0.05 No 14 (45.16) 113 (63.84) Bulky disease Yes 10 (32.26) 37 (20.90) 0.2 No 21 (67.74) 140 (79.10) Extranodal localization Yes 14 (45.16) 84 (47.46) 0.8 No 17 (54.84) 93 (52.54) Mediastinum mass Yes 6 (19.35) 12 (6.78) 0.02 No 25 (80.65) 165 (93.22) Khorana score ≥3 (Continues) | 20457634, 2021, 21, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.4280 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 7590    BASTOS-­OREIRO et al. TABLE 1 (Continued) VTE No VTE 31 (19.9) 177 (85.10) p value Yes 2 (6.45) 10 (5.65) 0.9 No 29 (93.55) 167 (94.35) ThroLy score ≥2 Yes 21 (67.44) 54 (30.51) 0.0001 No 10 (32.26) 123 (69.49) Non-­Hodgkin lymphoma (NHLs) were grouped according to their clinical aggressiveness into indolent and aggressive. Aggressive lymphomas included diffuse large cell lymphoma (DLBCL), mantle lymphoma, and plasmablastic lymphoma and T lymphomas. Indolent lymphomas included follicular lymphoma, marginal lymphoma, lymphocytic lymphoma and lymphoplasmacytic lymphoma. Among the aggressive ones, a distinction was made between diffuse large cell lymphoma (DLBCL) due to its frequency. The same among the indolent with follicular lymphoma (FL). TABLE 2 Multivariable analysis p value HR 95% CI p value Mediastinum mass 0.00119 4.5562 1.1091–­18.7174 0.00119 Ann Arbor 0.0425 0.9007 0.7312–­0.9994 0.0425 GRS 0.0179 2.6581 1.1161–­6.3309 0.0179 Immovilization 0.0217 2.6856 1.0519–­6.8566 0.0217 Type of lymphoma 0.0487 1.2175 1.0505–­1.7497 0.0487 History of VTE 0.0032 4.1622 1.4598–­11.8674 0.0032 Variables independently associated with VTE risk in lymphoma patients at diagnosis. T A B L E 3 Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPP), area under the curve (AUC) and confidence interval 95% (95%CI) Sensitivity Specificity PPV NPV AUC 95% CI p value TiC-­LYMPHO 93.55 54.49 26.36 97.94 0.78 0.7231–­0.837 0.0001 Khorana 6.45 94.01 16.60 84.41 0.503 0.431–­0.574 0.902 ThroLy 19.35 96.43 50 86.63 0.57 0.50–­0.648 0.0319 often cause thrombopenia.27,28 In the last decade, multi- mobility, extranodal disease, neutropenia and a hae- ple randomized clinical trials, including in patients with moglobin concentration of <100 g/L. However, it does lymphoma,29 have shown the efficacy and safety of oral not take into account any genetic variable. This model and parenteral thromboprhophylaxis30 in the ambula- shows a PPV of 65.2% for identifying patients at high tory setting. risk for VTE (4/7 points or more). Although this has The Khorana score8 is certainly one of the most been validated, it is important to note that there are also commonly used risk scores for predicting VTE in pa- studies that show its accuracy to be limited in patients tients with cancer. However, it is of limited use in lym- with lymphoma.18,32 Indeed, the present results high- phoma,31 probably because it understands it as a single light the inaccuracy of both the Khorana and ThroLy entity, with no distinction among different histologies, scores. For example, the Khorana score showed a non-­ tumour burdens or locations.31 The ThroLy score is a significant AUC (p = 0.503) and very poor sensitivity new score for assessing VTE risk in patients with lym- (6.45%), and for a value of ≥4 the ThroLy score showed phoma, which classifies them as being at low, interme- a low AUC (albeit statistically significant at p = 0.032) diate and high risks.13 The variables included in this and identified just 6 of the 31 patients who experi- score are previous venous and/or arterial events, medi- enced a VTE. It also had a sensitivity of just 19.35%. astinal involvement of lymphoma, BMI >30, reduced Based on these results, the ThroLy score would not | 20457634, 2021, 21, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.4280 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BASTOS-­OREIRO et al.    7591 have predicted 80% of the VTEs recorded. Moreover, PPV and NPV and, importantly, a much higher sensitivity of the 12 patients with a ThroLy score of ≥4, only six (93%). experienced a VTE (PPV 50%). However, the test did identify 162 of 168 with no VTE (specificity 98.43%). Similarly, of the 187 patients with a ThroLy score of 5 | CONC LUSIONS ≤1, just 25 went on to experience a VTE (NPV 86%). The main objective of the application of these scores The incorporation of genetic and clinical variables as- should be to reduce the VTE, and it is clear that this sociated with thrombosis into the TiC-­LYMPHO score is not adequately achieved with the scores available so allows the risk of VTE in patients with lymphoma to far. This is probably the reason why these scores have be much better identified, offering the opportunity to not been incorporated into management guidelines for prescribe individualized thromboprophylaxis. The pre- lymphoma patients. sent results also contribute to the validation of the TiC-­ The proposed TiC-­LYMPHO score identified 29 of the ONCO score. 31 patients who experienced a VTE (sensitivity 93.55%). Had this result been used to guide the prescription of CONFLICT OF INTEREST prophylactic treatment, only 6.4% of the patients who Authors declare no conflict of interest. had needed prophylaxis would not have received it. A high-­risk TiC-­LYMPHO score identified 97 of the 178 ORCID patients who did not experience a VTE (PPV 54.49%); Mariana Bastos-­Oreiro https://orcid. thus, part of the present population would have been org/0000-0002-9431-4646 over-­treated. However, almost all patients at risk can be Eduardo Salas https://orcid.org/0000-0002-6837-2471 given prophylaxis safely as long as they are adequately Ismael Buño https://orcid.org/0000-0003-4931-9170 monitored. Considering the comorbidities that a VTE generates in this type of patients, requiring admission, REFERENCES anticoagulation at full doses and taking into account a 1. Falanga A, Marchetti M, Russo L. Venous thromboembolism in difficult management since many of these patients fre- the hematologic malignancies. Curr Opin Oncol. 2012;24(6):702-­ quently suffer thrombopenia associated with chemo- 710. doi:10.1097/CCO.0b013​e3283​592331 2. Kekre N, Connors JM. Venous thromboembolism incidence therapy, we understand that the benefit of identifying in hematologic malignancies. Blood Rev. 2019;33:24-­32. the vast majority of patients at risk is greater than the doi:10.1016/j.blre.2018.06.002 harm of overtreating with low doses of heparin. Despite 3. 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