Tumores hematológicos: riesgo de ETV y de hemorragiaR. LecumberriServicio de Hematología.Clínica Universidad de Navarra. IdISNA. CIBERCV.

SAES.ENO.20.02.0157a FEBRERO 2020

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Conflictos de interés

Research Support/P.I. Rovi

Employee N/A

Consultant N/A

Major Stockholder N/A

Speakers Bureau BMS, Daiichi-Sankyo, Leo Pharma, Sanofi, Rovi.

Honoraria N/A

Scientific Advisory Board Leo Pharma

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Epidemiología ETV asociada a cáncer

• Incidencia 13 casos/1000 personas-año (x 6-10 veces)• Según tipo de tumor: hasta 20%• 2ª causa de mortalidad en pacientes con cáncer

Gomes M. Semin Thromb Haemost 2014; 40: 319-24. Timp JF. Blood 2013; 122: 1712-23.

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Peso relativo de cada factor no bien conocido y variable (dinámico) en el tiempo: necesidad de modelos “multi-estado” flexibles

Carmona-Bayonas A, et al. Thromb Haemost 2019.

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Incidencia ETV en tumores hematológicos

Muchas en el dx.

LNH-SNC hasta 50%RPCa adquirida

Kekre N & Connors JM. Blood Rev 2019; 33: 24-32.

(5-30%)

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Impacto en supervivencia no claro

Ku GH, et al. Blood 2009; 113: 3911-7.

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Caruso V, et al. Blood 2010; 115: 24-32.

3,8% de los episodios presentes al diagnóstico (compresión adenopática) 95% durante el tratamiento 1,2% tras completar el tratamiento

Meta-análisis cohortes 18.018 pacientes con linfoma y 1.149 eventos trombóticos (84% ETV)

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Kristinsson SY, et al. Blood 2008; 112: 3582-6.

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Labrador J et al. Haematologica, 2013; 98(3)

Thromboembolic and bleeding events in 431 allogeneic hematopoetic stem cell transplantation

The cumulative incidence of a bleeding episode was 21.3% (95% CI: 17.7–25.5%; 237 patients at risk) at 1 year, 26.1% (95% CI: 22.1–30.8%; 100 patients) at 5 years, 28.9% (95% CI: 24.3–34.4%; 34 patients) at 10 years, and 30.2% (95% CI: 25.2–36.2%; 3 patients) at 14 years.

Cumulative incidence of a venous TEE was 3.6% (95% CI: 2.2–5.9%; 256 patients at risk) at 1 year, 4.8% (95% CI: 3.1–7.5%; 104 patients) at 5 years, 8.1% (95% CI: 5.2–12.6%; 37 patients) at 10 years, and 11.8% (95% CI: 7.1–19.6%; 3 patients) at 14 years.VTE S

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Thromboembolic and bleeding events in 431 allogeneic hematopoetic stem cell transplantation

supervivencia

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Franchini M, et al. Semin Thromb Haemost 2013; 39: 94-100.

Case-fatality rate hemorragia > ETV

¿Dintel de transfusión?¿Antifibrinolíticos?

Causas de hemorragia en tumores hematológicos

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Kekre N & Connors JM. Blood Rev 2019; 33: 24-32.

¿Ibrutinib?

Profilaxis TEV en tumores hematológicos

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Brown JR . Br J Haematol 2019; 184: 558-569.

- Any grade bleeding: 40%- Low grade bleeding: 35% (vs 15%)- Major bleeding: 4.4% (vs 2.8%)- Incidence adjusted for treatment exposure: 3.2 vs 3.1 per 1000 person-months.

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Administrar profilaxis con HBPM a todo paciente con cáncer hospitalizado por patología médica aguda o con movilidad reducida y ausencia de contraindicación

Profilaxis en pacientes oncológicos hospitalizados por patología médica

Carrier et al. Am J Med, 2014;127:82-86.

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CUESTIÓN ANTECEDENTES SUGERENCIAS

2. En los pacientes con cáncer hospitalizados por patología aguda médica, ¿en qué circunstancias está contraindicada la profilaxis antitrombótica farmacológica?

• Los pacientes oncologicos hospitalizados presentan un alto riesgo de TEV y, de ser posible, se deben adoptar medidas preventivas (1-5).

• Sin embargo, no existen estudios que evaluen la relación riesgo-beneficio en esta poblacion especifica (26).

• En las decisiones clinicas se debe prestar especial atencion a la seguridad.

• Contraindicación absoluta: • Sangrado reciente en SNC; sangrado mayor activo; recuento

plaquetario <20x109/L.• Contraindicación relativa:

• Sangrado crónico significativo (duración >48 h); postoperatorio temprano de neurocirugía; lesiones espinales o intracraneales de alto riesgo de sangrado; recuento plaquetario 20-50x109/L; disfunción plaquetaria grave; coagulopatía subyacente.

• Esperar 12 h tras administración de HBPM para punción lumbar o anestesia raquídea.

• Aplicar profilaxis antitrombótica con medidas físicas en caso de contraindicación para la farmacológica.

• No se requiere tromboprofilaxis si hospitalización exclusivamente para tratamiento oncológico (excepto si inmovilización).

Tabla 1. Resumen de las recomendaciones

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Figueroa R, et al. Plos One 2018.Figueroa R, et al. TH Open 2019.

Total Solid Hematologic p

N 1,072 855 (79.8%) 217 (20.2%)Age (mean ± SD) 62.1 ± 13.3 61.7 ± 13.3 63.4 ± 13.4 nsSex (male/female) 626/446 493/362 133/84 nsLength of stay (days) (median, range)

5 (1–140) 5 (1–97) 5 (1–140) ns

Cancer site (n, %) –Colorectal 177 (16.5%) 177 (20.7%)Lung 161 (15.0%) 161 (18.8%)Gastrointestinal 96 (9.0%) 96 (11.2%)Gynecologic 80 (7.5%) 80 (9.4%)Pancreas 77 (7.2%) 77 (9.0%)Renal/Urinary 44 (4.1%) 44 (5.1%)Breast 42 (3.9%) 42 (4.9%)Prostate 37 (3.5%) 37 (4.3%)Other solid 141 (13.2%) 141 (16.5%)Lymphoma 136 (12.7%) 136 (62.7%)Myeloma 56 (5.2%) 56 (25.8%)Leukemia 21 (2.0) 21 (9.7%)Other hematologic diseases 4 (0.4%) 4 (1.8%)

Metastatic disease (n, %) – 578 (67.6%) –

Chemotherapy (n, %) 880 (82.1%) 694 (81.1%) 186 (85.7%) ns

Platelets <50 × 109/L (n, %) 63 (5.9%) 30 (3.5%) 33 (15.2%) <0.001

PRETEMED score (median, range) 5 (3–13) 5 (3–13) 5 (3–13) ns

PRETEMED ≥ 4 points (n, %) 989 (92.3%) 786 (91.9%) 203 (93.5%) ns

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Tasa de profilaxis (HBPM) 72% (+23% con alguna contraindicación)En pacientes hematológicos: 50%

TEV durante hospitalización + alta (30 días):~ 3% (80% profilaxis)

Hemorragia mayor durante hospitalización + alta ~ 3% (no influida por profilaxis)

Figueroa R, et al. Plos One 2018.Figueroa R, et al. TH Open 2019.

Table 2. Multivariate analysis of variables that influence thromboprophylaxis use in hospitalized cancer patients

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30 TEV durante seguimiento- 5 hematológicos (80% TVP-CVC)

- 3/5 no profilaxis- 1/5 <50.000 plaquetas

- 25 tumor sólido (24% TVP-CVC)- 3/25 no profilaxis

Figueroa R, et al. Plos One 2018.Figueroa R, et al. TH Open 2019.

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Risk Factors for Cancer-Associated Venous Thromboembolism: The Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTE-PACC) Study

Douce DR et al. J Thromb Haemost. 2019;17:2152-2159

Unadjusted hazard ratio Hazard ratio adjusted for khorana risk factorsa

187 total VTE events over 1709 person-years

HospitalizationHospitalization + 90 days 2.87 (2.06, 4.00) 2.69 (1.92, 3.75)

Hospitalization + 30 days 3.09 (2.12, 4.51) 2.87 (1.97, 4.20)

Hospitalization only 1.75 (0.72, 4.28) 1.30 (0.47, 3.51)

Type of cancera 6 month incidence (95%CI) Rate per person-year (95% CI)

All Types 8.2% (6.8, 9.6) 10.9% (9.5, 12.5)

Lung 12.4% (8.0, 18.0) 16.9% (11.3, 24.0)

Breast 2.6% (0.1, 5.6) 3.8% (2.0, 6.5)

Gastrointestinal 11.9% (8.2, 16.3) 17.8% (13.5, 22.8)

Genitourinary 9.0% (4.6, 15.5) 16.3% (10.3, 24.1)

Hematologic 7.2% (5.0, 10.1) 8.2% (6.0, 10.9)

Gynecologic 6.7% (2.7, 13.3) 18.4% (10.1, 30.1)

Other 7.8% (4.8, 11.9) 9.6% (6.4, 13.7)

Table 2. Six Month incidence and rate per person‐year of VTE overall and by cancer type

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LymphomaAvert: 25%Cassini: 7%

2019 international clinical practice guidelines for thetreatment and prophylaxis of venous thromboembolism inpatients with cancer

Farge et al. Lancet Oncol, 2016;20:e566-81

Primary prophylaxis with LMWH, vitamin K antagonists, or direct oral anticoagulants in ambulatory patients receiving systemic anticancer therapy is not recommended routinely (grade 1B). Values and preferences: subcutaneous injections.

Primary pharmacological prophylaxis of VTE with LMWH is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer treated with systemic anticancer therapy and who have a low risk of bleeding (grade 1B). Values and preferences: subcutaneous injections.

Primary pharmacological prophylaxis of VTE with LMWH is not recommended outside of a clinical trial for patients with locally advanced or metastatic lung cancer treated with systemic anticancer therapy, including patients who have a low risk of bleeding (guidance).

Primary prophylaxis with direct oral anticoagulant (rivaroxaban or apixaban) is recommended in patients who are ambulatory who are receiving systemic anticancer therapy at intermediate-to-high risk of VTE, identified by cancer type (ie, pancreatic) or by a validated risk assessment model (ie, a Khorana score ≥2), and not actively bleeding or not at a high risk of bleeding (grade 1B).

In patients treated with immunomodulatory drugs combined with steroids or other systemic anticancer therapies, VTE primary pharmacological prophylaxis is recommended (grade 1A); in this setting, vitamin K antagonists at low or therapeutic doses, LMWH at prophylactic doses, and low-dose aspirin can be used and have shown similar effects with regard to preventing VTE (grade 2C). Values and preferences: subcutaneous injections.

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• N=1108 (5% hematológicos)• Profilaxis ambulatoria HBPM seguimiento (3 meses): 157 (14%)

• Mediana: 42 días

• TEV durante seguimiento: 58 (5,2%)• Predictores TEV:

• Páncreas: OR 3.04; 95%CI, 1.20-7,71 • Pulmón: OR 2.47; 95%CI, 1.21-5.01• TEV previo: OR 4.23; 95%CI, 1.26-14.27• Profilaxis ambulatoria: OR 0.30; 95%CI, 0.10-0.95

Characteristics OR 95% CI pAge (>70) 1.61 0.99 – 2.62 0.053Tumor site:GastrointestinalGynecologicHematologic

1.762.340.19

1.11 – 2.801.05 – 5.260.04 – 1.03

0.0170.0390.054

No previous chemotherapy 1.48 0.97 – 2.23 0.072

Past history of VTE 19.11 9.61 – 37.98 <0.001Intercurrent hospitalization 5.40 3.57 – 8.16 <0.001

Profilaxis en pacientes oncológicos ambulatorios

Panizo E, et al. Thromb Res 2015

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Tratamiento del TEV asociado a cáncer

Tumor hematológico• CLOT: 70/676• CATCH: 94/900• LITE-cancer 23/200• CANTHANOX: 16/146• ONCENOX: ?/101• Hokusai-VTE cancer: 111/1050• Select-D: 28/406VTE S

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HOKUSAI-VTE Cancer

Mulder FY et al. Thromb Res 2020; 185: 13-19

Breast cancer Hematological malignancy

Edoxaban Dalteparin Risk difference Edoxaban Dalteparin Risk difference

(n = 65) (n = 60) (95% CI) (n = 56) (n = 55) (95% CI)

12-month study period - primary outcome and secondary outcomes

Primary outcome: first recurrent VTE or major bleeding 2 (3.1%) 7 (11.7%) −8.6 (−19.3 to 2.2) 5 (8.9%) 6 (10.9%) −2.0 (−13.1 to 9.1)

Secondary outcome: recurrent VTE 2 (3.1%) 5 (8.3) −5.3 (−15.0 to 4.5) 2 (3.6%) 4 (7.2%) −3.7 (−13.9 to 6.5)

Secondary outcome: on-treatment major bleeding 0 (0%) 2 (3.3%) −3.3 (−9.5 to 2.8) 1 (1.8%) 2 (3.6%) −1.9 (−9.7 to 6.0)

First 6 months – primary outcome and secondary outcomes

Primary outcome: first recurrent VTE or major bleeding 2 (3.1%) 4 (6.7%) −3.6 (−12.8 to 5.6) 3 (5.4%) 5 (9.1%) −3.7 (−0.15 to 7.7)

Secondary outcome: recurrent VTE 2 (3.1%) 3 (5.0%) −1.9 (−10.5 to 6.6) 1 (1.8%) 3 (5.5%) −3.7 (−12.4 to 5.1)

Secondary outcome: on-treatment major bleeding 0 (0%) 1 (1.7%) −1.7 (−6.5 to 3.2) 1 (1.8%) 2 (3.6%) −1.9 (−9.7 to 6.0)

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Conclusiones

• Tumores hematológicos presentan particularidades clínicas y biológicas que confieren al mismo tiempo incremento del riesgo trombótico y hemorrágico

• Posible comportamiento clínico diferente en este sentido a otros tumores

• Escasa representación en estudios de prevención y tratamiento del TEV

• ¿Necesidad de estudios específicos?

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