Management of Venous Thromboembolism in Patients with Hematologic Malignancies

Jai N. Patel, PharmD, BCOP, CPP

Chief, Pharmacology Research

Associate Professor, Division of Hematology/Oncology

Levine Cancer Institute, Atrium Health

Disclosures

• Consulting fees and research funding from Janssen Research & Development

• This presentation will review off label uses of medications

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Learning Objectives

1. Describe the pathophysiology and risk factors for venous thromboembolism (VTE) in patients with hematologic malignancies

2. Identify pharmacological options for VTE prophylaxis and treatment in patients with hematologic malignancies

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Prevalence of VTE in Cancer

Cancer associated thrombosis (CAT) is the second leading cause of death in cancer

patients

The risk of VTE is four-fold to seven-fold higher in cancer patients than in those without

cancer

It is estimated that about 4–20% of patients with cancer experience CAT

The annual incidence of VTE in cancer patients undergoing chemotherapy is about 10.9%

The highest rate of VTE is seen in the initial period after diagnosis, and mortality from VTE

is highest one year after diagnosis

Elyamany G, et al. Clin Med Insights Oncol. 2014;8:129-374

Summary of VTE Incidence in Hematologic Malignancies

Kekre N, Connors JM. Blood Rev. 2019;33:24-325

Pathophysiology of CAT – Direct Mechanisms

Abdol Razak NB, et al. Cancers (Basel). 2018; 10: 380.

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TF-tissue factor; PDPN-podoplanin; PAI-plasminogen activation inhibitor; CP-cancer procoagulant; PS-phosphatidyl serine; CLEC-C-type lectin-like receptor; PAR-protease-activated receptors;

Pathophysiology of CAT – Indirect Mechanisms

Abdol Razak NB, et al. Cancers (Basel). 2018; 10: 380. 7NETs-neutrophil extracellular traps

Kraaijpoel N, Carrier M. Blood. 2019;133(4):291-298. 8

Risk factors for VTE in cancer patients

Patient-relatedAdvanced age

Comorbidities

Immobilization or hospitalization

Previous VTE

Hereditary thrombophilia

Tumor-relatedTumor type

- Very high risk: gastric, pancreas, brain

- High risk: lung, lymphoma, gynecologic, renal, bladder

Cancer stage

Histological tumor grade

Localized tumor compression

Treatment-relatedChemotherapy (e.g. cisplatin-based, antiangiogenesis agents)

Hormonal therapy

Red blood cell transfusions and erythropoiesis-stimulating agents

Surgery

Radiotherapy

Central venous catheters

International Myeloma Working Group guidelines for VTE management: Risk Factors

• Obesity (BMI > 30kg/m2)

• Previous venous thromboembolism

• Central venous catheter or pacemaker

• Associated disease

— Cardiac disease

— Chronic renal disease

— Diabetes

— Acute infection

— Immobilization

• Surgery

— General surgery

— Any anesthesia

— Trauma

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International Myeloma Foundation. IMWG Guidelines for the Prevention of Thalidomide and Lenalidomide-Associated Thrombosis in Myeloma. https://www.myeloma.org/resource-library/imwg-guidelines-prevention-thalidomide-lenalidomide-associated-thrombosis-myeloma. Accessed December 19, 2019.

• Medications

— Erythropoietin

• Blood clotting disorders

• Myeloma therapy (all are to be considered high-

risk factors)

— High-dose dexamethasone

— Doxorubicin

— Multiagent chemotherapy

Khorana Risk Score

Khorana AA, et al. Blood. 2008;111(10):4902-4907.10

Patient characteristics Risk score

Site of cancer

Very high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, bladder, testicular

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1

Prechemotherapy platelet count ≥ 350,000/mm3 1

Hemaglobin level < 10 g/dL or use of red cell growth factors 1

Prechemotherapy leukocyte count > 11,000/mm3 1

Body mass index ≥ 35 kg/m2 1

VTE Rates According to Scores from the Risk Model in the Derivation and Validation Cohorts

11Khorana AA, et al. Blood. 2008;111:4902-4907.

Ay C, et al. Blood. 2010;116:5377-5382.

VTE

rat

es

Learning Assessment Question #1

Which of the following are recognized risk factors for VTE?

A. Obesity

B. Prior history of VTE

C. Cancer treatments, such as immunomodulatory drugs

D. Red blood cell transfusion or use of erythropoietin stimulating agents

E. All of the above

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VTE Prophylaxis

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Patterns of VTE Prophylaxis During Treatment of Acute Leukemia: Results of a North American Survey

Lee EJ, et al. Clin Lymphoma Myeloma Leuk. 2015;15(12):766-770. 14TED-thromboembolic deterrent; SCD-sequential compression device; LMWH-low molecular weight heparin; AL-acute leukemia

16.6% 35.8% 20.5% 24.5% 2.6%

13.2% 37.1% 15.2% 31.8% 2.6%

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VTE Prophylaxis in Multiple Myeloma

• Thromboprophylaxis in multiple myeloma patients treated with lenalidomide – a systematic review

—1125 adults treated with lenalidomide-based therapy with thromboprophylaxis with ASA or LMWH

—VTE risk on ASA was 1.5 per 100 patient-cycles with a total VTE incidence 10.7% [95% CI: 8.86–12.88] compared to 1.4% [95% CI: 0.48–4.09] with LMWH

• Evaluation of an oral direct anti-Xa anticoagulant, apixaban, for the prevention of venous thromboembolism in patients with myeloma treated with IMiDcompounds

—104 patients enrolled, 2 VTE events registered (2%), one major (1%) and 11 (11%) CRNM hemorrhages were reported

• NCT02749617 (single arm phase 2 trial with apixaban) and NCT03428373 (randomized trial of ASA vs rivaroxaban)

Al-Ani F, et al. Thrombosis Res. 2016;141:84-90.

Pegourie B, et al. J Clin Oncol. 2017;35:15_suppl 8019.15

ASA: aspirin; LMWH: low molecular weight heparin; IMiD: immunomodulatory drugs; CI: confidence interval; CRNM: clinically relevant non-major

Key Prophylaxis Trials in “High-Risk” Patients

Carrier M, et al. N Engl J Med. 2019;380(8):711-719.

Khorana AA, et al. N Engl J Med. 2019;380:720-728.16

DOAC: direct oral anticoagulant; HR: hazard ratio; CI: confidence interval

N=57476 lymphoma patients

7 myeloma patients

N=84159 lymphoma patients

Trial VTE (DOAC) VTE (placebo) HR (95% CI), p-value

AVERT (apixaban)

Intention to treat 4.2% 10.2% 0.41 (0.26-0.65), p<0.001

On treatment 1.0% 7.3% 0.14 (0.05-0.42), p<0.001

Major bleeding 3.5% 1.8% 2.00 (1.01-3.95), p=0.046

CASSINI (rivaroxaban)

Intention to treat 5.9% 8.8% 0.66 (0.40-1.09), p=0.1

On treatment 2.6% 6.4% 0.40 (0.20-0.80), p=0.007

Major bleeding 2.0% 1.0% 1.96 (0.59-6.49), p=0.26

ASCO VTE Prophylaxis Guidelines (2019)

Pharmacological thromboprophylaxis should be administered to:

Hospitalized patients who have active malignancy and acute medical illness or reduced mobility in the absence of bleeding or other contraindications

High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen), provided there are no significant risk factors for bleeding and no drug interactions

Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone

Those undergoing major surgical intervention unless contraindicated because of active bleeding, or high bleeding risk

Key NS, et al. J Clin Oncol. 2019;37:1-25.17

International Myeloma Working Group Guidelines for VTE Management: Prophylaxis (last updated in 2008)

• If no risk factor, or any one risk factor is present, aspirin 81-325 mg once daily is recommended

• If two or more risk factors are present, LMWH (equivalent of enoxaparin 40 mg once daily) or full-dose warfarin, international normalized ratio (INR) 2-3, is recommended

• If any myeloma therapy-related risk factor is present, then LMWH (equivalent of 40 mg enoxaparin once daily) or full-dose warfarin is recommended

• If patients are receiving lenalidomide plus high dose dexamethasone then LMWH or full-dose warfarin is recommended

International Myeloma Foundation. IMWG Guidelines for the Prevention of Thalidomide and Lenalidomide-

Associated Thrombosis in Myeloma. https://www.myeloma.org/resource-library/imwg-guidelines-prevention-

thalidomide-lenalidomide-associated-thrombosis-myeloma. Accessed December 19, 2019.18

Algorithm for VTE Prevention in Hematologic Malignancies

19Kekre N, Connors JM. Blood Rev. 2019;33:24-32.

Algorithm for VTE Prevention in Hematologic Malignancies

20Kekre N, Connors JM. Blood Rev. 2019;33:24-32.

VTE Treatment

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DOAC versus LMWH: Hokusai VTE Cancer Trial

Gaskob GE, et al. N Engl J Med. 2018;378:615-24.22

Trial VTE + bleed (Edoxaban)

VTE + bleed(dalteparin)

HR (95% CI), p-value

Overall (n=1046) 12.8%(7.9% VTE)

13.5%(11.3% VTE)

0.97 (0.70-1.36), p=0.006 for noninferiority

Hematologic malignancy (n=111)

8.9%(3.6% VTE)

10.9%7.3% VTE)

Not reported

SELECT-D (rivaroxaban vs. dalteparin): 10 patients with hematologic malignancies, no subset analysisADAM-VTE (apixaban vs. dalteparin): 28 patients with hematologic malignancies, no subset analysis

ASCO VTE Treatment Guidelines

Initial anticoagulation may involve LMWH, UFH, fondaparinux, or rivaroxaban

For long-term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred

Anticoagulation with LMWH, DOACs, or VKAs beyond the initial 6 months should be offered to select patients with active cancer

The insertion of a vena cava filter may be offered as an adjunct to anticoagulation in patients with progression of thrombosis despite anticoagulation

Incidental pulmonary embolism and deep vein thrombosis should be treated in the same manner as symptomatic VTE

Key NS, et al. J Clin Oncol. 2019;37:1-25.23

VTE Treatment Considerations in Patients with Hematologic Malignancies

• Full-dose anticoagulation for those with a platelet count of 50× 109 per liter or higher

• Full dose anticoagulation in conjunction with platelet transfusions to achieve a platelet count > 50 × 109 per liter for the first 2 to 4 weeks from diagnosis of VTE

• For patients with a high risk of bleeding who cannot receive or are refractory to platelet transfusions, an inferior vena cava filter placement can be considered

• For patients in whom the VTE is not acute, reduce anticoagulation to half dose for platelet counts of 25 to 50 × 109 per liter and hold anticoagulation completely for a platelet count < 25 × 109 per liter

Kekre N, Connors JM. Blood Reviews. 2019;33:24-32.24

Safety of Anticoagulation Administration in Patients with Thrombocytopenia

Khanal N, et al. Am J Hematol. 2016;91(11):E468-472.25

Considerations for Using DOACs

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Administration/

dosing schedules

Compliance

Organ dysfunction

Bleeding risk

Drug interactions

Food interactions

Schwarb H, Tsakiris DA. Dent J. 2016;4:1-11.

Learning Assessment Question #2

Which of the following statements regarding VTE prophylaxis in patients with

hematological malignancies is FALSE?

A. Hospitalized patients who have active malignancy should be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications

B. Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients

C. Routine pharmacologic thromboprophylaxis should not be offered to all outpatients with cancer

D. Leukemia patients with a high Khorana risk score should be offered thromboprophylaxis

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Suggested References

• Wun T, White RH. Thrombosis Res. 2010;125:S96-S102.

• Kraaijpoel N, Carrier M. Blood. 2019;133(4):291-298.

• Kekre N, Connors JM. Blood Reviews. 2019;33:24-32.

• Key NS, et al. J Clin Oncol. 2019;37:1-25.

• Bellesoeur A, et al. Crit Rev Oncol Hematol. 2018;129:102-112.

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Management of Venous Thromboembolism in Patients with Hematologic Malignancies

Jai N. Patel, PharmD, BCOP, CPP

Chief, Pharmacology Research

Associate Professor, Division of Hematology/Oncology

Levine Cancer Institute, Atrium Health