During the ICTHIC webinar “CAT management: challenges in different cancer populations,” Prof Darko Antic talked about thrombosis management in hematological cancers vs solid tumors to clarify the management of cancer-associated thrombosis (CAT) in different hematological cancers.
This article will summarize the key messages of his presentation. You can watch Antic’s talk in the video below, and you can watch the full webinar recording here.
VTE and cancer: incidence, mortality, risk factors and hospitalization costs
Venous thromboembolism (VTE) is a leading cause of morbidity and mortality among hospitalized patients with locally advanced and distant metastatic cancer. Recent data showed that VTE is diagnosed in up to 6% of patients with solid tumors, lymphoma, and leukemia .
In-hospital mortality was reported in 5.5% of cancer patients without VTE and 15.0% of those with VTE .
The strongest risk factors for VTE are infectious complications, including sepsis, invasive candidiasis, pneumonia, and intravenous line infections. “Definitely, the combination of malignancy, infections, pneumonia and the use of specific drugs leads to an increased risk of developing thromboembolic events,” said Prof Antic.
The estimated average daily cost of hospitalization for patients with cancer and VTE increased by nearly 50% between 1995 (US$2,256) and 2012 (US$3,297) .
The incidence of thromboembolic events in patients with hematological malignancy varies between different types, with the highest rates for leukemia, myeloproliferative neoplasms, lymphoma and multiple myeloma .
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is a cancer of the blood and bone marrow that progresses rapidly with production of immature cells. The “key messages” raised by Antic speech are that:
- VTE is a common complication of asparaginase-based chemotherapy regimens for ALL treatment; in fact, asparaginase can disrupt the hemostatic balance with decreased production or secretion of native anticoagulant proteins (antithrombin, protein C, and protein S).
- Steroid administration and placement of central venous catheters are other risk factors for developing VTE in ALL.
- Antithrombin levels should be monitored weekly during asparaginase therapy. Antithrombin administration is recommended for patients with a high risk of VTE, such as cerebral venous thrombosis or central pulmonary embolism, and for those with antithrombin levels <60%. A repletion target in the 80–120% range is highly recommended.
In the THROMBOTECT pediatric study, the use of thromboprophylaxis with low-molecular-weight heparin (LMWH) was associated with a lower rate of VTE. Thus, LMWH thromboprophylaxis should be used during the induction phase of ALL therapy if it includes asparaginase and during acute VTE management. Moreover, monitoring anti-Xa factor levels is strongly suggested due to increased variability in antithrombin concentrations .
Lastly, the standard duration of anticoagulation for the treatment of CAT is 6 months or until complete cancer remission .
Acute promyelocytic leukemia
Acute promyelocytic leukemia (APL) is an aggressive type of acute myeloid leukemia (AML) in which there are too many promyelocytes in the blood and bone marrow, leading to a reduction of normal white and red blood cells and platelets .
The incidence of VTE in APL is up to 20%, and the most common locations of thrombosis are brain (cerebral infarction), legs (deep vein thrombosis), lung (pulmonary embolism), and heart (acute myocardial infarction) .
European LeukemiaNet recommends using heparin with dose modification in APL patients based upon the degree of thrombocytopenia for severe thrombosis .
Myeloproliferative neoplasms (MPNs) are clonal disorders of the hematopoietic stem cell, characterized by an uncontrolled expansion of myeloid precursors in the bone marrow and an excess of differentiated erythrocytes, platelets, and leukocytes in the peripheral blood. Besides transforming into secondary myelofibrosis or AML, thrombotic events are a major cause of morbidity and mortality in these patients .
The incidence of VTE in MPN patients is up to 30%, with a bleeding risk of up to 8%; a specific type of thrombotic events in MPNs patients are splanchnic and portal vein thrombosis, and these result in an increased risk of developing Budd-Chiari syndrome .
Experts recommend using aspirin (ASA) prophylaxis of VTE in MPNs patients; the dosage is strictly dependent on other risk factors . To date, it seems reasonable to use aspirin twice daily in patients with arterial thrombosis or the presence of cardiovascular risk factors associated with older age or JAK2 mutations. In extreme thrombocytosis, the use of ASA can lead to bleeding complications .
In summary, recommendations include the use of high-dose of ASA in case of previous arterial or venous thrombosis, use of low-dose in asymptomatic patients, and no use of ASA in case of thrombocytosis or leukocytosis to avoid bleeding complications 
In MPNs patients at high risk of VTE (in which VTE and splanchnic vein thrombosis are recurrent), life-long anticoagulant treatment is recommended; in MPNs patients at low-risk of VTE (provoked VTE or distal deep vein thrombosis), anticoagulant therapy can be switched to ASA usage .
The incidence of VTE in patients with lymphoma is up to 50%. The ThroLy Score is a simple model based on individual clinical and patient laboratory characteristics (previous VTE, reduced mobility, obesity, mediastinal involvement) that classifies the VTE risk in lymphoma patients; if the score value is ≥2, the patients are candidates for thromboprophylaxis .
Multiple myeloma (MM) is a hematological cancer caused by a proliferation of clonal plasma cells, leading to anemia, renal failure, and hypercalcemia . Immunomodulatory imide drugs (IMiDs) have contributed to the marked improvement in outcomes for patients with MM .
Regarding thromboprophylaxis for MM-VTE prevention:
- In patients at low risk for VTE development, the use of ASA is recommended
- LMWH is the best option for patients at higher risk .
After 4 months of treatment, LMWH should be switched to ASA. In case of thrombosis despite thromboprophylaxis, IMiDs therapy must be stopped:
- If VTE occurs during aspirin therapy, ASA should be replaced with therapeutic LMWH, warfarin, or direct oral anticoagulants (DOAC).
- If VTE occurs during LMWH therapy, LMWH dose should be increased to a therapeutic dose level 
The main causes of adverse arterial events (ATE) in patients with hematological malignancies are:
- Radiation therapy (especially in lymphoma patients)
- Development of antiphospholipid antibody syndrome, disseminated intravascular coagulation, and heparin-induced thrombocytopenia
- Specific therapies (e.g., bone marrow transplantation)
- Use of hematopoietic growth factors (e.g., erythropoietin) 
In the case of a patient with ATE, arteriography should be performed for a proper diagnosis. The underlying incriminating agent (thyroxine kinase inhibitors, immunomodulatory agents, growth factors) should be withheld, and appropriate measures taken to improve the blood supply to the vascular territory. Treatment usually involves a multidisciplinary approach, and the algorithm treatment is based on the clinical scenario, underlying hematological disorder, pre-existing comorbidities, identifiable hypercoagulable state, and previous treatment received by the patient.
Patients with hematological malignancy are underrepresented groups in thrombosis research. In the near future, there is a need to develop more specific risk assessment methods and an increased awareness about preventive measures. Furthermore, a controlled balance between anticoagulation therapy and bleeding complications is critically important.
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