This study investigates the efficacy and safety of direct oral anticoagulants (DOACs) in comparison with standard low-molecular-weight heparin (LMWH) for the prevention of venous thromboembolism in patients with hematological malignancies. Eligible participants will be randomized to receive reduced-dose apixaban, reduced-dose rivaroxaban, or standard-dose LMWH. The primary objective is to evaluate the incidence of venous thromboembolism during a 6-month follow-up period. Secondary objectives include assessment of bleeding complications, overall survival, and treatment adherence. The results of this study may provide evidence for safer and more convenient thromboprophylaxis strategies in patients with blood cancers.

Patients with hematologic malignancies are at high risk of developing venous thromboembolism (VTE). Low-molecular-weight heparin (LMWH) is currently the standard of care for thromboprophylaxis in this population; however, daily subcutaneous administration is burdensome and may impair adherence. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, have demonstrated efficacy in the prevention and treatment of VTE in patients with solid tumors, but data in hematologic malignancies are limited.

This study is designed as a prospective, randomized, open-label, parallel-group trial to compare the efficacy and safety of reduced-dose apixaban and rivaroxaban with standard-dose LMWH in patients with hematologic malignancies requiring primary thromboprophylaxis.

Approximately 100 patients will be randomized in a 1:1:1 ratio to receive:

Apixaban 2.5 mg orally twice daily, Rivaroxaban 10 mg orally once daily, or LMWH (enoxaparin 40 mg subcutaneously once daily or equivalent). The primary endpoint is the incidence of symptomatic or objectively confirmed VTE within 6 months of randomization. Secondary endpoints include major and clinically relevant non-major bleeding events (as defined by ISTH), treatment adherence, and overall survival at 6 months.

This study aims to address the unmet clinical need for optimized, patient-friendly thromboprophylaxis in hematologic malignancies and to provide high-quality data that may guide future clinical practice.

Inclusion Criteria:

• Active hematologic malignancy at the time of initiation of systemic therapy, including multiple myeloma, myeloproliferative neoplasm, lymphoma or other hematologic cancer with a Khorana score ≥ 2 points (intermediate or high risk of venous thromboembolism, VTE)
• Use of anticoagulant agents for primary thromboprophylaxis, including direct oral anticoagulants (DOACs) at reduced doses (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) or low-molecular-weight heparin (LMWH) (enoxaparin 40 mg subcutaneously once daily).

Exclusion Criteria:

• Major bleeding within the last month (including gastrointestinal or intracranial bleeding).
• Active major bleeding.
• Hemoglobin concentration < 8 g/dL.
• Thrombocytopenia with platelet count <30 × 10⁹/L.
• ECOG performance status of 3 or 4.
• Expected survival <6 months.
• History of mechanical heart valve or severe mitral stenosis.
• Estimated glomerular filtration rate (eGFR) < 25 mL/min.
• Hepatic impairment (ALT ≥ 3× upper limit of normal or bilirubin ≥ 2× upper limit of normal).
• Acute coronary syndrome or ischemic stroke within the last 6 months.
• Anticipated significant drug-drug interactions between DOACs and anticancer agents.
• Known antiphospholipid syndrome (APS).

Individual participant data (IPD) will not be shared because this is a non-commercial, single-center academic study with no external data sharing agreements in place.

This is an open-label study; no masking will be applied.