This study is a multi-center, open-label, single-arm, non-randomized phase II clinical study in order to evaluate the safety and efficacy of zanubrutinib, lenalidomide plus R-CHOP (ZR2-CHOP) as the first-line therapy for treatment-naive high-risk diffuse large B-cell lymphoma patients.

Inclusion Criteria:

1. Histologically-confirmed and previously untreated Diffuse Large B-cell Lymphoma (DLBCL) with median to high risk (including but not limited to double/triple-hit, double expression and median-to-high risk aaIPI).
2. Male or female patients above 18 years old.
3. No prior exposure to treatment except a limited-field radiotherapy, short-term use of glucocorticoid =<25mg/day prednisone equivalent (must discontinue prior to day 1 of cycle 1) and/or cyclophosphamide due to an urgent lymphoma-related clinical situation (e.g. epidural spinal cord compression, superior vena caval syndrome and etc.).
4. At least one measurable disease, as defined as radiographically apparent disease with the longest axis >=1.5cm.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤3 (Patients with ECOG PS 3 should only be included if investigators deem that decline of status due to lymphoma and is reversible).
6. Serum bilirubin <1.5 Upper Limit of Normal (ULN), other than gilbert syndrome (defined as unconjugated bilirubin >80%); Aspartate transaminase (AST) and Alanine aminotransferase (ALT) ≤3 ULN or <5 ULN (if abnormality due to lymphoma).
7. Enough reserve function of bone marrow, regarded as absolute neutrophil count (ANC) > 1.0×109/L and Platelets > 75 ×109/L except that abnormality is due to lymphoma involvement in the bone marrow and felt reversible by investigators.
8. Creatinine clearance rate (Ccr) ≥30 ml / min calculated by Cockcroft-Gault formula.
9. Patients must give consent to transfusions of blood products.
10. Able to take aspirin (100mg) or alternative therapy daily as prophylactic anticoagulation.
11. With life expectancy more than 3 months.
12. All study participants must give consent to follow-up. Patients are fully aware of disease they have and sign informed consent on their own in order to join this study and receive treatment and follow-up.

Exclusion Criteria:

1. Any serious medical condition including but not limited to uncontrolled hypertension, uncontrolled congestive heart failure within past 6 months prior to screening (class 3 [moderate] or class 4 [severe] cardiac disease as defined by the New York Heart Association Functional Classification), uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction (LVEF) less than 55%, renal failure, active infection, history of invasive fungal infection, moderate to severe hepatic disease (Child Pugh class B or C), active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form; patients with history of cardiac arrhythmias should have cardiac evaluation and clearance.

2. Pregnant or lactating females.

3. Known hypersensitivity to lenalidomide or thalidomide, Bruton's Tyrosine Kinase (BTK) inhibitor, rituximab, vincristine, doxorubicin, cyclophosphamide, or prednisone.

4. Patients with active hepatitis B infection (HBV-DNA detectable) and active hepatitis C infection; patients with other acquired or congenital immunodeficiency disease, including but not limited to human immunodeficiency virus (HIV) infection.

5. All patients with central nervous system involvement with lymphoma; patients with primary mediastinal large B cell lymphoma; patients with Richter Syndrome (aggressive DLBCL transformed from indolent CLL).

6. Patients diagnosed as other malignancy except lymphoma, not including:

   Patients received curable treatment and no occurrence of active malignancy more than 5 years prior to study entry; successfully treated basal cell carcinoma without disease symptoms (except melanoma); successfully treated "in situ" cervix carcinoma.

7. Significant neuropathy (grade 2 or grade 1 with pain) within 14 days prior to enrollment.

8. Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis not due to lymphoma.

9. Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment).

10. Patients with severe bradycardia (heart rate < 40 beats per minute [bpm], hypotension, light-headedness, syncope).

11. Major surgery within 3 weeks of study entry, or wound that is not healed from prior surgery or trauma.

12. History of stroke or intracranial hemorrhage within 6 months prior to study entry.

13. Requires anticoagulation with warfarin or equivalent vitamin K antagonists.

14. Requires chronic treatment with strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors.

15. Vaccinated with live, attenuated vaccines within 4 weeks of study entry.