This is a prospective, single-arm, noninferiority trial involving patients with previously untreated CD20-positive DLBCL. The aim of this study is to determine the efficacy and safety of treatment stratified based on ctDNA dynamic changes after one cycle of chemotherapy and the targeted therapy based on DLBCL genotype.

A total of 108 patients were planned to be enrolled in this trial, and the patients were stratified according to the dynamic changes of ctDNA after one cycle of chemotherapy: the chemotherapy-sensitive group continued the original R-CHOP regimen, and the potential drug resistance group received genotype-guided targeted drug combination. The whole trial included a screening period (day -28 to day -1), a treatment period, and a 2-year follow-up period.

Inclusion Criteria:

• Signed Informed Consent Form
• Age 18-75 years at the time of signing Informed Consent Form and willingness to comply with study protocol procedures
• Previously untreated participants with CD20-positive DLBCL
• IPI score 2-5
• ECOG Performance Status of 0, 1, or 2
• Life expectancy ≥ 6 months

Exclusion Criteria:

• Contraindication to any of the individual components of R-CHOP or Obutinib or Decitabine or Lenalidomide or Chidamide

• Have received systemic or local treatment including chemotherapy in the past

• Have received autologous stem cell transplantation in the past

• Past medical history of other malignant tumors, except basal cell carcinoma of the skin and cervical cancer in situ

• Accompanied by uncontrolled cardiovascular and cerebrovascular diseases, coagulopathy, connective tissue diseases, severe infectious diseases and other diseases

• Primary central nervous system lymphoma

• Left ventricular ejection fraction ≦50%

• Other concurrent and uncontrolled situation which will affect the patient's medical status based on researchers' decision

• Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma):

  • ANC < 1.0 x 10^9/L
  • PLT < 75 x 10^9/L
  • Hb < 100g/L
  • Serum AST and ALT ≥ 2.5 x ULN
  • Total bilirubin ≥ 1.5 x ULN
  • Serum creatinine ≥ 1.5 x ULN

• Psychiatric patients or other patients who are known or suspected to be unable to fully accomplish with the research protocol

• Pregnant or lactating women

• Patients with positive HbsAg test results need to undergo HBV-DNA test and can be admitted to the group after turning negative. In addition, if the HBsAg test result is negative, but the HBcAb test is positive (regardless of the HBsAb status), HBV-DNA is also required；if the result is positive, patients also need to be treated to become negative before entering the group

• Patients living with HIV