• Patients must have a documented pathologic diagnosis of DLBCL at any stage.

• Must have documented MYD88 L265P, CD79B, or NOTCH1 truncation mutation or be CD5+ by IHC.

• Age ≥18 years on the day of signing the informed consent form.

• Patients must have measurable disease on Positron Emission Tomography-Computed Tomography scan (CT/PET) imaging.

• Patient must have received no more than one cycle of R-CHOP prior to enrollment. Length of time between first R-CHOP treatment and planned 2nd R-CHOP treatment should vary by no more than 21 days ± 3 days.

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.

• Adequate bone marrow function as defined by:

‣ Absolute neutrophil count (ANC) ≥1000/mm3, except for patients with bone marrow involvement in which ANC must be ≥500/mm3.

⁃ Platelet ≥75,000/mm3, except for patients with bone marrow involvement in which the platelet count must be ≥30,000/mm3.

⁃ Hemoglobin ≥7 g/dL, after transfusion if necessary

• Adequate organ function defined as:

‣ Creatinine clearance ≥30 mL/min as estimated by the Cockcroft-Gault equation.

⁃ Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤2.5 × upper limit of normal (ULN).

⁃ Serum total bilirubin ≤3 x ULN (except patients with Gilberts syndrome 3g/dl).

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment.

• Women of childbearing potential and men must agree to use one of the following highly effective forms of birth control during the treatment and for 1 month following completion of study treatment for women and for 1 week following completion of study treatment for men.

‣ combined (estrogen and progestogen containing) hormonal contraception:

• oral

• intravaginal

• transdermal

‣ progestogen-only hormonal contraception associated with inhibition of ovulation

• oral

• injectable

• implantable

‣ intrauterine device (IUD)

⁃ intrauterine hormone-releasing system (IUS)

⁃ bilateral tubal occlusion

⁃ vasectomized partner

⁃ heterosexual abstinence

• Patients must not have any known allergies, hypersensitivity or intolerance to corticosteroids or monoclonal antibodies.

• Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.