Zanubrutinib in Patients With DLBCL and MYD88 or NOTCH1 Mutation or CD5+

The purpose of this study is to compare effects of adding zanubrutinib to the usual chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) who have an MYD88 L265P mutation, a CD79B mutation, a NOTCH1 truncation, or who are CD5+ by IHC. In those patients with mutations or IHC result, we propose treating with zanubrutinib plus rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone (R-CHOP). Patients will be monitored with standard imaging; minimal residual disease (MRD) testing will be optional. The primary outcome is the complete response rate. The secondary outcome is EFS at 2 years. When available, MRD studies will be correlated to response. Patients with aggressive B-cell lymphoma with MYC and BCL-2 and/or BCL-6 mutations will be excluded, as will patients with HIV. Zanubrutinib will be first administered on Cycle 2 Day 1 of R-CHOP. It is up to the discretion of the treating physician how many cycles of R-CHOP the treatment would require, but it is not to exceed 6 cycles of R-CHOP and 5 cycles of zanubrutinib. The number of cycles of R-CHOP should be per standard of care, with the number of zanubrutinib cycles being 1 less than the number of total R-CHOP cycles. Patients will be followed up every 3 months for 24 months after removal from protocol therapy or until death, whichever occurs first. There will be an extended follow-up period of up to 5 years from end of study treatment.