The term “Diffuse Large B-Cell Lymphoma” (DLBCL) covers an extremely heterogeneous range of aggressive hematological tumors of lymphoid origin. The recommended standard first-line treatment R-CHOP is still the leading therapy for newly diagnosed DLBCL. However, the outcomes of the unified approach to chemotherapy disregarding a high clinical and molecular genetic heterogeneity of this variant of non-Hodgkin lymphoma are evaluated as unsatisfactory. This paper is the first in the Russian Federation to report the personal experience with the use of the combination of R-CHOP regimen as basic therapy and chemotherapeutic agent acalabrutinib, one of Bruton tyrosine kinase inhibitors, with respect to Sanger sequencing results.