R-CHOP in B cell non-Hodgkin lymphoma: balancing anti-tumor efficacy and NK-cell functionality

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Abstract Combining the anti-CD20 antibody rituximab with the chemotherapeutic drugs vincristine, doxorubicin, and cyclophosphamide plus the corticosteroid prednisone (R-CHOP) has been the standard first line-line therapy for many non-Hodgkin lymphomas including diffuse large B-cell lymphoma (DLBCL) for more than 20 years. Natural killer (NK) cells are considered major mediators of rituximab-induced antibody-dependent cellular cytotoxicity (ADCC). While the anti-tumor effects of vincristine, doxorubicin, and cyclophosphamide are well-documented, their impact on NK cell viability and effector function remains poorly characterized. We evaluated the single-agent and combinatorial efficacy of vincristine, doxorubicin, and the cyclophosphamide surrogate mafosfamide in four DLBCL cell lines (TMD8, WSU-DLCL2, U-2932, and RI-1) relative to their impact on NK cell survival and effector function. In single-agent experiments, vincristine eradicated all B-cell lines in a dose-dependent manner at clinically relevant concentrations, whereas doxorubicin and mafosfamide required higher doses to achieve comparable efficacy. Although all three agents reduced NK cell viability over time at clinically relevant concentrations, impaired NK cell cytotoxicity was observed only at supra-clinical doses. Combinatorial experiments revealed antagonistic interactions between vincristine and doxorubicin, without evidence of significant synergistic effects. Incorporating tumor and NK cell survival into a mathematical model support a measurable trade-off between tumor cell reduction and immune cell viability. To assess the translational relevance of our in vitro findings, we analyzed a cohort of 32 patients with B-cell non-Hodgkin lymphoma. We confirmed NK cell depletion during R-CHOP and R-mini-CHOP therapy, however NK cell loss was significantly less pronounced in patients receiving dose-reduced R-mini-CHOP. Notably, the intrinsic cytotoxicity of residual NK cells was preserved under both treatment regimens, with a trend toward enhanced cytotoxicity during R-mini-CHOP treatment. These findings suggest that R-CHOP predominantly affects NK cell abundance rather than function and support the translational relevance of the in vitro results.

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