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Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells., Lay abstract The standard treatment of chronic lymphocytic leukemia and follicular lymphoma is chemotherapy in combination with anti-CD20 monoclonal antibodies, resulting in the destruction of the immune system, or a ‘Kamikaze effect’. Unfortunately, immunotherapy with rituximab or obinutuzumab may be of limited efficacy when the immunological system is overwhelmed by abundant tumor cells or is diminished by chemotherapy, which eliminates effector immune cells such as natural killer cells before they would be able to kill the whole tumor. Hence, it is important to measure the number of immune cells to ensure that during the encounter of effector cells with tumor cells, sufficient ‘warriors’ can win the battle against the tumor. Otherwise, something akin to the Battle of Thermopylae can happen where a limited number of Spartan warriors faced a huge army and were defeated in the end.

Aim: Obinutuzumab induces NK cell antibody-dependent cell-mediated cytotoxicity. Objective: Investigate the effects on the human immune system after obinutuzumab monotherapy treatment in patients with chronic lymphocytic leukemia (CLL). Method: To evaluate these effects, we analyzed the distribution of CD4+ and CD8+ T cells, B cells and NK cells in the peripheral blood of eight CLL patients who were treated with obinutuzumab in monotherapy. The distribution of peripheral blood lymphocytes was examined prior to each dose of obinutuzumab and 24–72 h after the first 1000 mg complete dose (cycle 1 day 2). We also repeated measurements 3 months after the last obinutuzumab dose. In total we obtained ten samples of each patient. Analyses were performed by flow cytometry with monoclonal antibodies against CD3, CD4, CD8, CD19 and CD56+. Results: After the first 1000 mg obinutuzumab infusion (cycle 1 day 2), CD4+ T cells and CD8+ T cells were significantly decreased in peripheral blood compared with prior to therapy. This reduction in the CD4+ T cells persisted after six cycles of obinutuzumab (1235 cells/μl basal vs 662 cells/μl after six cycles, p ≤ 0.05), but not in CD8+ T cells (987 cells/μl basal vs 837 cells/μl after six cycles). Interestingly, we also observed significant differences in the NK cell compartment after the first 1000 mg drug infusion (490 cells/μl basal vs 23 cells/μl postinfusion, p ≤ 0.05), and after cycle 6 (490 cells/μl basal vs 149 cells/μl after six cycles, p ≤ 0.05). Conclusion: Obinutuzumab induces depletion of NK cells in CLL.