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To study rituximab efficacy, we examined serial blood samples from CLL patients receiving initial monotherapy with high\u2010frequency low\u2010dose (HFLD) rituximab for 1 week followed by the addition of acalabrutinib. Low\u2010dose rituximab (intravenous infusion of 25\u2009mg over 1\u2009h) decreased the circulating CLL cell count by 85% with no additional changes during infusion of the next 25\u2009mg of rituximab. Limited clearance of CLL cells was not attributable to low concentrations of rituximab or complement and was most likely caused by exhaustion of innate immune cytotoxicity as previously described for larger rituximab doses. Circulating CLL counts and CD20 levels rebounded by 48\u2009h when subcutaneous administration of 50\u2009mg of rituximab caused a small but significant decrease in CLL cell counts. Administration of 100\u2009mg of rituximab in the first week of therapy decreased palpable lymphadenopathy by 66%. Addition of acalabrutinib, a second\u2010generation Bruton tyrosine kinase inhibitor (BTKi), on Day 8 of treatment was followed by decreases in CLL cell expression of\n                    <jats:italic>MS4A1<\/jats:italic>\n                    coding for CD20, CD20 levels, and CLL cell sensitivity to rituximab\u2010induced antibody\u2010dependent cellular phagocytosis. Based on these data and previous reports, we propose that rituximab therapy in CLL patients is optimized by HFLD regimens, which achieve maximum CLL cell clearance at dosing intervals sufficient for recovery of immune cytotoxicity. Our data also suggest that the efficacy of rituximab, and possibly other CD20\u2010targeting mAbs, could be decreased by the addition of acalabrutinib or other BTKi.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70430","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:06:13Z","timestamp":1783555573000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy of high\u2010frequency low\u2010dose rituximab and acalabrutinib in chronic lymphocytic leukemia"],"prefix":"10.1002","volume":"10","author":[{"given":"Charles C.","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Medicine University of Rochester Medical Center Rochester New York United\u00a0States"},{"name":"Wilmot Cancer Institute University of Rochester Medical Center Rochester New York United\u00a0States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare 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