Rituximab

Overview

Rituximab is a chimeric anti-CD20 (MS4A1) monoclonal antibody that depletes CD20-positive B cells through antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity, and direct apoptosis induction. It is FDA-approved and forms the backbone of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard frontline regimen for diffuse large B-cell lymphoma (DLBCLNOS). R-CHOP achieves approximately 60% 3-year event-free survival; the remaining ~40% largely die of disease, motivating genomic studies to identify additional therapeutic targets.

Evidence in the corpus

  • R-CHOP (including rituximab) is the standard of care for DLBCL; WES of 55 DLBCL tumors identified 58 significantly mutated genes across BCR signaling (CD79B, CARD11), NF-kB (MYD88), and epigenetic (EZH2, CREBBP, KMT2D) pathways that may inform combination or salvage strategies PMID:22343534.
  • Rituximab-refractory CLL cases included in WES cohort; NOTCH1 mutations associated with inferior outcome under chemo-immunotherapy PMID:23415222
  • Component of the FCR (fludarabine/cyclophosphamide/rituximab) chemoimmunotherapy arm of the CLL8 trial (n=538 CLL); TP53, SF3B1, and RPS15 mutations predicted shorter PFS under FCR; the eventual relapse clone was pre-treatment detectable in 30% of cases PMID:26466571.
  • All 1001 patients in the DLBCL genomic study received rituximab-containing immunochemotherapy as standard of care, providing a uniformly-treated reference cohort for biomarker discovery PMID:28985567

Resistance mechanisms

  • Approximately 40% of DLBCL patients fail R-CHOP; genomic analysis from the dlbc_broad_2012 cohort implicates BCR-signaling mutations (CD79B, CARD11), NF-kB pathway alterations (MYD88), and epigenetic deregulation (KMT2D) as potential resistance drivers PMID:22343534.

Cancer types (linked)

Sources

  • PMID:22343534 — DLBCL WES identifying genomic landscape in the R-CHOP treatment context.
  • PMID:26466571 — Landau et al. (Nature 2015). CLL8 trial genomics; FCR arm prognostic landscape in 538 CLL patients.

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