Treatment of Relapsed/Refractory CLL Patients With PI3Kδ Inhibitor and Anti-CD20 Antibody Rapidly Decreases Tumor Burden but Could Induce Resistance

Am J Hematol. 2025 Mar;100(3):523-526. doi: 10.1002/ajh.27569. Epub 2025 Jan 2.

Abstract

Multi-drug combination strategy targeting three different molecules involved in different pathways to overcome single-agent resistance in relapsed/refractory CLL patients. The clinical trial utilized 1)a therapeutic anti-CD20 monoclonal antibody (mAb), ublituximab, which destroys CLL cells by an antibody-dependent cellular phagocytosis (ADCP) mechanism; 2)a B cell receptor (BCR) signaling inhibitor, umbralisib, which blocks PI3Kẟ; 3)and an anti-apoptosis inhibitor, venetoclax, which blocks cell survival promoted by BCL-2 that stops mitochondria from initiating apoptosis. Our correlative study focused on the first two treatments prior to venetoclax addition. We found that patients respond to anti-CD20 antibody and BCR signaling inhibition with rapid reductions in CLL cell counts and CD20 levels. Standard high dose (375 mg/m2) anti-CD20 antibody treatment significantly decreased CLL surface CD20 levels, potentially limiting treatment efficacy. Anti-CD20 antibody plus B cell receptor signaling inhibition reduced CLL cell counts and lymph node tumors, enabling BCL-2 inhibitor treatment to avoid tumor lysis syndrome.

Keywords: immunology; immunotherapy; leukemia; lymphoma; signal transduction therapeutics.

Publication types

  • Letter

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antigens, CD20* / immunology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bridged Bicyclo Compounds, Heterocyclic* / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic* / therapeutic use
  • Class I Phosphatidylinositol 3-Kinases* / antagonists & inhibitors
  • Drug Resistance, Neoplasm* / drug effects
  • Female
  • Heterocyclic Compounds, 4 or More Rings
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Male
  • Middle Aged
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors / therapeutic use
  • Recurrence
  • Sulfonamides* / pharmacology
  • Sulfonamides* / therapeutic use
  • Tumor Burden / drug effects

Substances

  • Sulfonamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Class I Phosphatidylinositol 3-Kinases
  • venetoclax
  • Antigens, CD20
  • PIK3CD protein, human
  • ublituximab
  • umbralisib
  • Phosphoinositide-3 Kinase Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Heterocyclic Compounds, 4 or More Rings