Approach to a patient with "double refractory" chronic lymphocytic leukemia: "Double, double toil and trouble" (Shakespeare)

Am J Hematol. 2022 Nov:97 Suppl 2:S19-S25. doi: 10.1002/ajh.26682.


As patients continue to live longer with chronic lymphocytic leukemia, it has become evident that there is an unmet treatment need for patients who have progressed on multiple lines of therapy. In this article, we attempt to define the "double refractory" patient as resistant to both Bruton's tyrosine kinase inhibitors (BTKi) and venetoclax for which prognosis is poor and there remains no standard of care. We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non-covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development.

Publication types

  • Case Reports
  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / therapeutic use
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell* / genetics
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use
  • Receptors, Chimeric Antigen* / therapeutic use


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Receptors, Chimeric Antigen