Third-line therapy for chronic myeloid leukemia: current status and future directions

J Hematol Oncol. 2021 Mar 18;14(1):44. doi: 10.1186/s13045-021-01055-9.


Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.

Keywords: Chronic myeloid leukemia; Emerging therapies; Third line; Tyrosine kinase inhibitors.

Publication types

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

MeSH terms

  • Aniline Compounds / therapeutic use
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Clinical Trials as Topic
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Homoharringtonine / therapeutic use
  • Humans
  • Imidazoles / therapeutic use
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Molecular Targeted Therapy
  • Niacinamide / analogs & derivatives
  • Niacinamide / therapeutic use
  • Nitriles / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / therapeutic use
  • Pyridazines / therapeutic use
  • Quinolines / therapeutic use


  • Aniline Compounds
  • Antineoplastic Agents
  • BCR-ABL1 fusion protein, human
  • Imidazoles
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridazines
  • Quinolines
  • asciminib
  • Niacinamide
  • ponatinib
  • bosutinib
  • Homoharringtonine
  • Fusion Proteins, bcr-abl