BCL2 Inhibitors: Insights into Resistance

  • Mary Ann Anderson
  • Andrew W. Roberts
  • John F. Seymour
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 17)


Over the last decade, improved understanding of the mechanisms and structures of proteins integral to apoptosis have enabled therapeutic targeting of BCL2 to become more specific, less toxic and ultimately more clinically effective. The first BCL2-selective inhibitor, venetoclax, is now approved for use in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) in multiple countries. Early phase clinical trials demonstrated an 80% overall response rates in patients with relapsed/refractory CLL, independent of traditional risk factors, without undue toxicity. Venetoclax is also highly active in other lymphoid malignancies that express high levels of its target, BCL2, such as mantle cell lymphoma. However, there is a cumulative incidence of disease progression while on therapy. Ongoing follow-up of the early phase trials is only now enabling elucidation of the incidence and risk factors for disease progression and treatment failure. Preventing development of resistance to BCL2 inhibition requires further research aimed at delineating the genetic and epigenetic drivers of disease progression. This will facilitate targeting of resistance mechanisms through the use of rational drug combinations, help to prospectively identify patients most likely to benefit and abet early identification of emerging resistance. These therapies are improving outcomes for patients with previously poor prognosis disease.


BCL2 (B cell lymphoma 2) Apoptosis Venetoclax Chronic lymphocytic leukemia 



Acute myeloid leukemia


B cell lymphoma 2


B cell receptor


BCL2 homology


Burtons tyrosine kinase


Confidence interval


Chronic lymphocytic leukemia


Complete remission


Complete remission, incomplete count recovery


Deletion 11q


Deletion 17p


Diffuse large B cell lymphoma


Dose limiting toxicity


Duration of response


Half maximal effective concentration


Event free survival


Freedom from progression


Follicular lymphoma




Hodgkin lymphoma


Isocitrate dehydrogenase


Immunoglobulin variable region heavy chain




Mantle cell lymphoma


Mixed lineage leukemia


Multiple myeloma


Minimal residual disease


Maximum tolerated dose


Marginal zone lymphoma


Not applicable


Non-Hodgkin lymphoma




Overall response rate


Overall survival


Progressive disease


Progression free survival


Phosphoinositide 3 kinase


Partial response


Recommended phase 2 dose


Richter’s transformation


Small lymphocytic lymphoma


Tumor lysis syndrome


Time to progression


Waldenstrom’s macroglobulinemia


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Mary Ann Anderson
    • 1
    • 2
  • Andrew W. Roberts
    • 1
    • 2
    • 3
  • John F. Seymour
    • 1
    • 3
  1. 1.Department of HaematologyRoyal Melbourne Hospital & Peter MacCallum Cancer CentreParkvilleAustralia
  2. 2.Division of Cancer and HaematologyWalter and Eliza Hall InstituteParkvilleAustralia
  3. 3.The University of MelbourneMelbourneAustralia

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