BCL2 Inhibitors: Insights into Resistance

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

Abstract

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.

Keywords

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

Abbreviations

AML

Acute myeloid leukemia

BCL2

B cell lymphoma 2

BCR

B cell receptor

BH

BCL2 homology

BTK

Burtons tyrosine kinase

CI

Confidence interval

CLL

Chronic lymphocytic leukemia

CR

Complete remission

CRi

Complete remission, incomplete count recovery

Del11q

Deletion 11q

Del17p

Deletion 17p

DLBCL

Diffuse large B cell lymphoma

DLT

Dose limiting toxicity

DOR

Duration of response

EC50

Half maximal effective concentration

EFS

Event free survival

FFP

Freedom from progression

FL

Follicular lymphoma

G

Grade

HL

Hodgkin lymphoma

IDH

Isocitrate dehydrogenase

IGVH

Immunoglobulin variable region heavy chain

IHC

Immunohistochemistry

MCL

Mantle cell lymphoma

MLL

Mixed lineage leukemia

MM

Multiple myeloma

MRD

Minimal residual disease

MTD

Maximum tolerated dose

MZL

Marginal zone lymphoma

NA

Not applicable

NHL

Non-Hodgkin lymphoma

nM

Nano-molar

ORR

Overall response rate

OS

Overall survival

PD

Progressive disease

PFS

Progression free survival

PI3κ

Phosphoinositide 3 kinase

PR

Partial response

RP2D

Recommended phase 2 dose

RT

Richter’s transformation

SLL

Small lymphocytic lymphoma

TLS

Tumor lysis syndrome

TTP

Time to progression

WM

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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