ASH 2017 | BCL-2 family members implicated in ibrutinib and venetoclax resistance in CLL

On Saturday December 9^th, 2017 during an oral abstract session at the 59^th Annual meeting American Society of Hematology (ASH), Eric Eldering of the Academic Medical Center in Amsterdam, Netherlands, on behalf of his colleagues, presented results from an in vitro study in which they endeavored to understand the contribution of distinct BCL-2 family members to resistance against ibrutinib or venetoclax in chronic lymphocytic leukemia (CLL). The investigators underscored the need to further elucidate the contribution of distinct BCL-2 family members to resistance against these single drugs in order to design more effective, long-term therapy combinations.

This abstract (#262), “Dissecting the Role of Individual Bcl-2 Members in Response and Resistance to Ibrutinib or Venetoclax in CLL,” was presented during Oral Session: 641. “Biology and Pathophysiology, excluding Therapy: Therapeutic Resistance in CLL.” In the summary below, data from the live session at ASH is used and therefore may supersede information in the pre-published Abstract.

 Highlights

• Venetoclax and ibrutinib, both used for treatment of chronic lymphocytic leukemia (CLL), are rendered ineffective over time
• Changes in the expression of BCL-2 family members are implicated in the resistance to these treatments, but their distinct contributions are not yet well defined
• Investigators measured changes in pro-survival BCL-2 members in lymph node (LN) emigrants versus returning cells in peripheral blood (PB) samples of responding and relapsed patients on ibrutinib treatment, and during venetoclax ramp-up treatment
  • In pretreatment blood samples, recent LN emigrants have higher BCL-XL and MCL-1 expression than returning cells.
  • This collapses in response to ibrutinib, which indicated that although peripheral blood cell counts rose, blocking access to the LN effectively lowered expression of protective BCLXL and MCL-1 in vivo
• The study uncovered the contribution of individual BCL-2 members in determining CD40-induced resistance to venetoclax by BH3 mimetic profiling), and by stapled peptides targeting BFL-1
  • Venetoclax resistance in CD40-treated CLL cells can be reverted to almost pre-stimulation susceptibility by combined antagonism of BCL-XL and BFL-1.
  • However, in patients that develop ibrutinib resistance (N=9), the MCL-1 or BCL-XL pre-treatment profile reappears
• Venetoclax treatment was associated with rapid reduction of CLL cells from PB and LN (n=8), but in contrast to Ibrutinib no changes in BCL-2 members in LN emigrants versus immigrants were observed

 While small in size, this study strongly indicated that BCL-2 members can be used as both a drug target and markers of response and relapse. The hope is that larger studies will yield treatment strategies that leverage a combination of venetoclax and ibrutinib that prevent access to the protective LN, and perhaps establish a new, effective long-term treatment regimen in CLL.