Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) 
remains a clinical challenge. Relapsed disease has a poor prognosis despite the 
use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive 
(Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and 
chimeric antigen receptor T cells. Targeting aberrant cell survival pathways 
with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, 
S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. 
We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in 
vitro. The combination demonstrated greater efficacy than standard 
chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, 
Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with 
dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic 
combination appeared superior in vitro in a variety of Ph-like ALL samples. In 
PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ 
B-ALL cases, although fatal tumor lysis was observed in some instances of high 
tumor burden. We conclude that a dual BH3-mimetic approach is highly effective 
in diverse models of high-risk human B-ALL and warrants assessment in clinical 
trials that incorporate tumor lysis precautions.