期刊
BLOOD ADVANCES
卷 4, 期 12, 页码 2762-2767出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2019001416
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资金
- National Health and Medical Research Council [GNT1113577, GNT1060179, GNT1122783]
- Cancer Council Victoria
- Victorian Cancer Agency
- Leukaemia Foundation of Australia
- Leukemia and Lymphoma Society (Specialized Center of Research) grant [20454683]
- Australian Cancer Research Foundation
- Monash Partners
- Alfred Foundation
- Medical Research Future Fund
- Children's Cancer Foundation
- Department of Health and Human Services through the Victorian Cancer Agency
- Australian Government Independent Research Institute Infrastructure Support Scheme
- Victorian Government Operational Infrastructure Support
- Servier
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.
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