Developmental Plasticity of Acute Myeloid Leukemia Mediates Resistance to Venetoclax-Based Therapy

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.185-185
• Main Authors: Pei, Shanshan, Pollyea, Daniel A, Gustafson, Annika, Minhajuddin, Mohammad, Stevens, Brett M., Ye, Haobin, Inguva, Anagha, Amaya, Maria L, Krug, Anna, Jones, Courtney L, Adane, Biniam, Winters, Amanda, Khan, Nabilah, Ponder, Jessica, Schowinsky, Jeffrey, Hammes, Andrew, Abbott, Diana, Myers, Jason R, Ashton, John M, Gutman, Jonathan A, Purev, Enkhtsetseg, Ramsey, Haley E., Savona, Michael R., Fesik, Stephen W., Smith, Clayton, Jordan, Craig T
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-131390

Recent clinical trials have reported that in combination with hypomethylating agents, the BCL-2 inhibitor venetoclax can induce responses in over 70% of older previously untreated AML patients who are unfit for conventional chemotherapy. These findings led to the recent United States Food and Drug Administration approval of this regimen for this population, and it is now considered to be the standard care. However, a significant minority of patients do not achieve a remission and are refractory. In addition, the majority of patients who do achieve a remission ultimately relapse. It is therefore critical to identify AML patients who are likely to be resistant to venetoclax-based therapy. To initially address this question, we retrospectively reviewed 75 newly diagnosed AML patients who received venetoclax + azacitidine (VEN+AZA) at our institution and analyzed several baseline clinical features to determine the ability of each to predict disease that was refractory to treatment (defined as a lack of complete remission [CR], CR with incomplete recovery of peripheral blood counts [CRi], partial remission, or morphological leukemia free state [MLFS]). Both univariate and multivariate analyses revealed the presence of FAB-M5 to be associated with disease that was refractory to VEN+AZA (Table 1). Given that FAB-M5 represents AML with monocytic differentiation, these findings indicate a strong correlation between myeloid differentiation status and resistance to venetoclax. Using multicolor flow cytometry, we show bone marrow specimens of typical FAB-M5 patients who were refractory to VEN+AZA presented dominant monocytic disease that has an immunophenotype of CD45-bright/SSC-high/CD117-/CD11b+/CD68+ (Figure A). In contrast, bone marrow specimens of typical FAB-M0/M1/M2 patients who achieved CR with VEN+AZA presented as a single dominant disease population that is CD45-med/SSC-low/CD117+/CD11b-/CD68- (Figure B). In a subset of AML patients, we observed the co-existence of both phenotypically primitive and monocytic populations, which we term “MPM” AML (for Mixed Primitive/Monocytic). We observe that after attaining CR with VEN+AZA treatment and subsequent relapse, MPM-AML showed almost complete loss of the primitive subpopulation, and evolved to a dominant monocytic disease (Figure C). These data indicate that VEN+AZA treatment induces strong selection of the monocytic phenotype. Importantly, when we compared the immunophenotype of six pairs of diagnostic/relapse s