Combination of Venetoclax and Midostaurin Efficiently Suppressed Relapsed t(8;21)Acute Myeloid Leukemia With Mutant KIT After Failure of Venetoclax Plus Azacitidine Treatment

Abstract

Acute myeloid leukemia (AML) with t(8;21) is categorized as favorable-risk AML, but KIT mutations show a significantly poor prognostic impact in such patients. Persistent vulnerability to relapse is a major challenge in the treatment of this subtype of patients. Venetoclax is a BCL-2 selective inhibitor. The venetoclax+HMA strategy is also a notable salvage regimen that achieves good clinical outcomes in the treatment of relapsed or refractory (R/R) AML. However, in our clinical practice, we found that disease progressed rapidly even after venetoclax+azacitidine (AZA) therapy in two relapsed t(8;21) AML patients with KIT mutations. We report for the first time the therapeutic potential of venetoclax+midostaurin as a new combination therapy for relapsed t(8;21) AMLs with KIT mutations showing resistance to venetoclax+AZA therapy. Our ex vivo study also showed that midostaurin alone could inhibit proliferation and induce apoptosis of Kasumi-1 cells (e.g. Midostaurin induced G2 phase cell arrest, down-regulated p-KIT and BCL-2, while Bax protein levels were up-regulated) and observed a synergistic anti effect when the two drugs were combined. Our study shows that the venetoclax+midostaurin regimen may be a promising treatment option for R/R t(8;21) AML with KIT mutations.

Efficacy of venetoclax combined with hypomethylating agents in young, and unfit patients with newly diagnosed core binding factor acute myeloid leukemia

“…In a multicenter, phase 2 trial of VEN + azacitidine plus homoharringtonine in R/R AML, 6 patients with t(8;21) were included, and all achieved remission after treatment [ 12 ]. Similarly, we recently reported that midostaurin showed synergistic effects with VEN in an ex vivo study, and the combination therapy rescued two relapsed t(8;21) AML patients with KIT mutations who progressed rapidly after VEN + azacitidine therapy [ 13 ].…”

Pharmaco‐phosphoproteomic analysis of cancer‐associated KIT mutations D816V and V560G

“…While epigenetic modifiers azactidine and decitabine have been shown to be growth inhibitory in KIT‐mutant mast cell leukaemia cell lines [37], D816V‐mutant KIT has been associated with progression on midostaurin and azacitidine combination treatment in a patient with systemic mastocytosis [38]. Disease progression on venetoclax and azacitidine therapy was also reported for two AML patients with tyrosine kinase domain KIT mutations [39]. Thus, mutant KIT may be associated with poor response to these hypomethylating therapies.…”

Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia

“…Gilteritinib and quizartinib were approved for relapsed/refractory (R/R) AML patients with FLT3 mutation in 2018 and 2019, respectively [ 16 , 17 ]. In addition to FLT3, other receptor tyrosine kinases (RTKs) like KIT are targets of RTK inhibitors such as midostaurin, sorafenib, dasatinib, and bemcentinib [ 18 , 19 ]. Besides, the inhibitors of IDH2 (enasidenib) and IDH1 (ivosidenib) were also approved for the treatment of R/R AML with corresponding mutants in 2017 and 2018, respectively [ 20 , 21 ].…”