Researchers from the University of Hong Kong found that therapy with the synergistic combination of quizartinib and omacetaxine mepesuccinate (QUIZOM) in acute myeloid leukaemia (AML) patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations produced high rates of composite complete remission (CRc), allowing more AML patients to be bridged to allogeneic haematopoietic stem cell transplantation (HSCT).
The open-label phase II trial included 40 patients with FLT3-ITD AML (35 relapsed/refractory [R/R] patients ≥18 years old, and five newly diagnosed patients ≥65 years old) who were unfit for conventional chemotherapy. Of the 35 R/R patients, 14 had previously received a FLT3 inhibitor. Patients received oral quizartinib 30 mg QD + intravenous (IV) omacetaxine 2 mg QD for 7 days (1st cycle), then 5 days (subsequent cycles) for every 21–28 days until HSCT or disease progression. Patients achieving complete remission (CR) or complete remission with incomplete haematologic recovery (CRi) were referred for HSCT. Quizartinib was given as post-HSCT maintenance for at least 24 months after engraftment at doses ranging from 30 mg QD twice weekly to 30 mg QD, depending on tolerability. [Nat Commun 2026;doi:10.1038/s41467-026-71186-5]
The regimen produced a CRc rate of 83 percent (33/40; CR, 15 percent; CRi, 68 percent), a median leukaemia-free survival (LFS) of 10 months (range, 0.7–68.2 months), and a median overall survival (OS) of 12.9 months (range, 1.8–69.2 months).
Of the 33 CRc patients, 13 (39 percent) received allogeneic HSCT after a median of 143 days (range, 53–367 days). For those bridged to HSCT, median LFS and OS were not reached at analysis (median follow-up, 4.7 years). By contrast, median LFS was 3.3 months and median OS was 9.9 months among patients who did not undergo HSCT.
Notably, 29 patients achieved remission after one cycle of QUIZOM, and four patients after two cycles. Median time to response was 23 days (range, 17–62 days). CRc rates were 86 percent in the R/R group and 60 percent in the newly diagnosed group. Higher response rates were observed in patients with co-mutations in NPM1 (95 vs 67 percent; p=0.038), DNMT3A (95 vs 67 percent; p=0.038), and wild-type WT1 (91 vs 20 percent; p=0.002).
Treatment-emergent adverse events were mainly myelosuppression and infection. Grade 3/4 cytopenias (>60 percent) and febrile neutropenia (60 percent) were common, and 20 percent of the patients developed bacteraemia requiring IV antibiotics. Importantly, QTc prolongation was not observed at the study dose.
The research team had earlier identified FLT3-ITD as a target for intervention in R/R AML. They found that QUIZOM co-inhibited FLT3-ITD signal and protein translation by synergistic suppression of the most critical FLT3-ITD survival signals (including mitochondrial respiration and proteostasis), which induced apoptosis and pro-inflammatory response. [Nat Commun 2026;doi:10.1038/s41467-026-71186-5]
They also identified a leukaemic stem cell (LSC) subpopulation with activated JNK/JUN/HSPA1B axis via PLD1-driven phosphatidylcholine metabolism, which promoted proteostasis and drove QUIZOM resistance. PLD1-inhibitor remodelled phospholipid metabolism, induced ferroptosis and restored QUIZOM response in LSC.
FLT3-ITD mutations occur in around 30 percent of AML cases and are linked to frequent relapse. While FLT3 inhibitors can induce remissions, responses are often transient unless patients proceed to HSCT. The unmet clinical need to identify oncogenic vulnerabilities in FLT3-ITD AML and develop mechanism-driven therapeutic strategies at relapse to bridge more patients to HSCT provided impetus for the study.
“Our findings shed light on the therapeutic and resistance mechanisms of QUIZOM and pave the way for targeted interventions in this AML subtype,” concluded the authors.