In newly diagnosed AML patients ineligible for induction, tuspetinib plus venetoclax and azacitidine delivered a 90% CR/CRh rate across 40, 80, and 120 mg tuspetinib cohorts, with 100% CR/CRh at the 80 and 120 mg dose levels. Among responders, 78% achieved MRD negativity by central flow. The triplet showed no dose-limiting toxicities, no reported differentiation syndrome, QTc prolongation, or drug-related deaths, and febrile neutropenia occurred in 16.7% of patients. Eight of ten evaluable patients attained red cell and platelet transfusion independence for more than eight weeks after best response. Early, non-poster observations at a newly opened 160 mg cohort suggest rapid blast clearance and MRD negativity within the first weeks.
The update, presented at ASH from the Phase 1/2 TUSCANY study, positions tuspetinib as a frontline add-on to standard azacitidine and venetoclax in an unfit population. Activity was reported across FLT3 wildtype and ITD, NPM1c, TP53/complex karyotype, RAS, and MDS-related mutations, and two patients bridged to transplant and returned for tuspetinib maintenance. As an oral multi-kinase inhibitor of SYK, FLT3, KIT, JAK1/2, and RSK2, tuspetinib is being advanced on the thesis that broad pathway coverage may counter venetoclax resistance mechanisms while avoiding overlapping toxicities.
Strategically, this is a bid to break beyond mutation-siloed triplets and claim a broader frontline AML segment anchored on HMA/ven backbones. The headline response and MRD rates exceed historical doublet benchmarks, but the field’s recent experience with triplets has been defined by cytopenias, infections, and early mortality that eroded perceived benefit. The company is emphasizing the absence of dose-limiting toxicities and lack of prolonged cycle 1 myelosuppression in remitters, a profile that, if durable at scale, would differentiate from other add-ons that have struggled to clear the tolerability bar. The choice of a multi-kinase agent rather than a single-target add-on is also a deliberate hedge against clonal heterogeneity and the high prevalence of FLT3 wildtype disease where FLT3-directed triplets have limited reach.
For sites, the operational proposition is a once-daily oral add-on without biomarker gating, which can reduce screening friction and simplify pharmacy workflow relative to antibody or inpatient-intensive regimens. Central MRD readouts will demand consistent sampling and logistics but align with evolving endpoint expectations. Supportive care intensity will remain critical given venetoclax-driven cytopenias; the reported transfusion independence signal, if confirmed prospectively, could become a pragmatic differentiator for patient management and bed utilization. Sponsors and CROs should see in this dataset the contours of the next wave of frontline AML trials: randomized comparisons versus azacitidine/venetoclax with MRD, duration of remission, and healthcare utilization as co-equal decision variables alongside OS. Regulators will expect evidence that deeper responses translate into survival and do not come at the cost of infection burden, dose interruptions, or hospitalization rates that neutralize benefit.
The key watch items are scale and durability. The dataset appears small and early, and the 160 mg cohort needs mature safety and efficacy readouts. Prolonged cytopenias beyond cycle 1, serious infection rates, and early mortality will determine whether the safety narrative holds outside escalation. Randomized design details, including inclusion of TP53-mutated and secondary AML, venetoclax dosing management, and MRD methodology standardization, will signal regulatory intent. Competitive context also matters: multiple triplets are chasing the same backbone, and differentiation will come from operational simplicity, tolerability, and demonstrable survival and utilization gains rather than incremental response rates alone.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
