Clinical Experience With Venetoclax-Based Combinations for Relapsed/Refractory or MRD-Positive NPM1-Mutated Acute Myeloid Leukemia.

To the Editor, NPM1 mutations occur in ~30% of acute myeloid leukemia (AML) [1] and define a distinct entity according on current WHO and ICC classification [2, 3]. NPM1mut AML shows het- erogeneous clinical behavior: some patients respond well to chemotherapy with rapid measurable residual disease (MRD) clearance, while others experience primary refractoriness or early relapse. Co-mutations, particularly FLT3-ITD, contribute to this variability [4]. While first-line treatment of NPM1mut AML is well established [1], optimal management of relapsed/ refractory (R/R) disease remains uncertain. Furthermore, in case of primary refractory or early relapsing patients, chemore- sistance represents an issue [5]. For patients treated with cura- tive intent, salvage chemotherapy followed by allogeneic stem cell transplantation (ASCT) is standard approach, although such regimens are burdened by toxicities that delay or prevent ASCT in some cases. In elderly and HSCT ineligible patients, therapeutic options are limited. Recently, favorable toxicity pro- file and efficacy of venetoclax (VEN) in combination with hy- pomethylating agents (HMAs) or low- dose cytarabine (LDAC) in NPM1mut AML was reported in first line [6, 7] and the R/R setting [8–10]. Moreover, considering the evolving therapeutic scenario, the role of MRD- directed intervention in NPM1mut AML, based on early detection of impending relapse at the mo- lecular level, is unclear. Although the study was not powered to assess the im- pact of co-mutations on CR achievement and survival, im- proved outcomes were observed in patients with IDH1 or IDH2 mutations, consistent with previous reports [7, 9, 10]. In FLT3mut patients, while FLT3 inhibitor-based regimens remain preferred, VEN-based approaches may represent a potential option. Notably, patients treated for MRD relapse or persistence achieved high MRD clearance and favorable survival. The tolerability and activity of VEN-based reg- imens support their potential role in MRD- directed ther- apy, currently being investigated in a phase II GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) trial (NCT04867928). The favorable toxicity profile of VEN-based regimens may offer an advantage over conventional salvage chemotherapy, particularly as bridge-to-transplant in R/R NPM1 mut AML. Interestingly, the durable CRs were observed in some patients even without ASCT, warranting further investigation