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Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30–35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.

A patient with clonal hematopoiesis of indeterminate potential (CHIP) received the diagnosis of lymphoma with activation of RHOA . Approximately 1 year later, NPM1 -mutated acute leukemia developed with the same CHIP mutations but without mutated RHOA .

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1 -mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1 -mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1 -mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1 -mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1 -mutated AML that deserves further investigation in larger clinical studies.

Initial evidence of CPX-351 activity in patients younger than 60 years emerged from a phase I trial [1]; however, subsequent pivotal phase III trial focused on older patients (≥60 years), where CPX-351 demonstrated superiority over conventional ‘7 + 3’ induction, in in secondary acute myeloid leukemia (sAML), including therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC), showing higher overall response rates (ORR), improved overall survival (OS) and increased haematopoetic stem cell transplantation (HSCT) rate [2]. Since CPX-351 is approved for all adult sAML, we conducted a multicentric retrospective study in patients <60. No differences in event-free survival (EFS) were observed according to clinical and laboratory parameters (Supplementary Table S10). [...]those transplanted with active disease had poor outcomes, with mOS of 9.6 months.In the landmark analysis, patients transplanted in first CR had not reached mOS, while no significant OS differences were observed by CK presence (Fig. 2C). The UK NCRI AML19 trial further compared CPX-351 with FLAG-Ida in younger adults with high-risk AML/MDS, showing no OS difference but improved RFS with CPX-351, particularly in patients with MDS-related gene mutations [12].

Brugada syndrome (BS) is a genetic condition that predisposes individuals to life-threatening arrhythmias, posing a challenge in the management of chronic lymphocytic leukemia (CLL). While BTK inhibitors have been associated with ventricular arrhythmias, data on the cardiac safety of venetoclax and obinutuzumab in BS patients remain limited. We describe the case of a 60-year-old CLL patient with a baseline type 2 Brugada ECG pattern who was treated with venetoclax plus obinutuzumab due to concerns over BTK inhibitor-associated cardiac risks. During the first obinutuzumab infusion, the patient experienced an infusion-related reaction with hypotension, hypokalemia, and transient conversion to a type 1 Brugada ECG pattern. Supportive measures, including electrolyte correction, led to ECG normalization. Venetoclax was well tolerated, and the patient achieved a complete response with undetectable measurable residual disease. This case underscores the importance of cardiac monitoring in CLL patients with BS and suggests that venetoclax plus obinutuzumab may represent a safe and effective therapeutic alternative when BTK inhibitors are contraindicated.

Despite the greater biological understanding and the new drugs available, acute myeloid leukaemia (AML) patients who are refractory to intensive induction chemotherapy represents an unmet clinical need, especially in young/fit adults who are eligible for bone marrow transplantation. Since venetoclax/azacitidine (ven/aza) was introduced in AML management in 2020, survival of elderly/unfit patients has dramatically improved, especially in those carrying NPM1 or IDH2 mutations. However, the use of ven/aza in young and fit adults remains limited, raising ongoing debate about its potential role beyond patients ineligible to intensive chemotherapy. Here, we discuss three under 60 years chemorefractory AML patients, who, given the concomitant IDH2 mutations, were started to ven/aza as bridge-to-transplant and successfully treated. These cases confirm the extraordinary sensitivity of IDH2 -mutated AML to aza/ven even in the refractoriness setting and show that such less-intensive regimen can be driven by genetics offering a promising alternative to intensive salvage chemotherapy, while preserving patient fitness for allo-transplant.