Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a disease with poor outcomes. They are more effective than standard chemotherapy with a good safety profile. For “fit patients” in first-line, the combination of gemtuzumab ozogamicin or midostaurin with intensive chemotherapy or Vyxeos is now considered the “standard of care” for selected patients. On the other hand, for “unfit patients”, azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development. Nevertheless, global survival results, especially in relapsed or refractory patients, remain unfavorable. New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies (“triplets”) and maintenance strategies guided by measurable residual disease.

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5 ′ -azacitidine (5 ′ -Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5 ′ -Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5 ′ -Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2 -mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

This multicenter retrospective study by GETH-TC validates the prognostic value of the Allo-HCT Refined ELN 2022 risk classification in allografted AML patients. The new classification refines the ELN 2022 risk classification, dividing adverse-risk patients into two subgroups: Adv-Plus (AdvP), including those with complex karyotype, MECOM (EVI1) rearrangement, or TP53 mutations/del(17p), and an additional adverse group (Adv*). The study included 651 AML patients treated with at least one line of anthracycline-based induction therapy and in complete remission. According to the Allo-HCT Refined ELN 2022 risk classification, 19.4% (n = 126) patients were classified into the Favorable (Fav) risk, 38.1% (n = 248) into the Intermediate (Int) risk, 27.2% (n = 177) in the Adv* and 15.4% (n = 100) in the AdvP. Outcomes were significantly poorer for patients allocated in the AdvP risk group (5-year OS rate: 32.3%, 5-year LFS rate: 24.3%, both p < 0.001 with the rest of subgroups) and a higher CIR (5-year CIR: 64.3%, p < 0.001). Patients in the Adv* risk group had similar outcomes than patients in the Int risk group (5-year OS rate: 70.2% vs. 66.7%, p = 0.69, 5-year LFS rate: 63.8% vs. 55.9%, p = 0.33). Multivariate analysis confirmed the dismal outcomes for AdvP patients for OS: Hazard Ratio (HR) = 3.05, and LFS: HR = 2.66, both p < 0.001. Our findings validate the Allo-HCT Refined ELN 2022 classification as a robust prognostic tool, particularly highlighting the poor outcomes for the AdvP subgroup.

Acute myeloid leukemia (AML) in the elderly remains a clinical challenge, with a five-year overall survival rate below 10%. The current ELN 2017 genetic risk classification considers cytogenetic and mutational characteristics to stratify fit AML patients into different prognostic groups. However, this classification is not validated for elderly patients treated with a non-intensive approach, and its performance may be suboptimal in this context. Indeed, the transcriptomic landscape of AML in the elderly has been less explored and it might help stratify this group of patients. In the current study, we analyzed the transcriptome of 224 AML patients > 65 years-old at diagnosis treated in the Spanish PETHEMA-FLUGAZA clinical trial in order to identify new prognostic biomarkers in this population. We identified a specific transcriptomic signature for high-risk patients with mutated TP53 or complex karyotype, revealing that low expression of B7H3 gene with high expression of BANP gene identifies a subset of high-risk AML patients surviving more than 12 months. This result was further validated in the BEAT AML cohort. This unique signature highlights the potential of transcriptomics to identify prognostic biomarkers in in elderly AML.

Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workups. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and fluorescence-activated cell sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly diagnosed patients with AML. Presence of dysplasia according to MFC and World Health Organization criteria had no prognostic value in older adults. NGS of dysplastic cells and blasts isolated at diagnosis identified 3 evolutionary patterns: stable (n = 12 of 21), branching (n = 4 of 21), and clonal evolution (n = 5 of 21). In patients achieving complete response (CR), integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in ∼80% of patients with newly diagnosed AML, using techniques other than single-cell multiomics.