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Despite allogeneic hematopoietic stem cell transplant (allo-HCT) and the development of novel FLT3 inhibitors in both induction (midostaurin) and in the relapsed/refractory setting (gilteritinib), FLT3-ITD mutated leukemia (FLT3- ITD+ AML) still represents a challenge for modern hematology. Sorafenib is, to this date, the only inhibitor that demonstrated efficacy in improving both progression-free and overall survival as post-HCT maintenance therapy, even if its use in this setting has not been approved so far by regulatory agencies. The aim of our study was to evaluate the feasibility, safety, and efficacy of sorafenib maintenance in preventing early relapse in FLT3-ITD+ AML after HCT in a singlecenter experience. We analyzed 26 consecutive patients who received post-HCT 2-year maintenance with sorafenib at our center between 2017 and 2023. The median time from HCT to sorafenib start was 130 days, and the median dosage was 200 mg per day. Two (8%) and three (12%) patients discontinued maintenance due to toxicity and disease relapse, respectively. Eight (31%) patients terminated the 2-year maintenance and stopped sorafenib, while 13 patients are still under treatment. Overall, 21/26 patients (81%) are alive and in stable complete remission as outlined by a 2-year disease-free survival of 83.61%. No major long-term toxicity was reported at the last follow-up. Our real-world experience supports the use of sorafenib as a feasible and effective therapeutic option in post-HCT maintenance for FLT3-ITD+ AML. [ABSTRACT FROM AUTHOR]

Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder characterized by variable risk of evolution to acute myeloid leukemia; to date, allogeneic stem cell transplantation is the only curative treatment. We report a case of choroidal involvement in a woman affected by CMML and presenting only with visual impairment. The patient was initially evaluated for an intensive therapeutic approach, but after biopsy the ocular lesion spontaneously regressed. Thus a "watch and wait" strategy was preferred. One year and a half after initial diagnosis, the patient is alive, with stable hematological disease and without any ocular involvement. Therefore, a close, not invasive follow up could be useful to tailor treatment for patients affected by single ocular lesions in CMML. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts. Relapse within acute myeloid leukaemia may be driven by the presence of leukaemia stem cells. Here, the authors use single cell RNA-seq seq to characterise leukemia stem cells, and show miR-126 as a potential marker of resistance. [ABSTRACT FROM AUTHOR]

The prognosis of newly diagnosed patients with acute myeloid leukemia is still unfavorable in the majority of cases within the intermediate and mainly adverse genetic risk group but also in a considerable fraction of favorable-risk patients, mainly due to recurrence of disease after complete remission achievement or, less frequently, primary refractoriness. Besides genetic classification at diagnosis, post-treatment prognostic factors include measurable residual disease evaluation in patients in complete remission and in most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention. Currently, the most commonly used methods for detection of minimal residual disease are multiparameter flow cytometry and quantitative PCR, applicable to around 90% and 50% of patients, respectively. In addition, in > 90% of acute myeloid leukemia (AML) patients, molecular aberrations can be identified by next-generation sequencing, a technology that is widely used in clinical practice for the initial mutational screening at the time of diagnosis but more often, for MRD detection because its flexibility allows almost every mutated gene to be used as an MRD marker. Threshold levels of residual disease and correlation with outcome have been thoroughly studied and established in younger patients treated with intensive induction and consolidation chemotherapy as well as after allogeneic transplantation. Yet, experience on MRD monitoring and interpretation in patients treated with low-intensity regimens, including new agents, is still limited. The updated armamentarium of antileukemic agents includes the BCL-2 inhibitor venetoclax, which demonstrated good tolerability, high response rates, and prolonged overall survival when combined with hypomethylating agents or low dose cytarabine in patients considered elderly/”unfit” to tolerate intensive regimens. Although remissions with negative minimal residual disease clearly translated into improved outcomes after intensive treatments, data supporting the same evidence in patients receiving low-intensity venetoclax-based treatments are not still consolidated. We here review and discuss more recent data on the minimal residual disease interpretation and role in AML patients treated with venetoclaxbased combinations. [ABSTRACT FROM AUTHOR]

In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the search for additional and synergistic therapeutic rationales. It is increasingly evident that the bone marrow immune environment of AML patients is profoundly altered, contributing to the severity of the disease but also providing several windows of opportunity to prompt or rewire a proficient antitumor immune surveillance. In this Review, we present current evidence on immune defects in AML, discuss the challenges with selective targeting of AML cells, and summarize the clinical results and immunologic insights from studies that are testing the latest immunotherapy approaches to specifically target AML cells (antibodies, cellular therapies) or more broadly reactivate antileukemia immunity (vaccines, checkpoint blockade). Given the complex interactions between AML cells and the many components of their environment, it is reasonable to surmise that the future of immunotherapy in AML lies in the rational combination of complementary immunotherapeutic strategies with chemotherapeutics or other oncogenic pathway inhibitors. Identifying reliable biomarkers of response to improve patient selection and avoid toxicities will be critical in this process. [ABSTRACT FROM AUTHOR]

Despite the considerable progress in understanding the molecular bases of acute myeloid leukemia (AML), new tools to link disease biology to the unpredictable patient clinical course are still needed. Herein, high-throughput metabolomics, combined with the other "-omics" disciplines, holds promise in identifying disease-specific and clinically relevant features. In this study, we took advantage of nuclear magnetic resonance (NMR) to trace AML-associated metabolic trajectory employing two complementary strategies. On the one hand, we performed a prospective observational clinical trial to identify metabolic changes associated with blast clearance during the first two cycles of intensive chemotherapy in nine adult patients. On the other hand, to reduce the intrinsic variability associated with human samples and AML genetic heterogeneity, we analyzed the metabolic changes in the plasma of immunocompromised mice upon engraftment of primary human AML blasts. Combining the two longitudinal approaches, we narrowed our screen to seven common metabolites, for which we observed a mirror-like trajectory in mice and humans, tracing AML progression and remission, respectively. We interpreted this set of metabolites as a dynamic fingerprint of AML evolution. Overall, these NMR-based metabolomic data, to be consolidated in larger cohorts and integrated in more comprehensive system biology approaches, hold promise for providing valuable and non-redundant information on the systemic effects of leukemia. [ABSTRACT FROM AUTHOR]

Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation ( HSCT) for FLT3- ITD-positive acute myeloid leukemia ( AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off-label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post-transplantation FLT3- ITD-positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand-foot syndrome. None of the patients developed graft-vs.-host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T-cell infusions. Six patients are alive and in remission at the last follow-up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3- ITD-positive post-transplantation relapses, manageable also in combination with other therapeutic strategies. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy. [Display omitted] • The proteogenomic features of 58 acute myeloid leukemia (AML)-specific antigens • AML antigens result mainly from epigenetic changes and intron retention • AML antigens are coded by transcripts expressed in leukemic blasts and stem cells • AML antigens elicit CD8 T cell responses in vitro and in vivo The lack of suitable targets is the main obstacle to immunotherapy of acute myeloid leukemia (AML). Ehx et al. reveal the structure and genomic origin of 58 AML-specific antigens. Epigenetic changes and intron retention are instrumental in the biogenesis of these antigens that represent attractive targets for AML immunotherapy. [ABSTRACT FROM AUTHOR]