Myelofibrosis (MF) splenomegaly reflects not only extramedullary hematopoiesis (EMH) but a compartmental organization of the splenic microenvironment into spatially distinct niches. Using Spatial whole transcriptome profiling on FFPE spleen tissue from three MF patients, we interrogated three anatomically defined compartments: Intravascular (IV), Perivascular (PV) and Red Pulp (RP). Differential expression was estimated through pairwise compartment contrasts with Benjamini-Hochberg false discovery rate correction (FDR < 0.05, |log2FC|≥1), and compartment “core signatures” were defined by directional concordance across the two contrasts relevant to each compartment. IV regions of interest (ROIs) showed an endothelial/adhesion and vascular stress program (e.g., PECAM1, VCAM1; antioxidant enzymes). PV ROIs were characterized by fibro-remodeling and immune-structured signals (COL1A1/COL3A1, LOXL1, MMP2/TIMP1; HLA‑DRA/CD74) including CXCL12, consistent with a PV niche coupling extracellular matrix remodeling to hematopoietic retention cues. RP ROIs captured an EMH-associated erythroid/heme program (ALAS2, FECH, BLVRB) with stress and inflammatory alarmins (S100A8/S100A9). Together, these findings support a compartmental “division of labor” in MF spleen, vascular interface activation, PV remodeling/chemokine niches, and RP EMH/redox stress, providing a spatial framework to interpret splenomegaly as structured niche dependencies and to prioritize candidate microenvironmental dependencies for follow‑up validation.

ABSTRACT:CPX-351, a novel liposomal formulation of cytarabine and daunorubicin, represents the standard of care in fit patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and therapy-related AML (t-AML). Considering its better safety profile than conventional intensive chemotherapy, we investigated its cost-to-benefit ratio, in terms of overall survival and of mortality, in a large multicentric series of AML-MRC and t-AML receiving CPX-351 outside clinical trials between 2019 and 2022. Patients were classified as fit or unfit for intensive chemotherapy through a comprehensive evaluation of age, comorbidities, and performance status by adopting Italian Society of Hematology/Italian Society of Experimental Hematology/Gruppo Italiano per il Trapianto di Midollo Osseo (SIE/SIES/GITMO) criteria. Disease risk was defined according to the European LeukemiaNet 2017 classification. Before treatment start, 328 of 403 (81.4%) patients were classified as fit and 75 of 403 (18.6%) as unfit. Three hundred and ninety-six had a full genetic/cytogenetic profile, with 17 (4%) being categorized as favorable risk, 162 (41%) intermediate risk, and 217 (55%) adverse risk according to European LeukemiaNet 2017. After induction, 230 of 403 (57.1%) patients achieved complete remission, with no differences between fit (57.3%) and unfit (56%) patients. However, the 2 groups significantly differed in terms of survival (median overall survival, 18 months vs 8 months for fit and unfit patients, respectively) and of 28- and 100-day mortality (4.6% vs 10.7% at 28 days and 14.3% vs 32% at 100 days for fit and unfit patients, respectively). In conclusion, the SIE/SIES/GITMO criteria distinguished patient subgroups with different short- and long-term outcomes after treatment with CPX-351. The update or design of dedicated fitness criteria could represent a future and valid strategy to optimize the use of this specific treatment.

Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, has emerged as a targetable vulnerability in cancer. ACSL4 is the rate-limiting enzyme that dictates ferroptosis sensitivity by channeling polyunsaturated fatty acids into membrane phospholipids. In acute myeloid leukemia (AML), monocytic subtypes resist BCL2 inhibition with venetoclax, yet their metabolic dependencies remain poorly defined. Here, we integrated PRISM drug-sensitivity data (6,790 compounds) and DepMap CRISPR dependencies (18,435 genes) across 15 adult AML cell lines to map drug-gene co-dependencies. A multi-cohort validation strategy — filtering 50 discovery candidates (29 testable in BeatAML) through ex vivo drug-response data in 476 primary AML specimens and clinical outcomes in 140 adults with de novo AML (TCGA-LAML) — converged on a single axis linking SRC family kinase inhibition to ACSL4 expression. ACSL4-high blasts showed enhanced dasatinib sensitivity (r = -0.25, P = 4.3 x 10-8). A composite SRC/ACSL4 signature stratified overall survival (HR 1.27; 95% CI 1.10-1.47; P = 0.0014), remaining significant after age adjustment. Single-cell atlas projection localized this signature to the monocytic compartment. The SRC/ACSL4-high state displayed a ferroptosis gene expression profile characterized by co-upregulation of ACSL4, HMOX1, and LPCAT3 with failure to upregulate the principal ferroptosis defense axis GPX4/SLC7A11. Conversely, ACSL4-high blasts showed significant ex vivo resistance to venetoclax (r = 0.36, P = 2.5 x 10-12), linking the ferroptosis-primed monocytic state to BCL2 inhibitor failure. These findings nominate ACSL4-driven ferroptosis susceptibility as a lineage-specific vulnerability rendering monocytic AML selectively sensitive to SRC-directed therapy while resistant to BCL2 inhibition.

Acute myeloid leukemia (AML) develops within a bone marrow environment that influences leukemic stem-cell behavior, residual disease, and response to therapy. This review examines evidence that the marrow microenvironment is not only a site of leukemic growth, but can actively shape AML initiation, maintenance, and treatment resistance. Clinical observations such as donor cell leukemia after allogeneic transplantation, together with experimental models in which stromal or osteolineage abnormalities induce myeloid disease, suggest that altered niches may contribute to leukemogenesis in selected settings. In established AML, vascular and endosteal compartments provide adhesive, chemokine, inflammatory, and metabolic signals that promote leukemic-cell retention, quiescence, survival, and chemotherapy tolerance. AML cells also remodel the surrounding marrow, suppressing normal hematopoiesis and generating stromal, endothelial, osteoblastic, adipocytic, and immune-cell programs that favor leukemic persistence. These interactions are especially relevant to drug resistance, including resistance to venetoclax-based therapy, where cytokine-mediated changes in apoptotic dependence, fatty-acid metabolism, mitochondrial adaptation, and stromal support may all contribute. Several therapeutic approaches have attempted to disrupt niche-mediated protection, including targeting CXCL12/CXCR4 signaling, adhesion pathways, inflammatory circuits, Hedgehog signaling, and metabolic dependencies. Although early-phase studies have shown activity in some AML subsets, randomized evidence remains limited and results have been inconsistent. We discuss how a better understanding of microenvironmental biology may help define when niche-directed therapy is most likely to complement conventional and molecularly targeted AML treatment.

Artificial intelligence (AI) and machine learning (ML) now reach into every stage of AML care. Deep learning models read therapy-relevant mutations directly from bone marrow smears; automated flow cytometry gating reproduces expert calls in under a minute; and the first AI pathology devices for hematology have cleared regulatory review and entered clinical use. Beyond diagnosis, ML captures the age-dependent weight of individual mutations that categorical ELN scoring misses, drug response prediction for venetoclax–azacitidine has been validated across multiple external cohorts, and large language models are being tested for tumor board support and trial matching. The next wave, from clonal architecture modeling and single-cell foundation models to digital twins and reinforcement learning for adaptive dosing, could move AML management from reactive toward predictive, evolution-aware care. This review departs from existing AI-in-hematology surveys in three ways: we (i) restrict the scope to AML and organize the field around clinical decision points rather than technology categories, (ii) grade every tool on a five-tier author-defined clinical readiness level (CRL-AML 1–5), which exposes hundreds of models clustered at CRL-AML 1–2 and none yet in prospective clinical evaluation, and (iii) close with a numbered three-year agenda naming the consortia, datasets, and pragmatic trials needed to carry the field from publication to practice.

The inhibition of bromodomain and extra-terminal domain (BET) protein family achieved promising preclinical results as epigenetic therapy in acute myeloid leukemia (AML), although clinical activity of bromodomain inhibitor (BETi) as single agent remains limited. Combination strategies, including BETi with BCL-2 inhibition (e.g., Venetoclax), have been explored to enhance therapeutic efficacy. Our study aimed to investigate the role of hypoxia in the response of AML cells to BET inhibition in order to identify a novel therapeutic combination targeting leukemia stem-progenitor cells (LSPCs) in their niche. AML cells were treated with BETi (GSK1210151A) in hypoxia and normoxia (1

A real-life study on CPX-351 and the standard arm (‘7 + 3’) of the CPX-351 registrative trial in adults with secondary Acute Myeloid Leukemia were compared by an unanchored Matching-adjusted indirect comparison (MAIC), in order to evaluate the efficacy and toxicity of CPX-351. Results of this study are important to confirm the role of CPX-351 in significantly improving survival and remission rates compared with ‘7 + 3’ with a good safety profile in AML patients with high-risk features, a target group traditionally with a very poor prognosis. Moreover, this pilot analysis underlines the potentiality of the statistical method to compare studies with strong differences.

Acute myeloid leukemia (AML) is mainly a disease of the elderly: however, knowledge about the outcomes of treatment of core-binding factor (CBF) AML in an older population is limited. We retrospectively collected data on 229 patients with CBF-AML followed long-term in the last two decades. The 5-year overall survival was 44.2% (95% confidence interval [95% CI]: 39.9-47.5) and the 5-year event-free survival was 32.9% (95% CI: 25.5-40.1). In a subgroup of patients ≥70 years old who completed intensive therapy (induction + ≥3 courses of consolidation including autologous stem cell transplantation: 10 patients) the median event-free survival was 11.8 months (95% CI: 9.4-15.2) and overall survival was 40.0% (95% CI: 36.4- 44.1) at 5 years. In univariate analysis, age ≥70 years (hazard ratio [HR]=1.78, 95% CI: 1.15-2.54, P=0.008), failure to achieve remission following induction (HR=8.96, 95% CI: 5.5-13.8; P<0.0001), no consolidation therapy (HR=0.75, 95% CI: 0.47-1.84, P=0.04) and fewer than three cycles of consolidation (HR=1.48, 95% CI: 0.75-3.2; P=0.0004) predicted poorer event-free survival. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a complete remission seems to be the most important first step and at least three cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.

Purpose:This study investigates the theranostic potential of doped ferrite nanoparticles (NPs) with self-regulating temperature (SRT) properties, termed M55, coated with glucose (GM55), chitosan (CM55), and poly-ethylene glycol (PM55). The NPs were assessed for their physicochemical attributes, magnetic fluid hyperthermia (MFH) efficacy, dual-imaging capabilities in Magnetic Resonance Imaging (MRI) and Magnetic Particle Imaging (MPI), cytocompatibility, and cellular uptake. Methods:Physicochemical characterization was conducted using Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and zeta potential measurements. The biocompatibility and cellular uptake were evaluated in MDA-MB-231 breast cancer cells, and MFH performance was tested in vitro. Following intravenous administration, MRI and MPI functionalities were analyzed through phantom studies and in vivo murine models. Results:Coated M55 NPs displayed high colloidal stability in water and effective functionalization. The specific absorption rate (SAR) of 24.4 ± 1.4 W/g confirmed their suitability for MFH applications. In vitro assays indicated excellent biocompatibility and substantial cellular internalization, with GM55 showing the highest uptake and MFH efficiency, reducing cell viability to 50.62 ± 3.92% post two treatment cycles, compared to 67.71 ± 6.11% (CM55) and 71.39 ± 5.84% (PM55). MRI transverse relaxivity (r2) values were notably high across all coatings, enhancing imaging contrast. MPI analysis demonstrated superior cell labeling sensitivity, with GM55 achieving the most pronounced detection. In vivo imaging confirmed effective NPs accumulation in the liver, underscoring their utility as dual MRI/MPI contrast agents (CAs). Conclusion:Coated M55 NPs exhibit significant promise as multifunctional theranostic agents for cancer treatment. GM55, in particular, offers superior MFH efficacy and cellular uptake, while CM55 and PM55 may present unique advantages for alternative biomedical applications. The dual-imaging capabilities of these NPs provide a robust platform for real-time monitoring of distribution and therapeutic outcomes. Future investigations will focus on optimizing NPs formulations and expanding in vivo assessments to advance clinical translation.

Abstract CPX-351 has been approved for Acute Myeloid Leukemia (AML) with myelodysplasia related changes (AML-MRC) and therapy-related (t-AML) induction. The likelihood of TP53 mutations (TP53m) in this setting is 20-35% but, considering the many variables of TP53m topography and configuration, the assessment of the prognostic impact of TP53 lesions may be challenging. This is the largest subanalysis about the outcome of TP53m AML-MRC and t-AML patients (pts) homogeneously treated with CPX-351 and has been conducted between January 2019 and December 2021 within the italian retrospective real world study about 513 pts (Guolo F. and Todisco E., paper submitted to American Journal of Hematology). Over 335 evaluable pts, in 51 (15%), 39 AML-MRC and 12 t-AML, TP53m were detected by Sanger (n=5) or Next Generation Sequencing (n=28) analysis or both (n=18). Median age was 63 years (range 23-73). Among the 286 TP53 wild-type pts (TP53w), 162 (57%) had complex karyotype (CK) and 10 (3%) del(17p) (9 of which in the context of CK) while, among the 51 TP53m pts, CK was found in 29 (57%) and del(17p) in 6 (12%) (5 of which with CK). According to Grob T. et al., Blood 2022, 26 of 50 evaluable TP53m pts (51%) were classified as biallelic. We also analysed the TP53m population according to Bahaj W. et al., Journal of Hematology & Oncology 2023 (applicable in 40 pts) finding substantial overlap in the assignment of allelic status. According to both classifications, a CK was significantly more frequent among biallelic mutated pts: 22 CK/26 biallelic mutated pts (85%), vs 6/24 (25%) among monoallelic (p<0.05) while all pts with a del(17p) had a biallelic mutation. Twenty-four of 51 TP53m pts (47%) and 162 of 286 TP53wt pts (57%) obtained complete remission or complete remission with incomplete hematologic recovery (CR/CRi) (p .096). In multivariate analysis for CR considering molecular and cytogenetic characteristics including allelic TP53 status, del(17p) resulted the only variable with independent negative prognostic impact (p .018, HR 1.05-1.55). In fact, among the 6 pts with del(17p), none achieved CR. Overall, 122/286 (43%) TP53wt pts and 15/51 (29%) of the TP53m cohort underwent allogeneic stem cell transplantation (allo-SCT). Among the 15 TP53m transplanted pts, 40% (n=6) had a biallelic mutation, 33% (n=5) had CK (but none with del(17p). After a median follow up of 23,67 months (m) (CI 95% 21.47-25.86), median OS (mOS) of the TP53w population was 17,1 m (range 16.7-20.27) vs 9,5 m (range 6.8-12.4) for TP53m, p .064; no significative difference but a trend was observed between TP53w and TP53 mono vs biallelic (mOS 17.1 m and 18.53 m vs 8.2 m respectively, p .110). We have therefore performed analyses based on the presence of CK: mOS was 19,3 m for TP53w pts without CK and 14,6 m for those carrying CK (p .117) vs respectively 32,5 m and 11,5 m (p .053) within TP53m cohort. A CK was not significantly related to a worse survival regardless of allelic status (mOS not reached and 10.3 m for pts without CK with mono and biallelic mutation vs respectively 4.7 m and 7.9 m for those with CK, p .496). Within the TP53m cohort, the presence of a missense TP53m vs other mutations (frameshift, nonsense, splice or intronic) resulted in non significant survival difference (p .213) as between canonical or non canonical missense TP53m (p .265). Furthermore, we did not find any impact on survival when we considered co-mutations (available only in 35 of 51 TP53m pts), their number or combinations. Del(17p) was instead the only factor having a negative impact on survival (mOS 4,7 m with del(17p) vs 13,6 m without, p.005). In a landmark analysis of TP53m pts alive and in 1st CR at 3 m who underwent allo-SCT (n=15, 62% of those achieving CR), mOS was not reached vs 10,3 m for not transplanted pts (p .347). We were unable to perform further subanalyses in this context because of the small population size. Although the incidence of TP53 mutations is likely underestimated due to the retrospective nature of the study, our analysis shows that CPX-351 is a feasible therapeutic option as bridge to allo-SCT also in a difficult subset like TP53m AML-MRC and t-AML unless if del(17p) is also present. We are conducting a retrospective and prospective expansion of the study in order to verify our findings on a larger sample size.

In the registration clinical trial 301 (NCT01696084), CPX-351 has shown to be superior to conventional 3 + 7 in secondary AML (s-AML). However, the optimal duration of treatment, the best timing for allogeneic stem cell transplantation (allo-HSCT), and the activity of CPX-351 in specific s-AML subgroups are unclear. To evaluate these aspects, a total of 513 s-AML patients (median age 65.6 years, 19-79) treated with CPX-351 were retrospectively analyzed. Complete remission (CR) rate after induction was 297/513 (58%), increasing to 340/513 (66%) after cycle 2. Among the 340 responding patients, 118 (34.7%), 137 (40.3%), and 85 (25%) received none, one, or two consolidation cycles of CPX-351, respectively. Overall, 230/513 patients (48.8%) received allo-HSCT. Median follow up was 23.66 months and median overall survival (OS) was 16.23 months. Patients with mutated NPM1 or with ELN 2017 favorable risk (p < 0.05) had a significantly longer OS (p < 0.05). In a landmark analysis, receiving allo-HSCT was associated with a longer survival (Median OS not reached vs. 16.3 months for patients receiving or not receiving allo-HSCT, p < 0.05). Completion of all allowed CPX-351 cycles was beneficial only in patients not proceeding to transplant (p < 0.05), whereas in transplanted patients additional CPX-351 cycles did not improve outcome. Our analysis suggests that also s-AML patients with NPM1 mutations and those belonging to the ELN 2017 favorable risk category benefit from CPX-351. In eligible patients, allo-HSCT should be performed as soon as a CR is achieved, whereas patients not undergoing transplant benefit from a complete CPX-351 schedule.

BACKGROUND:Inotuzumab ozogamicin (IO) has helped to change the treatment paradigm in B-cell acute lymphoblastic leukemia (B-ALL) but real-world data are limited. METHODS:The INO-CD22 study is a multicenter retrospective cohort study of adult patients with relapsed/refractory B-ALL treated with IO in 24 Italian centers from 2014 to 2019, with the aim of assessing the response, survival, and toxicity of IO. RESULTS:Data for 73 eligible patients were obtained: the median age at the start of IO treatment was 52.7 years (I-III quartiles, 51.9-53.5 years), the median number of previous lines was three (I-III quartiles, two to four), and prior exposure to induction standard chemotherapy and blinatumomab occurred in 85% and 57.5% of cases, respectively. IO was administered following the label schedule. A 74.0% overall response rate was achieved, with a 69.8% complete remission rate and a 4.1% complete remission with incomplete hematologic reconstitution rate. The median duration of response was 4.4 months (I-III quartiles, 2.3-11.2 months). With a median follow-up of 37.2 months, the median overall survival (OS) was 7.9 months (95% CI, 6.08-12.42 months) with a 3- and 5-year OS of 21.2% (95% CI, 11.9%-32.3%) and 5.3% (95% CI, 9.6%-29.8%), respectively. Overall, 37% of patients were able to proceed to allogeneic hematopoietic stem cell transplantation. Eight patients (11.0%) experienced veno-occlusive disease/sinusoidal obstruction syndrome; the most frequent grade ≥3 nonhematologic adverse events were liver toxicities and pneumonia (two grade 4 and one grade 5, respectively). CONCLUSIONS:Despite the limitations of retrospective studies, the INO-CD22 study highlights the favorable safety profile and clinical activity of IO within a real-world context.

Background: Nucleophosmin-1 (NPM1) mutation accounts for 30% of acute myeloid leukemia (AML) cases and defines either low- or intermediate-risk AML, depending on FLT3-ITD mutation. New combination regimens (NCRs), adding midostaurin and gemtuzumab ozogamicin (GO) to the 3 + 7 scheme, are commonly used, though there are no data that compare NCRs with intensive induction chemotherapy. Methods: To evaluate the efficacy and safety of NCRs and FLAI in NPM1+ AML, we retrospectively analyzed 125 patients treated with FLAI (n = 53) or NCRs (n = 72) at seven Italian Centers. Results: The median age was 61 years and 51/125 (41%) were FLT3-ITD+. The complete remission (CR) rate was 77%, slightly better with NCRs (83% vs. 68%; p = 0.054). NCRs yielded a superior median overall survival (OS) (not reached (NR) vs. 27.3 months; p = 0.002), though the median event-free survival (EFS) was similar (NR vs. 20.5 months; p = 0.07). In low-risk AML, CR was higher in NCRs (94% vs. 72%, p = 0.02), as were median OS (NR vs. 41.6 months; p = 0.0002) and EFS (NR vs. 17.8 months; p = 0.0085). In intermediate-risk AML (FLT3-ITD+), there were no differences in CR (60% vs. 71%; p = 0.5), OS (p = 0.27), or EFS (p = 0.86); only allogeneic transplantation improved OS (NR vs. 13.4 months; p = 0.005), regardless of induction regimen. The safety profile was similar, except for delayed platelet recovery with FLAI (22 vs. 18 days; p = 0.0024) and higher-grade II–IV gastrointestinal toxicity with NCRs (43% vs. 18.8%; p = 0.0066). Conclusions: Our data suggest the superiority of NCRs over FLAI in low-risk patients, while all outcomes were comparable in intermediate-risk patients, a setting in which only transplants positively impacted on survival.

The term "purinergic signaling" was coined in 1972 by Geoffrey Burnstock to indicate the signaling system formed by nucleotides and nucleosides, the concentrations of which are finely regulated in the extracellular milieu by specific cell surface receptors (purinoceptors P1, P2X, and P2Y), ectoenzymes (alkaline phosphatases, E-NTDPases [ectonucleoside triphosphate-phosphohydrolase]), E-NPP (ectonucleoside pyrophosphatase/phosphodiesterase), 5'-NT (5'snucleotidase), transporters (NTs), and ion channels. Also referred to as the "purinome", it is deputed to fine-tune cell-to-cell interactions, chemokine, and cytokine secretion, redox biology modulation, proliferation, migration, and differentiation of both mature and immature cells, including hematopoietic (HSCs), neural (NSCs), and mesenchymal (MSCs) stem cells. The expression patterns of purinoceptors and ectonucleotidases in tissues and infiltrating immune cells shape a specific response to extracellular nucleotides and nucleosides in health and disease. This chapter focuses on purinergic system and discusses the role of extracellular adenosine triphosphate (ATP), diphosphate (ADP), monophosphate (AMP), and adenosine (Ado) in the regulation of cell growth with a special focus on stem cells.

The introduction of antibody–drug conjugates represents a significant advancement in targeted therapy of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Our study aims to investigate the role of the DNA damage response pathway and the impact of PARP1 inhibition, utilizing talazoparib, on the response of AML and ALL cells to Gemtuzumab ozogamicin (GO) and Inotuzumab ozogamicin (INO), respectively. AML and ALL cells were treated with GO, INO and γ-calicheamicin in order to induce severe DNA damage and activate the G2/M cell-cycle checkpoint in a dose- and time-dependent manner. The efficacy of PARP1 inhibitors and, in particular, talazoparib in enhancing INO or GO against ALL or AML cells was assessed through measurements of cell viability, cell death, cell cycle progression, DNA damage repair, accumulation of mitotic DNA damage and inhibition of clonogenic capacity. We observed that both ALL and AML cell lines activate the G2/M cell-cycle checkpoint in response to γ-calicheamicin-induced DNA damage, highlighting a shared cellular response mechanism. Talazoparib significantly enhanced the efficacy of INO against ALL cell lines, resulting in reduced cell viability, increased cell death, G2/M cell-cycle checkpoint override, accumulation of mitotic DNA damage and inhibition of clonogenic capacity. Strong synergism was observed in primary ALL cells treated with the combination. In contrast, AML cells exhibited a heterogeneous response to talazoparib in combination with GO. Our findings suggest a potential link between the differential responses of ALL and AML cells to the drug combinations and the ability of talazoparibto override G2/M cell-cycle arrest induced by antibody–drug conjugates. PARP1 emerges as a key player in the response of ALL cells to INO and represents a promising target for therapeutic intervention in this leukemia setting. Our study sheds light on the intricate interplay between the DNA damage response pathway, PARP1 inhibition, and response of γ-calicheamicin-induced DNA damages in AML and ALL. These findings underscore the importance of targeted therapeutic strategies and pave the way for future research aimed at optimizing leukemia treatment approaches.

Type 2 inflammation is a heterogeneous condition due to the complex activation of different immunological pathways. Rapid progress in research to evaluate the efficacy of biologics for chronic rhinosinusitis with nasal polyps and asthma has led to the availability of effective therapeutic options. These drugs are safe, but temporary iatrogenic hypereosinophilia may sometimes be associated with clinical symptoms or organ damage. Here, we describe a case of severe hypereosinophilia in a patient with chronic rhinosinusitis with nasal polyps and asthma treated with dupilumab and a subsequent therapeutic shift to mepolizumab that led to maintenance of symptom control and concomitant normalization of blood eosinophil count.

Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%–8% of acute myeloid leukemia (AML). Worse outcomes and consequently shortened survival are associated with t-MNs as compared with de novo AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included.

According to the current European Leukemia Network guidelines (ELN 2022) for diagnosis and treatment of acute myeloid leukemia (AML) the prognostic risk stratification is based on molecular and cytogenetic characterization. Due to the small number of prospective Minimal Residual Disease (MRD) driven studies, the MRD role in AML risk stratification is not clearly defined. The aim of this study was to evaluate the effect of MRD in a real-life setting. We retrospectively analyzed 124 patients with Favorable (FAV) or Intermediate (INT) risk AML treated with intensive chemotherapy from January 2017 to June 2023 at the Hematological Centers of the REV-network. MRD was tested by RT-PCR. The MRD negativity was defined as undetectable MRD level, MRD Low Positive (MRD Low+) as MRD < 10-3, and MRD High Positive (MRD High+) was set at level ≥ 10-3. Univariate statistical analysis was performed with χ2-test, log-rank test for survival outcomes (OS and PFS), and Grey-test for cumulative incidence of relapse (CIR). Cox regression analysis and Fine-Gray proportional hazard regression model were used in multivariate analysis. The statistical significance was set at ≤ 0.05. Patient characteristics were: male/female ratio 59/65, median age 60 years (range 20-74), ECOG 0 (range, 0-4), Charlson Comorbidity Index modified sec. Deyo 2 (range, 0-5). Fifty- nine patients (48%) had FAV-risk and 65 (52%) INT-risk AML, with the following cytogenetic/molecular features: normal karyotype (75%), core binding factor alterations (6%; 4 RUNX1-RUNX1T1, 4 CBFB-MYH11), NPM1 mutations (73%), FLT3-ITD mutations (40%), FLT3-TKD mutations (7%), and CEBPA bZIP mutations (1%). MRD was evaluable in 80 patients (65%) and in 44 MRD was unknown (MRDu). OS and PFS of the whole cohort were 69% and 60% at 2 years (2y), and 65% and 60% at 3 years; 2y-CIR was 28%. FAV and INT patients did not show significant differences in clinical presentation, complete response (CR) rate, MRD negativity rate, OS, PFS and CIR. In univariate analysis, factors associated with higher 2y-OS were post induction CR (76% vs 8%, p<0.0001), MRD negativity after 2 chemotherapy cycles (2CT MRD- 100% vs MRD Low+81% vs MRD High+ 62% vs MRDu 57%, p=0,009), and with End of Treatment (EoT) MRD negativity (EoT MRD- 97% vs MRD Low+ 76% vs MRD High+ 47% vs MRDu 50%, p<0,0001). In multivariate analysis, EoT MRD High+ and EoT MRDu retained a significant negative impact on OS (HR 3,5, p=0,0001 and HR 3,2, p<0,0001). In univariate analysis, 2y-PFS was negatively influenced by: age > 60 (50% vs 69% p=0.02), PLT < 69 x 103/mL (53% vs 67%, p=0,04), 2CT MRD High+ (MRD- 100% vs MRD Low+ 73% vs MRD High+ 37% vs MRDu 50%, p=0,006) and EoT MRD High+ (MRD- 87% vs MRD Low+ 65% vs MRD High+ 30% vs MRDu 44%, p<0,0001). Multivariate analysis confirmed EoT MRD High+ and EoT MRDu as negative predictors for PFS (HR 2,8 p<0,0001 and HR 2,3 p=0,006). CIR correlated with GB count > 31,3 x 103/mL (37% vs 19%, HR 2,09, p=0,03) and with EoT MRD+ regardless of MRD value (38% vs 21%, HR 1,9, p=0,04). A stratified analysis was performed to evaluate the HSCT-effect depending on MRD status. HSCT positively affected outcomes in patients 2CT MRD High+ (PFS and OS, 50% vs 25%, p=0,04), 2CT MRD+(Low/High) (2y OS 74% vs 56%, p=0,04; 2y PFS 70% vs 54%, p=0,04), and in EoT MRD+ (2y OS 87% vs 52%, p=0,04; 2y PFS 73% vs 40%, p=0,04). HSCT+ and HSCT- patients did not show different outcomes for MRD-, MRD Low+ and MRDu status. In HSCT+ subgroup, 2y OS and PFS were higher in patients with pre HSCT MRD- (100% vs 66%, p=0,04; 00% vs 62%, p=0,04) and with CR1 vs CR>2 status at transplant (81% vs 62%, p<0,0001; 80% vs 12%, p<0,0001). In our real-life subset of FAV-INT ELN 2022 AML patients, MRD status is the main prognostic factor. This result highlights the relevance of improving MRD evaluation in INT risk patients for driving therapeutic decisions. Despite the relevant negative prognostic impact of pre HSCT MRD positivity, allograft is still necessary to ensure the best survival for MRD+ patients. In MRD negative patients, on the contrary, performing HSCT does not affect the outcome. Given the retrospective design and the relatively small number of patients, further studies in a larger population could be useful to confirm our findings, as well as for answering the main open question: is allogenic transplantation still a cornerstone in intermediate risk AML patients who reach MRD negativity?