Objectives:To compare the efficacy of pre-emptive antifungal therapy (PAT) and empirical antifungal therapy (EAT) in patients with febrile neutropenic acute leukaemia (AL) with/without anti-mold prophylaxis. Methods:We included 92 patients with AL and neutropenia with fever unresponsive to empiric antibiotics, stratified by posaconazole prophylaxis to receive EAT (n = 40) or PAT (n = 52). In the PAT group, a standardized diagnostic workup for the detection of invasive fungal infection (IFI) was performed. The study endpoints were antifungal therapy initiation, IFI documentation, safety, and cost. Results:Posaconazole prophylaxis was equally distributed among the patients (overall 55.4%). Antifungal therapy was started in 58% of the patients in the PAT group versus 100% in the EAT group (P < 0.01; 95% CI: 0.42 [0.28-0.55]). In the EAT and PAT groups, overall proven/probable IFI rates were 2% and 17%, respectively (P = 0.02; 95%CI: -0.14 [-0.26 to -0.03]) and 4% and 10% in patients with posaconazole prophylaxis, respectively (P = 0.3; 95% CI: -0.06 [-0.20-0.07]). At hospital discharge, mortality was 19% in the EAT and 5% in the PAT groups (P = 0.02; 95% CI: -0.14 [-0.26 to -0.03]), unrelated to the use of posaconazole prophylaxis, and no IFI-related death was observed. The mean costs per patient were €7681 and €3344 in the EAT and PAT groups, respectively (P = 0.003; 95% CI: €4337 [€1814-6860]). Adverse reactions to antifungals were similar between the groups. Conclusions:In patients with persistently febrile neutropenic AL, PAT was safe and effective and reduced the use and costs of antifungals, irrespective of anti-mold prophylaxis, compared with empirical treatment.

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Background Human metapneumovirus (hMPV) is an increasingly recognized respiratory pathogen in immunocompromised patients, but its impact in haematological malignancies is poorly defined. Unlike influenza or SARS-CoV-2, hMPV has no specific treatment or vaccine, contributing to underdiagnosis and underestimation of its clinical relevance.Method We performed a multicentre retrospective cohort study within the Epidemiology of COVID-19 in patients with hematological malignancies: A European Haematology Association Survey/ Epidemiology of respiratory viral infections in patients with hematological malignancies: A European Haematology Association Survey registry of haematological patients with hMPV (January 2023-December 2024), comparing clinical features and outcomes with matched influenza and SARS-CoV-2 cohorts.Results The study included 130 patients with hMPV. Median age was 58.5 years; 57% were male. Plasma cell neoplasms (25%), lymphoma (23%), and acute myeloid leukemia (20%) were the most common hematological malignancies. Hospitalization occurred in 64%, intensive care unit (ICU) admission in 19%, and 30-day mortality was 8%. Most cases (73%) received supportive care only. Secondary infections were common (24%). Chronic renal disease significantly increased mortality risk (hazard ratio 20.9 11.05, P = .014). Compared with influenza and SARS-CoV-2, hMPV patients had comparable severity and outcomes, with 18.5% ICU admission rates versus 25.9% for influenza (P = .316) and 20.9% versus 4.7% for SARS-CoV-2 (P = .006), and 30-day mortality of 5.6% versus 11.1% for influenza (P = .489) and 7.0% versus 2.3% for SARS-CoV-2 (P = .277), yet received fewer targeted interventions.Conclusions hMPV causes clinically significant disease in patients with hematological malignancy, often necessitating hospital and ICU care, and leading to mortality. In the absence of specific treatments or vaccines, this virus remains an underrecognized pathogen in patients with hematological malignancy. Enhanced clinical awareness and investment in diagnostics, prevention, and therapeutics are needed.

Infections are a leading cause of morbidity, mortality, and treatment delays in AML and APL. While international guidelines emphasize intensive chemotherapy, they often overlook less intensive regimens, rely on outdated data, and ignore rising MDR infections. A GIMEMA survey across Italian centers revealed significant heterogeneity in antimicrobial prophylaxis, and vaccination practices. An expert panel reviewed 2012-2025 English literature with focus on infections via Delphi/nominal group methods, achieving ≥70% consensus. Prophylaxis with fluoroquinolones showed low agreement (28%) for intensive chemotherapy and venetoclax-based regimens due to no survival benefit, MDR pressure and microbiota disruption; not recommended for low-intensity/palliative care. Posaconazole is advised for intensive chemotherapy with or without FLT3 inhibitors, venetoclax-based regimens, HMA with or without ivosidenib (first 4 cycles), but not APL/palliative care. Antiviral prophylaxis is recommended for APL receiving arsenic trioxide; limited evidence elsewhere. The panel supports universal pneumococcal, influenza, SARS-CoV-2 and herpes zoster vaccination. Overall, these consensus statements aim to harmonize practice and highlight key areas requiring specifically designed prospective studies.

Hypomethylating agents (HMA) alone or in combination with venetoclax (VEN) are a mainstay for disease control in elderly acute myeloid leukemia (AML). We evaluated the non-inferiority of HMA monotherapy compared to HMA/VEN combination in 227 AML patients aged ≥ 75 years receiving HMA or HMA/VEN combination. No difference in overall survival (OS) was observed between the two groups, with HMA monotherapy demonstrating statistical non-inferiority. HMA-treated patients with favorable performance status had longer OS. The HMA/VEN group experienced higher mortality and worse QoL. HMA monotherapy offers comparable survival outcomes to HMA/VEN with reduced toxicity in elderly AML patients.

Chimeric antigen receptor (CAR) T cells are considered human gene therapy products in which T lymphocytes are genetically modified to recognize a specific target antigen for therapeutic purposes. CAR-T cell therapy has shown particular success in the treatment of hematological neoplasms and, to date, the FDA has approved six commercial products for the treatment of relapsed/refractory B-cell malignancies. Because CAR-T cell therapy is associated with considerable toxicities, mainly cytokine release syndrome and neurological toxicity, it is reserved for patients with advanced-stage disease who have not responded to previous therapies and have no other treatment options. However, the efficacy of CAR-T cell therapy is highly variable, and approximately 30% to 50% of treated patients experience relapse after administration. Several variables, including the type of CAR construct, manufacturing procedure, infusion volume, quality of the manipulated T cells, and the patient's tumor burden, may influence the fate and efficacy of CAR-T cells. In this review, specific attention is focused on molecular monitoring after infusion and on the potential occurrence of uncontrolled events, such as insertional mutagenesis, clonal T-cell expansion, or the onset of secondary T-cell lymphomas.

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.

RUNX1A is the shortest and least expressed of the RUNX1 three main isoforms (A, B, C); despite this, the leukemogenic role of its overexpression has been clearly described. Several studies have shown RUNX1A involvement in different blood cancers and pilot observations in acute leukemia have been reported. In this context, we evaluated RUNX1 isoforms expression in a cohort of acute myeloid leukemia (AML) patients, finding overexpression of RUNX1A and RUNX1B, with higher median levels in thrombocytopenic cases. No difference was observed for RUNX1C. RUNX1A overexpression is higher in more immature AML phenotypes. According to the mutational profile, FLT3 internal tandem duplication (ITD) positive cases have the highest RUNX1A levels and the presence of FLT3-ITD was the only molecular variable able to influence RUNX1A expression. RUNX1A overexpression is disease-related, associated with a specific transcriptional profile, and reappears at relapse, with no clear kinetics except in FLT3-ITD cases. Overall, we demonstrate RUNX1A overexpression in AML and its association with the FLT3-ITD molecular subtype. Our data shed light on the dark side of RUNX1 deregulation, paving the way for further investigations.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the best consolidative treatment for high-risk acute lymphoblastic leukemia (ALL). The Campus ALL study group analyzed the clinical outcomes of patients treated in the real-life with the pediatric-inspired and minimal/measurable residual disease (MRD)-oriented GIMEMA LAL1913 protocol who underwent alloHSCT. Key factors impacting on outcomes were MRD and remission status (1st complete remission vs 2nd complete remission) at transplant. MRD positivity was associated with poorer outcomes, with 3-year overall survival (OS) and disease-free survival (DFS) of 47% and 41% in MRD-positive patients compared to 80% and 70% in MRD-negative patients. Additionally, MRD negativity was associated with improved outcomes also for patients in 2nd complete remission with 3-year OS and DFS rates of 60% and 56%, respectively, compared to only 13% for both outcomes in MRD-positive cases. Patients older than 55 years showed survival rates comparable to younger patients, despite having a slightly higher non-relapse mortality, which remained below 20% at 3 years. These findings underscore the crucial role of alloHSCT in high-risk ALL and emphasize the importance of an early accurate disease risk allocation. The adverse outcome observed with MRD positivity advocates for early pre-transplant intervention with immunotherapy, whenever possible.

Hepatic Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a severe complication following hematopoietic stem cell transplantation (HSCT), traditionally diagnosed based on clinical criteria. This study aimed to evaluate the diagnostic performance of liver stiffness measurement (LSM) as a non-invasive tool for non invasive diagnosis of VOD/SOS. A multicentre clinical trial was conducted in Italy from April 2018 to December 2021, screening 1089 patients across 25 centers. VOD/SOS diagnosis followed established clinical guidelines, and patients underwent comprehensive clinical, laboratory, and imaging evaluations up to +100 days post-HSCT or until VOD/SOS diagnosis. LSM was measured pre-HSCT and on specific post-transplant days (ClinicalTrials.gov: NCT03426358). The study enrolled 774 adults and 167 children. The +100-day incidence of VOD/SOS HSCT was 5.53 and 5.26 in the overall and allo-HSCT population, higher in children (14.3

The adoption of pediatric-inspired regimens for the treatment of Ph-negative acute lymphoblastic leukemia (ALL) in adults has improved prognosis. However, the feasibility of these intensive regimens in older patients is limited, due to the increased incidence of therapy-related side effects, including those related to asparaginase. In this sub-analysis carried out by the Campus ALL network, 90 ALL patients aged 55 or more (median age 59 years) homogeneously treated in real-life according to the GIMEMA LAL1913 program, were analyzed to evaluate the feasibility and tolerability of pegaspargase (PEG-ASP) treatment. Among the 90 patients analyzed, 86 (96

The introduction of pediatric-inspired regimens in adult Philadelphia-negative acute lymphoblastic leukemia (Ph- ALL) has significantly improved patients' prognosis. Within the Campus ALL network, we analyzed the outcome of adult Ph- ALL patients treated according to the GIMEMA LAL1913 protocol outside the clinical trial to compare the real-life data with the study results. We included 421 consecutive patients; median age 42 years. The complete remission (CR) rate after the first course of chemotherapy was 94%, and measurable residual disease (MRD) negativity after the third course was achieved in 72% of patients. The 3-year overall survival (OS) and disease-free survival (DFS) were 67% and 57%, respectively. In a multivariate analysis, MRD positivity negatively influenced DFS. In a time-dependent analysis including only very high-risk (VHR) and MRD positive cases, transplanted (hematopoietic stem cell transplantation [HSCT]) patients had a significantly better DFS than non-HSCT patients (P=0.0017). During induction, grade ≥2 pegaspargase-related hepato-toxicity was observed in 25% of patients (vs. 12% in the GIMEMA LAL1913 trial, P=0.0003). In this large, real-life cohort of Ph- ALL, we confirmed the very high CR rate and a superimposable OS and DFS compared to the GIMEMA LAL1913 clinical trial (CR rate after C1, 94% vs. 85%, P=0.0004; 3-year OS, 67% vs. 67%, P=0.94; 3-year DFS, 57% vs. 63%, P=0.17). HSCT confirms its important role in VHR and MRD-positive patients. The rate of pegaspargase-related toxicity was significantly higher in the real-life setting, emphasizing the importance of dose adjustment in the presence of risk factors to avoid excessive toxicity.

Abstract Introduction Inotuzumab ozogamicin (Ino) is an anti-CD22 immuno-conjugated monoclonal antibody, which has improved the clinical outcome of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The use of Ino in the clinical practice is well consolidated, while data on retreatment in patients previously exposed to the drug are very limited (Alban J, et al; JCO Precis Oncol. 2022). Methods Within the framework of the Campus ALL network in Italy, we retrospectively analyzed the clinical outcomes of a population of adult patients with R/R ALL who underwent retreatment with Ino. The studied population must have previously received treatment with Ino, intended as the first exposure to the drug, either for hematologic relapse of ALL or for minimal residual disease (MRD) positivity, and a second exposure, Ino retreatment, in a subsequent line of therapy. We included patients receiving Ino either as a single agent or in combination with other treatments (radiotherapy, chemotherapy, tyrosine kinase inhibitors, etc.), regardless of the dosage. This criterion applied to both first treatment and retreatment with Ino. Patients could have received a retreatment with Ino to bridge to another therapy, such as allogeneic transplant (alloHSCT), CAR-T, or no further therapy. The outcomes included in the analysis were the complete remission rate (CR and CR with incomplete hematological recovery, CRi), incidence of hematologic and extra-hematologic toxicity (graded according to CTCAE V. 5.0), cumulative incidence of relapse (CIR), progression-free survival (PFS), and overall survival (OS). Results We included 26 patients for this analysis, of which 20 had Philadelphia-negative (Ph-) ALL and 6 Philadelphia-positive (Ph+) ALL. The median age of the study population was 39 years (range 16-66), and the median follow-up was 5 months (range 0.3-26). According to the GIMEMA LAL1913 baseline risk stratification (Bassan R. et al, Blood Advances 2023), 11/20 Ph- ALL patients had a high risk or a very high-risk profile, including 6 Ph-like ALL cases. Regarding the first Ino exposure, 24 of 26 patients received Ino for hematologic relapse, and the remaining 2 for MRD positivity. Among the 24 patients receiving Ino for R/R disease, a CR/CRi rate of 79% was observed. Both patients receiving Ino for MRD positivity had a logarithmic reduction of MRD levels. At the time of retreatment with Ino, the median number of previous lines of treatment was 3 (range 2-7). Concerning disease characteristics at retreatment, 15 patients (58%) had more than 50% of blasts and 7 (27%) had extramedullary disease (EMD). The median number of Ino cycles was 1 (range 1-4), with 6 cases of dose reduction primarily due to medical decisions. The CR rate was 61.5%, with 31% of patients achieving a MRD negativity, similar to what observed during their first exposure to the drug. Factors, such as high burden disease, EMD, or the number of previous lines of therapy (> or < 3) did not significantly affect the CR rate. All patients achieving a CR/CRi were successfully bridged to the planned subsequent treatment, either alloHSCT or CAR-T cell therapy. Of these patients 28.5% subsequently relapsed. After a median follow-up of 5 months, the 1-year OS and PFS for responders vs non-responders to retreatment were 51% (95%CI, 29%-91%) vs 11% (95%CI, 2%-70%, p 0.0015) and 42% (95%CI, 22%-79%) vs 0% (p <0.001), respectively. Among the 10 patients who responded to retreatment with Ino followed by CAR-T cell therapy, the 1-year OS and PFS were 71% (95%CI 45%-100%) and 56% (95%CI, 31%-100%), respectively. Among the responders who underwent consolidation with alloHSCT, which was a second transplantation in 4 out of 5 patients, the OS and PFS were 40% (95%CI 45%-100%) and 20% (95%CI, 31%-100%), respectively. In terms of grade 2-4 toxicities, we observed 15% of self-limiting transaminitis (no cases of veno-occlusive disease), 23% of infectious complications (including 1 fatal event), and 46% of hematologic toxicities. Notably, the incidence of these toxicities was not significantly higher than those reported during the first Ino exposure. Conclusions This study indicates that retreatment with Ino is a valuable option associated with a high CR rate and acceptable safety, even in heavily pretreated relapsed patients. Notably, the clinical outcomes for patients who responded to Ino retreatment and were subsequently bridged to CAR-T therapy were particularly encouraging.

Splenomegaly is an event occurring in a variable range between 10–40