While marginal zone lymphoma (MZL) is generally indolent, outcomes following relapse remain poorly defined. This study utilized the indolent Non Follicular 10 (NF10) prospective database to characterize survival and identify prognostic drivers in patients failing initial systemic therapy. The study analysed 122 patients with relapsed MZL. The primary end-point was progression-free survival from first relapse (2PFS), with survival after relapse (SAR) as the secondary end-point. The median 2PFS was 24 months, with a 2-year 2PFS rate of 49% and a 2-year SAR rate of 66%. Multivariable analysis identified advanced age, progression of disease within 24 months (POD24) and high MZL International Prognostic Index (MZL-IPI) scores as significant predictors of inferior survival. Patients with splenic and disseminated subtypes also demonstrated worse outcomes. Relapse following systemic therapy often marks a transition to an aggressive clinical course. Time to progression and the MZL-IPI are robust tools for risk stratification, highlighting an urgent need for novel therapeutic strategies for high-risk relapsed MZL populations.

Older patients with classic Hodgkin lymphoma experience poorer outcomes than younger individuals, due to comorbidities and functional limitations affecting treatment tolerance. In this retrospective single-centre study of 140 patients, we evaluated treatment patterns, outcomes and the prognostic value of two geriatric scores: the Age, Comorbidities and Albumin (ACA) Index and the Frailty Score. Most patients (87.9%) received standard ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine)/AVD (doxorubicin, vinblastine and dacarbazine) regimens. At median follow-up (65 months), 5-year progression-free survival (PFS) and overall survival (OS) were 65% and 78.5%, respectively; treatment-related mortality was 7.8%. First-line therapy (AVD-based versus other) significantly influenced PFS (61.8% vs. 23.5%, p = 0.002) and OS (69.1% vs. 35.3%, p = 0.001). ACA Index stratified patients into four risk categories with progressively lower 5-year OS (92%-64.3%, p = 0.003). According to Frailty Score, 37.9% were fit, 54.3% unfit and 7.8% frail, with corresponding 5-year OS of 79.2%, 59.2% and 36.4% (p < 0.0001). Multivariate analysis identified age ≥80 years, extra-nodal involvement and advanced stage according to German Hodgkin Study Group (GHSG) classification as independent predictors of PFS; age ≥80 years, advanced stage (GHSG) and Frailty Score independently predicted OS. Our findings confirm that standard therapies achieve favourable outcomes in older patients, but chronological age alone is insufficient for treatment decisions. The Frailty Score offers an accessible prognostic tool to guide therapy, supporting the integration of geriatric assessment into treatment planning for this underrepresented population.

7074 Background: Bone marrow biopsy (BMB) is an invasive staging procedure for follicular lymphoma (FL) and its results are needed to calculate FLIPI2 and PRIMA-PI scores. Beyond conventional biopsy bone marrow can also be assessed through FDG-PET bone staging (PETb). We report preliminary data on a comparison of BMB and PETb in assessing BM involvement among FL patients enrolled in the FIL-FOLL12 trial. Methods: Untreated stage II–IV FL patients requiring therapy were included. Patients were balanced according to treatment received and arm. BMBs were assessed by morphology and immunohistochemistry. PET/CT scans were reviewed by two expert nuclear medicine physicians. Pathological bone uptake (PETb+) was defined as mono- or multifocal, or diffuse FDG uptake in bone segments higher than liver activity (SUVmax). Results: This analysis included 179 patients; no significant differences in disease characteristics were observed between the revised cohort and the remaining patients enrolled in the FOLL12 trial. High-risk FLIPI2 was noted in 35.4%, and β2-microglobulin was increased in 53% of patients. BMB involvement was present in 58.5% (median infiltration 30%, range 0.5–95%). PETb was positive in 38 cases (21%), including 14% with focal or multifocal involvement and 7% with diffuse increased uptake. Concordant results between BMB and PETb were observed in 53.6%: among 103 BMB+ patients, 30 were PETb+ (29%). PETb identified BM involvement in 8 cases missed by BMB. While BMB+ was not associated with a different risk of PFS compared to BMB-, we observed a significant impact of PETb+ on PFS: PETb+ had 41% 5-year PFS (CI 25-72, p=0.003), while BMB+/PETb- showed 74% (CI 62-83, p=0.27) and BMB-/PETb- 66%(CI 52-72, reference).We then calculated FLIPI2 and PRIMA-PI using either conventional BMB or PETb to define BM involvement. The agreement between BMB and PETb scores was 87% for FLIPI2 and 67% for PRIMA-PI and the main disagreement was due to reallocation to lower risk groups; FLIPI2 0-2 patients raised from 65% to 74.3% according to FLIPI2-PET. FLIPI2 was confirmed prognostic for PFS and its c-Harrel increased from 0.582 to 0.602 when BMB was substituted with PETb (Table 1), with a 52% (CI 39-64) 5-Year PFS for conventional high risk FLIPI2 shifting to 41% (CI26-56) for high risk FLIPI2-PET. Conclusions: Although BMB detects marrow involvement in most patients, this does not uniformly translate into adverse prognosis. PETb, while less sensitive, identifies metabolically active and prognostically relevant bone disease. A FDG-PET-based assessment of bone involvement could refine risk stratification in FL and spare BMB in most patients Score HR for High risk CI c-Harrell FLIPI2 2.03 1.25-3.31 0.582 FLIPI2-PET 2.58 1.57-4.26 0.602 PRIMA-PI 1.23 0.67-2.23 0.537 PRIMA-PI-PET 1.47 0.85-2.54 0.550

Promyelocytic blast crisis (BC) of CML is an extremely rare event, with only seven cases described as arising during therapy with TKIs. We present a 68-year-old male who developed promyelocytic blast crisis 12 months after CML diagnosis and start of Imatinib therapy, confirmed by the concomitant presence of the t(15;17) and t(9;22) translocations in the leukemic cells. Molecular remission for the PML-RARA clone was achieved with standard acute promyelocytic leukemia induction therapy with ATRA and idarubicin. However, BCR-ABL showed resistance to first-line Dasatinib and second-line Ponatinib, principally due to the presence of multiple mutations in ABL1 kinase domain, including T315I. Hematological and molecular response was achieved with Asciminib, a first‐in‐class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor in combination with pulsed ATRA as post-remission strategy. Of the 7 cases of promyelocytic BC reported in the era of TKI therapy for CML, this is the first case effectively treated with Asciminib therapy.

Acute myeloid leukemia (AML), especially therapy-related (t-AML) or secondary AML (s-AML), presents complex therapeutic challenges. CPX-351, a liposomal formulation of cytarabine and daunorubicin, has demonstrated superior outcomes compared to standard 7 + 3 chemotherapy. However, optimal post-remission strategies are debated. This retrospective study evaluates the feasibility and efficacy of intermediate-dose ARA-C (IDAC), total dose of 8–9 g/m², following CPX-351 in 47 patients from three Italian centers. Median patient age was 69, with 64

Background: Hepatitis C virus (HCV) chronic infection has been unequivocally associated with a wide spectrum of B-cell lymphoproliferative disorders, ranging from mixed cryoglobulinemia to overt B-cell non-Hodgkin's lymphomas (B-NHL), including both indolent, especially marginal zone lymphomas (MZL), and diffuse large B-cell lymphomas (DLBCL). HCV has been estimated as associated with up to 20% of B-NHL cases in Italy, 14% in Japan and 11% in United States, with suggested decrease of the actual incidence in last decades. Hepatitis B virus (HBV) infection accounts for chronic hepatitis and cirrhosis. HBV is also recognized as oncogenic, leading to increased risks of B-NHL (Odds ratio around 2) in addition to hepatocellular carcinoma. Moreover, although the role for antivirals to prevent HBV reactivation is well known in HBV+ patients (pts) receiving chemo-immunotherapy, their influence on outcome is undetermined. Data on HCV and HBV role in lymphomas are based on retrospective epidemiological studies; here we present the HCV and HBV data in the NF10 observational multicentric prospective international study promoted by Fondazione Italiana Linfomi (FIL). Methods: The NF10 Project was started in 2010 as a prospective registry specifically conceived to investigate the prognosis of Indolent Non-Follicular B-Cell Lymphomas (INFL). All pts with a histologic confirmed diagnosis of INFL were eligible with no exclusion criteria. Pts were followed based on local institution guidelines, and progression-free survival (PFS) was defined as the time from the date of diagnosis to progression, re-treatment, or death due to any cause. Results: Between July 2010 and July 2018, 1340 INFL cases had been registered by 65 centres in Europe and South America. HCV serology was available for 1267 (MZLs 768, 327 ENMZL, 255 SMZL, 81 NMZL, 105 disseminated MZL) and was positive in 6.6% ranging from 2% in SLL to 12% in in NMZL and disseminated MZL. Age > 70 years (yrs), female sex, absolute lymphocyte count (ALC) < 1 x 109/L, MZL histology and early yrs of registration (2010-2016) were associated with higher rates of positive HCV serology; in multivariate analysis, age, female sex, were independently correlated with HCV infection, while MZL subtypes had only a trend towards higher positivity rate vs non MZLs. 5-y PFS was 71% for the entire series and was 71% for HCV- and 66% for HCV+ (HR 1). No difference in OS was observed. HBV status was available in 1232 cases and was considered positive if HBsAg+ or HBcAb+; MZLs were 752 (320 ENMZL, 250 SMZL, 81 NMZL, 101 disseminated MZL). Overall, HBV positivity was detected in 16.4% (2.2% HbsAg+ and 14.2% HBcAb+) ranging from 10% in CD5- NHL NOS to 21% in SMZL. LDH > Upper Normal Limiti (UNL), hemoglobin (Hb) < 12 g/dl, need of treatment and early years of registration (2010-16) were associated with higher HBV+ rates; MZL histology was of borderline significance. Considering HbsAg+, in multivariable multinomial logistic regression analysis, the Relative Risk Ratio (RRR) was higher for age < 70 yrs, males, LDH > UNL and MZL histology (borderline significance). Considering HBcAb+, in multivariable analysis RRR was significant only for Hb < 12 g/dl. 5-y PFS was 71% for entire series and was 73% for HBV-, and 61% for HBV+ (p = 0.01) (59% for HBsAg+ and 62% for HBcAb+ cases). In multivariate analysis, considering the entire series, PFS was negatively associated with HBV+, age > 70 yrs, B symptoms, LDH > UNL, PS > 1, Hb < 12 g/dl, platelets < 100.000/mmc, and non-MZL histology. 5-y OS was 86% for the entire series and was 87% for HBV- and 83% for HBV+ (p = 0.013) (79% for HBsAg+ and 84% for HBcAb+ cases). Conclusions: With this NF10 sub-study we provide prospective data about HCV and HBV positivity in INFL. Regarding HCV, we observed higher prevalence of HCV+ in nodal and disseminated MZL without any effect on survival. Conversely, HBV positivity was associated with poorer outcomes. Finally, the observation of higher positivity rates among pts registered in the earlier phase of enrollment, suggests a declining role of the two

Background/Objectives: The treatment of older patients with classic Hodgkin lymphoma (eHL) remains a challenge. Methods: This study reports the first real-life survey of eHL treated with contemporary therapies in Italy. One hundred and fifty eHL patients were treated between 2013 and 2018: seventy-one were aged 60-69 years and seventy-nine ≥70 years (median age 70.5 years; range = 60-89). Curative treatments included ABVD-like regimens and attenuated approaches alternating ABVD-like regimens with non-anthracycline-containing cycles. Results: After a median follow-up of 81 months, the 5-year overall survival (OS) was 87% for patients aged 60-69 and 62% for those aged ≥70. Among 132 patients (88%) treated with curative intent, the 5-year cancer-specific survival (CSS) was 93% for the 60-69 group and 70% for the ≥70 group, while event-free survival (EFS) was 78% and 58%, respectively (p < 0.001). Multivariate analysis showed that age ≥ 70, omission of radiotherapy (RT), and failure to achieve complete remission (CR) after chemotherapy were significant predictors of OS, CSS, and EFS. Synthetic data analysis confirmed that omitting RT worsens outcomes at all stages, while reduced-dose anthracycline regimens are non-inferior to full-dose schedules. Conclusions: This survey highlights key prognostic factors and supports the optimization of future treatment strategies including targeted drugs.

Background. The aim of intensive induction treatment in acute myeloid leukemia (AML) is the achievement of complete remission (CR). After the establishment of “3+7” regimen as the standard induction, several efforts were pursued for improvement through different modalities, among which the increase of anthracycline and cytarabine doses. All these approaches provided a survival advantage in specific subgroups, generally offset by increased toxicity. Since 2017, novel agents have received approval for frontline treatment of selected patient categories, changing the uniform management to a targeted diversification of therapeutic approaches: the incorporation of the FLT3 inhibitor Midostaurin for FLT3-mutated patients, the use of CPX-351 for therapy-related AML and AML with myelodysplasia-related changes, the implementation of Gemtuzumab ozogamicin prominently in patients with favorable-risk cytogenetics. Nonetheless, induction treatment is still conceived as a single treatment block, the response to which is appreciated only 3-4 weeks after its completion. We previously provided evidence that the kinetics of blast reduction in the peripheral blood (PB) during the first days of “3+7” course might reflect AML chemosensitivity. The analytical approach was based on the quantification of leukemia-associated aberrant immuno-phenotype(s) (LAIP) by multi-parameter flow cytometry (MFC) in PB before starting the induction on day 1 (baseline), and daily thereafter up to day 8. We defined the “clearance of peripheral blast cells” (PBC) as the logarithmic ratio between the absolute blast count on the day of chemo start and the values measured daily. In an exploratory cohort of 61 patients, followed by prospective analysis in the of NILG 02-06 randomized clinical trial, we showed the potential of PBC to predict the achievement of CR and measurable residual disease (MRD) negative status. Rationale. We reasoned that an early appraisal of chemosensitivity based on PBC might support the modulation of induction regimen. Accordingly, we envisioned to continue standard induction in patients where PBC data predict a good response, while in patients with a low clearance of PB blasts, immediate switching to an intensified induction could be offered. Such a PBC-driven approach is meant to increase the rate of CR, but with lower overall toxicity, by early identification of patients with lower probability to achieve CR. The second component of this personalized approach regards the early assessment of disease-associated risk: based on the correlation of PBC with survival and MRD, PBC-low patients will be considered as high-risk and early allocated to allogeneic HSCT. The rationale is to avoid delaying HSCT and prevent delivering of additional chemotherapy courses that are predicted to have very low chance to improve the response depth. Study design. AMELIORATE is a phase 3, randomized, trial aiming to personalization of treatment in FLT3-mutated AML (EudraCT number 2019-003936-21). The study is sponsored by GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) and co-funded by MYNERVA (MYeloid NEoplasms Research Venture AIRC). Key eligibility criteria are a diagnosis of untreated AML according to WHO 2016 and the presence of FLT3 mutation, either ITD and/or TKD. PBC is calculated on day 4 of induction as a logarithmic ratio between the absolute PB LAIP+ cell count on day 1 (baseline) and on day 4. A threshold of 2.0 log is decisional to assign patients to different arms. Patients with PBC >2 (PBC-high) complete the standard induction course and are managed according to standard practice. Patients with PBC≤2 (PBC-low) are randomized at day 4 between a standard (analogue to PBC-high) and an experimental approach providing two main modifications: the immediate switch to intensified induction with high-doses cytarabine (1500 mg/m2 bid on days 5, 6 and 7); and the early allocation to high-risk category, to be refined later, based on ELN stratification and post-induction MRD status. All patients receive Midostaurin as per standard practice. Event free survival (EFS) is selected as the primary endpoint. Recruitment. Between April 2020 and June 2025, 28 study sites adhered to the trial and 147 FLT3-mut pts were enrolled so far. Based on the expected distribution of patients into PBC-high and PBC-low category, a total of 172 subject is to be recruited to include 86 PBC-low patients suitable for randomization to the conventional and experimental arm

OBJECTIVES:Azacitidine (AZA) combined with venetoclax (VEN) as an outpatient treatment of unfit patients with acute myeloid leukemia (AML) has been infrequently investigated. METHODS:We report on 65 elderly AML patients: 35 patients received AZA + VEN as first-line and 30 after progression on prior treatment with AZA (R/R group). Thirty-eight patients were treated as outpatients, while 27 were hospitalized. The overall survival (OS) and event-free survival (EFS) were calculated, and predictive factors were assessed using Cox regression models. RESULTS:Inpatients were slightly younger, with a median age of 72 versus 74 years in outpatients (p = 0.015). Median WBC was higher in inpatients (median 7.3 × 109/L vs. 2.9 × 109/L, p = 0.020). Median marrow blast count was 43% in inpatients versus 25.5% in outpatients (p = 0.042). Treatment setting emerged as a key predictive factor for infection development during Cycle 1 in both univariate (p = 0.016) and multivariate analysis (p = 0.043), in the overall cohort. Inpatients had a significantly higher infection rate (81.4%) versus outpatients (44.7%, p = 0.004). In R/R group, 1-year EFS was 68% for outpatients versus 38% for inpatients (p = 0.009). One-year OS was 77% in outpatients versus 38% in inpatients (p = 0.052). CONCLUSIONS:In most instances, outpatient administration of Cycle 1 of AZA + VEN should be preferred as a beneficial option.

Synchronous and sequential diagnosis of Multiple Myeloma (MM) and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) is a rare event with no cases described with a need for concomitant treatment for both diseases. Here we describe a case of a 58 years old male patient diagnosed with CLL and then MM, needing concomitant treatment for both diseases. We treated the patient with a BELLINI trial-like regimen including Bortezomib, Venetoclax and Dexamethasone, obtaining a good response for both the malignancies.

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is an aggressive malignancy primarily affecting the sinonasal region, with a strong association with Epstein-Barr virus (EBV) infection. The disease is significantly more prevalent in Asian and Latin American populations. Diagnosis is particularly challenging in nonendemic regions. We present the case of a 78-year-old male with a one-year history of nasal lesions, later diagnosed with ENKTCL-NT. The patient was treated with curative-intent radiotherapy, achieving a complete clinical response. Radiation therapy, particularly utilizing advanced techniques such as Volumetric Modulated Arc Therapy (VMAT), resulted in favorable outcomes with minimal toxicity. This case emphasizes the importance of early diagnosis, accurate staging, and personalized radiotherapy in the management of ENKTCL-NT. Ongoing research into the molecular pathogenesis, treatment strategies, and prognostic factors is crucial for improving outcomes, particularly in advanced-stage disease.

Introduction: In Italy, Brentuximab vedotin (Bv) with AVD (adriamycin, vinblastine, dacarbazine) received approval for the first-line treatment of stage IV classical Hodgkin lymphoma (cHL) in September 2021, with no upper age restriction. Considering the upcoming novel standards for the first-line therapy of advanced stage cHL and the issue of older patients, factors impacting the efficacy and toxicity of Bv+AVD outside clinical trials are of interest. Methods: A retrospective multicentric study involving 13 Italian centres aimed to analyze toxicity and efficacy of Bv+AVD in adult patients with stage IV cHL, treated outside clinical trials, compared to a control cohort of stage IV cHL patients treated with ABVD from 2018 to 2021. Progression-free survival (PFS) was defined as occurrence of progression, relapse or death for any cause. The Frailty score (Lia R et al. Haematologica; doi: 10.3324/haematol.2025.287509), based on age >=70 years, ECOG performance status (PS)>=2 and Cumulative Illness Rating Scale-Geriatric (CIRS-G)>=8, was applied to identify fit (0), unfit (1-2) or frail (3 points) patients. PET data were collected from revising clinical files. Results: By March 2025, 132 patients treated with Bv+AVD and 87 with ABVD were collected. Baseline characteristics were not significantly different. Median age was 37 years (range 17-83), 48% were female, 18% were >60 years old, 30% had bulky disease and 62% reported B-symptoms. Age was >70 years in 8% (n=18), ECOG performance status was 2-4 in 10% (n=21), CIRS-G was >4 in 6% (n=12) and >8 in 2% (n=4). Any grade (G) peripheral neuropathy (PN) was significantly higher in the Bv+AVD group compared to ABVD (48% vs 21%, p<0.001), with comparable G3-4 PN (16% vs 18%, p=0.9). Any G neutropenia was comparable in the Bv+AVD vs ABVD group (44% vs 55%, p=0.14), as well as G3-4 infections (5% vs 8%, p=0.2). Eighty% of Bv+AVD patients received primary prophylaxis with G-CSF vs 61% of ABVD group. Toxicity-treatment modifications (TTM) such as treatment schedule delays (32% vs 13%, p=0.001), dose adjustment (25% vs 6%, p=0.001) and dose number reduction (12% vs 2% p=0.009) were more frequent in the Bv+AVD group. No difference was observed in the complete response rate (Deauville score, DS 1-3) at interim PET/CT, performed in 212/219 patients (80% Bv+AVD vs 80% ABVD, p=0.9), neither at final PET/CT (Bv+AVD 87% vs ABVD 91%, p=0.4). Of note, 7/14 patients in the Bv+AVD group had excisional biopsy proven false positive final PET (DS4-5), of which 4 had autoimmune comorbidity and none relapsed at current follow-up. Treatment intensification was performed in 12% of ABVD patients and only in 5% of Bv+AVD (p=0.042). After a median follow-up of 25.6 months for the Bv+AVD and 53.5 months for the ABVD group, with the limits of a historical comparison and of the different follow-up, PFS rates for Bv+AVD vs ABVD were 84% vs 78% at 2 years and 84% vs 72% at 3 years. OS rates were comparable (3y-OS 94% vs 96%, p=0.49). Positive interim-PET was predictive of inferior outcome also within the Bv+AVD group with 3-y PFS of 53% vs 93% (p<0.0001) and 3-y OS of 79% vs 99% (p= 0.001). The advantage of Bv+AVD vs ABVD was significant only in young patients <60 years old (3y PFS 87% vs 74%, p=0.048) and in patients who did not receive TTM (3y PFS 91% vs 71%, p=0.018). Among Bv+AVD group, age>60 years (HR 2.83, CI 1.11-7.19, p=0.029), age>70 years (HR 4.47, CI 1.61-12.4, p=0.004), ECOG-PS >2 (HR 4.79, CI 1.88-12.2, p=0.001) and CIRS-G score (HR 1.21, CI 1.03-1.42, p=0.021) were associated with reduced PFS. According to the Frailty Score, among patients treated with Bv+AVD, unfit (17%, n=22) and frail patients (1%, n=1) showed an inferior PFS (HR 3.96, CI 1.59-9.87, p=0.003), compared to fit patients. Conclusions: In a real-life population of stage IV adult cHL, the Bv+AVD regimen efficacy on PFS is influenced by TTM, interim PET DS4-5 (that also impacted on OS), age, ECOG-PS and CIRS-G. The Frailty score appears useful to select who can benefit less from Bv-AVD and could represent a tool to better stratify patients in the era of novel standards for the first-line therapy of advanced stage cHL.