BACKGROUND:Invasive fungal infections (IFI) are a prominent cause of morbidity and mortality among patients with haematological malignancies (HMs). Diagnostic work-up excluding IFI is mandatory in case of persistent fever while antifungal treatment (AFT) is started. OBJECTIVES:We aimed to describe antifungal prophylaxis (AFP) and AFT among haematological patients with IFI managed in clinical practice, focusing on microbiological and radiological characteristics, 30-day outcome and therapeutic options after AFT failure. PATIENTS AND METHODS:We enrolled 461 consecutive adult and paediatric patients with HMs, in which an intravenous AFT was started from September 2019 to December 2021. After serum galactomannan (GM) and chest CT scan, they were stratified as presenting with proven, probable, and possible IFI according to 2008 EORTC-MSG criteria. Fungal isolates were detected from culture tests in 17.5% and from biopsy in 1.5% of patients. Mould active and non-active AFP was used in 42.3% and 16.5% of cases, respectively. RESULTS:Use of AFP significantly impact on serum GM negativity (p < 0.001 for mould active and p = 0.04 for mould non active, respectively). Use of mould non-active prophylaxis significantly correlates with radiological imaging (typical p = 0.0037, IC (0.370-0.825) and negative -p = 0.0031, IC (0.241-0.750)). Toxicity, progression, and drug interaction were responsible for therapy change in 58 (12%) patients: 18 patients with proven/probable IFI needed multiple courses of AFT. At 30 days from starting AFT, overall mortality with IFI was 23/461 (5%). CONCLUSIONS:In this observational study, we recorded an impact of AFP on serum GM results and radiological imaging. Need of AFT should be carefully evaluated, as diagnostic work-up might be affected not only by specific disease risk but also by previous AFP.

In Acute Myeloid Leukemia (AML) patients, Febrile Neutropenia (FN) is the main cause of non-relapse mortality, especially occurring during induction chemotherapy. As the most frequent complications are gram-negative bloodstream infections (BSI) caused by mucosal barrier disruption during chemotherapy, current guidelines still recommend Fluoroquinolone (FQ) prophylaxis in high-risk hematological patients with severe and prolonged neutropenia (>7 days), despite a consolidated clear benefit on Infectious Related Mortality (IRM). Indeed, given the lack of robust real-life evidence in favour of FQ administration and the progressive increase of Multi Drug Resistant (MDR) bacteria rate due to prolonged antibiotic exposition, the role of FQ prophylaxis in AML neutropenic patients receiving chemotherapy should be carefully reassessed. In this light, Italian epidemiology showed a progressively increasing MDR bacteria rate thus prompting several Hematology Units to omit FQ prophylaxis as local policy.AIM: INFLUENCER study is a retrospective observational multicentric real-life study aiming to evaluate the incidence of FN, BSI, bacterial infections and IRM in AML adult patients undergoing induction chemotherapy, with or without FQ prophylaxis during a 6 years time frame.METHODS AND RESULTS: From January 2018 to December 2023, we enrolled a total of 1016 AML patients treated in 19 Italian hematological centers belonging to SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) net.The median age was 59 years, with 536/480 male/female ratio (53%, 47%). The novo and secondary AML (myelodysplastic and therapy related) were 68% and 32%, respectively. According to ELN risk, 35% scored as high-risk AML, 41% intermediate and 24% low.Regarding antibiotic prophylaxis, 418/1016 (41%) patients received FQ, while in 598/1016 (59%) patients it was omitted. Comparative data below are referred to the induction course. Median length of hospitalization was 38 days in the FQ group versus 35 days in the no-prophylaxis group, with statistically significant difference (p<0.001). Median length of neutropenia (ANC<500/mmc) was 27 and 25 days in the FQ group and no-prophylaxis group, respectively (p<0.001). Of note, granulocyte stimulating colony factor was used in 20,2% of prophylaxed patients and in 27,6% of not prophylaxed ones (p=0.009).We documented 399/418 (95,5%) FN in FQ patients versus 521/598 (87,1%) in no-prophylaxis patients (p<0.01), while BSI were similar in the two groups: 162/399 (40,6%) and 217/521 (41,7%) in FQ group and in no-prophylaxis group, respectively. Particularly, we recorded a gram-positive prevalence in both groups, with a higher rate in the prophylaxis group (65,8% versus 51,3%, p=0.022). Furthermore, organ infection rate was significantly higher in the FQ group (208/418 (49,8%)) compared to the no-prophylaxis group (175/598 (29,3%)), (p<0.001).On the contrary, we recorded 3,1% septic shocks in FQ patients, an incidence significantly lower if compared to 6,5% septic shocks documented in the no-prophylaxis group (p=0.023). However, if considering overall death rate within 60 days (86/1016, 8,5%), IRM was 66,7% in FQ group and 47,6% in no-prophylaxis one, without a significant difference (p=0.187), suggesting that overall survival is not related to FQ prophylaxis use.CONCLUSIONS: To our knowledge, INFLUENCER study is the first real-life study analysing a wide homogeneous population of AML patients, reporting infectious bacterial complications during induction chemotherapy according to FQ prophylaxis. These results do not confirm a negative effect of omitting FQ prophylaxis considering incidence of infections, indeed they question FQ prophylaxis real role, highlighting the need to revise its use, considering local epidemiology and rising MDR.

Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy associated with significant toxicity, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As CAR-T usage expands, hyperinflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) syndrome are increasingly recognized. Immune effector cell-associated HLH-like syndrome (IEC-HS) describes HLH-like symptoms attributable to CAR-T cell therapy, often presenting as CRS resolves. Treatments for IEC-HS are adapted from primary HLH, including corticosteroids, the recombinant human interleukin (IL)-1 receptor antagonist anakinra and the Janus Kinase inhibitor ruxolitinib. Emapalumab, an anti-IFN-γ antibody, is promising but underexplored in adult IEC-HS cases. We report an adult B-cell acute lymphoblastic leukemia (B-ALL) patient treated with brexucabtagene autoleucel (brexu-cel). The patient developed CRS, refractory neurotoxicity, and IEC-HS with worsening multiorgan failure and hyperinflammatory markers. Treatment included tocilizumab, high-dose corticosteroids, anakinra, siltuximab, and ruxolitinib. Despite aggressive management, hyperinflammation and neurotoxicity persisted. Emapalumab was initiated on day +11, resulting in normalization of the biochemical parameters and full neurological recovery by day +21. The patient recovered from IEC-HS and underwent allogeneic stem cell transplantation. This case highlights the role of emapalumab in managing refractory IEC-HS and persistent neurotoxicity in adults, underscoring the need for targeted interventions in severe CAR-T complications.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven lymphoproliferative disease that usually arises in the context of reduced immunological surveillance. Based on histology, two forms of the disease are recognized, namely low-grade and high-grade LYG. Clinically, LYG universally involves the lungs and, frequently, also the skin, central nervous system, liver, and kidneys. Here, we present the case of a 55-year-old woman with a difficult-to-diagnose low-grade LYG with symptomatic lung involvement, who concomitantly was newly diagnosed with human immunodeficiency virus (HIV) infection. Rapid immune recovery achieved through antiretroviral therapy led to a complete and sustained clinical and radiological remission of LYG.

Castleman disease (CD) is a group of lymphoproliferative disorders that share common histopathological features yet have widely different aetiologies, clinical features and grades of severity as well as treatments and outcomes. Siltuximab is currently the only therapy approved by the FDA and EMA for idiopathic multicentric CD and is recommended as first-line therapy in treatment guidelines. Despite the extensive characterization of siltuximab treatment in clinical trials, available evidence from real-world practice is still scant. This collection of clinical experiences focuses on patients treated with siltuximab therapy, particularly regarding the idiopathic multicentric CD diagnostic work-up, and on treatment administration in patients with complex disease entering differential diagnosis with CD or concomitant diseases. Thus, these data help further characterize and improve the use of siltuximab in real practice in terms of effectiveness and safety of long-term administration as well as consequences of treatment interruption.

Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and subsequent coronavirus (20)19 disease (COVID-19)-related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID-19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS-CoV-2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow-up was 52 days for the entire cohort and 83 days for survivors. Three-hundred and three patients died (24%) and COVID-19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 x 109/L was found to be protective. This data suggests that MM patients remain at risk of SARS-CoV-2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic.

Acquired Aplastic Anemia (AAA) is a rare disease involving primary bone marrow failure with consequent pancytopenia. The addition of the synthetic thrombopoietin-receptor agonist eltrombopag (ELT) to standard immunosuppression for the treatment of AAA has led to improvements in hemopoietic outcomes of AAA. Most of the data on the use of ELT for AAA was based on a maximum of 6 months of therapy. However, in clinical practice, a longer use of ELT is often required. This paper presents a monocentric real-life experience with prolonged use of ELT in 10 patients with AAA, showing data on effectiveness and safety. In our cohort, a high rate of response to ELT added to standard immunosuppression in patients with varying grades of severity of AAA was reported. After a median (range) observation time of 47.5 (31-75) months, the treatment with ELT was feasible with an overall response probability of 70% and was not associated with any concerning adverse event. Two episodes of relapse were reported; no signs of evolution have been reported so far. In conclusion, ELT as a dose-response-adjusted prolonged therapy associated with standard immunosuppression in AAA patients not eligible for transplant seems to be feasible to consolidate and maintain the response.

Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.

Background: Venetoclax (Ven) in combination with Azacitidine (AZA) is the standard of care for newly diagnosed or relapsed/refractory (R/R) patients with Acute Myeloid Leukemia (AML) aged 75+ or unfit for intensive chemotherapy. The registration VIALE-A trial mandated inpatient therapy initiation, due to the risks of Tumor Lysis Syndrome (TLS) and infection. To enhance patient quality of life, reduce the risk of hospital-acquired infections and alleviate healthcare costs, our study investigates the feasibility of administering the first cycle of therapy in an outpatient setting. Aims and Methods: This is a retro-prospective single-center study. Inclusion criteria encompassed newly diagnosed or R/R AML patients, aged 18+, receiving their first cycle of Azacitidine-Venetoclax and treated in either an inpatient or outpatient setting at our center. Therapy regimen followed standard guidelines. All received TLS prophylaxis with rasburicase and/or allopurinol depending on baseline uric acid levels and TLS risk. Our primary endpoint was to evaluate differences in infection and TLS rates between inpatient and outpatient setting, with infection defined as any condition requiring antibiotic therapy (either intravenous or oral) other than anti-infectious prophylaxis, while TLS was defined according to Cairo-Bishop Criteria (Cairo MS, Bishop M, Br J Haematol). Secondary endpoints were evaluation of differences in Overall Survival (OS) and Progression Free Survival (PFS) between the two cohorts. Statistical analysis was performed with Graphpad Prism V 10.2. Results: Thirty-seven consecutive patients (21 males, 16 females; median age 72 years, range 34-80) diagnosed between June 2020 and May 2024 were included in the study. Among these, 30 patients (81.1%) had newly diagnosed AML, while 7 patients (18.9%) had R/R AML. Eighteen patients (48.6%) received their first cycle of Azacitidine-Venetoclax (C1 AZA-Ven) in an outpatient setting (outpts), whereas 19 patients (51.4%) were hospitalized at the time of therapy initiation (inpts). The two cohorts were well balanced, with no statistically significant differences in sex, karyotype complexity, hemoglobin (Hb), leukocytes, neutrophils, platelets, and creatinine levels at diagnosis. However, outpts were older than inpts, with a median age of 75 years (range 67-80) compared to 66 years (range 34-75) for inpts (p<0.01). Median time from diagnosis to treatment was 20 days (Confidence Intervals (CI) 9-35 days) for inpts and 27 days (CI 20-40) for outpts. Regarding the primary endpoint of infection rates, no significant differences were observed between outpts and inpts (38.9% vs. 52.6%, respectively; Odds Ratio 1.7; CI 0.47 to 5.92; p=0.52). Additionally, there were no significant differences in the occurrence of TLS (p=0.48), thus meeting the primary endpoint. Cox-regression analysis with a 30-day censoring revealed no increased Hazard Risk (HR) of infection in outpts compared to inpts (HR 0.71; CI 0.2-1.8; p=0.48). Three (42.8%) of the 7 infected outpts were hospitalized within 7 days from the start of C1 AZA-Ven, while 2 (28.6%) within 30 days. Hospitalizations were primarily for intravenous antibiotic therapy, except for one case of invasive cryptococcal infection. Considering baseline patients features, only Hb resulted in a higher risk of infection, with infected patients having lower median Hb levels (median 8.6 vs. 10.15 g/dL; p=0.019). No differences were seen in leukocytes, neutrophils and platelet count between infected and not infected patients. Regarding secondary endpoints, between the two cohorts there was no significant difference in OS at 12 months (inpts: 51.6%, CI 21.6-74.5; outpts: 40.5%, CI 15.2-64.8; p=0.75) or PFS (median PFS: inpts not reached; outpts 21.14 months; p=0.59). Conclusions: Our preliminary results, based on a retro-prospective analysis, suggest that outpatient administration of C1 AZA-Ven could be a viable alternative to inpatient care, potentially improving patient quality of life and reducing healthcare costs. Further studies with larger sample sizes are warranted to confirm these findings and to identify patients suitable for therapy initiation in an outpatient setting and to determine what baseline characteristics, if any, can aid in risk stratification for TLS or early hospitalization.

Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV -associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV -associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double -/triple -hit lymphomas, and 33 had isolated MYC rearrangement (single -hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R) CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5 -year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV -associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS.

Background Invasive fungal infections (IFI) are a relevant cause of morbidity and mortality among patients with haematological neoplasms (HMs). Since 2002, a classification of IFI based on host factors, clinical and radiological features and mycological tests was published for research purpose. ObjectivesThese criteria are widely used in clinical practice to identify patients at risk for IFI. The aim of the study was to evaluate the clinical applicability of EORTC/MSG 2008 criteria for the diagnosis of IFI in daily practice. Patients/Methods This multicentre, non-interventional, observational, prospective study gathered all consecutive inpatients with HMs in which an intravenous antifungal treatment was started. Exclusion criteria were a previous or concomitant transplant procedure, outpatient status and oral antifungal therapy. EORTC/MSG 2008 criteria were used to classify patients at the beginning of antifungal therapy and at 30 days. An independent board reviewed the classification of IFI given by local clinicians at T0 and T30. Results The highest percentage of agreement was found for possible IFI (96%), while a lower agreement was reported for proven IFI (74%), and the highest variability was observed for probable IFI (56%). At T30, the board re-evaluation confirmed a strict agreement for possible IFI only (98%). Among 306 patients classified as possible, 156 (51%) patients showed non-typical radiological findings and 45 (15%) patients presented host factors only. Conclusions In real life, the EORTC/MSG criteria can be applicable only for possible IFI. As non-typical radiological findings are reported in possible IFI, introducing a new IFI category should be considered.

Historically, the admission of hematological patients in the ICU shortly after the start of a critical illness is associated with better survival rates. Early intensive interventions administered by MET could play a role in the management of hematological critically ill patients, eventually reducing the ICU admission rate. In this retrospective and monocentric study, we evaluate the safety and effectiveness of intensive treatments administered by the MET in a medical ward frame. The administered interventions were mainly helmet CPAP and pharmacological cardiovascular support. Frequent reassessment by the MET at least every 8 to 12 h was guaranteed. We analyzed data from 133 hematological patients who required MET intervention. In-hospital mortality was 38%; mortality does not increase in patients not immediately transferred to the ICU. Only three patients died without a former admission to the ICU; in these cases, mortality was not related to the acute illness. Moreover, 37% of patients overcame the critical episode in the hematological ward. Higher SOFA and MEWS scores were associated with a worse survival rate, while neutropenia and pharmacological immunosuppression were not. The MET approach seems to be safe and effective. SOFA and MEWS were confirmed to be effective tools for prognostication.

AbstractMidostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3‐mutated acute myeloid leukemia. Chemotherapy‐induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin‐related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real‐life study to evaluate (i) how often concerns around PCZ‐midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ‐midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ‐midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin) was greater than three times higher than reported; moreover, midostaurin Cmin, maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin‐related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin‐treated patient.

Anaplastic large T-cell lymphoma (ALCL) is an aggressive disease that presents in pediatric or adult patients with advanced stage disease, extranodal involvement, and constitutional symptoms. 1 Approximately 50% of ALCLs are characterized by constitutive activity of the anaplastic lymphoma kinase (ALK) gene because of chromosomal translocations, most frequently a t(2;5) leading to an NPM1-ALK gene fusion. 2 ALK alterations can be detected also in other lymphoma histotypes, histiocytosis, and nonhematological cancers. 2,3 In rare cases, ALK fusions with NPM1 or other partners can be driver events also in diffuse large B-cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL), 4,5 but the optimal management of these rare diseases is unknown. In ALK + ALCLs, anthracycline-based chemotherapy regimens are associated with an overall responserate(ORR)of80%to85% 1 anda3-yearoverallsurvival(OS)of82%isreportedinpatientsattaining complete remission (CR). However, more than 50%of patients relapse and need

OBJECTIVES:Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail.METHODS:We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy.RESULTS:The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment.CONCLUSION:These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.