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.

This comprehensive narrative review aims to provide an in-depth analysis of Human herpesvirus-8/Kaposi Sarcoma-associated herpesvirus (HHV-8/KSHV) and Kaposi sarcoma herpesvirus-associated diseases (KADs), with a special focus on malignancies in the setting of transplantation, by addressing the major issues related to clinical presentations, epidemiology, pathological features, diagnosis, treatment, and outcome. HHV-8/KSHV is an oncogenic virus belonging to the family of the γ-herpesvirus responsible for a wide range of KADs such as Kaposi’s Sarcoma (KS), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), diffuse large B cell lymphoma not otherwise specified (DLBCL-NOS), and KSHV inflammatory cytokine syndrome (KICS). In solid organ transplant (SOT) recipients, the incidence of HHV-8/KSHV-related malignancies are becoming more frequent because of prolonged life expectancy, and related aging and immunosenescence. HHV-8/KSHV infection in SOT is a rare but serious complication associated with significant morbidity and mortality. Enhanced clinical awareness of the diverse manifestations of KADs is critical for early diagnosis and improved outcomes. Multidisciplinary management is essential, given the complexity of these cases. Future research should focus on establishing standardized protocols for screening, diagnosis, and treatment to improve clinical outcomes. Targeted donors and recipients serological screening strategies, combined with vigilant post-transplant monitoring have the potential to enhance patient care.

Background/Objectives: Tissue niches, such as those in the spleen, bone marrow, and lymph nodes, are crucial for the survival and growth of leukemic cells in chronic lymphocytic leukemia (CLL). Methods: A growing amount of research over the last 20 years has shown how important the tumor microenvironment (TME) is to the pathophysiology, development, and resistance to treatment of CLL. This protective environment, which is made up of various cell types (including stromal and immune cells), extracellular matrix components, and soluble factors, supports CLL cells and encourages their survival, growth, and drug resistance. Even in the absence of mutations, Notch2 is functionally activated in the CLL system, in addition to the well-known Notch1. This occurs because leukemic cells aberrantly express the ligand Jagged1/2, which activates the Notch2 receptor on both stromal and CLL cells themselves. Notch2 activation on stromal cells leads to the triggering of the Wnt/β-catenin program in CLL cells, whereas the activation of Notch2 in CLL cells promotes the expression of Mcl-1, which confers drug tolerance (especially in cases with trisomy 12). Results: In addition to these mechanisms, Notch2 acts as a transcription factor that directly controls the expression of key targets, such as CD23 and Hes1, that are fundamental for B cell proliferation, differentiation, and survival in CLL. Conclusions: All of these circuits represent important therapeutic targets and help explain the cells' dependence on their niche, the formation of proliferation centers, and resistance to modern targeted agents.

The incidence of HHV-8/KSHV-associated diseases (KADs) among solid organ transplant (SOT) recipients has shown a relative increase, likely reflecting the growing population of long-term SOT survivors and heightened recognition and reporting due to greater clinician awareness. The real impact of HHV-8/KSHV in the SOT setting remains difficult to determine due to regional variations in seroprevalence and non-universal screening practices. Neoplastic KAD reported in SOT includes Kaposi sarcoma (KS), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and other rare lymphomas. Increasing attention has focused on Kaposi's Sarcoma-associated Herpesvirus Inflammatory Cytokine Syndrome (KICS), a non-malignant syndrome characterized by uncontrolled inflammation, fever, pancytopenia and elevated HHV-8/KSHV DNAemia, resembling viral sepsis that can progress to shock and multi-organ failure. A clinical protocol including testing donors and recipients, monitoring for DNAemia in recipients at risk, switching CNI to mTOR inhibitors, treatment with antivirals, and rituximab for KICS may mitigate the impact of HHV-8/KSHV infection in SOT recipients. However, standardized serological testing is not available and the role of monitoring, preemptive management and treatment of HHV-8/KSHV DNAemia should be studied in larger prospective studies. Severe donor-derived KICS and KS, often presenting without skin involvement, underscore the need for reliable serologic tests for identification of at-risk recipients (especially D+/R-), heightened clinical awareness to ensure timely diagnosis and prompt treatment. This review provides an updated overview of KADs with a particular focus on KICS in SOT, highlights knowledge gaps for future research, and summarizes recent advances in the screening and management of HHV-8/KSHV infection following transplantation.

Kaposi’s sarcoma (KS) is one of the most frequent malignancies observed in solid organ transplant (SOT) recipients, and it is associated with human herpes virus 8/Kaposi’s sarcoma-associated herpesvirus (HHV-8/KSHV) infection. The incidence varies according to the prevalence of HHV-8/KSHV in the population, the intensity of the immunosuppression and serological status of organ donor and recipient. Both latent and lytic phases of the HHV-8/KSHV life cycle play crucial role in the pathogenesis, influencing oncogenesis, immune evasion, and inflammasome activation. KS can be the result of reactivation of HHV-8/KSHV latent infection in the immunosuppressed recipient or be the consequence of a primary infection (either donor- or non-donor-derived), the latter possibly associated with a more aggressive clinical course. KS usually presents with cutaneous lesions, however post-transplant KS is characterized by visceral and/or lymph node involvement, frequently in absence of cutaneous lesions, underlying the challenges associated with KS diagnosis in SOT and the need of high clinician suspicion. The mainstay of post-transplant KS management is reduction of immunosuppression, along with conversion to mTOR inhibitors, while in visceral forms chemotherapy with liposomal doxorubicin is usually the first choice. Active surveillance and personalized management strategies, based on risk stratification and multimodal therapeutic approaches, are essential to optimize outcomes in transplant recipients affected with KS.

CONTEXT:Early palliative care (EPC) improves patient-centered outcomes in solid tumors but remain underutilized in acute myeloid leukemia (AML), where evidence on EPC content and implementation is limited. OBJECTIVES:We aimed to characterize the core components...associations with palliative care quality indicators and end-of-life (EOL) care intensity. METHODS:We conducted a single-center retrospective observational study including consecutive adults with AML/HR-MDS receiving outpatient EPC. We reviewed electronic medical records to identify EPC components across all visits. We assessed temporal trends by comparing the first versus last three visits. Mixed-effects logistic regression examined associations between EPC components and quality indicators; univariate models assessed associations with EOL care aggressiveness. RESULTS:A total of 180 patients received 1175 EPC visits (median six visits/patient). EPC components most frequently addressed symptoms (89.9%), coping support (74.6%), and illness understanding (71.2%). Over time, EOL planning increased (11.0% in first vs. 68.3% in last three visits; P < 0.001), as did family engagement (45.2% vs. 61.9%; P = 0.025). In multivariable models, more illness-understanding visits increased prognostic awareness discussions (OR 1.34; 95% CI: 1.16-1.55; P < 0.001), whereas coping-focused visits were associated with lower odds of documented goals-of-care conversations (OR 0.86; 95% CI: 0.78-0.96; P = 0.006). More EOL planning-focused visits increased the likelihood of receiving ≥1 quality indicator (OR 1.65; 95% CI: 1.40-1.94; P < 0.001) and ACP documentation (OR 2.91; 95% CI: 2.25-3.76; P < 0.001). Higher EPC exposure was associated with lower chemotherapy use in the last 30 days of life (OR 0.73; 95% CI: 0.53-1.00; P = 0.049), and coping-focused visits were associated with lower odds of in-hospital death (OR 0.77; 95% CI: 0.60-0.94; P = 0.010). CONCLUSIONS:EPC in AML/HR-MDS has distinct components that vary over time and are associated with established indicators of high-quality care, including EOL outcomes. These findings support a scalable, content-driven EPC model with direct implications for clinical implementation and future trials in hematologic malignancies.

B-cell prolymphocytic leukemia (B-PLL) is a rare B-cell neoplasm that presents splenomegaly, lymphocytosis, minimal or absent lymphoadenopathy, at least 55% of prolymphocytes in peripheral blood and a variable clinical course. Complex/composite karyotype and recurrent structural variants (SVs), including TP53 aberrations (mutations/deletion) and MYC abnormalities (translocation or gain) are genetic features typically seen in B-PLL. We applied the genome-wide technology of optical genome mapping (OGM) in 3 cases with B-PLL, finding multiple genomic aberrations, including SVs, copy number variations (CNVs) and aneuploidies. MYC aberrations were not observed in our cases, whereas all B-PLL showed concomitant deletion 17p and TP53 mutations. TP53-disrupted B-PLL cells showed additional genomic alterations that affect genes implicated in extrinsic and intrinsic apoptotic pathways i.e., TNFRSF10, FAS, MDM2, BCL2, and BCL2L11 and genes involved in cell-cycle regulation i.e., IKBKB, CDK2, CDK4, and RB1, suggesting that a convergent multifactorial pathogenetic mechanism may be involved in B-PLL. Applying the OGM technology on cytogenetically complex rare hematological neoplasia may be useful to improve the genetic definition and differential diagnosis of B PLL/SBLPN and related splenic B cell neoplasms.

INTRODUCTION:While pediatric-based protocols have significantly improved survival rates in adolescents and young adult (AYA) patients with Philadelphia-negative acute lymphoblastic leukemia (Ph- ALL), limited information is available on the applicability of pediatric-like chemotherapy in real life outside of clinical trials. METHODS:We retrospectively collected clinical data from 36 AYA patients (median age 21 years, range 18-38) with Ph- ALL (28) or lymphoblastic lymphoma (LL) (8) who received a frontline treatment inspired by the GIMEMA LAL1308 pediatric protocol in a multicenter real-life setting, across centers participating in the Campus ALL network. RESULTS:A morphologic or radiologic/metabolic complete remission was documented in 31/36 (86.1%) ALL/LL patients after induction Phase Ib. Measurable residual disease (MRD) negativity was reached in 17/23 (73.9%) evaluable ALL patients at the prognostic timepoint at the end of Ib induction cycle. Consolidation/maintenance approaches followed risk-adapted indications, with 20 (55.6%) patients receiving an allogeneic hematopoietic stem cell transplantation (allo-HSCT) because of either adverse prognostic factors, resistance to induction treatment, morphologic relapse, or MRD positivity. The 5-year overall, disease-free, and event-free survival rates were 76.4%, 69.1%, and 59%, respectively. No significant differences in outcomes were observed according to the ALL/LL diagnosis, B/T lineage, risk stratification, allo-HSCT procedure, and, surprisingly, MRD status, probably due to the limited sample size or to optimal risk-adapted and MRD-driven intensification strategies. CONCLUSIONS:The implementation of this unmodified pediatric regimen to Ph- AYA ALL patients appears feasible in a real-life context, with results that compare favorably to those of other pediatric-based regimens not yet incorporating frontline immunotherapy.

Abstract We report the case of a young woman who developed aplastic anemia (AA), following a serologically confirmed primary Epstein–Barr virus (EBV) infection, occurring with fever and pharyngotonsillitis, in the absence of either palpable lymph nodes or enlarged spleen. Pancytopenia persisted after EBV DNA clearance, requiring multiple red blood cell and platelet transfusions. Given the availability of a human leukocyte antigen (HLA)-matched sibling donor (MSD), hematopoietic stem cell transplantation (HSCT) from bone marrow source was performed after a non-myeloablative conditioning regimen with cyclophosphamide and thymoglobulin. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A and methotrexate. EBV reactivation occurred, one month post-HSCT, peaking at 28,838 DNA copies/ml in peripheral blood, without evidence of post-transplant lymphoproliferative disorder. Two pre-emptive doses of rituximab were administered, resulting in sustained EBV DNA negativity. Subsequent bone marrow evaluation showed normal cellularity and restoration of peripheral counts. After two years of follow-up, the patient remains transfusion-independent, with stable hematologic recovery, no signs of GVHD, and persistent mixed chimerism (70–75% host cells in peripheral blood; about 60% donor CD3 + lymphocytes). To our knowledge, this is the only second reported case of EBV-related AA successfully treated with MSD HSCT. This case underscores the importance of assessing EBV serology in all patients with AA, since EBV infection may be mild or subclinical, and highlights the efficacy of early rituximab administration in high-level EBV DNA reactivation after transplantation.

OBJECTIVES:To describe longitudinal changes in quality of life (QOL) and symptoms among patients with acute myeloid leukaemia (AML) receiving real-world early palliative care (EPC) during the first year after diagnosis. METHODS:This prospective observational study enrolled consecutive adults with AML followed in an outpatient EPC clinic. QOL and symptoms were assessed monthly using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), the Edmonton Symptom Assessment Scale (ESAS) and the Hospital Anxiety and Depression Scale (HADS). Scores were analysed through joint modelling, integrating longitudinal and survival data, and sensitivity analyses. RESULTS:Thirty-eight patients contributed 169 FACT-Leu, 151 ESAS and 111 HADS questionnaires. From baseline, median FACT-Leu scores improved from 108.7 to 135.7 at 4 months and remained stable through 8 and 12 months (p≤0.011), while ESAS scores decreased from 25.2 to 5.7 by 4 months and remained low through 12 months (p<0.001), indicating sustained symptom improvement. HADS scores showed no statistically significant changes, although a modest anxiety improvement was noted. Trajectories remained consistent across all sensitivity analyses. CONCLUSIONS:In AML patients receiving EPC in a real-world outpatient setting, QOL and symptom burden showed sustained improvement over time. These descriptive findings highlight the potential effectiveness and clinical relevance of EPC in routine AML care and provide real-world reference data for future controlled studies.

Decitabine, including its new oral formulation (decitabine-cedazuridine, DEC-C), is commonly used in AML and MDS, particularly in older or unfit patients. While its clinical efficacy and tolerability are well documented, evidence regarding patient-reported outcomes (PROs) and health-related quality of life (HRQoL) remains limited. We conducted a review of the available literature on PROs in patients with AML and MDS treated with decitabine, with the aim of evaluating its impact on HRQoL, symptom burden, and patient preferences. A systematic literature search of PubMed up to October 2024 identified studies evaluating HRQoL or PROs in adult AML and/or MDS patients receiving decitabine, regardless study design. Ten studies met the inclusion critera. Decitabine-based regimens were associated with preservation of HRQoL compared with intensive chemotherapy and improvements in fatigue and physical functioning versus best supportive care. In patients with AML, baseline HRQoL scores were found to be predictive of survival outcomes. Surveys consistently indicated strong patient preference for oral DEC-C due to reduced treatment burden and greater convenience, though longitudinal data remain limited. In conclusion, currently available HRQoL evidence for decitabine provides meaningful insight to guide further research. Findings from patient surveys and the availability of decitabine in both intravenous and oral formulations emphasize new treatment aspects that can be effectively captured through PROs. Their systematic integration may help uncover critical issues such as symptom burden, adherence, and patient priorities, ultimately fostering more patient-centered care.

PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways.

Abstract Myelofibrosis (MF) originates from the stepwise acquisition of somatic mutations in Hematopoietic Stem and Progenitor Cells (HSPCs). Alongside driver events triggering JAK-STAT pathway hyperactivation, several additional mutations, usually affecting the epigenetic machinery, contribute defining therapeutic response. Specifically, JAK-inhibition (JAKi) relieves MF symptoms but rarely eradicates the neoplastic clone. To elucidate clonal dynamics associated with JAKi, we conducted a longitudinal single-cell proteogenomic study on 6 responders and 6 non-responders MF patients. Mutational analysis revealed that the mutation acquisition order determines JAKi sensitivity. Indeed, driver -only clones are highly sensitive to JAKi, while co-mutated clones persist after treatment. JAKi response is mainly limited to the differentiated myeloid compartment, while mutant HSPCs are often maintained in JAKi-responders. Co-mutated clones may evade JAKi and outcompete other neoplastic cell populations, thus contributing to disease persistence.

BACKGROUND:Patients with acute leukemia frequently receive aggressive treatments near the end of life (EOL) . Goals-of-care (GOC) conversations may improve EOL quality, yet few studies have investigated their impact in hematological malignancies. OBJECTIVE:To evaluate sociodemographic and clinical factors associated with GOC conversations and the impact of GOC conversations on EOL care. METHODS:A retrospective study was conducted among patients with acute leukemia and high-risk myelodysplastic syndromes, treated over a 15-year period at authors' Institution. RESULTS:Of 390 patients, 44.4% had GOC conversations. Palliative care specialists documented the first GOC discussion in 157 patients. 133 (76.9%) patients received GOC conversations within a program of early palliative care (EPC) . In multivariable analysis, age≥60 (OR 4.85; 95% CI: 2.18-10.78) , ≥2 comorbidities (OR 2.52; 95% CI: 1.03-6.2) , non-White race (OR 7.97; 95% CI: 1.13-56.32) , prior allogeneic transplantation (OR 8.74; 95% CI: 2.09-36.58) , and EPC integration (OR 16.28; 95% CI: 4.21-62.92) were significantly associated with higher likelihood of GOC discussions. Concerning EOL care, GOC conversations were associated with reduced odds of chemotherapy in the last 90 days (OR 0.41; 95% CI: 0.21-0.79) , ICU admission in the last 30 days (OR 0.20; 95% CI: 0.05-0.85) , and in-hospital death (OR 0.35; 95% CI: 0.18-0.69) . CONCLUSIONS:GOC conversations were infrequently performed and the primary factor that increased their likelihood of occurrence was EPC. When GOC conversations took place, patients experienced higher-quality EOL care. These results support increasing EPC for patients with hematologic malignancies to improve GOC conversations and their overall EOL care and, suggest EPC as a prime intervention for trials in this setting.

BACKGROUND:The management of severe complications arising from newly diagnosed or existing cancer, as well as acute therapy-related side effects, is traditionally provided by General Emergen-cy Departments (GED). To address the specific needs of oncologic and hematologic patients, the University Hospital of Modena established a dedicated Oncology-Hematology Emergency Room (OHER) in 2001 as an integral part of the Oncology and Hematology Department. AIM AND METHODS:This study aims to analyze the clinical characteristics and outcomes of cancer patients admitted to OHER between 2009 and 2019, including hospitalization rates, and compare them with those of cancer patients admitted to GED over the same period. A dedicated electronic tool was developed to process medical records. The OHER staff includes oncologists and hematol-ogists trained in internal medicine, supported by a specialized nurse who is available during daytime workdays. RESULT:A total of 28.680 OHER admissions were recorded, involving 11.239 patients. Among them, 5.326 (47%) had a single visit, while 165 (0.6%) died during their monitoring in OHER. Admis-sions peaked in January (10%; 2,900 visits) and were lowest in December (6.8%; 1,952 visits). The busiest day was Monday (6,926 visits), at least in terms of hospitalization and mortality rates. At our Center, OHER serves as the primary point of reference for oncology and hematological patients who present with unexpected clinical deterioration. CONCLUSION:Our analysis aims to provide clinical data from a dedicated oncology and hematology emergency room, comparing them with those observed in the general emergency room. In our ex-perience, the OHER enhances the delivery of patient-centered oncology care and the quality of comprehensive oncology and hematology care through its innovative integration of various clinical and organizational aspects.