The therapeutic landscape of chronic lymphocytic leukemia (CLL) has been profoundly transformed by the introduction of Bruton tyrosine kinase and BCL-2 inhibitors. Despite improved survival outcomes, treatment selection remains complex, particularly in older patients with comorbidities, frailty, and increased infectious vulnerability. To address areas of clinical heterogeneity and support real-world decision-making, a two-round Delphi consensus process was conducted among 15 hematologists from 15 hematology departments across two Italian regions, Calabria and Sicily. A steering committee developed 12 statements covering key clinical and organizational aspects of CLL management, including infectious risk assessment, frailty evaluation, and the role of TP53 alterations in therapeutic choice. Agreement was assessed using a four-point Likert scale, with consensus predefined as ≥ 70% agreement or disagreement. All invited clinicians participated in both rounds (100% response rate). In the first round, consensus was achieved for 8 of 12 statements (66.7%). Following reformulation of unresolved items, two additional statements reached consensus in the second round. Overall, strong agreement was observed for five statements, while moderate convergence persisted for others. Panelists emphasized that infectious risk assessment should systematically inform treatment decisions and that structured frailty tools, including ECOG Performance Status and the Clinical Frailty Scale, may improve patient stratification. Although TP53 alterations were recognized as critical biological determinants, therapeutic decisions in older patients should balance genetic risk with age, comorbidities, frailty, and socioeconomic context. This regional initiative highlights priorities for patient-centered, multidimensional CLL management and may inform the development of optimized care pathways within coordinated regional networks.

Primary refractory Diffuse Large B-Cell Lymphoma is associated with poor outcomes and limited responsiveness to conventional salvage therapies. Although CAR T-cell therapy represents the standard of care in this setting, a substantial proportion of patients cannot receive it despite meeting disease-related criteria. In this review, "unsuitable" refers to patients who are temporarily or functionally unable to undergo CAR T-cell therapy because of reversible clinical conditions, rapidly progressive disease requiring immediate cytoreduction, or logistical and social barriers, rather than permanent contraindications. For these patients, prompt alternative strategies are required. Conventional platinum-based or gemcitabine- and bendamustine-containing regimens retain a role for short-term disease control but offer limited durability. In contrast, novel antibody-based therapies, including polatuzumab-containing combinations, loncastuximab tesirine, and tafasitamab plus lenalidomide, have expanded treatment options with improved tolerability. Most notably, CD20 × CD3 bispecific antibodies represent a major therapeutic advance, providing off-the-shelf immune engagement with predominantly outpatient administration. From a practical perspective, early identification of reversible barriers to CAR T-cell therapy and timely use of bispecific antibodies or other antibody-based regimens are critical to achieve rapid disease control, preserve organ function, and, when feasible, restore eligibility for cellular therapy.

Diffuse large B-cell lymphoma (DLBCL) remains the most common aggressive lymphoma, representing a biologically heterogeneous disease with diverse clinical behaviors. For more than two decades, R-CHOP has been the cornerstone of frontline treatment, curing approximately two-thirds of patients. Despite this success, a substantial subset-particularly those with high-risk biology, double-hit genetics, activated B-cell-like (ABC) subtype, or adverse clinical features-still experience relapse or refractory disease. Recent advances in lymphoma biology, immunotherapy, and targeted therapy have stimulated intense interest in improving frontline outcomes. Strategies include optimizing cytotoxic backbone regimens, incorporating antibody-drug conjugates (ADCs), immunomodulatory agents (IMiDs), bispecific antibodies, and exploring the feasibility of frontline CAR-T cell therapy. This review provides a comprehensive and discursive synthesis of the biological rationale, clinical evidence, trial results, and practical considerations shaping contemporary frontline treatment. We highlight the emerging role of molecular subtyping, the tumor microenvironment, and high-risk biomarkers, while discussing ongoing challenges and opportunities in integrating novel modalities into standard practice. Although R-CHOP remains the universal backbone, the therapeutic landscape is entering a transformative era, with polatuzumab-based regimens, bispecific combinations, and precision-guided approaches positioned to redefine frontline care for selected subgroups.

Acute lymphoblastic leukaemia (ALL) in older adults represents a growing clinical challenge, driven by an ageing population, adverse disease biology, and reduced tolerance to intensive chemotherapy. Although pediatric-inspired regimens have improved outcomes in younger adults with Philadelphia chromosome (Ph)-negative ALL, survival in older patients remains poor, with high rates of treatment-related toxicity, early death, and relapse. Age-related comorbidities, impaired organ function, and unfavorable cytogenetic and molecular features, including low hypodiploidy and TP53 mutations, further compromise prognosis. In this context, monoclonal antibodies such as blinatumomab and inotuzumab ozogamicin (InO), used alone or in combination with reduced-intensity chemotherapy, have emerged as promising frontline approaches capable of deep remissions with improved tolerability. Moreover, CAR T-cell therapy is increasingly recognized as a potentially effective strategy for relapsed/refractory disease in selected older adults, particularly in the setting of low disease burden, with acceptable safety in carefully monitored cohorts. However, issues such as antigen loss, lineage switch, the management of T-cell ALL, and the optimal sequencing of immunotherapies remain unresolved. Across all treatment strategies, comprehensive geriatric assessment appears more informative than performance status alone in predicting tolerability and outcome, supporting its integration into trial design and routine decision-making. Overall, the refinement of immunotherapeutic approaches, coupled with biologically and geriatrically tailored treatment algorithms, offers the most promising avenue to improve long-term outcomes for older patients with ALL.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and is mechanistically distinct from apoptosis, necrosis and pyroptosis. Increasing evidence indicates that ferroptosis plays a critical role in cancer biology, including lymphoproliferative disorders, where chronic redox imbalance, dysregulated iron metabolism, and metabolic rewiring create a permissive environment for ferroptotic vulnerability. In these malignancies, altered iron handling, elevated reactive oxygen species, and a strong reliance on antioxidant systems such as glutathione and glutathione peroxidase 4 tightly control ferroptotic sensitivity. Dysregulation of key components, including SLC7A11, lipid metabolism pathways, and intracellular iron homeostasis, further shapes the susceptibility of malignant lymphoid cells to ferroptosis. Importantly, emerging preclinical studies suggest that therapeutic targeting of ferroptosis may overcome resistance to conventional chemotherapy, targeted agents, and immunotherapy, offering novel opportunities particularly in relapsed or refractory disease. This review provides a comprehensive overview of the molecular mechanisms governing ferroptosis in lymphoproliferative disorders, highlights the interplay between ferroptosis and major cellular and metabolic pathways, and discusses current and emerging strategies to pharmacologically induce ferroptosis, with an emphasis on biomarker-driven clinical translation.

ABSTRACT:Bruton tyrosine kinase inhibitors (BTKis) have dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL), with ibrutinib, first-in-class, demonstrating durable efficacy even in high-risk patients. However, off-target adverse events (AEs) have raised concerns, prompting the development of more selective second-generation BTKis, such as zanubrutinib, designed to improve tolerability while maintaining efficacy. Despite encouraging results from clinical trials, real-world data comparing zanubrutinib with ibrutinib remain limited. In this multicenter, retrospective study, we analyzed 934 patients with CLL treated outside clinical trials, including 393 receiving zanubrutinib and 541 receiving ibrutinib. We evaluated time to treatment discontinuation (TTD) and time to next treatment or death (TTNTD) in both the overall cohort and a propensity score-matched population. Patients who were treated with zanubrutinib experienced lower 12-month discontinuation rates (overall: 12.6% vs 21.4%; matched: 12.4% vs 20.2%) and higher 12-month TTNTD rates (overall: 91.9% vs 83.0%; matched: 93.2% vs 83.4%). Multivariable analyses confirmed zanubrutinib as an independent predictor of longer TTD and TTNTD, whereas high-risk features, including age, relapsed/refractory disease, Binet stage C, TP53 disruption, Eastern Cooperative Oncology Group 2 to 3, and congestive heart failure, were consistently associated with poorer outcomes. AEs leading to discontinuation, particularly atrial fibrillation, bleeding, and infections, were less frequent with zanubrutinib, reflecting its favorable safety profile. These findings provide real-world evidence that zanubrutinib offers more durable disease control and improved persistence compared with ibrutinib, reinforcing its clinical value as a preferred second-generation BTKi. Nevertheless, the relatively short follow-up for zanubrutinib warrants cautious interpretation of long-term outcomes, and underscores the need for ongoing observation to fully characterize its durability and safety.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts and the persistence of leukemic stem cells (LSCs) within a profoundly remodeled bone marrow (BM) microenvironment. Despite advances in molecular stratification and the introduction of targeted agents, long-term outcomes remain unsatisfactory, particularly in older and high-risk patients. Increasing evidence indicates that leukemogenesis and treatment resistance are critically sustained by a permissive immune milieu, in which LSCs, myeloid-derived suppressor cells, leukemia-associated macrophages, and dysfunctional T and NK cells shape an immunosuppressive "leukemic niche." This evolving understanding has renewed interest in immune-based strategies capable of restoring effective antitumor immunity. Bispecific antibodies (bsAbs) are engineered molecules designed to engage AML-associated antigens while simultaneously recruiting and activating immune effector cells, most commonly T cells or NK cells. By promoting immune synapse formation independently of major histocompatibility complex expression and conventional co-stimulatory pathways, bsAbs can overcome several mechanisms of immune escape. In this review, we summarize the biological rationale for immunotherapy in AML, with a focus on the role of the BM microenvironment and immune dysregulation. We then discuss the structural and functional properties of IgG-like and non-IgG-like bsAbs, key antigenic targets such as CD33, CD123, CD70 and others, and the main T-cell- and NK-cell-engaging platforms under clinical investigation. Finally, we highlight emerging clinical data, principal toxicities, and the challenges of integrating bsAbs into existing treatment algorithms, including combinations with hypomethylating agents, BCL-2 inhibitors, and allogeneic stem cell transplantation. A deeper understanding of AML immune biology and antigen expression patterns will be essential to optimize bsAb design, maximize therapeutic benefit, and minimize on-target off-tumor toxicity.

Mature T-cell lymphomas comprise a heterogeneous group of aggressive non-Hodgkin lymphomas with limited therapeutic options in the relapsed or refractory setting. Among them, anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) represents a biologically distinct subtype driven by constitutive activation of ALK fusion proteins, which promote oncogenic signalling through signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase (PI3K)/AKT Serine/Threonine Kinase 1 (AKT)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase pathways. This molecular dependency provides a strong mechanistic rationale for targeted ALK inhibition. Small-molecule ALK inhibitors, including crizotinib, have demonstrated high overall response rates (67%-88%) and complete remission rates (~60%-80%) in relapsed or refractory ALK-positive ALCL, often with rapid clinical responses. Next-generation ALK inhibitors have shown activity in patients who progress on crizotinib, supporting the concept of sequential ALK-targeted therapy to overcome acquired resistance. Resistance mechanisms include secondary ALK kinase domain mutations, such as L1196M and G1202R, as well as activation of compensatory signalling pathways, including PI3K/AKT/mTOR, underscoring the importance of molecular reassessment at relapse and the potential role of rational combination strategies. This review critically summarizes the molecular basis of ALK-driven lymphomagenesis, evaluates the clinical evidence supporting ALK-targeted therapy and discusses mechanisms of resistance. In addition, it explores emerging strategies for integrating ALK inhibitors into precision-based management of T-cell lymphomas, including combination approaches with chemotherapy, immunotherapy or antibody-drug conjugates. Collectively, these developments highlight a paradigm shift towards biology-driven, personalized therapy in ALK-positive ALCL.

Extranodal marginal zone lymphoma (EMZL) represents a unique paradigm among indolent B-cell neoplasms, in which lymphomagenesis is frequently driven by chronic antigenic stimulation within tissue-specific microenvironments. Persistent infectious or autoimmune triggers promote the development of ectopic lymphoid tissue and sustain B-cell activation, while recurrent genetic alterations-most prominently those that converge on NF-κB signaling-enable progressive escape from antigen dependence. This dual biological foundation explains both the indolent clinical course of most cases and the remarkable therapeutic vulnerability of early-stage, infection-driven disease. Clinically, EMZL arise across a wide range of anatomical sites, each characterized by distinct etiologic associations and patterns of progression. As a result, management strategies must be tailored to disease site, stage, and biological context, with a consistent preference for the least intensive intervention capable of achieving durable disease control. Pathogen-directed antibiotic therapy and involved-site radiotherapy can be curative in localized disease. In contrast, systemic anti-CD20-based immunochemotherapy and targeted agents are reserved for disseminated, refractory, or biologically autonomous lymphomas. Recent advances in molecular profiling, functional imaging, and response assessment are refining risk stratification and treatment selection, shifting therapeutic goals toward early depth of response and quality of life rather than maximal cytotoxic intensity. EMZL thus serves as a model for biologically informed, precision-oriented management of indolent lymphoid malignancies.

Relapsed and refractory multiple myeloma (RRMM) remains associated with poor outcomes, particularly in patients exposed or refractory to proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. Targeting B-cell maturation antigen (BCMA) has emerged as an effective therapeutic strategy, prompting the development of bispecific antibodies that redirect T-cell cytotoxicity toward malignant plasma cells. Elranatamab is a humanized BCMA × CD3 bispecific antibody that has demonstrated clinically meaningful activity in heavily pretreated RRMM. This review summarizes and critically appraises available evidence on elranatamab, focusing on its mechanism of action, clinical efficacy, safety profile, patient-reported outcomes, and comparative positioning within the evolving BCMA-directed treatment landscape. Across studies, elranatamab has shown high response rates, durable disease control, and manageable toxicity, with predominantly low-grade cytokine release syndrome and limited neurotoxicity when administered with step-up dosing. Emerging data indicate preserved efficacy in patients previously exposed to BCMA-targeted therapies and feasibility in selected high-risk populations, including those with severe renal impairment. Nevertheless, uncertainties remain regarding optimal sequencing, long-term survival benefit, infection risk management, and mechanisms of resistance. Overall, elranatamab represents a valuable addition to the therapeutic armamentarium for RRMM. Ongoing studies and real-world experience will be critical to refine its positioning, identify patients most likely to benefit, and define its role in combination strategies.

The integration of measurable residual disease (MRD) into the management of chronic lymphocytic leukemia (CLL) has emerged as a major advance in risk stratification and trial design, particularly in the context of time-limited, targeted regimens. High-sensitivity MRD assessment, enabled by multicolor flow cytometry, allele-specific oligonucleotide PCR, and next-generation sequencing (NGS), provides a robust, quantifiable measure for depth of remission and long-term outcomes. Landmark trials-including CLL14, MURANO, CAPTIVATE, and GLOW-have consistently demonstrated that achieving undetectable MRD (uMRD) strongly predicts prolonged progression-free survival (PFS) and overall survival (OS), within a range of chemoimmunotherapy and venetoclax-based time-limited regimens. In selected clinical trials, MRD assessment has been prospectively incorporated into strategies exploring time-limited therapy and MRD-adapted discontinuation, although routine MRD-guided decision-making in clinical practice remains investigational. CLL research is increasingly focused on treatment-free observation in select patients achieving deep and sustained remissions, with MRD playing a central prognostic role. Emerging technologies, including circulating tumor DNA (ctDNA) monitoring and artificial intelligence (AI)-driven predictive modeling, promise to further refine risk stratification and personalize therapy. This review summarizes the current evidence supporting MRD as a prognostic biomarker and clinical trial endpoint, discusses investigational MRD-adapted strategies, and outlines future directions-including ctDNA and AI-based tools-that may ultimately support more individualized treatment duration and treatment-free observation in CLL.

Acute Myeloid Leukemia predominantly affects older adults, who often present with comorbidities, functional impairment, and frailty, limiting eligibility for intensive chemotherapy or allogeneic transplantation. Historically, treatment options were restricted to hypomethylating agents, low-dose cytarabine, hydroxyurea, or supportive care, with poor outcomes. The introduction of hypomethylating agents combined with Venetoclax and the availability of targeted therapies have expanded therapeutic possibilities, challenging the notion that elderly AML is uniformly incurable. In this evolving context, accurate assessment of fitness and frailty is essential to guide treatment decisions. This review summarizes current concepts of frailty in older AML patients, including general geriatric tools and hematology-specific indices. It discusses the role of Comprehensive Geriatric Assessment, frailty phenotypes, and comorbidity scores such as the transplantation-specific comorbidity index and the Charlson index, alongside AML-focused tools like the Ferrara criteria and integrated molecular risk models. Most existing tools were developed in intensively treated cohorts, and their applicability to patients receiving non-intensive regimens remains uncertain. Fitness is increasingly recognized as a dynamic, multidimensional construct incorporating clinical, functional, cognitive, social, and biological factors. A multiparametric approach is proposed, integrating these variables into decision-making models, potentially enhanced by artificial intelligence to optimize treatment selection in older AML patients.

Multiple myeloma (MM) is predominantly a disease of older adults, yet the randomized clinical trials (RCTs) that define standards of care are conducted largely in younger, fitter, and less comorbid populations. This creates a systematic mismatch between the populations generating evidence and those receiving treatment in routine practice, which can be characterized by comparing eligibility criteria, baseline characteristics, treatment exposure, and outcomes across RCTs and large real-world cohorts. Real-world data (RWD) have emerged as an essential complement to RCTs, capturing treatment effectiveness, tolerability, and patterns of care in unselected populations. Still, their use in clinical decision-making remains inconsistent. In this review, we use MM as a model to examine the divergence between trial efficacy and real-world effectiveness. Outcomes observed in RCTs are reproducible primarily in patients who resemble trial populations. In contrast, in older, frail, and comorbid patients, effectiveness is frequently attenuated by increased toxicity, reduced dose intensity, and early treatment discontinuation. We summarize how differences in comorbidity burden, frailty status, treatment intensity, and early discontinuation contribute to attenuated outcomes in routine care. Frailty, rather than chronological age alone, appears to be the principal determinant of this divergence. Despite its strong prognostic and predictive value, frailty is inconsistently measured in both RCTs and RWD, limiting the translation of evidence into practice. We highlight the prognostic and predictive value of formal frailty assessment and its current under-use in both RCTs and RWD. On this basis, we propose a pragmatic, patient-centered approach that uses trial-derived estimates of regimen efficacy together with real-world data on toxicity, dose intensity, and treatment persistence to enable systematic adaptation of regimen choice, dose, and schedule. Finally, we outline methodological priorities for future research, including standardized data elements, robust causal-inference approaches, routine incorporation of frailty, and closer alignment between RCTs and RWD. Although focused on MM, this framework has broader implications across hematologic malignancies, where bridging the gap between efficacy and effectiveness is essential to ensure that therapeutic advances translate into meaningful benefit for patients seen in everyday clinical practice.