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Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%–40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.

Circulating tumor cells (CTCs) have emerged as a key prognostic factor in newly diagnosed multiple myeloma (NDMM). However, it remains unclear if high CTC counts represent a mere surrogate of tumor burden or might reflect a distinct genomic or transcriptomic entity. In this study, we characterized the genomic and transcriptomic features associated with CTC burden and assessed their combined prognostic value in NDMM patients. We analyzed 540 NDMM patients from the CoMMpass dataset with available baseline CTC information and matched bone marrow transcriptomic (n = 374) and genomic (n = 460) sequencing data. We then validated the results on an external cohort of 135 NDMM patients with CTCs enumerated by next-generation flow cytometry. Higher CTC levels were significantly associated with high-risk clinical features (e.g., ISS or IMS/IMWG 2024). Furthermore, genomic analyses revealed that high CTC counts were associated with complex genomic features such as chromothripsis, APOBEC mutagenesis, and loss of key tumor suppressors, typically linked to high-risk disease. Transcriptomic analyses revealed that elevated CTCs were enriched in cell cycle and proliferation (PR) genes while presenting a reduced association with immune response. Importantly, CTCs also emerged as a surrogate for PR transcriptomic signatures and demonstrated prognostic superiority, potentially simplifying application in the clinical setting. Elevated CTC levels reflect aggressive biological features of multiple myeloma and outperform prognostic markers such as PR signatures. Integrating CTC data into genomic and transcriptomic classifiers could enhance risk stratification and provide a streamlined and powerful tool for clinical decision-making in NDMM.

Frustaci AM, Zappaterra A, Galitzia A, et al. Salvage treatment after covalent BTKi failure: An unmet need in clinical practice in Waldenstrom macroglobulinemia. HemaSphere. 2025;9(2):e70094. doi:10.1002/hem3.70094

In the Funding section, the funder was incorrectly listed. The funder statement now reads: “Open access publishing facilitated by Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, as part of the Wiley – SBBL agreement.”

The original article has been updated. We apologize for this error.

Large B-cell lymphoma (LBCL), including its most common subtype diffuse LBCL, is the most frequent aggressive lymphoma, accounting for 30%–40% of cases worldwide. It is a clinically heterogeneous disease, with outcomes influenced by molecular subtypes, comorbidities, and access to effective treatment. Although R-CHOP has long been the standard of care, approximately 30%–40% of patients relapse or are refractory to first-line therapy. Historically, salvage chemotherapy followed by autologous stem cell transplantation offered a potential cure, but only about half of patients are eligible, leaving a large unmet need for alternative therapies.¹

Since 2018, the therapeutic landscape has rapidly evolved with the approval of nine new treatments across 12 indications in Europe, including CAR-T therapies, bispecific antibodies, antibody–drug conjugates, and targeted immunotherapies such as tafasitamab–lenalidomide. These advances have broadened the treatment arsenal beyond chemotherapy, offering potentially curative options for chemotherapy-resistant patients and effective alternatives for those ineligible for intensive approaches. This shift toward more targeted and less toxic therapies represents a significant step forward in addressing prior treatment limitations.

However, access to these innovations remains uneven across Europe. Disparities stem from fragmented national reimbursement systems, inconsistent use of early access programs (EAPs), and geographic variations in clinical trial availability. While 29 out of 35 European countries have implemented EAPs,² differences in structure, funding, and transparency create unequal opportunities for early treatment access. Furthermore, health technology assessments (HTAs) and pricing negotiations often delay or restrict reimbursement, particularly in lower income or decentralized healthcare systems. The EU HTA Regulation (effective 2025) may harmonize clinical evaluations^3-6 but will not resolve national pricing autonomy.^{7, 8} To achieve equitable access, stronger coordination, pricing transparency, and integration of real-world patient outcomes into decision-making are urgently needed to ensure that innovation benefits all LBCL patients, regardless of geography or system structure.

While developing the European LBCL guidelines,⁹ the writing committee identified substantial variability in access to innovative therapies across Europe. To assess how these disparities could impact guideline implementation, the committee conducted an analysis of clinical trial activity and national reimbursement patterns. Data were obtained from EU CTIS, ClinicalTrials.gov, and direct consultations with industry stakeholders on the reimbursement status of EMA-approved therapies. The analysis focused on two areas: (I) the geographic distribution of active LBCL trials and (II) national reimbur

Sickle cell disease (SCD) is characterized by chronic hemolysis, resulting in the release of extracellular heme, which contributes to oxidative stress and inflammation. Heme oxygenase-1 (HO-1), an inducible enzyme that degrades heme into cytoprotective by-products, plays a critical role in mitigating heme-induced toxicity. This study analyzed serum HO-1 levels in 2309 individuals with SCD (53% female; median age: 12 years) from the SickleGenAfrica cohort, comprising 57% hemoglobin SS disease (Hb SS), 30% hemoglobin SC disease (Hb SC), 3.1% Hb sickle beta plus thalassemia (Sβ+ thalassemia), and 9.9% Hb S-hereditary persistence of fetal hemoglobin (Hb S-HPFH). Median HO-1 levels were threefold higher in children under 16 years (69.8 ng/mL; interquartile range [IQR]: 29.8–137.6) compared to adults (23.1 ng/mL; IQR: 7.8–62.4; P < 0.001), with peak levels observed in the 6–10-year age group. Across all subgroups, including sex, genotype, and hydroxyurea use, children consistently exhibited higher HO-1 levels than adults, with Hb SS patients showing the highest levels. Haptoglobin and hemopexin, key scavengers of hemoglobin and heme, respectively, were depleted in all patients, particularly in children. Overall, HO-1 levels in SCD patients were markedly elevated compared to healthy populations. These findings highlight the pronounced elevation of HO-1 in pediatric SCD patients, suggesting its potential protective role against heme-induced toxicity, especially during childhood.

Enblad AP, Krali O, Gezelius H, et al. Ex vivo drug responses and molecular profiles of 597 pediatric acute lymphoblastic leukemia patients. HemaSphere. 2025;9(7):e70176. doi:10.1002/hem3.70176

The supplemental methods mentioned in the subsection titled “DNA methylation and RNA-sequencing data” was not included in the Supporting Information. This file has been added and cited at the applicable instance in the article.

We apologize for this error.