European Journal of Haematology最新文献

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.

Objective: Laparoscopic adrenalectomy is standard in adults, but evidence in children remains limited. This study describes a standardised transperitoneal laparoscopic adrenal compartment resection technique and evaluates its safety, reproducibility and outcomes.

Methods: All paediatric patients undergoing transperitoneal laparoscopic adrenalectomy at our centre from 2022 to 2025 were retrospectively reviewed. Clinical and intraoperative data were collected. Procedures were standardised with lateral positioning, three to four subcostal trocars and dissection along embryological avascular planes, avoiding direct gland manipulation.

Results: Eleven patients were included, median age 4.3 years. Nine had neuroblastic tumours and two had adrenocortical tumours. Mean tumour volume was 197 cm³, mean diameter 39.7 mm. Conversion to open surgery occurred in two IDRF-positive neuroblastomas (18%) due to bleeding and adherence to renal vein. Mean operative time was 157 min; mean hospitalisation 5.2 days. No postoperative complications occurred. All patients had complete macroscopic resection; four (36.4%) showed microscopic margin infiltration. No local recurrences; one high-risk neuroblastoma progressed with metastases.

Conclusions: Standardised laparoscopic adrenal compartment resection is safe and reproducible in selected paediatric patients, feasible even in IDRF-positive tumours. Exclusive dissection along avascular embryological planes ensures oncological radicality, maintaining minimally invasive benefits.

Covalent Bruton tyrosine kinase inhibitor (cBTKi)-based regimens have redefined therapy for chronic lymphocytic leukemia (CLL). However, continuous treatment with BTKis can select for therapy resistance, typically associated with BTK C481 mutations and fosfolipasi C gamma 2 (PLCγ2) activation. In addition, continuous BTKi therapy poses challenges for treatment interruptions and dose modifications, with implications for clinical outcomes. Pirtobrutinib, a highly selective, reversible (noncovalent) BTKi, inhibits BTK independently of C481 and maintains sustained target engagement. In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade-offs; and (4) prospective scenarios, including combination strategies and time-limited regimens.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for paroxysmal nocturnal hemoglobinuria (PNH). Post-transplant cyclophosphamide (PTCy) has improved HSCT safety in other diseases, but its use in PNH is poorly characterized.

Methods: In this retrospective study, we analyzed outcomes of 19 patients with large PNH clones (≥ 50%) undergoing HSCT (2016-2025). Seven patients received a PTCy-based platform (fludarabine-busulfan-cyclophosphamide conditioning with PTCy-based graft-versus-host disease [GvHD] prophylaxis), whereas 12 received conventional prophylaxis.

Results: Patients' median age was 32 years; 68% had PNH with bone marrow failure. After a median follow-up of 1349 days, overall and event-free survival rates were 100% and 94.4%, respectively. All patients engrafted rapidly with full donor chimerism. No cases of chronic or grades II-IV acute GvHD occurred in the PTCy group (0/7); however, chronic GvHD and grades II-IV acute GvHD occurred in 15.8% and 10.5% of patients in the conventional group, respectively. No transplant-related mortality or thrombotic events occurred.

Conclusion: This study, representing the largest reported experience with PTCy-based HSCT for PNH, suggests that this platform is feasible and associated with excellent survival and a promising GvHD profile. These preliminary findings support further investigation of PTCy in transplant strategies for PNH.

Modern therapies have clearly marked the history of multiple myeloma (MM), leading to undisputed advantages in terms of sustained responses and prolonged survival, while progressively improving patients' quality of life. Nonetheless, disease recurrence and resistance to available therapies underscore the importance of identifying additional treatment options, especially in hard-to-treat patients, or when access to cutting-edge immunotherapies is limited. Melflufen (melphalan-flufenamide) plus dexamethasone has been approved by the European Medicines Agency for triple-class-refractory MM patients after ≥ 3 prior therapies, but current data from real-world settings are scarce. We herein report data from a single-center experience of 17 relapsed/refractory MM patients treated with melflufen-dexamethasone outside clinical trials between December 2021 and July 2025 in Bologna (Italy). The overall response rate was 41%. At a median follow-up (mFU) of 8 months, mPFS was 3.7 months (95% CI 1.8-NR) in the overall population, being 9.0 months (95% CI 7.8-NR) in responders (mFU 10 months), while mOS has not been reached (95% CI 13.5-NR) either in the total population or in subgroups. Notably, 11/17 patients received subsequent therapies (seven receiving novel immunotherapeutic approaches), achieving deeper and more durable responses than those receiving conventional regimens. Grade ≥ 3 hematologic toxicities were common (35% anemia, 53% neutropenia, 53% thrombocytopenia), while grade ≥ 3 nonhematologic events were less frequent (mainly fatigue: 6%, and infections: 23.5%). No secondary primary malignancies were recorded. Collectively, our data confirmed the efficacy previously reported with melflufen-dexamethasone and its manageable safety profile, even in elderly patients likely more fragile and more heavily pretreated than those included in the trials. Overall, melflufen-dexamethasone may represent a treatment option, especially for patients refractory to novel immunotherapies or those who are not ideal candidates to receive such treatments while still preserving access to subsequent T-cell redirecting therapies, thereby addressing a significant unmet need in this hard-to-treat patient population.

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.

Background: Whether long-term oral anticoagulation (OAC) is necessary after apparently successful atrial fibrillation (AF) ablation remains uncertain. Guidelines recommend continuation based on CHA₂DS₂-VASc score rather than procedural success, yet contemporary evidence, including randomized trials, has produced conflicting results. We aimed to provide an updated and comprehensive assessment of OAC discontinuation following AF ablation.

Methods: We conducted a systematic review and meta-analysis in patients who discontinued versus continued OAC after AF ablation. Outcomes included thromboembolic events (TE) and major bleeding events (MBE). Random-effects models with Hartung-Knapp correction were applied. Heterogeneity, publication bias, influence analyses, subgroup analyses, and risk-of-bias domains were assessed.

Results: In 28 studies (267 443 patients), OAC discontinuation significantly reduced the composite of TE and MBE (RR 0.44, 95% CI 0.32-0.61), driven by a marked decrease in bleeding (RR 0.25, 95% CI 0.16-0.39), without excess thromboembolic risk (RR 0.84, 95% CI 0.64-1.12). Findings remained consistent across subgroup analyses (study design, CHA₂DS₂-VASc, geographic region), with sensitivity and meta-regression confirming robustness and no significant effect modifiers. Funnel plots showed no significant asymmetry for TE, whereas MBE demonstrated evidence of small-study effects.

Conclusions: Discontinuation of OAC after successful AF ablation markedly reduces MBE without a statistically significant increase in TE, highlighting the need for individualized post-ablation anticoagulation strategies. Randomized trials are needed to confirm the safety of tailored oral anticoagulant discontinuation in selected patients, supported by careful long-term follow-up and shared decision-making.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-cancerous condition that precedes plasma cell dyscrasias, including multiple myeloma (MM). Current clinical guidelines report that MGUS's rate of malignant progression to haematological malignancy (HM) is ~1% per year; however, reported rates have varied widely. To address this discrepancy, a systematic review was conducted, investigating MGUS's rate of malignant progression to HM and MM alone. Four electronic databases were searched from inception to 28 March 2024 for articles reporting these outcomes; articles were summarised using meta-analysis and narrative synthesis. Findings were incorporated from n = 46 studies, published between 1991 and 2024 and conducted across n = 17 countries. Median follow-up ranged from 1.3 to 34.2 years and sample sizes ranged from n = 63 to 17,963. In random-effects meta-analysis, n = 13 studies reported on MGUS progression to HM and n = 12 reported on progression to MM. The overall estimates of malignant progression events were 12 per 1000 person-years to HM, equivalent to 1.2% per year (95% CI: 1.0%-1.5%) and 8 per 1000 person-years to MM or 0.8% per year (95% CI: 0.7%-1.1%), with substantial heterogeneity between studies (I²: 96.7% and 95.8%, respectively). Progression rates varied widely in narrative synthesis; at 10 years, studies reported annual MGUS progression rates of 6.6%-33.6% to HM and 7.0%-28.5% to MM. While progression rates aligned with clinical guidelines overall, studies' varied findings present opportunities for further research, exploring the impact of world region, follow-up duration, and study methods. Considering this, caution should be taken when informing clinicians and patients about the risk of progression from MGUS to MM.

Introduction: Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) can elicit a graft-versus-leukemia (GvL) effect in pediatric patients with hematological malignancies. We report our single-center experience with prophylactic DLI in high-risk pediatric patients with leukemia or lymphoma, focusing on feasibility, safety, and efficacy.

Methods: In total, 10 high-risk patients received prophylactic DLI following allo-SCT. Donors were either matched (n = 5) or haploidentical (n = 5). CD3+ T-cell doses of up to 1 × 10⁷ cells/kg body weight were administered, in some cases over extended periods exceeding three years.

Results: The treatment was associated with a favorable toxicity profile. In our cohort, 40% of patients developed moderate acute (n = 2) or chronic (n = 2) graft-versus-host disease (GvHD); no cases of severe or high grade GvHD occurred. Given the high-risk profile of our cohort, outcomes were encouraging, with relapse-free survival (RFS) of 70% and overall survival (OS) of 80% at a median follow-up of 20.5 months. Especially, the two subgroups of patients with acute myeloid leukemia (AML) after relapse and patients who were transplanted in first complete remission (CR1) showed outcomes superior to currently reported data. One AML patient, who had experienced three relapses, received prophylactic DLI after a third allo-SCT and remains in complete remission (CR), more than 3 years after the last allo-SCT.

Conclusion: These data suggest that prophylactic DLI may represent a safe and effective treatment option for pediatric patients with hematological malignancies at high risk of posttransplant relapse.