Early relapse remains a major limitation of chimeric antigen receptor T cell (CAR-T) in relapsed or refractory large B-cell lymphoma (LBCL), particularly for high-risk disease or suboptimal early response. The prospectiv...Early relapse remains a major limitation of chimeric antigen receptor T cell (CAR-T) in relapsed or refractory large B-cell lymphoma (LBCL), particularly for high-risk disease or suboptimal early response. The prospective RESTART protocol evaluated a risk-adapted integration of radiotherapy (RT) with CAR-T. Patients were assigned to RT-dominant (Pathway A) or systemic bridging (Pathway B) based on disease distribution and biology. A key innovation was response-adapted consolidation RT for patients with Deauville score (DS) 4-5 at 1-month post-infusion, or DS 3 and baseline high-risk lesions (≥5 cm and/or maximum standard uptake value [SUVmax] ≥15). Consolidation RT was delivered 6-8 weeks post-infusion using CAR-T-sparing techniques to minimise circulating blood dose. Among 190 patients, 55 (29%) received RT. Local control within irradiated volumes was 89%, including 92% following consolidation RT. At a median follow-up of 12.4 months, the 1-year progression-free survival (PFS) and overall survival (OS) for the entire cohort were 57% and 71% respectively. Patients receiving consolidation RT, despite high-risk features, achieved a 1-year PFS of 54% and OS of 95% with no evidence of excess systemic relapse due to a negative effect on CAR-T. This protocol demonstrates that response-adapted, CAR-T-sparing consolidation RT is feasible and associated with favourable outcomes in high-risk LBCL.
Elderly transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) often cannot tolerate standard-dose lenalidomide-dexamethasone (Rd), leading to frequent dose reductions. We evaluated an upfront frailt...Elderly transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) often cannot tolerate standard-dose lenalidomide-dexamethasone (Rd), leading to frequent dose reductions. We evaluated an upfront frailty-adapted Rd dosing strategy using the revised Myeloma Comorbidity Index (R-MCI) in this frail population. In a multicentre phase II trial, patients ≥70 years classified as intermediate-fit (R-MCI 4-6) or frail (R-MCI ≥7) received Rd with starting doses stratified by frailty (intermediate-fit: lenalidomide 25 mg + dexamethasone 20 mg; frail: lenalidomide 15 mg + dexamethasone 10 mg). Two-year progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), overall response rate (ORR) and safety. Among 70 enrolled patients (69 evaluable; median age 80), 54% were intermediate-fit and 46% frail. ORR was 86.9%, with ≥VGPR (very good partial response) in ~36% of both groups. Two-year PFS was 37.4% (95% confidence interval [CI]: 26.9%-57.8%; median PFS 15.6 months) and 2-year OS was 63.0% (95% CI: 51.6%-77.0%), with no statistically significant differences between intermediate-fit and frail patients in this exploratory analysis. Grade ≥3 neutropenia occurred in 24.3% and 40.6% of intermediate-fit and frail patients, respectively, while grade ≥3 infectious complications were observed in 10.8% and 12.5%, respectively, without significant differences between groups. The frailty-guided, dose-attenuated Rd regimen in elderly unfit NDMM yielded high response rates and clinically meaningful survival with manageable toxicity. These exploratory findings suggest that frail patients may achieve outcomes approaching those of intermediate-fit patients despite reduced starting doses, warranting confirmation in adequately powered prospective studies.
Duminuco A, Leotta D, Allegra A
… +19 more, Caracciolo D, Caruso L, Chiarenza A, Del Fabro V, Di Martina V, Figuera A, Fiumara PF, Gentile M, Innao V, Mancuso S, Martino EA, Mosca A, Motta G, Pedalino F, Rossi M, Stagno F, Tona G, Di Raimondo F, Palumbo GA
Chronic lymphocytic leukaemia (CLL) primarily affects elderly patients with comorbidities, yet real-world data on acalabrutinib, a second-generation Bruton's Tyrosine Kinase (BTK) inhibitor, remain limited outside clinic...Chronic lymphocytic leukaemia (CLL) primarily affects elderly patients with comorbidities, yet real-world data on acalabrutinib, a second-generation Bruton's Tyrosine Kinase (BTK) inhibitor, remain limited outside clinical trials, particularly in Italy. This retrospective multicentre study evaluated acalabrutinib monotherapy across 10 Italian haematology centres (2021-2025), including 155 adults with CLL/small lymphocytic lymphoma (SLL) (median age 74 years, 44.5% ≥75 years, 35.5% relapsed/refractory, 59.4% cardiovascular comorbidities, 24.5% del17p/TP53). Primary end-point was time-to-discontinuation (TTD ≥28 days interruption/progression/death); secondary included response rates (based on International Workshop on Chronic Lymphocytic Leukemia criteria), haematological recovery, overall survival (OS) and safety. Median TTD was not reached (16 months follow-up), overall response rate 84.5% (32.9% clinical complete remission, reinforced by bone marrow evaluation in four cases), OS median not reached (78.7% alive), reporting rapid haematological recovery occurred (at 6 months haemoglobin 11.1-12.6 g/dL, platelets 146-160 × 10/L, lymphocytes 57.5-12.3 × 10/L; p < 0.001), uniform across subgroups (no TTD differences by age/line/cardiovascular comorbidities/biology; p > 0.05), without reduction of neutrophils (p = 0.48). Discontinuation was 20% (primarily due to adverse events), with low cardiovascular toxicity (one grade 3 atrial fibrillation). This study confirms acalabrutinib's durable effectiveness and tolerability in unselected real-world CLL, above in patients with prior cardiovascular comorbidities, confirming clinical trial results also in frail elderly/high-risk patients, supporting its broad adoption in routine care.
Primary central nervous system lymphoma (PCNSL) has poor outcomes despite high-dose methotrexate-based therapy. The Endothelial Activation and Stress Index (EASIX) is associated with prognosis in systemic lymphomas but h...Primary central nervous system lymphoma (PCNSL) has poor outcomes despite high-dose methotrexate-based therapy. The Endothelial Activation and Stress Index (EASIX) is associated with prognosis in systemic lymphomas but has not been evaluated in PCNSL. Define the association of baseline EASIX in multivariate analysis with Memorial Sloan Kettering Cancer Center (MSKCC) score risk factors. A multicentre retrospective cohort included 128 immunocompetent adults with biopsy-proven diffuse large B-cell PCNSL. EASIX was calculated and the optimal cut-off (0.751) was determined by receiver operating characteristic (ROC) analysis. The primary end-points were overall survival (OS) and progression-free survival (PFS) in the low-EASIX and high-EASIX groups. The median age was 60 years. High EASIX (≥0.751, n = 55) was associated with Eastern Cooperative Oncology Group (ECOG) ≥2 (p = 0.002), elevated lactate dehydrogenase (LDH) (p < 0.001), deep brain lesions (p = 0.007) and cellular myelocytomatosis oncogene/B-cell lymphoma-2 (MYC/BCL-2) double expression (p = 0.01). After a median follow-up of 37 months, high EASIX was associated with inferior OS (27.4 months vs. not reached; p = 0.001) and PFS (25.6 months vs. not reached; p < 0.001). Multivariable Cox analysis confirmed high EASIX as an independent adverse factor for OS (hazard ratio [HR] 4.75) and PFS (HR 4.99), with additional prognostic discrimination within MSKCC risk groups. Baseline EASIX could potentially improve risk stratification and prognostic modelling in PCNSL.
Lymphoma-associated haemophagocytic lymphohistiocytosis (HLH) represents a rare and life-threatening hyperinflammatory syndrome with a dismal prognosis, largely due to its poorly understood pathogenesis and unclear disti...Lymphoma-associated haemophagocytic lymphohistiocytosis (HLH) represents a rare and life-threatening hyperinflammatory syndrome with a dismal prognosis, largely due to its poorly understood pathogenesis and unclear distinctions from non-lymphoma associated HLH (NLAHS). To elucidate these differences, we performed an integrated multiomics analysis on peripheral blood samples from patients with newly diagnosed lymphoma-associated HLH (LAHS), NLAHS and healthy controls (NC). Single-cell ribonucleic acid sequencing (scRNA-seq) analysis (4 LAHS, 3 NLAHS, 2 NC) revealed that LAHS is characterized by enhanced glycolytic activity in significantly expanded monocyte populations, notably within a distinct subset of pituitary tumor-transforming gene 1 (PTTG1) monocytes. Metabolomic profiling (21 LAHS, 11 NLAHS, 7 NC) further confirmed elevated levels of glycolytic products, such as lactate and pyruvate. Clinically, hyperlactataemia (>5.1 mmol/L, n = 84) emerged as a significant independent predictor of poor survival in LAHS, with a median overall survival of only 43.5 days (p < 0.001). Remission induced by treatment was associated with a reversal of this hypermetabolic phenotype. Cell communication analysis revealed upregulated thrombospondin signalling from PTTG1 monocytes, linked to glycolytic activity. Our findings indicate that LAHS is characterized by a pronounced Warburg-like metabolic state, primarily involving glycolytic monocytes. Hyperlactataemia is associated with adverse outcomes and may guide the development of novel therapeutic strategies targeting immunometabolic pathways.
Caracciolo D, Lombardo MR, Reitano G
… +12 more, Napoli C, Fiorillo L, Callerame C, Garritano M, Bulotta A, Munir M, Pensabene G, Barbieri E, Bavieri A, Tassone P, Tagliaferri P, Luminari S
Relapsed/refractory follicular lymphoma (R/R FL) remains a clinically challenging condition, with progressively declining benefit across consecutive lines of therapy. While anti-Cluster of Differentiation 20 (CD20) antib...Relapsed/refractory follicular lymphoma (R/R FL) remains a clinically challenging condition, with progressively declining benefit across consecutive lines of therapy. While anti-Cluster of Differentiation 20 (CD20) antibodies remain the therapeutic backbone, the optimal targeted or immune-based partner remains undefined. A systematic review and network meta-analysis (NMA) of 5 phase III and 1 phase II trials (2500 patients) evaluated seven anti-CD20-based combination strategies. Primary end-points were overall survival (OS) and progression-free survival (PFS); secondary end-points included objective response rate (ORR) and grade ≥3 adverse events. Treatments were ranked using surface under the cumulative ranking (SUCRA) values. Immune-activating strategies ranked highest across efficacy end-points. Epcoritamab plus rituximab (R) achieved the top SUCRA rankings for OS, PFS and ORR, while tafasitamab plus R consistently ranked second, with a better safety profile. R alone showed intermediate efficacy and good tolerability, whereas zanubrutinib plus anti-CD20 demonstrated modest efficacy with lower toxicity. Bortezomib and copanlisib-based combinations ranked lowest for efficacy, with phosphoinositide 3-kinase (PI3K) inhibitor-based regimens showing the least favourable benefit-risk profile. Anti-CD20 monotherapy was the safest but least effective option. This NMA indicates that immune-centric, anti-CD20-anchored combinations represent the most effective chemotherapy-free strategies for R/R FL. Combinations incorporating anti-CD19 or CD20/CD3 bispecific antibodies appear to offer deeper disease control, particularly in high-risk and rituximab-refractory disease.
This study shows that sickle cell disease patients have elevated high-sensitivity cardiac troponin I (hs-cTnI) that is not considered clinically significant but are outside of the normal range. Elevated hs-cTnI was assoc...This study shows that sickle cell disease patients have elevated high-sensitivity cardiac troponin I (hs-cTnI) that is not considered clinically significant but are outside of the normal range. Elevated hs-cTnI was associated with low haemoglobin and a history of heart failure.
Methaemoglobin (MetHb) is an oxidised form of haemoglobin (Hb) unable to bind oxygen. Raised levels of MetHb reduce the blood's oxygen-carrying capacity, causing potentially severe hypoxaemia and possible death. The cond...Methaemoglobin (MetHb) is an oxidised form of haemoglobin (Hb) unable to bind oxygen. Raised levels of MetHb reduce the blood's oxygen-carrying capacity, causing potentially severe hypoxaemia and possible death. The condition arises from three main pathologies: mutations in globin genes causing Haemoglobin-M, inherited deficiency of the enzyme cytochrome b5 reductase (CytB5R) responsible for reducing MetHb back into functional Hb, and exposure to some oxidising agents. Well-documented causative agents include dapsone and cocaine-derived anaesthetics, with emerging evidence highlighting an increasing contribution from recreational and non-prescribed exposures. As the concentration of MetHb level increases, the oxygen-carrying capacity of the blood decreases. MetHb levels are usually measured by co-oximetry. Patients are typically asymptomatic at MetHb concentrations <10% with symptoms developing as levels increase, including cyanosis, confusion, arrhythmias, coma and death. These features will present alongside misleadingly normal partial pressure of oxygen in arterial blood and arterial oxygen saturation values on arterial blood gas and will not improve with supplemental oxygen. Management depends on severity, with intravenous methylene blue remaining first-line treatment for symptomatic cases. Alternative therapies include high-dose vitamin C, exchange transfusion and potentially hyperbaric oxygen, although there is little evidence to suggest how these should be used. Due to the potentially confusing acute presentation of the condition, the diagnosis can easily be missed.
Diffuse large B-cell lymphoma (DLBCL) type Richter transformation (DLBCL-RT) in patients with chronic lymphocytic leukaemia (CLL) has a worse prognosis compared to de novo DLBCL (dnDLBCL). We investigated outcomes of pat...Diffuse large B-cell lymphoma (DLBCL) type Richter transformation (DLBCL-RT) in patients with chronic lymphocytic leukaemia (CLL) has a worse prognosis compared to de novo DLBCL (dnDLBCL). We investigated outcomes of patients with DLBCL-RT with or without previous CLL-directed therapy compared to dnDLBCL between 2002 and 2022. We included 6525 patients with dnDLBCL and 383 patients with DLBCL-RT, of whom 260 had Richter transformed treatment-naïve CLL (RT:TN-CLL) and 123 had Richter transformed treatment exposed CLL (RT:TE-CLL). Median time to next treatment or death (TTNTd) was 4.83 years, 1.43 years and 0.46 years for patients with dnDLBCL, RT:TN-CLL and RT:TE-CLL respectively. Median overall survival (OS) following first-line treatment was 9.42, 5.22 and 0.72 years for dnDLBCL, RT:TN-CLL and RT:TE-CLL respectively (p < 0.001). In a high-validity subcohort, OS did not differ significantly between RT:TN-CLL and dnDLBCL (median OS 9.85 years [CI: 9.16-10.70] for dnDLBCL, 6.07 years [CI: 4.23-not estimable] for RT:TN-CLL and 1.15 years [CI: 0.76-3.66] for RT:TE-CLL). In conclusion, patients with RT:TE-CLL had inferior TTNTd and OS compared to RT:TN-CLL and dnDLBCL. RT:TN-CLL demonstrated inferior TTNTd compared to dnDLBCL, but OS approached that of dnDLBCL. This indicates that for patients with RT:TN-CLL, chemoimmunotherapy may still be an effective modality, while patients with RT:TE-CLL need novel treatment options.
Ottaviano G, Lanino E, Nademi Z
… +16 more, James B, Powys M, Amrolia P, Rao K, Silva J, Lazareva A, Lawson S, Patrick K, Furness C, Tatarinova O, Doncheva B, Irwin A, Cherungonath A, Standing JF, Warris A, Chiesa R
The optimal strategy to prevent and treat invasive fungal infections (IFIs) in children receiving allogeneic haematopoietic stem cell transplantation (HSCT) is not well established. A paediatric bone marrow transplant (B...The optimal strategy to prevent and treat invasive fungal infections (IFIs) in children receiving allogeneic haematopoietic stem cell transplantation (HSCT) is not well established. A paediatric bone marrow transplant (BMT) working group set up UK national guidelines for the management of IFI and conducted a prospective study to assess the impact of these on incidence and outcomes. From March 2017 to December 2021, 358 children who received HSCT were prospectively included. Most children (82%) received either itraconazole (41%) or liposomal amphotericin B (41%) prophylaxis with a median duration of 170 days (interquartile range [IQR] 101-279). Cumulative incidence of possible/probable/proven IFI at 1 year was 17.6%, with no significant differences in children receiving itraconazole or liposomal amphotericin B (15.7% vs. 15.9%, 0.997). In multivariate analysis models (Fine-Gray hazard ratio) underlying malignant disease and low azoles therapeutic drug monitoring levels were independently associated with development of IFI. Children with probable/proven IFI had a higher 1-year transplant-related mortality (22% vs. 5.7%, Gray's test, p < 0.001). By adopting standardized anti-fungal prophylaxis, the incidence of proven/probable IFI in a large cohort of transplanted children was 5% and these showed significant decreased survival, warranting tailored prophylactic strategies in high-risk patients.
Congenital factor XII (FXII) deficiency is a rare disorder resulting from F12 gene mutations and its precise contribution to thrombotic or haemorrhagic risk has yet to be established. We identified the same mutation of t...Congenital factor XII (FXII) deficiency is a rare disorder resulting from F12 gene mutations and its precise contribution to thrombotic or haemorrhagic risk has yet to be established. We identified the same mutation of the F12 gene across five pedigrees, yet the clinical manifestations varied markedly, ranging from asymptomatic to thrombotic and haemorrhagic phenotypes. Haematological assessments and deoxyribonucleic acid sequencing were conducted in five pedigrees. All five probands displayed prolonged activated partial thromboplastin time, markedly reduced FXII activity and an identical frameshift mutation in F12 (c.303_304delCA, p.H101Qfs*36), leading to the loss of functional domains. In Pedigree A, characterized by thrombotic clustering, thrombotic events were documented in 4 of 6 mutation carriers and 4 of 13 non-carriers. In Pedigree B, the proband experienced bleeding events, and her father died of intracerebral haemorrhage. Probands C and D remained asymptomatic. Proband E was diagnosed with essential thrombocythaemia and thrombosis. Across all pedigrees, haemorrhagic or thrombotic events could be attributed to additional contributing factors. The identified apolipoprotein E and butyrophilin subfamily 2 member A1 variants were consistently associated with thrombotic events in Pedigree A. This F12 variant does not appear to independently drive pathological coagulation phenotypes but may potentiate susceptibility to thrombosis in the presence of additional genetic or acquired risk factors.
Neutropenia in general is defined as a blood neutrophil count of less than 1.5 × 10/L, in severe neutropenia counts drop to less than 0.5 × 10/L, but the definition of neutropenia varies according to the patient's ethnic...Neutropenia in general is defined as a blood neutrophil count of less than 1.5 × 10/L, in severe neutropenia counts drop to less than 0.5 × 10/L, but the definition of neutropenia varies according to the patient's ethnic origin and age. For Caucasian adults, the absolute neutrophil count (ANC) threshold of 1.8 × 10/L is adopted for the definition of neutropenia according to the World Health Organization (see Fioredda et al. (1)). It can be inherited or acquired, and it is an uncommon haematological finding in adult outpatient clinics. Neutropenia can result from decreased production of neutrophil precursors in the bone marrow, as in the case of severe congenital neutropenia, or from increased utilization of neutrophils in some bacterial infections, or accelerated destruction as is the case with drug-induced neutropenia, viral infections and autoimmune neutropenia. Severe chronic neutropenia increases susceptibility to bacterial or fungal infections. Treating severe chronic neutropenia patients with granulocyte colony-stimulating factor (G-CSF) can increase neutrophil counts for most types of neutropenia. This article will provide guidance on diagnosing and managing severe chronic neutropenia in adult patients and provides a transition programme from adolescence to adulthood.
Immunodeficiency can precede and directly contribute to cancer development, particularly in B-cell lymphoproliferative disorders (B-CLPDs), where immune dysfunction is often intrinsic to the disease. A subset of such pat...Immunodeficiency can precede and directly contribute to cancer development, particularly in B-cell lymphoproliferative disorders (B-CLPDs), where immune dysfunction is often intrinsic to the disease. A subset of such patients initially classified as having secondary immunodeficiency (SID) resulting from the BCLP may harbour underlying primary immunodeficiencies (PIDs). Recognizing the pattern of these hidden PID patients not only refines disease classification but also expands our understanding of the genetic determinants of cancer-associated immunodeficiency. Identification of tumour somatic variants that overlap with germline genes causative of PID uncovers novel mechanisms of immune dysfunction in B-CLPD, thereby providing new avenues for precision oncohaematology. This evolving host-centred perspective supports individualized, anticipatory care; enhances early detection of immune-mediated complications enabling tailored treatment responses; provides informed family counselling; and improves long-term outcomes for patients.
Haemoglobin SC (HbSC) disease is the second most prevalent form of sickle cell disease, but evidence for hydroxyurea (hydroxycarbamide; HU) to prevent pain episodes was limited until the prospective identification of var...Haemoglobin SC (HbSC) disease is the second most prevalent form of sickle cell disease, but evidence for hydroxyurea (hydroxycarbamide; HU) to prevent pain episodes was limited until the prospective identification of variables as outcomes for treatment (PIVOT) trial. To assess HU effectiveness and safety in adults with HbSC, we conducted a retrospective, single-centre, pre-post cohort study at the Centre hospitalier de l'Université de Montréal. Patients initiated HU between January 2010 and July 2025. Effectiveness analysis required ≥12 months of pre-HU follow-up; patients with shorter follow-up were included for the safety analysis only. The primary end-point was the change in the annual frequency of a vaso-occlusive crisis (VOC) composite (VOCC: VOC, acute chest syndrome, priapism, splenic/hepatic sequestration) from 12 months pre-HU to months 4-16 post-HU. Secondary end-points included adverse events (AEs), treatment effectiveness and reasons for HU discontinuation. Of 263 patients assessed, 110 were included in the safety analysis and 75 in the effectiveness analysis. HU reduced mean VOCC by 56% (0.57-0.25; Δ = -0.32 ± 0.84; 95% confidence interval [CI] [-0.51, -0.13]; p = 0.0015). Haematological AEs were mostly mild (thrombocytopenia, 32.7%; neutropenia, 23.6%; leucopenia, 20.9%); bilirubin elevations were the most frequent non-haematological AE (10.9%), all asymptomatic and without clinical hepatotoxicity. In conclusion, HU was associated with a meaningful reduction in VOCC and was generally well tolerated.
Chronic lymphocytic leukaemia (CLL) presents a complex biological and clinical landscape, strongly influenced by the tumour microenvironment (TME). To better capture this heterogeneity, we have developed patient-derived...Chronic lymphocytic leukaemia (CLL) presents a complex biological and clinical landscape, strongly influenced by the tumour microenvironment (TME). To better capture this heterogeneity, we have developed patient-derived lymphoma spheroids from CLL samples (CLL-PDLS), which recapitulate the cross-talk between malignant cells and the autologous immune microenvironment enabling efficient drug screening for further studies. CLL spheroids incorporate tumour B cells together with autologous T cells, which self-organize into a three-dimensional (3D) disc-shaped structure. Cultures can be maintained for up to 6 days under optimal conditions, preserving cell viability and high proliferative activity. T cells exhibit a range of activation and exhaustion phenotypes across both CD4+ and CD8+ subsets, including expression of Programmed Cell Death Protein 1 (PD-1), CD25, T cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD69. The cellular composition remains stable, with tumour B cells representing approximately 90% of the population and T cells comprising 10%. The model was further validated by assessing responses to conventional therapies, including ibrutinib and venetoclax. In conclusion, this 3D spheroid model captures key functional aspects of B-T interactions in CLL, maintaining the dynamic interactions between malignant B cells and their autologous immune components, partially reproducing microenvironmental features, and offering a promising platform for preclinical therapeutic evaluation.