Pirtobrutinib (PBN), a non-covalent BTK inhibitor, has been approved by the FDA for relapsed/refractory mantle cell lymphoma (MCL); however, resistance to PBN has been observed. To dissect the molecular dynamics driving...Pirtobrutinib (PBN), a non-covalent BTK inhibitor, has been approved by the FDA for relapsed/refractory mantle cell lymphoma (MCL); however, resistance to PBN has been observed. To dissect the molecular dynamics driving PBN resistance, we performed integrative single-cell multi-omic profiling (scRNA-seq, scATAC-seq, and scDNA-seq) on longitudinal MCL patient samples. Our analyses revealed both genetic and non-genetic routes of resistance: In some patients, resistance involves sequential copy number gains (e.g., 1q, 2p, and 8q) accompanied by transcriptomic reprogramming and epigenetic alterations, whereas in others, resistance occurs through non-genetic mechanisms driven by transcriptional and epigenetic remodeling. Integration of scATAC-seq and scRNA-seq enabled gene regulatory network inference and in silico perturbation analysis, highlighting RAD21 and SMC3, core components of the cohesin complex, as chromatin regulators whose downregulation may re-sensitize cells to PBN. A stem-like malignant B cell population enriched in resistant samples exhibited features of metabolic reprogramming and epithelial-mesenchymal transition. Together, our findings highlight heterogeneous, multi-layered mechanisms of PBN resistance and suggest chromatin regulators as potential therapeutic targets to overcome PBN resistance in MCL.
Fattizzo B, Sambruna E, Miyakawa Y
… +36 more, Michel M, Visco C, Fillitz M, Kannourakis G, Greve MB, Kleemiss M, Cid J, Patriarca A, Pavan L, Dizdari A, Maschio N, Sau A, Bitetti C, Colombo RM, Curreli L, Lame D, Markovic U, Pappagallo F, Pedone GL, Rapezzi D, Sammartano V, Tumedei N, Solimando AG, Marit J, Fianchi L, Khwaja J, De Vivo A, Lanza F, Vianello F, Oliva EN, Broome C, Passamonti F, Jaeger U, Jilma B, Moulis G, Barcellini W
Sutimlimab is a monoclonal antibody against complement fraction C1s approved for the treatment of hemolytic anemia due to cold agglutinin disease (CAD). Here, we analyzed and report the largest international CAD cohort o...Sutimlimab is a monoclonal antibody against complement fraction C1s approved for the treatment of hemolytic anemia due to cold agglutinin disease (CAD). Here, we analyzed and report the largest international CAD cohort of sutimlimab-treated patients ever reported to highlight its safety and effectiveness in the real-world setting. We accrued a cohort of 57 CAD patients (median age 73.5 years, 56% females). At baseline, patients had severe to moderate anemia (median Hb 8.9 g/dL) and active hemolysis, with a substantial transfusion burden despite a median of 2 prior therapies, including corticosteroids and rituximab. After sutimlimab initiation, median Hb increased by 2 g/dL within 2 weeks and reached 12 g/dL in 4 weeks, remaining stable up to 24 months. This improvement was paralleled by an early and durable normalization of hemolytic markers. Objective responses were observed in most patients by week 2, with complete responses in approximately 50% by Week 4 and 55%-60% during long-term follow-up. Peripheral cold-induced symptoms did not improve and were associated with reduced response rates. Inadequate reticulocytosis also predicted poorer response and suggests the combination with recombinant erythropoietin. Sutimlimab was generally well tolerated. Infections were the most frequent adverse events (23%); severe infections predominantly occurred in previously rituximab-treated individuals. Hemolytic exacerbations occurred in 16% of cases, mostly due to infections. Thrombotic complications were rare. Overall, sutimlimab demonstrated rapid, durable effectiveness and a favorable safety profile in heavily pretreated real-world CAD patients.
Mycosis fungoides (MF) is a rare extranodal T-cell lymphoma with primary cutaneous involvement. While it is the most common primary skin lymphoma, large-scale real-world data defining survival benchmarks and the prognost...Mycosis fungoides (MF) is a rare extranodal T-cell lymphoma with primary cutaneous involvement. While it is the most common primary skin lymphoma, large-scale real-world data defining survival benchmarks and the prognostic significance of specific nodal sites remain limited. To address this, we conducted a retrospective cohort study using the TriNetX global health research network and identified 25 467 patients with MF. The 5- and 10-year OS for the overall cohort was 83.4% and 74.7%, respectively. Patients with disease limited to the skin had 5- and 10-year OS rates of 86.1% and 78.0%, respectively. Nodal involvement at diagnosis was associated with significantly inferior survival [adjusted HR (aHR) = 1.60; 95% CI: 1.50-1.71; p < 0.001], exhibiting 5- and 10-year OS rates of 74.5% and 63.6%, respectively. Among patients with single-site lymphadenopathy, survival outcomes varied substantially by anatomical site, revealing a potential prognostic hierarchy: patients with inguinal/lower limb involvement exhibited the most favorable outcomes (5-year OS 80.2%), while those with visceral lymphadenopathy had the poorest prognosis (5-year OS 62.9%). In multivariable analysis, elevated LDH (aHR 3.06), lymphocytosis (aHR 1.37), and eosinophilia (aHR 1.29) were strong independent predictors of mortality, among others. To summarize, this study of over 25 000 MF patients represents the largest real-world analysis to date. Data suggest a potential prognostic divergence based on the anatomical site of nodal involvement. Additionally, our findings reinforce the prognostic value of LDH, eosinophils, lymphocytes and the hypopigmented and poikilodermatous variants as independent predictors of mortality, supporting their integration into routine risk stratification.
Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), the most common subtype of adult ALL, has undergone dramatic transformation in prognosis over the past two decades. Introduction of tyrosine kinas...Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), the most common subtype of adult ALL, has undergone dramatic transformation in prognosis over the past two decades. Introduction of tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 fusion protein has revolutionized frontline therapy, with successive generations of TKIs-from imatinib to dasatinib and most recently ponatinib-achieving progressively deeper and more durable molecular responses. Concurrently, the integration of immunotherapy, particularly blinatumomab, has enabled chemotherapy-sparing approaches further improving tolerability and efficacy. These advances have fundamentally challenged the historical paradigm that allogeneic hematopoietic cell transplantation (HCT) is indispensable for all Ph+ ALL patients in first complete remission. The role of allogeneic HCT is often debated and increasingly individualized, guided by measurable residual disease (MRD) assessment, TKI generation, depth and duration of molecular response, and patient-specific factors. Emerging data suggest that a subset of patients achieving early, deep MRD negativity with TKIs and immunotherapy may achieve durable remissions without transplant, though long-term follow-up remains limited. For patients proceeding to allogeneic HCT, optimization of transplant strategy-including donor selection, conditioning intensity, graft-versus-host disease prophylaxis, and posttransplant TKI maintenance-is critical to maximize graft-versus-leukemia effects while minimizing toxicity. Treatment-free remission strategies following prolonged TKI maintenance in non-transplant patients, and the integration of chimeric antigen receptor (CAR) T-cell therapy as bridge, consolidation, or salvage, represent emerging frontiers. This review critically examines the contemporary role of allogeneic HCT in Ph+ ALL and provides a framework for transplant decision-making in the contemporary era of targeted and cellular immunotherapy.
He J, Zhang L, Zhao J
… +16 more, Yang X, Wang T, Cui S, Cheng X, Yang X, Zhou J, Li M, Wang X, Zhang Y, Li Y, Shi J, You J, Jia Q, Xia ZL, Xing C, Wang QF
Circulating tumor cells (CTCs) have emerged as a key component of liquid biopsy in multiple myeloma (MM), reflecting the ability of malignant plasma cells to escape the bone marrow (BM) niche, disseminate systemically, a...Circulating tumor cells (CTCs) have emerged as a key component of liquid biopsy in multiple myeloma (MM), reflecting the ability of malignant plasma cells to escape the bone marrow (BM) niche, disseminate systemically, and contribute to disease progression. Their detection in peripheral blood is now feasible across the disease spectrum, from MGUS and smoldering myeloma to solitary plasmacytoma, symptomatic MM, and plasma cell leukemia, providing a dynamic window into tumor biology. Technological advances, including high-sensitivity flow cytometry and next-generation single-cell sequencing, have enabled accurate enumeration and molecular interrogation of CTC. Beyond their biological significance, CTC quantification has consistently demonstrated independent prognostic value at diagnosis, with even low levels predicting inferior survival outcomes. Recent proof-of-concept studies, such as MinimuMM-seq and SWIFT-seq, established that genomic and transcriptomic profiling of CTC can recapitulate canonical myeloma lesions, reveal clonal heterogeneity and track evolutionary dynamics under therapy. Importantly, persistent or reemergent CTC after are occasionally observed and, when present, may signal relapse, particularly, in patients with BM-MRD positivity, highlighting their potential as complementary biomarkers alongside established BM MRD assessment. Although methodological challenges remain-particularly, standardization, sensitivity, and integration into clinical workflows-CTC analysis holds the promise of transforming from a surrogate biomarker to a clinically actionable tool, advancing precision medicine in MM.
Morbidity and mortality in bone marrow failure syndromes such as acquired aplastic anemia (AA) are driven by severe and prolonged cytopenia. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is potentially cu...Morbidity and mortality in bone marrow failure syndromes such as acquired aplastic anemia (AA) are driven by severe and prolonged cytopenia. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is potentially curative and offers a rapid route to hematopoietic reconstitution. In 2026, reduced-toxicity conditioning, improved supportive care, and novel graft versus host disease prevention through post-transplant cyclophosphamide (PTCy)-based platforms have brought alternative donor transplantation into the mainstream. This review examines contemporary evidence, particularly looking at the expanded role of transplant outside the widely accepted setting of younger patients with matched sibling donors and offers a pragmatic framework for context-adapted decision-making.
Tsirigotis P, Garofalaki M, Lazana I
… +34 more, Liga M, Gigantes S, Kopsaftopoulou A, Tziotziou E, Roumelioti A, Tsintziloni E, Hatzis S, Konstantellos I, Benetatos L, Barbarousi D, Tzenou T, Asimakopoulos JV, Karagiannidi A, Barakos G, Delimpasi S, Stoumbos D, Stamouli M, Plata E, Valera K, Giannouli S, Chatzidimitriou C, Gkolfinopoulou G, Siakantaris MP, Kotsopoulou M, Voulgarelis M, Chondropoulos S, Zina V, Gkirkas K, Kapsali E, Matsouka C, Vassilakopoulos TP, Spyridonidis A, Angelopoulou M, Baltadakis I
The prognostic value of NPM1-mut Measurable Residual Disease (MRD) has been increasingly recognized. However, real-world data validating the prognostic impact of NPM1-mut MRD remains limited. The aim of this study was to...The prognostic value of NPM1-mut Measurable Residual Disease (MRD) has been increasingly recognized. However, real-world data validating the prognostic impact of NPM1-mut MRD remains limited. The aim of this study was to assess the prognostic value of NPM1-mut MRD and to explore optimal MRD thresholds for relapse prediction. One hundred forty-one patients with newly diagnosed NPM1-mut AML, from the Hellenic AML-Registry, in CR/CRi after the second cycle of induction and with bone marrow (BM) MRD assessment by RT-qPCR, were included in our study. Allogeneic stem cell transplantation (allo-SCT) in CR1 was not associated with any difference in RFS or OS between patients who achieved < 0.1% mutNPM1/ABL after the second cycle of chemotherapy, suggesting that this cut-off may effectively stratify relapse risk and possibly guide optimal use of allo-SCT. End-of-treatment (EOT) and during follow-up MRD assessment exhibited equally significant prognostic value, with high-level MRD positivity (≥ 0.1% mutNPM1/ABL) requiring early intervention to avoid imminent relapse, while those with undetectable or very low-level MRD (< 0.01% mutNPM1/ABL) being able to be safely monitored with no further intervention. Patients with low-level MRD positivity (≥ 0.01% and < 0.1%) require close MRD monitoring due to the substantial risk for progression to high-level MRD positivity. Overall, our results confirm the prognostic value of MRD assessment in BM samples at certain time points, with the cut-off of 0.1% after two cycles of chemotherapy enabling risk stratification and possibly informing transplant decisions, and during follow-up the cut-off of 0.01% being able to predict the 6-month relapse risk and guide further clinical management.
The use of immune checkpoint inhibitors (ICIs) has deeply improved the outcome of relapsed or refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) patients. However, real-world data are still limited, and several...The use of immune checkpoint inhibitors (ICIs) has deeply improved the outcome of relapsed or refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) patients. However, real-world data are still limited, and several aspects, including the need for consolidation strategies, remain to be fully elucidated. We report the results of the multicenter Italian retrospective observational PRIMICI study on R/R PMBCL patients treated with ICIs in a real-life (off-label) setting. Seventy-four patients, 42 treated with pembrolizumab and 32 with nivolumab-brentuximab vedotin (nivo-BV), were enrolled. The median follow-up was 34 months. The best overall response and complete response (CR) rates were 64% (n = 50) and 50% (n = 37), respectively. Of the 37 patients in CR, 11 received a consolidation treatment and 26 patients continued ICIs; CR were stable, independently from the use of consolidation, with a 4-year disease-free survival of 100%. The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 60.4% (95% confidence interval [C.I.] 48.3%-70.6%) and 77.5% (95% C.I. 65.8%-85.6%), respectively. Nivo-BV was associated with faster and higher response rates and better OS compared to pembrolizumab. OS significantly improved after 2020 due to the use of salvage treatment with CAR T-cells. In conclusion, this study supported the safety and effectiveness of pembrolizumab or nivo-BV as a salvage therapy in R/R PMBCL patients. Importantly, the chance to obtain long-lasting responses, regardless of the use of a consolidation treatment, indicates that ICIs may be used with a curative intent in a significant subset of patients.
Panigari A, Algeri M, Merli P
… +14 more, Mina T, Massa M, Agostini A, Acquafredda G, Lou TDB, Scattaglia F, Giorgiani G, Pianese J, Pili I, Quagliarella F, Pagliara D, Comoli P, Zecca M, Locatelli F
Cooper N, Broome CM, Miyakawa Y
… +18 more, McDonald V, Al-Samkari H, Khelif A, Cataland SR, Barcellini W, Yang R, Mei H, Matthijssens F, Hultberg A, Ciurlia G, Gandini D, Ayguasanosa J, De Beuf K, Pastouret S, Ghanima W, Rodeghiero F, Bussel JB, ADVANCE SC Investigator Trial Group
Primary autoimmune thrombocytopenia (ITP) is characterized by thrombocytopenia, bleeding, and reduced health-related quality of life. In the Phase 3 ADVANCE IV study, intravenous efgartigimod induced significant platelet...Primary autoimmune thrombocytopenia (ITP) is characterized by thrombocytopenia, bleeding, and reduced health-related quality of life. In the Phase 3 ADVANCE IV study, intravenous efgartigimod induced significant platelet count responses versus placebo in patients with chronic ITP. ADVANCE SC, a Phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study, evaluated the efficacy and safety of subcutaneous efgartigimod PH20 in adults with primary ITP. Participants with platelet counts < 30 × 10/L who received more than one prior ITP therapy. Between December 16, 2020, and October 9, 2023, 207 participants were randomized (2:1) to receive 1000 mg efgartigimod PH20 SC (n = 137) or placebo (n = 70) once weekly (visits 1-4), weekly or biweekly (depending upon response; visits 5-16), and at a fixed dosing interval (visits 17-24). Most (92.8% [192/207]) had chronic ITP and 74.9% (155/207) received at least three previous ITP treatments. The median time since diagnosis was 7.0 years. Superior efficacy of efgartigimod PH20 SC versus placebo was not demonstrated for the primary or secondary endpoints, with a comparable proportion of efgartigimod PH20 SC and placebo-treated participants achieving the primary efficacy endpoint (platelet count ≥ 50 × 10/L for at least four of the six visits during weeks 19-24): -13.7% [17/124] versus 16.2% [11/68], respectively; p = 0.51; adjusted difference in proportions, -3.5% [95% CI, -14.7-7.0]. Efgartigimod PH20 SC was well tolerated: most adverse events were mild to moderate and comparable between treatment groups. Platelet count increases from baseline were higher than expected with placebo and lower than expected with efgartigimod PH20 SC. Clinical Trial Registration: The ADVANCE SC trial is registered on ClinicalTrials.gov (NCT04687072).