M. Bakri Hammami, Rafael R. Canevarolo, Ariosto S. Silva, Melissa Alsina, Nagi Kumar, Rachid Baz, Kenneth H. Shain
Smoldering multiple myeloma (SMM) represents an intermediate clinical stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic multiple myeloma (MM). SMM carries a highly variable risk of progression to MM, requiring individualized risk stratification to guide management. Historically, risk models relied on static clinical markers reflective of tumor burden to predict progression. While useful, these models failed to capture the underlying biological heterogeneity of the disease. Recent advances have incorporated dynamic biomarkers, cytogenetics, and genomic profiling, providing a more nuanced understanding of disease trajectory. Immune dysregulation and subclonal evolution are now recognized as key drivers of progression, enabling the development of biologically informed risk models. Clinical trials have begun to challenge the traditional watch-and-wait approach by exploring early therapeutic interventions for high-risk SMM patients. However, uncertainty persists as clinicians balance the risks of overtreatment against therapeutic delay in the absence of clearly defined high-risk criteria. This review charts the evolution of SMM from a clinically defined entity to a biologically characterized precursor state, highlighting emerging tools and strategies aimed at improving risk prediction and patient outcomes. As personalized medicine continues to advance, integrating evolving molecular, immunologic, and clinical data will be pivotal in refining the management of SMM.
{"title":"Navigating the evolving management of smoldering multiple myeloma","authors":"M. Bakri Hammami, Rafael R. Canevarolo, Ariosto S. Silva, Melissa Alsina, Nagi Kumar, Rachid Baz, Kenneth H. Shain","doi":"10.1002/hem3.70275","DOIUrl":"10.1002/hem3.70275","url":null,"abstract":"<p>Smoldering multiple myeloma (SMM) represents an intermediate clinical stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic multiple myeloma (MM). SMM carries a highly variable risk of progression to MM, requiring individualized risk stratification to guide management. Historically, risk models relied on static clinical markers reflective of tumor burden to predict progression. While useful, these models failed to capture the underlying biological heterogeneity of the disease. Recent advances have incorporated dynamic biomarkers, cytogenetics, and genomic profiling, providing a more nuanced understanding of disease trajectory. Immune dysregulation and subclonal evolution are now recognized as key drivers of progression, enabling the development of biologically informed risk models. Clinical trials have begun to challenge the traditional watch-and-wait approach by exploring early therapeutic interventions for high-risk SMM patients. However, uncertainty persists as clinicians balance the risks of overtreatment against therapeutic delay in the absence of clearly defined high-risk criteria. This review charts the evolution of SMM from a clinically defined entity to a biologically characterized precursor state, highlighting emerging tools and strategies aimed at improving risk prediction and patient outcomes. As personalized medicine continues to advance, integrating evolving molecular, immunologic, and clinical data will be pivotal in refining the management of SMM.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stella Charalampopoulou, Silvia Ramos-Campoy, Marti Duran-Ferrer, Anna Puiggros, Joanna Kamaso, Florence Nguyen-Khac, Gian Matteo Rigolin, Antonio Cuneo, Rosa Collado, Rocío García-Serra, Claudia Haferlach, Margarita Ortega, Pau Abrisqueta, Francesc Bosch, Thorsten Zenz, María Laura Blanco, Rocío Salgado, Mª Dolores García-Malo, Eva Gimeno, Armando Lopez-Guillermo, Elias Campo, Laurence Etter, Jacqueline Schoumans, Blanca Espinet, Jose I. Martin-Subero
<p>Chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by extensive biological and clinical heterogeneity.<span><sup>1</sup></span> Immunogenetic, genetic, and epigenetic features have been described as major molecular traits strongly associated with clinical impact in CLL.<span><sup>2</sup></span> The levels of somatic hypermutation (SHM) of the immunoglobulin heavy chain variable (IGHV) region segregate cases into IGHV unmutated and mutated CLLs (U-CLL and M-CLL, respectively), being the former clinically more aggressive.<span><sup>1</sup></span> This dichotomous classification was further refined using DNA methylation imprints of normal B-cell maturation, leading to the identification of three distinct epigenetic subtypes or epitypes, including naive-like/low-programmed CLL (n-CLL), mostly corresponding to U-CLL, intermediate CLL and memory-like/high-programmed CLL, both of which belonging to M-CLL.<span><sup>3, 4</sup></span> In spite of this classification into three categories, a model in which CLLs derive from a continuum of mature B-cell maturation stages was proposed, suggesting that CLL could be potentially stratified into additional epitypes.<span><sup>4</sup></span> Apart from this link with normal B-cell maturation, the DNA methylome of CLL also reflects the past proliferative history and presents specific DNA methylation signatures related to its pathogenesis.<span><sup>5, 6</sup></span></p><p>In addition to IGHV subtypes and epitypes, specific genetic lesions and the presence of complex karyotypes (CKs) carry prognostic<span><sup>1, 2, 7, 8</sup></span> and predictive value.<span><sup>9</sup></span> Such CK has been frequently but not always associated with U-CLL and alterations affecting the <i>TP53</i> and <i>ATM</i> genes.<span><sup>10, 11</sup></span> To our knowledge, studies analyzing the potential link between CK and epigenetic features have not been reported. Therefore, we have here analyzed the DNA methylome of a U-CLL cohort (<i>n</i> = 52, Supporting Information S2: Table 1, all belonging to the n-CLL epitype according to a previously reported classifier<span><sup>5</sup></span>) that has been carefully selected based on distinct CK levels and the presence of <i>ATM</i> deletion (<i>ATM</i><sup>del</sup>) and/or <i>TP53</i> deletion or mutation (<i>TP53</i><sup>del/mut</sup>) status (Figure 1A). We used Illumina EPIC V1 arrays to generate DNA methylation profiles, which were analyzed as previously described<span><sup>5</sup></span> (Supporting Information S9: Supplementary Material).</p><p>An unsupervised principal component analysis (PCA) showed that CK and non-CK U-CLLs are intermingled (Figure 1B), and the same finding was made when analyzing additional principal components (Supporting Information S1: Figure 1A). In line with this observation, a differential methylation analysis revealed a small and heterogeneous signature of 59 differentially methylated (DM) CpGs betw
{"title":"Identification of two epitypes of IGHV unmutated chronic lymphocytic leukemia with distinct B-cell-related epigenetic imprinting and genetic alterations","authors":"Stella Charalampopoulou, Silvia Ramos-Campoy, Marti Duran-Ferrer, Anna Puiggros, Joanna Kamaso, Florence Nguyen-Khac, Gian Matteo Rigolin, Antonio Cuneo, Rosa Collado, Rocío García-Serra, Claudia Haferlach, Margarita Ortega, Pau Abrisqueta, Francesc Bosch, Thorsten Zenz, María Laura Blanco, Rocío Salgado, Mª Dolores García-Malo, Eva Gimeno, Armando Lopez-Guillermo, Elias Campo, Laurence Etter, Jacqueline Schoumans, Blanca Espinet, Jose I. Martin-Subero","doi":"10.1002/hem3.70211","DOIUrl":"https://doi.org/10.1002/hem3.70211","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by extensive biological and clinical heterogeneity.<span><sup>1</sup></span> Immunogenetic, genetic, and epigenetic features have been described as major molecular traits strongly associated with clinical impact in CLL.<span><sup>2</sup></span> The levels of somatic hypermutation (SHM) of the immunoglobulin heavy chain variable (IGHV) region segregate cases into IGHV unmutated and mutated CLLs (U-CLL and M-CLL, respectively), being the former clinically more aggressive.<span><sup>1</sup></span> This dichotomous classification was further refined using DNA methylation imprints of normal B-cell maturation, leading to the identification of three distinct epigenetic subtypes or epitypes, including naive-like/low-programmed CLL (n-CLL), mostly corresponding to U-CLL, intermediate CLL and memory-like/high-programmed CLL, both of which belonging to M-CLL.<span><sup>3, 4</sup></span> In spite of this classification into three categories, a model in which CLLs derive from a continuum of mature B-cell maturation stages was proposed, suggesting that CLL could be potentially stratified into additional epitypes.<span><sup>4</sup></span> Apart from this link with normal B-cell maturation, the DNA methylome of CLL also reflects the past proliferative history and presents specific DNA methylation signatures related to its pathogenesis.<span><sup>5, 6</sup></span></p><p>In addition to IGHV subtypes and epitypes, specific genetic lesions and the presence of complex karyotypes (CKs) carry prognostic<span><sup>1, 2, 7, 8</sup></span> and predictive value.<span><sup>9</sup></span> Such CK has been frequently but not always associated with U-CLL and alterations affecting the <i>TP53</i> and <i>ATM</i> genes.<span><sup>10, 11</sup></span> To our knowledge, studies analyzing the potential link between CK and epigenetic features have not been reported. Therefore, we have here analyzed the DNA methylome of a U-CLL cohort (<i>n</i> = 52, Supporting Information S2: Table 1, all belonging to the n-CLL epitype according to a previously reported classifier<span><sup>5</sup></span>) that has been carefully selected based on distinct CK levels and the presence of <i>ATM</i> deletion (<i>ATM</i><sup>del</sup>) and/or <i>TP53</i> deletion or mutation (<i>TP53</i><sup>del/mut</sup>) status (Figure 1A). We used Illumina EPIC V1 arrays to generate DNA methylation profiles, which were analyzed as previously described<span><sup>5</sup></span> (Supporting Information S9: Supplementary Material).</p><p>An unsupervised principal component analysis (PCA) showed that CK and non-CK U-CLLs are intermingled (Figure 1B), and the same finding was made when analyzing additional principal components (Supporting Information S1: Figure 1A). In line with this observation, a differential methylation analysis revealed a small and heterogeneous signature of 59 differentially methylated (DM) CpGs betw","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meral Beksac, Tulin Fıratlı Tuglular, Francesca Gay, Roberto Mina, Eirini Katodritou, Ali Unal, Michele Cavo, Guner Hayri Ozsan, Vincent H. J. van der Velden, Berna H. Beverloo, Michael Vermeulen, Mark van Duin, Guldane Cengiz Seval, Omur Gokmen Sevindik, Serena Merante, Kyriaki Manousou, Peter Sonneveld, Elena Zamagni, Evangelos Terpos
Novel therapies are needed for patients with multiple myeloma (MM) and extramedullary plasmacytomas. The prospective, Phase II EMN19 study assessed the efficacy and safety of daratumumab plus bortezomib, cyclophosphamide, and dexamethasone (DaraVCD) in 40 patients with newly diagnosed MM (NDMM; n = 29) or at first relapse (RMM; n = 11) and positron emission tomography or computed tomography (PET/CT)-confirmed extramedullary plasmacytomas (extraosseous [EMD] and/or paraosseous [PS]). DaraVCD was administered until disease progression or up to 3 years. The primary endpoint was hematological complete response (CR). Among patients, 22 (55.0%), 4 (10.0%), and 14 (35.0%) had EMD, EMD/PS, and PS plasmacytomas, respectively. Median patient age was 58.0 years, and 16 (40.0%), 12 (30.0%), and 10 (25.0%) patients were at International Staging System (ISS) Stages I, II, and III, respectively. Median circulating tumor cell (CTC) level was 0.002% (range, 0.000–0.353), significantly higher (P < 0.05) in patients with ISS Stage III and those with plasma cells > 60%. At a median follow-up of 30.0 months, all patients completed treatment (median duration: 19.8 months). The overall hematologic ≥CR rate was 47.5% (19/40; NDMM patients: 58.6% [17/29]; RMM patients: 18.2% [2/11]). Of patients with ≥CR, 80.0% (15/19) achieved minimal residual disease (MRD) negativity, and 68.4% (13/19) combined MRD negativity and complete metabolic response (CMR) on PET/CT. The overall median progression-free survival was 25.8 months, significantly longer in patients achieving hematologic ≥CR and/or CMR than others (not reached and 4.8 months, respectively; P < 0.001). DaraVCD showed encouraging efficacy in patients with MM and extramedullary plasmacytomas. Notably, this is the first report on CTC levels in EMD, and they were lower than previously reported NDMM thresholds.
多发性骨髓瘤（MM）和髓外浆细胞瘤需要新的治疗方法。这项前瞻性II期EMN19研究评估了daratumumab联合硼替佐米、环磷酰胺和地塞米松（DaraVCD）治疗40例新诊断的MM （NDMM, n = 29）或首次复发（RMM, n = 11）和正电子发射断层扫描或计算机断层扫描（PET/CT）确诊的髓外浆细胞瘤（骨外[EMD]和/或骨旁[PS]）患者的疗效和安全性。服用DaraVCD直至疾病进展或长达3年。主要终点是血液学完全缓解（CR）。其中，22例（55.0%）、4例（10.0%）、14例（35.0%）分别为EMD、EMD/PS和PS浆细胞瘤。患者中位年龄为58.0岁，分别有16例（40.0%）、12例（30.0%）和10例（25.0%）患者处于国际分期系统（ISS） I、II和III期。中位循环肿瘤细胞（CTC）水平为0.002%（范围0.000 ~ 0.353），ISS III期患者CTC水平显著高于浆细胞水平60% （P < 0.05）。在中位随访30.0个月时，所有患者完成治疗（中位持续时间：19.8个月）。总体血液学≥CR率为47.5% （19/40；NDMM患者：58.6% [17/29]；RMM患者：18.2%[2/11]）。在CR≥的患者中，80.0%（15/19）达到最小残留病（MRD）阴性，68.4%（13/19）在PET/CT上达到MRD阴性和完全代谢反应（CMR）。总体中位无进展生存期为25.8个月，达到血液学≥CR和/或CMR的患者明显比其他患者更长（分别为未达到和4.8个月；P < 0.001）。DaraVCD在MM和髓外浆细胞瘤患者中显示出令人鼓舞的疗效。值得注意的是，这是关于EMD中CTC水平的第一份报告，它们低于先前报道的NDMM阈值。
{"title":"Daratumumab-based quadruplet for patients with extramedullary multiple myeloma: Results from the Phase II prospective EMN19 study","authors":"Meral Beksac, Tulin Fıratlı Tuglular, Francesca Gay, Roberto Mina, Eirini Katodritou, Ali Unal, Michele Cavo, Guner Hayri Ozsan, Vincent H. J. van der Velden, Berna H. Beverloo, Michael Vermeulen, Mark van Duin, Guldane Cengiz Seval, Omur Gokmen Sevindik, Serena Merante, Kyriaki Manousou, Peter Sonneveld, Elena Zamagni, Evangelos Terpos","doi":"10.1002/hem3.70287","DOIUrl":"https://doi.org/10.1002/hem3.70287","url":null,"abstract":"<p>Novel therapies are needed for patients with multiple myeloma (MM) and extramedullary plasmacytomas. The prospective, Phase II EMN19 study assessed the efficacy and safety of daratumumab plus bortezomib, cyclophosphamide, and dexamethasone (DaraVCD) in 40 patients with newly diagnosed MM (NDMM; <i>n</i> = 29) or at first relapse (RMM; <i>n</i> = 11) and positron emission tomography or computed tomography (PET/CT)-confirmed extramedullary plasmacytomas (extraosseous [EMD] and/or paraosseous [PS]). DaraVCD was administered until disease progression or up to 3 years. The primary endpoint was hematological complete response (CR). Among patients, 22 (55.0%), 4 (10.0%), and 14 (35.0%) had EMD, EMD/PS, and PS plasmacytomas, respectively. Median patient age was 58.0 years, and 16 (40.0%), 12 (30.0%), and 10 (25.0%) patients were at International Staging System (ISS) Stages I, II, and III, respectively. Median circulating tumor cell (CTC) level was 0.002% (range, 0.000–0.353), significantly higher (P < 0.05) in patients with ISS Stage III and those with plasma cells > 60%. At a median follow-up of 30.0 months, all patients completed treatment (median duration: 19.8 months). The overall hematologic ≥CR rate was 47.5% (19/40; NDMM patients: 58.6% [17/29]; RMM patients: 18.2% [2/11]). Of patients with ≥CR, 80.0% (15/19) achieved minimal residual disease (MRD) negativity, and 68.4% (13/19) combined MRD negativity and complete metabolic response (CMR) on PET/CT. The overall median progression-free survival was 25.8 months, significantly longer in patients achieving hematologic ≥CR and/or CMR than others (not reached and 4.8 months, respectively; P < 0.001). DaraVCD showed encouraging efficacy in patients with MM and extramedullary plasmacytomas. Notably, this is the first report on CTC levels in EMD, and they were lower than previously reported NDMM thresholds.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdul-Hamid Bazarbachi, Saurabh Zanwar, Ute Hegenbart, Despina Trajanova, Divaya Bhutani, Morie A. Gertz, Angela Dispenzieri, Shaji Kumar, Anita D'Souza, Anannya Patwari, Andrew Cowan, GuiZhen Chen, Paolo Milani, Giovanni Palladini, Vaishali Sanchorawala, Geethika Bodanapu, Mohamad Mohty, Suzanne Lentzsch, Stefan O. Schönland, Eli Muchtar, Rajshekhar Chakraborty
Rapid and profound reduction of free light chains (FLCs) improves outcomes in AL amyloidosis; however, early FLC kinetics with daratumumab-based frontline therapy remain undefined. We retrospectively analyzed 315 patients treated with daratumumab–bortezomib–cyclophosphamide–dexamethasone (Dara–VCd) or Dara–Vd at eight centers. Involved FLC (iFLC), the difference between iFLC and uninvolved FLC (dFLC), and hematologic response (≥very good partial response [VGPR]) were assessed at baseline and at 1, 3, and 6 months, and correlated with light chain isotype, disease burden (bone-marrow plasma-cell percentage [%BMPC], baseline dFLC), and cytogenetics. Hematological ≥VGPR increased from 49.8% at 1 month to 66.0% at 3 months. The kappa isotype showed slower responses, with higher iFLC/dFLC and lower ≥VGPR at each time point compared to lambda. Higher %BMPC or baseline dFLC predicted persistently elevated iFLC/dFLC and reduced ≥VGPR. The t(11;14) translocation was associated with lower baseline FLC but similar subsequent kinetics. BMPC < 10% and dFLC < 18 mg/dL independently predicted early ≥VGPR (in ≤1 month). Early ≥VGPR conferred superior hematologic event-free survival (heme-EFS) and overall survival (OS) versus later responders (P < 0.001). At a 3-month landmark, achieving dFLC < 1 mg/dL further stratified prognosis, conferring longer heme-EFS and OS (P < 0.01). Frontline Dara-based therapy elicits rapid, deep responses in AL amyloidosis; early ≥VGPR (within 1 month) and dFLC < 1 mg/dL by 3 months predict durable EFS and OS, whereas higher baseline disease burden delays hematologic response.
{"title":"Kinetics of hematologic response in AL amyloidosis: Insights from clinical and cytogenetic subgroup analysis in the daratumumab era","authors":"Abdul-Hamid Bazarbachi, Saurabh Zanwar, Ute Hegenbart, Despina Trajanova, Divaya Bhutani, Morie A. Gertz, Angela Dispenzieri, Shaji Kumar, Anita D'Souza, Anannya Patwari, Andrew Cowan, GuiZhen Chen, Paolo Milani, Giovanni Palladini, Vaishali Sanchorawala, Geethika Bodanapu, Mohamad Mohty, Suzanne Lentzsch, Stefan O. Schönland, Eli Muchtar, Rajshekhar Chakraborty","doi":"10.1002/hem3.70276","DOIUrl":"10.1002/hem3.70276","url":null,"abstract":"<p>Rapid and profound reduction of free light chains (FLCs) improves outcomes in AL amyloidosis; however, early FLC kinetics with daratumumab-based frontline therapy remain undefined. We retrospectively analyzed 315 patients treated with daratumumab–bortezomib–cyclophosphamide–dexamethasone (Dara–VCd) or Dara–Vd at eight centers. Involved FLC (iFLC), the difference between iFLC and uninvolved FLC (dFLC), and hematologic response (≥very good partial response [VGPR]) were assessed at baseline and at 1, 3, and 6 months, and correlated with light chain isotype, disease burden (bone-marrow plasma-cell percentage [%BMPC], baseline dFLC), and cytogenetics. Hematological ≥VGPR increased from 49.8% at 1 month to 66.0% at 3 months. The kappa isotype showed slower responses, with higher iFLC/dFLC and lower ≥VGPR at each time point compared to lambda. Higher %BMPC or baseline dFLC predicted persistently elevated iFLC/dFLC and reduced ≥VGPR. The t(11;14) translocation was associated with lower baseline FLC but similar subsequent kinetics. BMPC < 10% and dFLC < 18 mg/dL independently predicted early ≥VGPR (in ≤1 month). Early ≥VGPR conferred superior hematologic event-free survival (heme-EFS) and overall survival (OS) versus later responders (P < 0.001). At a 3-month landmark, achieving dFLC < 1 mg/dL further stratified prognosis, conferring longer heme-EFS and OS (P < 0.01). Frontline Dara-based therapy elicits rapid, deep responses in AL amyloidosis; early ≥VGPR (within 1 month) and dFLC < 1 mg/dL by 3 months predict durable EFS and OS, whereas higher baseline disease burden delays hematologic response.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 12","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Gutiérrez-Herrero, Lourdes Martín-Martín, María Herrero-García, Borja Puertas, Eduarda da Silva Barbosa, María Victoria Mateos, Lucía López-Corral, Verónica González-Calle, Beatriz Rey-Búa, Ana África Martín-López, Estefanía Pérez-López, Fermín Sánchez-Guijo, Miriam López-Parra, Noemí Puig, Alberto Orfao, on behalf of the INCAR and Euroflow Consortium
Chimeric antigen receptor (CAR)-T-cell therapy has improved response rates in relapsed/refractory multiple myeloma (RRMM), yet long-term disease control remains limited, with only 20% of patients remaining progression-free at 5 years. Therefore, identifying early predictors of treatment success is critical. Here, we used next-generation flow cytometry to analyze T-cell populations in blood at leukapheresis, before infusion, and post-anti-BCMA CAR-T infusion, together with CAR-T-cell kinetics and phenotypes before, during, and after the expansion peak, in 53 RRMM patients. Anti-BCMA CAR-T cells peaked at Day +14 (72%), comprising >65 distinct populations, predominantly central memory (CM) T-helper (Th) 1 and Th1/2 CAR-TCD4+ and CM CAR-TCD8+ cells. Multivariate analyses revealed that higher frequencies of TCD4+ naive and Th22 transitional memory (TM) cells at leukapheresis, together with circulating tumor plasma cells (CTPCs) before infusion, but none of the specific CAR-T-cell populations, were predictors of progression-free survival (PFS). Based on these variables, we built a risk score that together with disease stage (International Staging System-Revised [ISS-R]) independently predicted, before CAR-T-cell infusion, which RRMM patients were most likely to benefit from anti-BCMA CAR-T therapy. These findings suggest that long-term PFS is primarily influenced by the patient's immune landscape and the tumor burden rather than anti-BCMA CAR-T-cell properties.
{"title":"Impact of the kinetics of circulating anti-BCMA CAR-T cells and normal lymphocytes on the outcome of MM patients","authors":"Sara Gutiérrez-Herrero, Lourdes Martín-Martín, María Herrero-García, Borja Puertas, Eduarda da Silva Barbosa, María Victoria Mateos, Lucía López-Corral, Verónica González-Calle, Beatriz Rey-Búa, Ana África Martín-López, Estefanía Pérez-López, Fermín Sánchez-Guijo, Miriam López-Parra, Noemí Puig, Alberto Orfao, on behalf of the INCAR and Euroflow Consortium","doi":"10.1002/hem3.70277","DOIUrl":"10.1002/hem3.70277","url":null,"abstract":"<p>Chimeric antigen receptor (CAR)-T-cell therapy has improved response rates in relapsed/refractory multiple myeloma (RRMM), yet long-term disease control remains limited, with only 20% of patients remaining progression-free at 5 years. Therefore, identifying early predictors of treatment success is critical. Here, we used next-generation flow cytometry to analyze T-cell populations in blood at leukapheresis, before infusion, and post-anti-BCMA CAR-T infusion, together with CAR-T-cell kinetics and phenotypes before, during, and after the expansion peak, in 53 RRMM patients. Anti-BCMA CAR-T cells peaked at Day +14 (72%), comprising >65 distinct populations, predominantly central memory (CM) T-helper (Th) 1 and Th1/2 CAR-TCD4<sup>+</sup> and CM CAR-TCD8<sup>+</sup> cells. Multivariate analyses revealed that higher frequencies of TCD4<sup>+</sup> naive and Th22 transitional memory (TM) cells at leukapheresis, together with circulating tumor plasma cells (CTPCs) before infusion, but none of the specific CAR-T-cell populations, were predictors of progression-free survival (PFS). Based on these variables, we built a risk score that together with disease stage (International Staging System-Revised [ISS-R]) independently predicted, before CAR-T-cell infusion, which RRMM patients were most likely to benefit from anti-BCMA CAR-T therapy. These findings suggest that long-term PFS is primarily influenced by the patient's immune landscape and the tumor burden rather than anti-BCMA CAR-T-cell properties.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 12","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>The Common Terminology Criteria for Adverse Events (CTCAE) have been used by most clinical trials globally since the 1980s to record the incidence and severity of toxicities associated with systemic anticancer therapy.<span><sup>1</sup></span> The most recent update (v6) was released in the summer of 2025 with planned implementation for clinical trials on January 1, 2026. One of the notable changes includes a significant update to the neutrophil grading criteria, which essentially translates neutrophil count grade up by one level, where absolute neutrophil count (ANC) < 1500–1000/µL is now Grade 1 (previously Grade 2), and Grade 4 is now ANC < 100/µL (Table 1).</p><p>The potential reasons for this timely and necessary CTCAE neutrophil count grade update were outlined in a previous HemaTopic and summarized in Figure 1.<span><sup>2</sup></span> The change is more inclusive for people with the Duffy null variant—a genetic variant commonly found in people with genetic ancestry from Sub-Saharan Africa or the Arabian Peninsula resulting in lower ANC without increased risk for infection.<span><sup>3</sup></span> Additionally, this update is likely an acknowledgment that many modern therapies are targeted and the mechanism of cytotoxicity (if any) is different than older therapies.<span><sup>2</sup></span> It also integrates decades of observational data on neutrophil levels correlated with the degree of concern for febrile neutropenia or serious infectious complications.<span><sup>4</sup></span> However, we now must grapple with the implications of a change to a key adverse event criterion for ongoing and future clinical trials.</p><p>Encouragingly, these CTCAE changes are in line with recent recommendations from the coalition for reducing bureaucracy in clinical trials (RBinCT).<span><sup>5</sup></span> This cross-disciplinary group involving patient advocates and medical societies has identified the need to streamline the communication of safety reports communicated to investigators to reduce “alarm fatigue” and ensure that investigators react quickly to relevant reports.<span><sup>5</sup></span> The updated neutrophil count grading criteria will help with this goal. For example, if safety reports are routinely generated for a Grade 3 or 4 neutrophil count, this will now trigger a report when ANC is <500/µL by CTCAE v6. A neutrophil count of 300/µL (Grade 3 by CTCAE v6) is much more concerning and urgently actionable (e.g., granulocyte colony-stimulating factor administration) than an ANC of 900/µL (Grade 3 by CTCAE v1–5). This will likely reduce excessive safety reports, which will help investigators respond quickly and appropriately to medically relevant concerns.</p><p>One potential issue to reconcile is the disconnect between the definition of febrile neutropenia and updated neutrophil count grading. In both CTCAE v5 and CTCAE v6, febrile neutropenia is defined as an ANC < 1000 with a temperature of >38.3°C or sustained at >38
{"title":"A paradigm shift in neutrophil adverse event grading: What now?","authors":"Lauren E. Merz","doi":"10.1002/hem3.70266","DOIUrl":"10.1002/hem3.70266","url":null,"abstract":"<p>The Common Terminology Criteria for Adverse Events (CTCAE) have been used by most clinical trials globally since the 1980s to record the incidence and severity of toxicities associated with systemic anticancer therapy.<span><sup>1</sup></span> The most recent update (v6) was released in the summer of 2025 with planned implementation for clinical trials on January 1, 2026. One of the notable changes includes a significant update to the neutrophil grading criteria, which essentially translates neutrophil count grade up by one level, where absolute neutrophil count (ANC) < 1500–1000/µL is now Grade 1 (previously Grade 2), and Grade 4 is now ANC < 100/µL (Table 1).</p><p>The potential reasons for this timely and necessary CTCAE neutrophil count grade update were outlined in a previous HemaTopic and summarized in Figure 1.<span><sup>2</sup></span> The change is more inclusive for people with the Duffy null variant—a genetic variant commonly found in people with genetic ancestry from Sub-Saharan Africa or the Arabian Peninsula resulting in lower ANC without increased risk for infection.<span><sup>3</sup></span> Additionally, this update is likely an acknowledgment that many modern therapies are targeted and the mechanism of cytotoxicity (if any) is different than older therapies.<span><sup>2</sup></span> It also integrates decades of observational data on neutrophil levels correlated with the degree of concern for febrile neutropenia or serious infectious complications.<span><sup>4</sup></span> However, we now must grapple with the implications of a change to a key adverse event criterion for ongoing and future clinical trials.</p><p>Encouragingly, these CTCAE changes are in line with recent recommendations from the coalition for reducing bureaucracy in clinical trials (RBinCT).<span><sup>5</sup></span> This cross-disciplinary group involving patient advocates and medical societies has identified the need to streamline the communication of safety reports communicated to investigators to reduce “alarm fatigue” and ensure that investigators react quickly to relevant reports.<span><sup>5</sup></span> The updated neutrophil count grading criteria will help with this goal. For example, if safety reports are routinely generated for a Grade 3 or 4 neutrophil count, this will now trigger a report when ANC is <500/µL by CTCAE v6. A neutrophil count of 300/µL (Grade 3 by CTCAE v6) is much more concerning and urgently actionable (e.g., granulocyte colony-stimulating factor administration) than an ANC of 900/µL (Grade 3 by CTCAE v1–5). This will likely reduce excessive safety reports, which will help investigators respond quickly and appropriately to medically relevant concerns.</p><p>One potential issue to reconcile is the disconnect between the definition of febrile neutropenia and updated neutrophil count grading. In both CTCAE v5 and CTCAE v6, febrile neutropenia is defined as an ANC < 1000 with a temperature of >38.3°C or sustained at >38","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 12","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thieblemont C, Gomes Da Silva M, Leppä S, et al. Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up. HemaSphere. 2025;9(9):e70207. doi:10.1002/hem3.70207.
The abbreviation CSF was incorrectly defined as “colony-stimulating factor” in the Abstract and Table 2. The correct definition is “cerebrospinal fluid.”
Additionally, in the author listing of the manuscript, the name of an author was incorrectly listed as Marie-José Kersten. The correct name is Marie José Kersten.
The original article has been updated. We apologize for these errors.
[这更正了文章DOI: 10.1002/hem3.70207.]。
{"title":"Correction to “Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up”","authors":"","doi":"10.1002/hem3.70273","DOIUrl":"10.1002/hem3.70273","url":null,"abstract":"<p>Thieblemont C, Gomes Da Silva M, Leppä S, et al. Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up. <i>HemaSphere</i>. 2025;9(9):e70207. doi:10.1002/hem3.70207.</p><p>The abbreviation CSF was incorrectly defined as “colony-stimulating factor” in the Abstract and Table 2. The correct definition is “cerebrospinal fluid.”</p><p>Additionally, in the author listing of the manuscript, the name of an author was incorrectly listed as Marie-José Kersten. The correct name is Marie José Kersten.</p><p>The original article has been updated. We apologize for these errors.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 12","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giovanni Caocci, Alessandro Costa, Francesca Palandri, Paola Guglielmelli, Andrea Patriarca, Alessandra Iurlo, Alessia Tieghi, Elisabetta Abruzzese, Thomas Baldi, Elena Rossi, Eloise Beggiato, Monia Marchetti, Carmen Fava, Simona Tomassetti, Elisa Rumi, Claudio Fozza, Mario Luppi, Fabrizio Pane, Sara Bigliardi, Massimo Breccia, Elena Maria Elli, Francesca Tartaglia, Olga Mulas, Paola Fazi, Marco Vignetti, Alessandro Maria Vannucchi, Fabio Efficace
Health-related quality of life (HRQoL) of patients with myeloproliferative neoplasms (MPNs) may be impaired across several domains. In this multicenter observational study, we evaluated HRQoL and symptoms in a cohort of MPN patients with validated measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), and the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) questionnaire. The primary objective was to compare the HRQoL profile of patients, by disease subtype, with that of the general population according to the EORTC QLQ-C30. A total of 572 patients with essential thrombocythemia (ET, n = 228), polycythemia vera (PV, n = 207), and myelofibrosis (MF, n = 137) were assessed. Worse statistically and clinically significant differences were observed for role functioning (ET: ∆ = 8.9, P < 0.001; PV: ∆ = 11, P < 0.001; MF: ∆ = 16.7, P < 0.001) and fatigue (ET: ∆ = 5, P < 0.001; PV: ∆ = 8.3, P < 0.001; MF: ∆ = 11.5, P < 0.001) in all three diagnostic groups. However, patients with MF also reported impairments in other important health domains. Fatigue was the most frequently reported and burdensome symptom, with greater severity correlating with a broader and more complex array of associated symptoms. Our analysis also revealed a substantial underestimation of symptoms by treating hematologists in paired physician–patient reports. Current findings may help to disentangle specific HRQoL limitations and symptomatology experienced by patients with MPNs, and underscore the importance of incorporating patient-reported outcomes into routine practice to better reflect the patient's perspective of the disease and treatment-related burden.
骨髓增生性肿瘤（mpn）患者的健康相关生活质量（HRQoL）可能在多个领域受到损害。在这项多中心观察性研究中，我们评估了一组MPN患者的HRQoL和症状，包括欧洲癌症研究与治疗组织生活质量问卷-核心30 （EORTC QLQ-C30）、骨髓增生性肿瘤症状评估表总症状评分（MPN- saf TSS）和慢性疾病治疗-疲劳量表（facit -疲劳）问卷。主要目的是根据EORTC QLQ-C30比较按疾病亚型划分的患者的HRQoL概况与普通人群的HRQoL概况。共有572例原发性血小板增多症（ET, n = 228）、真性红细胞增多症（PV, n = 207）和骨髓纤维化（MF, n = 137）患者被评估。两组在角色功能方面的差异有更大的统计学意义和临床意义(ET:∆= 8.9，P
{"title":"Health-related quality of life and symptom profile of patients with BCR::ABL1-negative myeloproliferative neoplasms: Real-world evidence from the GIMEMA-PROPHECY observational study","authors":"Giovanni Caocci, Alessandro Costa, Francesca Palandri, Paola Guglielmelli, Andrea Patriarca, Alessandra Iurlo, Alessia Tieghi, Elisabetta Abruzzese, Thomas Baldi, Elena Rossi, Eloise Beggiato, Monia Marchetti, Carmen Fava, Simona Tomassetti, Elisa Rumi, Claudio Fozza, Mario Luppi, Fabrizio Pane, Sara Bigliardi, Massimo Breccia, Elena Maria Elli, Francesca Tartaglia, Olga Mulas, Paola Fazi, Marco Vignetti, Alessandro Maria Vannucchi, Fabio Efficace","doi":"10.1002/hem3.70274","DOIUrl":"10.1002/hem3.70274","url":null,"abstract":"<p>Health-related quality of life (HRQoL) of patients with myeloproliferative neoplasms (MPNs) may be impaired across several domains. In this multicenter observational study, we evaluated HRQoL and symptoms in a cohort of MPN patients with validated measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), and the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) questionnaire. The primary objective was to compare the HRQoL profile of patients, by disease subtype, with that of the general population according to the EORTC QLQ-C30. A total of 572 patients with essential thrombocythemia (ET, <i>n</i> = 228), polycythemia vera (PV, <i>n</i> = 207), and myelofibrosis (MF, <i>n</i> = 137) were assessed. Worse statistically and clinically significant differences were observed for role functioning (ET: ∆ = 8.9, P < 0.001; PV: ∆ = 11, P < 0.001; MF: ∆ = 16.7, P < 0.001) and fatigue (ET: ∆ = 5, P < 0.001; PV: ∆ = 8.3, P < 0.001; MF: ∆ = 11.5, P < 0.001) in all three diagnostic groups. However, patients with MF also reported impairments in other important health domains. Fatigue was the most frequently reported and burdensome symptom, with greater severity correlating with a broader and more complex array of associated symptoms. Our analysis also revealed a substantial underestimation of symptoms by treating hematologists in paired physician–patient reports. Current findings may help to disentangle specific HRQoL limitations and symptomatology experienced by patients with MPNs, and underscore the importance of incorporating patient-reported outcomes into routine practice to better reflect the patient's perspective of the disease and treatment-related burden.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 12","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danielle M. Brander, Andrew W. Roberts, Thomas J. Kipps, Shuo Ma, Mary Ann Anderson, Michelle Boyer, Piers Blombery, Relja Popovic, Jordan Roser, Zhuangzhuang Liu, Brenda Chyla, John F. Seymour
<p>Treatment approaches for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have evolved significantly in recent years with the incorporation of novel therapies including those targeting Bruton tyrosine kinase (BTK) downstream of B-cell receptor signaling as well as venetoclax, a potent inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL2) protein.<span><sup>1, 2</sup></span> However, despite these therapeutic advances improving outcomes versus chemoimmunotherapy,<span><sup>3, 4</sup></span> CLL remains incurable for most patients. Time-limited approaches with these targeted agents are attractive due to the potential for fewer adverse events, reduced patient burden, lower costs, and, theoretically, a reduced risk of selection for resistance mutations.<span><sup>5, 6</sup></span> As most patients with CLL/SLL will suffer disease relapse after their first treatment, the need remains for understanding effective strategies in the relapsed/refractory (R/R) setting, including options for retreatment that have the potential to extend the duration of benefit of a drug class used previously.</p><p>Venetoclax is approved in combination with obinutuzumab for treatment-naive CLL, and venetoclax is approved in R/R CLL as monotherapy or in combination with rituximab; treatment with venetoclax plus rituximab (VenR) for up to 2 years has demonstrated durable remissions in patients with R/R CLL/SLL that can be sustained off treatment.<span><sup>1, 2</sup></span> In addition to limited cost and toxicities, fixed-duration regimens are of interest given their potential to avoid the resistance that could compromise the effectiveness of later lines of treatment independent of the drug target. Patients with double BTK inhibitor (BTKi)/BCL2 inhibitor (BCL2i) exposures have no standardized approach to their disease management; survival in this group of patients is discouragingly short, and the subsequent duration of response to recently approved noncovalent BTKi is also shortened in this group of patients.<span><sup>7-9</sup></span> It remains an area of interest to understand strategies to extend disease control with the available agents.</p><p>The M13-365, a Phase 1b study examining the safety and outcomes of patients treated with VenR,<span><sup>10</sup></span> was the first prospective trial demonstrating that patients with CLL in deep response (complete response [CR] or undetectable minimal residual disease [uMRD]) could stop therapy with venetoclax and achieve similar outcomes to those with continuous therapy. An analysis of 5-year outcomes of patients with R/R CLL/SLL treated with VenR with fixed-duration or continuous venetoclax in this study revealed that 74% of patients who achieved a deep response maintained their response for 5 years or longer.<span><sup>10</sup></span> Retreatment with venetoclax is of increasing importance given the recurrent nature of CLL/SLL, and there is great interest in understanding that this option may extend the
{"title":"Retreatment with venetoclax and rituximab following disease progression while off therapy in patients with chronic lymphocytic leukemia","authors":"Danielle M. Brander, Andrew W. Roberts, Thomas J. Kipps, Shuo Ma, Mary Ann Anderson, Michelle Boyer, Piers Blombery, Relja Popovic, Jordan Roser, Zhuangzhuang Liu, Brenda Chyla, John F. Seymour","doi":"10.1002/hem3.70284","DOIUrl":"10.1002/hem3.70284","url":null,"abstract":"<p>Treatment approaches for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have evolved significantly in recent years with the incorporation of novel therapies including those targeting Bruton tyrosine kinase (BTK) downstream of B-cell receptor signaling as well as venetoclax, a potent inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL2) protein.<span><sup>1, 2</sup></span> However, despite these therapeutic advances improving outcomes versus chemoimmunotherapy,<span><sup>3, 4</sup></span> CLL remains incurable for most patients. Time-limited approaches with these targeted agents are attractive due to the potential for fewer adverse events, reduced patient burden, lower costs, and, theoretically, a reduced risk of selection for resistance mutations.<span><sup>5, 6</sup></span> As most patients with CLL/SLL will suffer disease relapse after their first treatment, the need remains for understanding effective strategies in the relapsed/refractory (R/R) setting, including options for retreatment that have the potential to extend the duration of benefit of a drug class used previously.</p><p>Venetoclax is approved in combination with obinutuzumab for treatment-naive CLL, and venetoclax is approved in R/R CLL as monotherapy or in combination with rituximab; treatment with venetoclax plus rituximab (VenR) for up to 2 years has demonstrated durable remissions in patients with R/R CLL/SLL that can be sustained off treatment.<span><sup>1, 2</sup></span> In addition to limited cost and toxicities, fixed-duration regimens are of interest given their potential to avoid the resistance that could compromise the effectiveness of later lines of treatment independent of the drug target. Patients with double BTK inhibitor (BTKi)/BCL2 inhibitor (BCL2i) exposures have no standardized approach to their disease management; survival in this group of patients is discouragingly short, and the subsequent duration of response to recently approved noncovalent BTKi is also shortened in this group of patients.<span><sup>7-9</sup></span> It remains an area of interest to understand strategies to extend disease control with the available agents.</p><p>The M13-365, a Phase 1b study examining the safety and outcomes of patients treated with VenR,<span><sup>10</sup></span> was the first prospective trial demonstrating that patients with CLL in deep response (complete response [CR] or undetectable minimal residual disease [uMRD]) could stop therapy with venetoclax and achieve similar outcomes to those with continuous therapy. An analysis of 5-year outcomes of patients with R/R CLL/SLL treated with VenR with fixed-duration or continuous venetoclax in this study revealed that 74% of patients who achieved a deep response maintained their response for 5 years or longer.<span><sup>10</sup></span> Retreatment with venetoclax is of increasing importance given the recurrent nature of CLL/SLL, and there is great interest in understanding that this option may extend the ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 12","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Estelle Balducci, Thomas Steimlé, Agata Cieslak, Guillaume Charbonnier, Antoine Pinton, Mathieu Simonin, Charlotte Smith, Valentine Louis, Mélanie Féroul, Manon Delafoy, Sophie Kaltenbach, Audrey Bidet, Béatrice Grange, Lauren Rigollet, Patrick Villarese, Aurore Touzart, Hervé Dombret, André Baruchel, Nicolas Boissel, Vahid Asnafi
The T-cell Leukemia Homeobox 1 (TLX1) oncogene is frequently deregulated in T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). In most instances, TLX1 overexpression results from its juxtaposition with a T-cell receptor (TCR) locus caused by interchromosomal translocations. However, in the subset of non-TCR-translocated TLX1-positive (non-TCR TLX1+) T-ALL cases, the underlying mechanisms driving TLX1 overexpression and their clinico-biological implications remain unclear. By integrating high-resolution data from next-generation sequencing, fluorescence in situ hybridization, karyotyping, optical genome mapping, and long-read whole-genome sequencing across a cohort of 1122 adult and pediatric T-ALL/T-LBL cases, we identified TLX1 overexpression in 11% of T-ALL/T-LBL cases, with an unexpected 14% incidence of non-TCR TLX1+ cases among TLX1+ cases. Non-TCR TLX1 + T-ALL cases show distinct clinico-biological features, including a lower frequency of cortical phenotype compared to the TCR-translocated TLX1+ (TCR TLX1+) subgroup, regardless of TLX1 expression levels. In non-TCR TLX1⁺ cases, TLX1 deregulation results mostly (83%) from the hijacking of the ANKRD1 and PCGF5 enhancer at 10q23.31 through various chromosomal aberrations. Genomic analyses revealed that these aberrations juxtapose the ANKRD1 and PCGF5 enhancer with TLX1, driving its overexpression. Importantly, survival analysis revealed that non-TCR TLX1+ patients had significantly poorer outcomes compared to their TCR TLX1⁺ counterparts (3y-OS: 55% vs. 90%, P < 0.001 and 3y-DFS: 45% vs. 75%, P = 0.02). These findings, consistent with our previous observations in TAL1-driven T-ALL, confirm that the clinico-biological impact of an oncogene is influenced by the specific mechanism underlying its deregulation.
{"title":"TLX1 translocation variants and enhancer hijacking influence clinical outcome in T-cell acute lymphoblastic leukemia","authors":"Estelle Balducci, Thomas Steimlé, Agata Cieslak, Guillaume Charbonnier, Antoine Pinton, Mathieu Simonin, Charlotte Smith, Valentine Louis, Mélanie Féroul, Manon Delafoy, Sophie Kaltenbach, Audrey Bidet, Béatrice Grange, Lauren Rigollet, Patrick Villarese, Aurore Touzart, Hervé Dombret, André Baruchel, Nicolas Boissel, Vahid Asnafi","doi":"10.1002/hem3.70281","DOIUrl":"10.1002/hem3.70281","url":null,"abstract":"<p>The T-cell Leukemia Homeobox 1 (<i>TLX1</i>) oncogene is frequently deregulated in T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). In most instances, <i>TLX1</i> overexpression results from its juxtaposition with a T-cell receptor (<i>TCR</i>) locus caused by interchromosomal translocations. However, in the subset of non-<i>TCR</i>-translocated <i>TLX1</i>-positive (non-<i>TCR TLX1</i>+) T-ALL cases, the underlying mechanisms driving <i>TLX1</i> overexpression and their clinico-biological implications remain unclear. By integrating high-resolution data from next-generation sequencing, fluorescence in situ hybridization, karyotyping, optical genome mapping, and long-read whole-genome sequencing across a cohort of 1122 adult and pediatric T-ALL/T-LBL cases, we identified <i>TLX1</i> overexpression in 11% of T-ALL/T-LBL cases, with an unexpected 14% incidence of non-<i>TCR TLX1</i>+ cases among <i>TLX1</i>+ cases. Non-<i>TCR TLX1</i> + T-ALL cases show distinct clinico-biological features, including a lower frequency of cortical phenotype compared to the <i>TCR</i>-translocated <i>TLX1</i>+ (<i>TCR TLX1</i>+) subgroup, regardless of <i>TLX1</i> expression levels. In non-<i>TCR TLX1</i>⁺ cases, <i>TLX1</i> deregulation results mostly (83%) from the hijacking of the <i>ANKRD1</i> and <i>PCGF5</i> enhancer at 10q23.31 through various chromosomal aberrations. Genomic analyses revealed that these aberrations juxtapose the <i>ANKRD1</i> and <i>PCGF5</i> enhancer with <i>TLX1</i>, driving its overexpression. Importantly, survival analysis revealed that non-<i>TCR TLX1</i>+ patients had significantly poorer outcomes compared to their <i>TCR TLX1</i>⁺ counterparts (3y-OS: 55% vs. 90%, <i>P</i> < 0.001 and 3y-DFS: 45% vs. 75%, <i>P</i> = 0.02). These findings, consistent with our previous observations in <i>TAL1</i>-driven T-ALL, confirm that the clinico-biological impact of an oncogene is influenced by the specific mechanism underlying its deregulation.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 12","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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