Paula de Melo Campos, Kátia Borgia Barbosa Pagnano, Fernanda Soares Niemann, Rubia Isler Mancuso, Fernanda Isabel Della Via, Ada Congrains, Juan Luiz Coelho-Silva, Ângela Condotta Tinoco, Guilherme Rossi Assis-Mendonça, Leandro Luiz Lopes de Freitas, Fabiola Traina, Sara T. Olalla Saad
Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by the activation of the JAK-STAT pathway. Previous evidence showed that metformin might be a possible therapeutic option for treating JAK2-mediated myeloproliferative neoplasms. In vitro and in vivo studies demonstrated that metformin inhibits the JAK-STAT pathway, induces apoptosis in JAK2V617F-positive cell lines and reduces tumor burden and splenomegaly in Jak2V617F knock-in-induced mice. The FIBROMET trial, an open label phase II study, evaluated metformin effects on 10 primary myelofibrosis patients over 2 years of treatment. Primary endpoint was bone marrow fibrosis reduction. Secondary endpoints were constitutional symptoms, blood counts, spleen size modulation and exploratory evaluation of protein and gene expression. Metformin treatment reduced bone marrow collagen deposits, downregulated the STAT pathway and reduced the p85 subunit of PI3K enzymatic complex, together with endothelial maintenance genes, in PMF patients. These results raise new evidence regarding metformin, a cheap and widely available drug, as a possible adjuvant for the treatment of PMF patients.
{"title":"Metformin Downregulates the STAT Pathway and Reduces Bone Marrow Fibrosis in Primary Myelofibrosis Patients: Final Results of the Phase II FIBROMET Trial","authors":"Paula de Melo Campos, Kátia Borgia Barbosa Pagnano, Fernanda Soares Niemann, Rubia Isler Mancuso, Fernanda Isabel Della Via, Ada Congrains, Juan Luiz Coelho-Silva, Ângela Condotta Tinoco, Guilherme Rossi Assis-Mendonça, Leandro Luiz Lopes de Freitas, Fabiola Traina, Sara T. Olalla Saad","doi":"10.1002/hon.70163","DOIUrl":"10.1002/hon.70163","url":null,"abstract":"<p>Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by the activation of the JAK-STAT pathway. Previous evidence showed that metformin might be a possible therapeutic option for treating JAK2-mediated myeloproliferative neoplasms. In vitro and in vivo studies demonstrated that metformin inhibits the JAK-STAT pathway, induces apoptosis in JAK2<sup>V617F</sup>-positive cell lines and reduces tumor burden and splenomegaly in Jak2<sup>V617F</sup> knock-in-induced mice. The FIBROMET trial, an open label phase II study, evaluated metformin effects on 10 primary myelofibrosis patients over 2 years of treatment. Primary endpoint was bone marrow fibrosis reduction. Secondary endpoints were constitutional symptoms, blood counts, spleen size modulation and exploratory evaluation of protein and gene expression. Metformin treatment reduced bone marrow collagen deposits, downregulated the STAT pathway and reduced the p85 subunit of PI3K enzymatic complex, together with endothelial maintenance genes, in PMF patients. These results raise new evidence regarding metformin, a cheap and widely available drug, as a possible adjuvant for the treatment of PMF patients.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"44 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12744688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The optimal second-line chemotherapy regimen for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remains uncertain. We retrospectively compared efficacy and safety between gemcitabine, carboplatin, dexamethasone, and rituximab (GCD-R) and cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, and rituximab (CHASER) as second-line treatments for R/R DLBCL. We evaluated 68 R/R DLBCL patients receiving either GCD-R (n = 42) or CHASER (n = 26) as second-line treatment between 2004 and 2020. The primary endpoint was the complete response rate (CRR). Secondary endpoints included overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events. CRR (43% vs. 42%; p = 1.00) and ORR (60% vs. 50%; p = 0.46) were comparable between GCD-R and CHASER groups. Median OS (GCD-R 18.6 months, CHASER 11.2 months; p = 0.93) and median PFS (GCD-R 10.0 months, CHASER 4.6 months; p = 0.47) showed no significant differences between groups. Further, among patients who subsequently underwent autologous stem cell transplantation, OS was also comparable between groups (p = 0.44). However, febrile neutropenia was significantly less frequent with GCD-R (33%) than with CHASER (92%; p < 0.001). As GCD-R predominantly uses peripheral intravenous catheters, whereas CHASER frequently requires central venous access, catheter management was significantly simpler with GCD-R (p < 0.001). GCD-R demonstrated equivalent efficacy to CHASER with significantly reduced toxicity and improved patient management, supporting its use as an effective and well-tolerated salvage therapy for R/R DLBCL. GCD-R represents a feasible treatment option not only for elderly patients, but also for patients eligible for subsequent stem cell transplantation.
{"title":"Gemcitabine, Carboplatin, Dexamethasone, and Rituximab Versus High-Dose Cytarabine-Based Chemotherapy as Second-Line Treatments for Relapsed or Refractory Diffuse Large B-Cell Lymphoma","authors":"Yoshikazu Ikoma, Nobuhiko Nakamura, Junichi Kitagawa, Naoki Hayase, Eri Takada, Takuro Matsumoto, Yuhei Shibata, Hiroshi Nakamura, Kei Fujita, Shin Lee, Tetsuji Morishita, Nobuhiro Kanemura, Senji Kasahara, Hideko Goto, Kenji Fukuno, Takeshi Hara, Michio Sawada, Hisashi Tsurumi, Masahito Shimizu","doi":"10.1002/hon.70164","DOIUrl":"10.1002/hon.70164","url":null,"abstract":"<div>\u0000 \u0000 <p>The optimal second-line chemotherapy regimen for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remains uncertain. We retrospectively compared efficacy and safety between gemcitabine, carboplatin, dexamethasone, and rituximab (GCD-R) and cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, and rituximab (CHASER) as second-line treatments for R/R DLBCL. We evaluated 68 R/R DLBCL patients receiving either GCD-R (<i>n</i> = 42) or CHASER (<i>n</i> = 26) as second-line treatment between 2004 and 2020. The primary endpoint was the complete response rate (CRR). Secondary endpoints included overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events. CRR (43% vs. 42%; <i>p</i> = 1.00) and ORR (60% vs. 50%; <i>p</i> = 0.46) were comparable between GCD-R and CHASER groups. Median OS (GCD-R 18.6 months, CHASER 11.2 months; <i>p</i> = 0.93) and median PFS (GCD-R 10.0 months, CHASER 4.6 months; <i>p</i> = 0.47) showed no significant differences between groups. Further, among patients who subsequently underwent autologous stem cell transplantation, OS was also comparable between groups (<i>p</i> = 0.44). However, febrile neutropenia was significantly less frequent with GCD-R (33%) than with CHASER (92%; <i>p</i> < 0.001). As GCD-R predominantly uses peripheral intravenous catheters, whereas CHASER frequently requires central venous access, catheter management was significantly simpler with GCD-R (<i>p</i> < 0.001). GCD-R demonstrated equivalent efficacy to CHASER with significantly reduced toxicity and improved patient management, supporting its use as an effective and well-tolerated salvage therapy for R/R DLBCL. GCD-R represents a feasible treatment option not only for elderly patients, but also for patients eligible for subsequent stem cell transplantation.</p>\u0000 </div>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"44 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Conditioning regimens are critical for patients with relapsed/refractory (R/R) malignant hematologic diseases. Thiotepa, an alkylating agent with excellent cytotoxicity and blood‒brain barrier permeability, has been widely used in conditioning regimens for lymphoma and has recently been used in patients with acute leukemia with central nervous system involvement. The aim of this retrospective study was to observe the efficacy and safety of a conditioning regimen comprising thiotepa, busulfan, and cyclophosphamide (TBC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with R/R hematologic diseases. Between July 2022 and December 2023, 27 patients were selected. With a median follow-up of 609 (243–954) days, the 1-year and estimated 2-year overall survival (OS) rates were 85.2% ± 6.8% and 76.5% ± 8.5%, respectively. The 1-year and estimated 2-year disease-free survival (DFS) rates were 81.5% ± 7.5% and 62.8% ± 12.2%, respectively. Six patients experienced relapse, and the 1-year and estimated 2-year cumulative incidence of relapse (CIR) rates were 14.8% ± 6.8% and 31.0% ± 12.6%, respectively. Two patients died from graft-versus-host disease (GVHD) or infection. The 1-year and estimated 2-year nonrelapse mortality (NRM) rates were 4.2% ± 4.1% and 8.5% ± 5.8%, respectively. 14 (51.9%) patients received maintenance therapy after allo-HSCT. Regimen-related toxicities were mostly well tolerated. Multivariate analysis revealed that failure to achieve first complete remission (CR1) before HSCT and previous treatment with CAR-T cell were predictors of poor DFS. This study suggests that the TBC conditioning regimen may be a promising option for patients with R/R hematologic diseases undergoing allo-HSCT.
{"title":"Thiotepa and Busulfan Combined With Cyclophosphamide Conditioning Regimen Plus Maintenance Therapy Improved the Disease-Free Survival of Patients With Relapsed/Refractory Hematologic Malignancies After Undergoing Allogeneic Transplantation","authors":"Shulian Chen, Rui Cui, Yi He, Qiaoling Ma, Rongli Zhang, Xin Chen, Wenbin Cao, Jialin Wei, Donglin Yang, Aiming Pang, Sizhou Feng, Mingzhe Han, Weihua Zhai, Erlie Jiang","doi":"10.1002/hon.70138","DOIUrl":"10.1002/hon.70138","url":null,"abstract":"<div>\u0000 \u0000 <p>Conditioning regimens are critical for patients with relapsed/refractory (R/R) malignant hematologic diseases. Thiotepa, an alkylating agent with excellent cytotoxicity and blood‒brain barrier permeability, has been widely used in conditioning regimens for lymphoma and has recently been used in patients with acute leukemia with central nervous system involvement. The aim of this retrospective study was to observe the efficacy and safety of a conditioning regimen comprising thiotepa, busulfan, and cyclophosphamide (TBC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with R/R hematologic diseases. Between July 2022 and December 2023, 27 patients were selected. With a median follow-up of 609 (243–954) days, the 1-year and estimated 2-year overall survival (OS) rates were 85.2% ± 6.8% and 76.5% ± 8.5%, respectively. The 1-year and estimated 2-year disease-free survival (DFS) rates were 81.5% ± 7.5% and 62.8% ± 12.2%, respectively. Six patients experienced relapse, and the 1-year and estimated 2-year cumulative incidence of relapse (CIR) rates were 14.8% ± 6.8% and 31.0% ± 12.6%, respectively. Two patients died from graft-versus-host disease (GVHD) or infection. The 1-year and estimated 2-year nonrelapse mortality (NRM) rates were 4.2% ± 4.1% and 8.5% ± 5.8%, respectively. 14 (51.9%) patients received maintenance therapy after allo-HSCT. Regimen-related toxicities were mostly well tolerated. Multivariate analysis revealed that failure to achieve first complete remission (CR1) before HSCT and previous treatment with CAR-T cell were predictors of poor DFS. This study suggests that the TBC conditioning regimen may be a promising option for patients with R/R hematologic diseases undergoing allo-HSCT.</p>\u0000 </div>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"44 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pier Luigi Zinzani, Giulia Dell’Omo, Letizia Fusco, Ilaria Peduto, Carlotta Galeone, Federica Cavallo, Giuseppe Gritti
<p>Compassionate Use Programs (CUP) offers patients with severe diseases, early access to promising new drugs outside of clinical trial and prior to marketing approval. Data arising from CUP provides valuable insights on treatment pathways. In the last few years, the treatment landscape for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) has rapidly evolved based on the approval of several novel therapies, resulting in changing treatment patterns which benefit from assessment of modern retrospective data.</p><p>To address this, we retrospectively evaluated data of two large patient cohorts of r/r DLBCL within the polatuzumab vedotin and glofitamab Roche Global CUP opened in Italy [<span>1</span>], as was done in similar studies from other European countries [<span>2, 3</span>]. In fact, this analysis did not evaluate the effectiveness of the two products, that has been recently reported for polatuzumab vedotin [<span>4</span>].</p><p>The polatuzumab vedotin-rituximab +/− bendamustine CUP cohort included r/r DLBCL patients after at least 2 lines of treatment; with 208 patient requests received from 92 national centers between May 2019 and April 2020. The glofitamab CUP cohort included patients with r/r DLBCL, high-grade B-cell lymphoma (HGBCL) or primary mediastinal B cell lymphoma (PMBCL) after at least 3 lines of previous treatments; with 145 patient requests received from 59 national centers between March 2022 and April 2024. Cohort characteristics were compared using the Chi-square or Fisher's exact test for categorical data, and the Wilcoxon rank-sum test for continuous data.</p><p>Clinical characteristics of the patient population are summarized in Table 1. Both cohorts showed a prevalence of males. The median age (minimum-maximum range) at diagnosis was higher in the polatuzumab vedotin-rituximab +/− bendamustine cohort (63 years; range: 24–84 years) compared to the glofitamab cohort (60 years; range: 17–82 years, <i>p</i>-value = 0.002). Similarly, the median age at CUP request was higher in the polatuzumab vedotin-rituximab +/− bendamustine (67 years; range: 25–85 years) than in the glofitamab cohort (62 years; range: 19–85 years, <i>p</i>-value < 0.001). The median duration from diagnosis to CUP request was comparable in the two cohorts (median 2 years, range 0–22). In the polatuzumab vedotin cohort, 78% patients were previously treated with 2 (49%) or 3 (29%) lines of treatment, whereas the glofitamab cohort had 79% of patients previously treated with 3 (34%) or 4 (45%) lines of treatment (<i>p</i>-value = 0.004).</p><p>Treatment courses experienced by patients across the two cohorts are depicted in Figure 1. In the polatuzumab vedotin-rituximab +/− bendamustine cohort (Figure 1A), the most frequent frontline regimen was R-CHOP (66%), followed by R-CHOP like (e.g., R-COMP, R-COMP + rituximab, R-BENDA, etc; 23%) and by R-CHOP dose-dense chemotherapy (e.g., DA-EPOCH-R, MACOP-B, etc; 10%). The corresponding distribution
{"title":"Polatuzumab Vedotin and Glofitamab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in the Compassionate Use Program in Italy","authors":"Pier Luigi Zinzani, Giulia Dell’Omo, Letizia Fusco, Ilaria Peduto, Carlotta Galeone, Federica Cavallo, Giuseppe Gritti","doi":"10.1002/hon.70161","DOIUrl":"10.1002/hon.70161","url":null,"abstract":"<p>Compassionate Use Programs (CUP) offers patients with severe diseases, early access to promising new drugs outside of clinical trial and prior to marketing approval. Data arising from CUP provides valuable insights on treatment pathways. In the last few years, the treatment landscape for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) has rapidly evolved based on the approval of several novel therapies, resulting in changing treatment patterns which benefit from assessment of modern retrospective data.</p><p>To address this, we retrospectively evaluated data of two large patient cohorts of r/r DLBCL within the polatuzumab vedotin and glofitamab Roche Global CUP opened in Italy [<span>1</span>], as was done in similar studies from other European countries [<span>2, 3</span>]. In fact, this analysis did not evaluate the effectiveness of the two products, that has been recently reported for polatuzumab vedotin [<span>4</span>].</p><p>The polatuzumab vedotin-rituximab +/− bendamustine CUP cohort included r/r DLBCL patients after at least 2 lines of treatment; with 208 patient requests received from 92 national centers between May 2019 and April 2020. The glofitamab CUP cohort included patients with r/r DLBCL, high-grade B-cell lymphoma (HGBCL) or primary mediastinal B cell lymphoma (PMBCL) after at least 3 lines of previous treatments; with 145 patient requests received from 59 national centers between March 2022 and April 2024. Cohort characteristics were compared using the Chi-square or Fisher's exact test for categorical data, and the Wilcoxon rank-sum test for continuous data.</p><p>Clinical characteristics of the patient population are summarized in Table 1. Both cohorts showed a prevalence of males. The median age (minimum-maximum range) at diagnosis was higher in the polatuzumab vedotin-rituximab +/− bendamustine cohort (63 years; range: 24–84 years) compared to the glofitamab cohort (60 years; range: 17–82 years, <i>p</i>-value = 0.002). Similarly, the median age at CUP request was higher in the polatuzumab vedotin-rituximab +/− bendamustine (67 years; range: 25–85 years) than in the glofitamab cohort (62 years; range: 19–85 years, <i>p</i>-value < 0.001). The median duration from diagnosis to CUP request was comparable in the two cohorts (median 2 years, range 0–22). In the polatuzumab vedotin cohort, 78% patients were previously treated with 2 (49%) or 3 (29%) lines of treatment, whereas the glofitamab cohort had 79% of patients previously treated with 3 (34%) or 4 (45%) lines of treatment (<i>p</i>-value = 0.004).</p><p>Treatment courses experienced by patients across the two cohorts are depicted in Figure 1. In the polatuzumab vedotin-rituximab +/− bendamustine cohort (Figure 1A), the most frequent frontline regimen was R-CHOP (66%), followed by R-CHOP like (e.g., R-COMP, R-COMP + rituximab, R-BENDA, etc; 23%) and by R-CHOP dose-dense chemotherapy (e.g., DA-EPOCH-R, MACOP-B, etc; 10%). The corresponding distribution ","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"44 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12703129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pinto, Antonio, Carmelo Carlo-Stella, Monia Marchetti, et al. 2025. “Defining and Addressing the Current Unmet Medical Needs for the Frontline Treatment of Advanced Stage Aggressive Large B-Cell Lymphoma: A Perspective From an Ad Hoc Panel of Italian Experts,” Hematological Oncology 43: e70152. https://doi.org/10.1002/hon.70152.
In the article, there were errors in the author byline and Figure 3.
In the author byline, the author name “Marco Laddetto” was incorrect and should be “Marco Ladetto”.
Figure 3 was not the final version and should have been updated with the new figure as shown below.
{"title":"Correction to “Defining and Addressing the Current Unmet Medical Needs for the Frontline Treatment of Advanced Stage Aggressive Large B-Cell Lymphoma: A Perspective From an Ad Hoc Panel of Italian Experts”","authors":"","doi":"10.1002/hon.70158","DOIUrl":"10.1002/hon.70158","url":null,"abstract":"<p>Pinto, Antonio, Carmelo Carlo-Stella, Monia Marchetti, et al. 2025. “Defining and Addressing the Current Unmet Medical Needs for the Frontline Treatment of Advanced Stage Aggressive Large B-Cell Lymphoma: A Perspective From an Ad Hoc Panel of Italian Experts,” <i>Hematological Oncology</i> 43: e70152. https://doi.org/10.1002/hon.70152.</p><p>In the article, there were errors in the author byline and Figure 3.</p><p>In the author byline, the author name “Marco Laddetto” was incorrect and should be “Marco Ladetto”.</p><p>Figure 3 was not the final version and should have been updated with the new figure as shown below.</p><p>We apologize for these errors.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"44 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Livia Donzelli, Veronica Zullino, Giovanni Fernando Torelli, Maria Stefania De Propris, Mario Piazzolla, Franco Ruberto, Maurizio Martelli, Alice Di Rocco
Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized the treatment of hematological malignancies, achieving high response rates in patients with relapsed or refractory disease. Despite these benefits, CAR-T cell therapies are associated with unique toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune cell-associated hematotoxicity (ICAHT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which is characterized by a rare and life-threatening hyperinflammatory response. This paper presents a case of a 56-year-old woman with relapsed mantle cell lymphoma (MCL) treated with the CAR-T cell therapy, brexucabtagene autoleucel, who had subsequently developed CRS and later IEC-HS. Initial management included tocilizumab, corticosteroids, and anakinra, followed by the compassionate use of emapalumab, an interferon-γ blocker. To provide broader context, we conducted a literature review of CAR-T cell-related toxicities, focusing on IEC-HS and its management with emapalumab. Clinical and laboratory manifestations, such as elevated ferritin levels, cytopenias, and organ dysfunction, underpin the diagnostic criteria for IEC-HS. Vigilant monitoring and tailored therapeutic approaches are required to effectively manage toxicities associated with CAR-T cell therapy, to maximize its benefits and minimize adverse effects. In more severe IEC-HS cases, emapalumab may be used as an effective targeted therapy.
{"title":"Managing Treatment-Emergent Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome Following CAR-T Cell Therapy: A Case-Based Review of the use of Emapalumab","authors":"Livia Donzelli, Veronica Zullino, Giovanni Fernando Torelli, Maria Stefania De Propris, Mario Piazzolla, Franco Ruberto, Maurizio Martelli, Alice Di Rocco","doi":"10.1002/hon.70157","DOIUrl":"https://doi.org/10.1002/hon.70157","url":null,"abstract":"<p>Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized the treatment of hematological malignancies, achieving high response rates in patients with relapsed or refractory disease. Despite these benefits, CAR-T cell therapies are associated with unique toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune cell-associated hematotoxicity (ICAHT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which is characterized by a rare and life-threatening hyperinflammatory response. This paper presents a case of a 56-year-old woman with relapsed mantle cell lymphoma (MCL) treated with the CAR-T cell therapy, brexucabtagene autoleucel, who had subsequently developed CRS and later IEC-HS. Initial management included tocilizumab, corticosteroids, and anakinra, followed by the compassionate use of emapalumab, an interferon-γ blocker. To provide broader context, we conducted a literature review of CAR-T cell-related toxicities, focusing on IEC-HS and its management with emapalumab. Clinical and laboratory manifestations, such as elevated ferritin levels, cytopenias, and organ dysfunction, underpin the diagnostic criteria for IEC-HS. Vigilant monitoring and tailored therapeutic approaches are required to effectively manage toxicities associated with CAR-T cell therapy, to maximize its benefits and minimize adverse effects. In more severe IEC-HS cases, emapalumab may be used as an effective targeted therapy.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"44 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Delia, D. Lazzarotto, S. Imbergamo, F. Mosna, C. Papayannidis, C. Pasciolla, A. Mulè, N. Fracchiolla, M. Leoncin, M. I. Del Principe, M. Fumagalli, M. Olivi, F. Guolo, M. Lunghi, M. De Gobbi, F. Lussana, L. Santoro, L. Aprile, P. Zappasodi, M. Ciccone, F. Giglio, V. P. Gagliardi, M. Dargenio, A. Curti, M. Bonifacio, S. Chiaretti, P. Musto, R. Foà, A. Candoni
The introduction of pediatric-inspired chemotherapy protocols for acute lymphoblastic leukemia (ALL) in the setting of adult patients affected by lymphoblastic lymphoma (LL) has improved the results in terms of outcomes. Within the Campus ALL network, we retrospectively collected data on 50 LL-patients from 23 hematology centers in Italy treated according to the GIMEMA LAL1913 protocol, with the aim of confirming the ALL results and of testing the effectiveness of an approach based on higher cumulative doses of the non-myelosuppressive components such as steroids and pegylated asparaginase, in addition to earlier and more intensive central nervous system prophylaxis. After cycle 3 (high dose methotrexate and cytarabine, C3), the cumulative incidence (CI) of PET-based complete response (CR) was of 83% (median time to response from protocol start: 3.7 months; CI95%: 3.1–4.2). With a median follow-up of 27.5 months, the 2-year overall survival (OS), disease free survival (DFS) ed event free survival rates were of 77%, 76% and 69%, respectively. The 2-year CI of relapse was of 26%. Multivariable analysis identified ECOG ≥ 2 as an independent prognostic factor for OS (HR = 3.279; CI95% 1.035–10.389, p = 0.044) and DFS (HR = 13.00, ICI95%: 3.383–57.909, p < 0.001), respectively. No significant impact was observed for pegylated asparaginase dose (reduced and/or omitted versus (vs.) full doses), age (≥ 55 vs. < 55), stage (0–I vs. II–IV), CD1a (negativity vs. other than CD1a negativity), bone marrow involvement (absent vs. ≤ 20%), or allotransplantation. The results of this study show the appropriateness of the LAL1913 protocol for the management of LL patients. Survival outcomes reflect those expected, although this drug combination was never tested before in a real-life setting. Taken together, these results suggest that LAL1913 might be considered as a reference protocol for the frontline treatment of adult LL patients.
{"title":"Outcome of Adult Lymphoblastic Lymphoma Patients Treated in the Real Life According to the Gimema LAL1913 Protocol: A Campus ALL Multicenter Study","authors":"M. Delia, D. Lazzarotto, S. Imbergamo, F. Mosna, C. Papayannidis, C. Pasciolla, A. Mulè, N. Fracchiolla, M. Leoncin, M. I. Del Principe, M. Fumagalli, M. Olivi, F. Guolo, M. Lunghi, M. De Gobbi, F. Lussana, L. Santoro, L. Aprile, P. Zappasodi, M. Ciccone, F. Giglio, V. P. Gagliardi, M. Dargenio, A. Curti, M. Bonifacio, S. Chiaretti, P. Musto, R. Foà, A. Candoni","doi":"10.1002/hon.70153","DOIUrl":"10.1002/hon.70153","url":null,"abstract":"<div>\u0000 \u0000 <p>The introduction of pediatric-inspired chemotherapy protocols for acute lymphoblastic leukemia (ALL) in the setting of adult patients affected by lymphoblastic lymphoma (LL) has improved the results in terms of outcomes. Within the Campus ALL network, we retrospectively collected data on 50 LL-patients from 23 hematology centers in Italy treated according to the GIMEMA LAL1913 protocol, with the aim of confirming the ALL results and of testing the effectiveness of an approach based on higher cumulative doses of the non-myelosuppressive components such as steroids and pegylated asparaginase, in addition to earlier and more intensive central nervous system prophylaxis. After cycle 3 (high dose methotrexate and cytarabine, C3), the cumulative incidence (CI) of PET-based complete response (CR) was of 83% (median time to response from protocol start: 3.7 months; CI95%: 3.1–4.2). With a median follow-up of 27.5 months, the 2-year overall survival (OS), disease free survival (DFS) ed event free survival rates were of 77%, 76% and 69%, respectively. The 2-year CI of relapse was of 26%. Multivariable analysis identified ECOG ≥ 2 as an independent prognostic factor for OS (HR = 3.279; CI95% 1.035–10.389, <i>p</i> = 0.044) and DFS (HR = 13.00, ICI95%: 3.383–57.909, <i>p</i> < 0.001), respectively. No significant impact was observed for pegylated asparaginase dose (reduced and/or omitted versus (vs.) full doses), age (≥ 55 vs. < 55), stage (0–I vs. II–IV), CD1a (negativity vs. other than CD1a negativity), bone marrow involvement (absent vs. ≤ 20%), or allotransplantation. The results of this study show the appropriateness of the LAL1913 protocol for the management of LL patients. Survival outcomes reflect those expected, although this drug combination was never tested before in a real-life setting. Taken together, these results suggest that LAL1913 might be considered as a reference protocol for the frontline treatment of adult LL patients.</p>\u0000 </div>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145503564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Testing to discontinue imatinib already started some years after the advent of this new CML therapy. Since that time, despite many trials and studies in this field, there are still significant gaps, and many fundamental questions remain unanswered. Probably the most intriguing is the persistence of minimal residual disease, which does not lead to disease recurrence in all patients. Nevertheless, today's understanding enables TKI to be safely discontinued in eligible patients outside clinical trials. Notwithstanding, TKI cessation still has to be considered and indicated with caution, taking into account several important viewpoints, like: (i) why stop the therapy in a particular patient, and are all the eligible patients willing to cease the treatment? (ii) Will all the TKI-related side effects relieve upon stopping? (iii) are there any side effects after discontinuing treatment? This review covers extensively all aspects of treatment cessation, like history, theoretical background, eligible patients, monitoring after treatment discontinuation, trigger for retreatment, therapy restart, predictive factors for successful therapy cessation, immunological aspects, potential complications of TKI withdrawal, late molecular relapses, blast crisis development, kinetics of preexisting TKI-related side effects and laboratory values, and quality of life upon treatment cessation. The art of treatment cessation is to select the best candidate based on many diverse facts and information, and follow the patient in the most rational way with smartly anticipating the potential risks and side effects.
{"title":"Treatment Cessation in Chronic Myeloid Leukemia: Evidence and Uncertainties","authors":"Jiří Mayer","doi":"10.1002/hon.70155","DOIUrl":"10.1002/hon.70155","url":null,"abstract":"<p>Testing to discontinue imatinib already started some years after the advent of this new CML therapy. Since that time, despite many trials and studies in this field, there are still significant gaps, and many fundamental questions remain unanswered. Probably the most intriguing is the persistence of minimal residual disease, which does not lead to disease recurrence in all patients. Nevertheless, today's understanding enables TKI to be safely discontinued in eligible patients outside clinical trials. Notwithstanding, TKI cessation still has to be considered and indicated with caution, taking into account several important viewpoints, like: (i) why stop the therapy in a particular patient, and are all the eligible patients willing to cease the treatment? (ii) Will all the TKI-related side effects relieve upon stopping? (iii) are there any side effects after discontinuing treatment? This review covers extensively all aspects of treatment cessation, like history, theoretical background, eligible patients, monitoring after treatment discontinuation, trigger for retreatment, therapy restart, predictive factors for successful therapy cessation, immunological aspects, potential complications of TKI withdrawal, late molecular relapses, blast crisis development, kinetics of preexisting TKI-related side effects and laboratory values, and quality of life upon treatment cessation. The art of treatment cessation is to select the best candidate based on many diverse facts and information, and follow the patient in the most rational way with smartly anticipating the potential risks and side effects.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145503500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Suzanne I. M. Neppelenbroek, Afke Ekels, Marie José Kersten, Djamila E. Issa, Noortje Thielen, Lonneke V. van de Poll-Franse, Simone Oerlemans
We investigated the course of fatigue, neuropathy, psychological distress and their impact on HRQoL among diffuse large B-Cell Lymphoma (DLBCL) survivors up to 13 years after diagnosis, and compared it to an age- and sex-matched population. DLBCL survivors diagnosed between 2004 and 2011, who survived ≥ 1 year were selected from the Netherlands Cancer Registry. Survivors completed annual questionnaires 2009–2019, including EORTC QLQ-C30, EORTC CLL-17 and the Hospital Anxiety and Depression Scale. Linear mixed models were used to assess symptom trends and HRQoL associations over time. 302 survivors (response rate 84%) completed a median of three questionnaires. Fatigue improved slightly over time but neuropathy and psychological distress remained unchanged; persistent symptoms were reported by 25%, 28%, and 23% of survivors, respectively. Having two or more comorbidities was associated with higher symptom levels (βfatigue = 7.8, p-value < 0.001; βneuropathy = 6.7, p-value = 0.003; βpsychological distress = 2.2, p-value < 0.001). Having received seven to eight cycles of (R-)CHOP14 was associated with higher neuropathy levels (β = 14.5, p < 0.001) and non-(R-)CHOP treatments were associated to high fatigue levels (β = 14.0, p-value = 0.02) and psychological distress (β = 4.3, p-value = 0.01). Higher symptom levels were associated with poorer HRQoL. One in four DLBCL survivors reported persistent fatigue, neuropathy or psychological distress, negatively impacting their HRQoL. Routine symptom monitoring is essential to identify needs and guide supportive care referrals.
{"title":"Fatigue, Neuropathy and Psychological Distress and Their Association With Health-Related Quality of Life in Survivors of Diffuse Large B-Cell Lymphoma: A Prospective Cohort Study and Comparison With a Normative Population","authors":"Suzanne I. M. Neppelenbroek, Afke Ekels, Marie José Kersten, Djamila E. Issa, Noortje Thielen, Lonneke V. van de Poll-Franse, Simone Oerlemans","doi":"10.1002/hon.70151","DOIUrl":"https://doi.org/10.1002/hon.70151","url":null,"abstract":"<div>\u0000 \u0000 <p>We investigated the course of fatigue, neuropathy, psychological distress and their impact on HRQoL among diffuse large B-Cell Lymphoma (DLBCL) survivors up to 13 years after diagnosis, and compared it to an age- and sex-matched population. DLBCL survivors diagnosed between 2004 and 2011, who survived ≥ 1 year were selected from the Netherlands Cancer Registry. Survivors completed annual questionnaires 2009–2019, including EORTC QLQ-C30, EORTC CLL-17 and the Hospital Anxiety and Depression Scale. Linear mixed models were used to assess symptom trends and HRQoL associations over time. 302 survivors (response rate 84%) completed a median of three questionnaires. Fatigue improved slightly over time but neuropathy and psychological distress remained unchanged; persistent symptoms were reported by 25%, 28%, and 23% of survivors, respectively. Having two or more comorbidities was associated with higher symptom levels (β<sub>fatigue</sub> = 7.8, <i>p</i>-value < 0.001; β<sub>neuropathy</sub> = 6.7, <i>p</i>-value = 0.003; <i>β</i><sub>psychological distress</sub> = 2.2, <i>p</i>-value < 0.001). Having received seven to eight cycles of (R-)CHOP14 was associated with higher neuropathy levels (<i>β</i> = 14.5, <i>p</i> < 0.001) and non-(R-)CHOP treatments were associated to high fatigue levels (<i>β</i> = 14.0, <i>p</i>-value = 0.02) and psychological distress (<i>β</i> = 4.3, <i>p</i>-value = 0.01). Higher symptom levels were associated with poorer HRQoL. One in four DLBCL survivors reported persistent fatigue, neuropathy or psychological distress, negatively impacting their HRQoL. Routine symptom monitoring is essential to identify needs and guide supportive care referrals.</p>\u0000 </div>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xue Yang, Pu Wang, Tianhong Xu, Chenqi Yu, Yang Yang, Peng Liu
Despite the survival benefit observed in recent decades, early mortality (EM) remains critical in newly diagnosed multiple myeloma (NDMM) patients, with heterogeneous definitions and risk factors across studies. Besides, prognostic models for predicting EM are limited, especially in real-world scenarios. This single-center retrospective study performed comprehensive analyses as well as risk prediction models of 1093 NDMM patients diagnosed between 2007 and 2021 in China, finding the EM rate was 5.9% at 2 months, 8.8% at 6 months and 13.3% at 12 months. Infection and cardiac events were documented as the top two most common causes of early death. Risk factors that were independent predictors of both EM and OS mainly included cardiac amyloidosis, stroke, del (17p) and poor performance status. ISS stage, platelet count, treatment regimen and concomitant cardiac disease influenced OS rather than EM. Multivariate model-based nomograms were constructed to estimate 2-month, 6-month, 12-month mortality, plus OS, enabling individualized outcome prediction, validated via receiver operating characteristic (ROC) and calibration curves. EM is associated with multiple factors in MM patients, and early identification of patients with higher risk of EM may translate into tailored management in clinical practice.
{"title":"Real-World Data Analysis on Early Mortality in Chinese Multiple Myeloma Patients: Analysis of 1093 Patients During a 15-Year Period","authors":"Xue Yang, Pu Wang, Tianhong Xu, Chenqi Yu, Yang Yang, Peng Liu","doi":"10.1002/hon.70156","DOIUrl":"https://doi.org/10.1002/hon.70156","url":null,"abstract":"<div>\u0000 \u0000 <p>Despite the survival benefit observed in recent decades, early mortality (EM) remains critical in newly diagnosed multiple myeloma (NDMM) patients, with heterogeneous definitions and risk factors across studies. Besides, prognostic models for predicting EM are limited, especially in real-world scenarios. This single-center retrospective study performed comprehensive analyses as well as risk prediction models of 1093 NDMM patients diagnosed between 2007 and 2021 in China, finding the EM rate was 5.9% at 2 months, 8.8% at 6 months and 13.3% at 12 months. Infection and cardiac events were documented as the top two most common causes of early death. Risk factors that were independent predictors of both EM and OS mainly included cardiac amyloidosis, stroke, del (17p) and poor performance status. ISS stage, platelet count, treatment regimen and concomitant cardiac disease influenced OS rather than EM. Multivariate model-based nomograms were constructed to estimate 2-month, 6-month, 12-month mortality, plus OS, enabling individualized outcome prediction, validated via receiver operating characteristic (ROC) and calibration curves. EM is associated with multiple factors in MM patients, and early identification of patients with higher risk of EM may translate into tailored management in clinical practice.</p>\u0000 </div>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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