Pub Date : 2025-09-14DOI: 10.1016/s2352-3026(25)00228-5
Eric Tse,Christiane Querfeld,Kenji Ishitsuka,Yok-Lam Kwong
Mature T-cell and natural killer-cell neoplasms are a heterogenous group of uncommon lymphomas. Conventional therapy with mainly cytotoxic chemotherapy for this subgroup is suboptimal, and the treatment outcome is unsatisfactory. With the advances in the understanding of disease biology, considerable progress has been made in recent years. Monoclonal antibodies or antibody-drug conjugates targeting T-cell lymphoma surface antigens have been approved, including brentuximab vedotin, for the treatment of CD30-positive nodal and cutaneous T-cell lymphoma, and mogamulizumab, for mycosis fungoides and adult T-cell leukaemia/lymphoma. Furthermore, immune checkpoint blockade has also shown promise in the management of mycosis fungoides and extranodal natural killer/T-cell lymphoma. Epigenetic dysregulation is frequently found in mature T-cell and natural killer-cell lymphomas; hence, therapeutic agents acting on epigenetic regulators, such as histone deacetylase inhibitors, have been tested in clinical trials with promising results. Novel approaches including cell therapy and adoptive immunotherapy are currently being evaluated. In this Series paper, we discuss the limitations of the conventional treatment options and the use of these novel approaches for mature T-cell and natural killer-cell lymphomas.
{"title":"Emerging therapeutic strategies for mature T-cell and natural killer-cell lymphomas.","authors":"Eric Tse,Christiane Querfeld,Kenji Ishitsuka,Yok-Lam Kwong","doi":"10.1016/s2352-3026(25)00228-5","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00228-5","url":null,"abstract":"Mature T-cell and natural killer-cell neoplasms are a heterogenous group of uncommon lymphomas. Conventional therapy with mainly cytotoxic chemotherapy for this subgroup is suboptimal, and the treatment outcome is unsatisfactory. With the advances in the understanding of disease biology, considerable progress has been made in recent years. Monoclonal antibodies or antibody-drug conjugates targeting T-cell lymphoma surface antigens have been approved, including brentuximab vedotin, for the treatment of CD30-positive nodal and cutaneous T-cell lymphoma, and mogamulizumab, for mycosis fungoides and adult T-cell leukaemia/lymphoma. Furthermore, immune checkpoint blockade has also shown promise in the management of mycosis fungoides and extranodal natural killer/T-cell lymphoma. Epigenetic dysregulation is frequently found in mature T-cell and natural killer-cell lymphomas; hence, therapeutic agents acting on epigenetic regulators, such as histone deacetylase inhibitors, have been tested in clinical trials with promising results. Novel approaches including cell therapy and adoptive immunotherapy are currently being evaluated. In this Series paper, we discuss the limitations of the conventional treatment options and the use of these novel approaches for mature T-cell and natural killer-cell lymphomas.","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDThe combination of a hypomethylating agent with donor lymphocyte infusion as maintenance therapy after haematopoietic stem-cell transplantation (HSCT) in acute myeloid leukaemia and myelodysplastic syndrome might reduce the risk of relapse. We aimed to evaluate the activity and safety of oral decitabine and cedazuridine (ASTX727) as maintenance after allogeneic HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse post-transplantation.METHODSWe conducted a multicentre, single-arm, phase 2 study (GFM-DACORAL-DLI) at 12 centres in France. We enrolled patients aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0-2, without contraindication for HSCT, and with very high-risk disease (poor or very poor prognosis according to the revised International Prognostic Scoring System for myelodysplastic syndrome, adverse risk according to the 2017 European LeukemiaNet classification for acute myeloid leukaemia; unfavourable genetics; and acute myeloid leukaemia post-myelodysplastic syndrome or post-myeloproliferative neoplasm, or relapsing less than 2 years after complete response). Patients were included 5-45 days before transplantation. ASTX727 was orally administered at escalating doses (100 mg cedazuridine plus 35 mg decitabine starting at 1 day per cycle and increasing to 3 days) from day 40 post-HSCT, up to ten cycles. Donor lymphocyte infusion was recommended when patients had no contraindication after cycle 4. The primary endpoint was disease-free survival at 1 year after HSCT, assessed in the first 28 enrolled patients treated with ASTX7277. Safety was assessed in all participants who received at least one course of ASTX727. This study was registered with ClinicalTrials.gov (NCT04857645); enrolment is complete but follow-up is ongoing.FINDINGSBetween Sept 28, 2021, and March 1, 2023, 59 patients were screened and 51 patients underwent allogeneic HSCT (median age 62·0 years [IQR 56·5-65·0]; 22 [43%] female, 29 [57%] male). 34 patients received maintenance treatment with ASTX727; seven of them received at least one donor lymphocyte infusion. 14 (41%) patients completed the ten cycles. Median follow-up was 12·6 months (IQR 10·3-14·3). Among the first 28 enrolled patients treated with ASTX727, disease-free survival at 1 year after HSCT was 70·4% (95% CI 55·1-89·9). The most frequent grade 3 or worse adverse events were haematological, occurring in 25 (74%) of 34 patients (21 [62%] neutropenia, eight [24%] thrombocytopenia, four [12%] anaemia). Serious adverse events occurred in 14 (41%) of 34 patients, and were haematological in eight patients and gastrointestinal in three patients. One treatment-related death, due to thrombocytopenia, occurred.INTERPRETATIONASTX727 could be a potential treatment option after HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse. Further investigation is warranted to establish the effi
{"title":"Oral decitabine and cedazuridine maintenance after haematopoietic stem-cell transplantation in very high-risk acute myeloid leukaemia or myelodysplastic syndrome (GFM-DACORAL-DLI): a multicentre, single-arm, phase 2 trial.","authors":"Marie Robin,Maud D'Aveni,Aspasia Stamatoullas,Emmanuel Raffoux,Patrice Chevallier,Alice Garnier,Clémence Mediavilla,Martin Carre,Chantal Himberlin,Marie Sébert,Aurélie Ravinet,Kristell Desseaux,Hélène Labussière,Mustafa Alani,Marie-Thérèse Rubio,Anne Huynh,Lionel Adès,Régis Peffault de Latour,Franciane Paul,Fatiha Chermat,Raphael Petit,Chama Mokeddem,Amandine Charbonnier,Sylvain Thépot,Sylvie Chevret,Pierre Fenaux, ","doi":"10.1016/s2352-3026(25)00172-3","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00172-3","url":null,"abstract":"BACKGROUNDThe combination of a hypomethylating agent with donor lymphocyte infusion as maintenance therapy after haematopoietic stem-cell transplantation (HSCT) in acute myeloid leukaemia and myelodysplastic syndrome might reduce the risk of relapse. We aimed to evaluate the activity and safety of oral decitabine and cedazuridine (ASTX727) as maintenance after allogeneic HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse post-transplantation.METHODSWe conducted a multicentre, single-arm, phase 2 study (GFM-DACORAL-DLI) at 12 centres in France. We enrolled patients aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0-2, without contraindication for HSCT, and with very high-risk disease (poor or very poor prognosis according to the revised International Prognostic Scoring System for myelodysplastic syndrome, adverse risk according to the 2017 European LeukemiaNet classification for acute myeloid leukaemia; unfavourable genetics; and acute myeloid leukaemia post-myelodysplastic syndrome or post-myeloproliferative neoplasm, or relapsing less than 2 years after complete response). Patients were included 5-45 days before transplantation. ASTX727 was orally administered at escalating doses (100 mg cedazuridine plus 35 mg decitabine starting at 1 day per cycle and increasing to 3 days) from day 40 post-HSCT, up to ten cycles. Donor lymphocyte infusion was recommended when patients had no contraindication after cycle 4. The primary endpoint was disease-free survival at 1 year after HSCT, assessed in the first 28 enrolled patients treated with ASTX7277. Safety was assessed in all participants who received at least one course of ASTX727. This study was registered with ClinicalTrials.gov (NCT04857645); enrolment is complete but follow-up is ongoing.FINDINGSBetween Sept 28, 2021, and March 1, 2023, 59 patients were screened and 51 patients underwent allogeneic HSCT (median age 62·0 years [IQR 56·5-65·0]; 22 [43%] female, 29 [57%] male). 34 patients received maintenance treatment with ASTX727; seven of them received at least one donor lymphocyte infusion. 14 (41%) patients completed the ten cycles. Median follow-up was 12·6 months (IQR 10·3-14·3). Among the first 28 enrolled patients treated with ASTX727, disease-free survival at 1 year after HSCT was 70·4% (95% CI 55·1-89·9). The most frequent grade 3 or worse adverse events were haematological, occurring in 25 (74%) of 34 patients (21 [62%] neutropenia, eight [24%] thrombocytopenia, four [12%] anaemia). Serious adverse events occurred in 14 (41%) of 34 patients, and were haematological in eight patients and gastrointestinal in three patients. One treatment-related death, due to thrombocytopenia, occurred.INTERPRETATIONASTX727 could be a potential treatment option after HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse. Further investigation is warranted to establish the effi","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDBefore the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment for patients with newly diagnosed transplant-ineligible multiple myeloma, lenalidomide-dexamethasone was a standard of care. We aimed to explore whether addition of the second-generation proteasome inhibitor carfilzomib to lenalidomide-dexamethasone improved the rates of measurable residual disease (MRD) negativity and progression-free survival.METHODSEMN20 is a randomised, open-label, multicentre, phase 3 trial comparing weekly carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma, conducted in 27 centres in Italy. Key inclusion criteria included fit or intermediate-fit status according to the International Myeloma Working Group (IMWG) frailty score, measurable disease according to IMWG criteria, and Eastern Cooperative Oncology Group performance status lower than 3. Patients randomly assigned to the carfilzomib-lenalidomide-dexamethasone group received 28-day carfilzomib-lenalidomide-dexamethasone cycles (carfilzomib 20 mg/m2 intravenously on day 1 for cycle 1, followed by 56 mg/m2 intravenously on days 8 and 15 for cycle 1, then 56 mg/m2 intravenously on days 1, 8, and 15 for cycles 2-12, and 56 mg/m2 intravenously on days 1 and 15 from cycle 13 until 5 years after randomisation; lenalidomide 25 mg orally on days 1-21 until disease progression or intolerance; dexamethasone 40 mg orally on days 1, 8, 15, and 22 until disease progression or intolerance). Patients assigned to the lenalidomide-dexamethasone group received 28-day cycles with lenalidomide-dexamethasone (same dosing and schedule used in the carfilzomib-lenalidomide-dexamethasone group). Primary endpoints were MRD negativity by next-generation sequencing (sensitivity 10-5) after 2 years of treatment and progression-free survival; and were assessed in the intention-to-treat (ITT) population (all patients who were eligible to receive treatment and who were randomly assigned to one of the treatment groups). On Nov 23, 2021, after enrolling 30% of planned patients (101/340), the trial was prematurely stopped due to the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment in Italy, which caused the lenalidomide-dexamethasone control group to no longer be considered a standard treatment. This trial is registered with ClinicalTrials.gov, NCT04096066, and study recruitment is complete.FINDINGSBetween Nov 14, 2019, and Nov 23, 2021, 82 of 101 enrolled patients were assessed for eligibility and were randomised to receive carfilzomib-lenalidomide-dexamethasone (n=42) or lenalidomide-dexamethasone (n=40). In the ITT population, 35 (43%) of 82 patients were female and 47 (57%) were male. At data cutoff (March 29, 2024), the median follow-up was 35·2 months (IQR 30·3-38·7). The 2-year MRD negativity rates were 25 (60% 95% CI 43-74) of 42 patients with carfilzomib-lenalidomide-dexam
{"title":"Carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed myeloma ineligible for autologous stem-cell transplantation (EMN20): a randomised, open-label, multicentre, phase 3 trial.","authors":"Sara Bringhen,Lorenzo Cani,Elisabetta Antonioli,Daniele Derudas,Francesca Fazio,Alessandra Larocca,Sonia Ronconi,Claudia Cellini,Antonietta Pia Falcone,Fabrizio Accardi,Anna Marina Liberati,Piero Galieni,Angelo Belotti,Anna Maria Cafro,Roberto Ria,Giulia Benevolo,Iolanda Donatella Vincelli,Donato Mannina,Flavia Lotti,Benedetto Bruno,Vincenzo Marasco,Rita Mazza,Patrizia Tosi,Elena Rivolti,Mario Boccadoro,Mattia D'Agostino","doi":"10.1016/s2352-3026(25)00162-0","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00162-0","url":null,"abstract":"BACKGROUNDBefore the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment for patients with newly diagnosed transplant-ineligible multiple myeloma, lenalidomide-dexamethasone was a standard of care. We aimed to explore whether addition of the second-generation proteasome inhibitor carfilzomib to lenalidomide-dexamethasone improved the rates of measurable residual disease (MRD) negativity and progression-free survival.METHODSEMN20 is a randomised, open-label, multicentre, phase 3 trial comparing weekly carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma, conducted in 27 centres in Italy. Key inclusion criteria included fit or intermediate-fit status according to the International Myeloma Working Group (IMWG) frailty score, measurable disease according to IMWG criteria, and Eastern Cooperative Oncology Group performance status lower than 3. Patients randomly assigned to the carfilzomib-lenalidomide-dexamethasone group received 28-day carfilzomib-lenalidomide-dexamethasone cycles (carfilzomib 20 mg/m2 intravenously on day 1 for cycle 1, followed by 56 mg/m2 intravenously on days 8 and 15 for cycle 1, then 56 mg/m2 intravenously on days 1, 8, and 15 for cycles 2-12, and 56 mg/m2 intravenously on days 1 and 15 from cycle 13 until 5 years after randomisation; lenalidomide 25 mg orally on days 1-21 until disease progression or intolerance; dexamethasone 40 mg orally on days 1, 8, 15, and 22 until disease progression or intolerance). Patients assigned to the lenalidomide-dexamethasone group received 28-day cycles with lenalidomide-dexamethasone (same dosing and schedule used in the carfilzomib-lenalidomide-dexamethasone group). Primary endpoints were MRD negativity by next-generation sequencing (sensitivity 10-5) after 2 years of treatment and progression-free survival; and were assessed in the intention-to-treat (ITT) population (all patients who were eligible to receive treatment and who were randomly assigned to one of the treatment groups). On Nov 23, 2021, after enrolling 30% of planned patients (101/340), the trial was prematurely stopped due to the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment in Italy, which caused the lenalidomide-dexamethasone control group to no longer be considered a standard treatment. This trial is registered with ClinicalTrials.gov, NCT04096066, and study recruitment is complete.FINDINGSBetween Nov 14, 2019, and Nov 23, 2021, 82 of 101 enrolled patients were assessed for eligibility and were randomised to receive carfilzomib-lenalidomide-dexamethasone (n=42) or lenalidomide-dexamethasone (n=40). In the ITT population, 35 (43%) of 82 patients were female and 47 (57%) were male. At data cutoff (March 29, 2024), the median follow-up was 35·2 months (IQR 30·3-38·7). The 2-year MRD negativity rates were 25 (60% 95% CI 43-74) of 42 patients with carfilzomib-lenalidomide-dexam","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"16 1","pages":"e621-e634"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01DOI: 10.1016/s2352-3026(25)00195-4
Stephen P Hibbs,Lauren E Merz,Andrew Hantel
{"title":"Adverse event grading: the case of Duffy null-associated neutrophil counts.","authors":"Stephen P Hibbs,Lauren E Merz,Andrew Hantel","doi":"10.1016/s2352-3026(25)00195-4","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00195-4","url":null,"abstract":"","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"95 1","pages":"e567"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Research landscape of plasma cell disorders in South Asia: a call for collaboration.","authors":"Nikita Mehra,Karun Neupane,Ghulam Rehman Mohyuddin, ","doi":"10.1016/s2352-3026(25)00196-6","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00196-6","url":null,"abstract":"","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"30 1","pages":"e572-e573"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01DOI: 10.1016/s2352-3026(25)00205-4
The Lancet Haematology
{"title":"A new chapter in relapsed or refractory multiple myeloma.","authors":" The Lancet Haematology","doi":"10.1016/s2352-3026(25)00205-4","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00205-4","url":null,"abstract":"","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"26 1","pages":"e561"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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