Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs persist in vivo following chemotherapy exposure and exhibit elevated levels of DNA damage compared to wild-type cells. Our findings establish that CHEK2 loss promotes chemoresistance in HSPCs, offering new insights into the role of CHEK2 in therapy-related clonal hematopoiesis observed in cancer patients.
{"title":"CHEK2 loss endows chemotherapy resistance to hematopoietic stem cells.","authors":"Jing Zhou,Tianyuan Hu,Dian Li,Sanming Li,Minhua Li,Xiangguo Shi,Daisuke Nakada","doi":"10.1038/s41375-025-02850-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02850-w","url":null,"abstract":"Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs persist in vivo following chemotherapy exposure and exhibit elevated levels of DNA damage compared to wild-type cells. Our findings establish that CHEK2 loss promotes chemoresistance in HSPCs, offering new insights into the role of CHEK2 in therapy-related clonal hematopoiesis observed in cancer patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s41375-025-02857-3
Rohtesh S Mehta,Yosra M Aljawai,Partow Kebriaei,Gabriela Rondon,Warren Fingrut,Portia Smallbone,Betul Oran,Amanda Olson,Richard E Champlin,Elizabeth J Shpall
The prevailing fixed-hierarchy approach to donor selection for allogeneic hematopoietic cell transplantation (HCT) fails to capture critical interactions between donor age and type. We addressed this by analyzing 1713 adult recipients of matched related (MRD), matched unrelated (MUD), or haploidentical donors, receiving post-transplantation cyclophosphamide, using both regularized-Cox and XGBoost machine learning models. Our analysis revealed that the overall, independent association of donor age with survival was modest; however, its importance became pivotal within specific, context-dependent trade-offs. For example, while age-matched MRD and MUD were equivalent, a younger MUD was superior to an older MRD for elderly recipients. The survival advantage of MUD over haploidentical donors was consistent and magnified with increasing recipient age. We identified a non-linear relationship between baseline risk and the benefit of a matched versus a haploidentical donor; with the gain being maximal for intermediate-risk patients but attenuated in the highest-risk stratum. Our framework quantifies the gap that persists even between HLA-favorable haploidentical donors and matched donors. These findings provide a quantitative framework -the principles of which we have made explorable via an interactive web application -for a personalized, risk-adapted approach to donor selection. The clinical utility of this model must be confirmed in future validation studies.
{"title":"Modeling donor age and type trade-offs for personalized selection in allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide prophylaxis.","authors":"Rohtesh S Mehta,Yosra M Aljawai,Partow Kebriaei,Gabriela Rondon,Warren Fingrut,Portia Smallbone,Betul Oran,Amanda Olson,Richard E Champlin,Elizabeth J Shpall","doi":"10.1038/s41375-025-02857-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02857-3","url":null,"abstract":"The prevailing fixed-hierarchy approach to donor selection for allogeneic hematopoietic cell transplantation (HCT) fails to capture critical interactions between donor age and type. We addressed this by analyzing 1713 adult recipients of matched related (MRD), matched unrelated (MUD), or haploidentical donors, receiving post-transplantation cyclophosphamide, using both regularized-Cox and XGBoost machine learning models. Our analysis revealed that the overall, independent association of donor age with survival was modest; however, its importance became pivotal within specific, context-dependent trade-offs. For example, while age-matched MRD and MUD were equivalent, a younger MUD was superior to an older MRD for elderly recipients. The survival advantage of MUD over haploidentical donors was consistent and magnified with increasing recipient age. We identified a non-linear relationship between baseline risk and the benefit of a matched versus a haploidentical donor; with the gain being maximal for intermediate-risk patients but attenuated in the highest-risk stratum. Our framework quantifies the gap that persists even between HLA-favorable haploidentical donors and matched donors. These findings provide a quantitative framework -the principles of which we have made explorable via an interactive web application -for a personalized, risk-adapted approach to donor selection. The clinical utility of this model must be confirmed in future validation studies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"1 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s41375-025-02859-1
Andreas Burchert, Franck E. Nicolini, Philipp le Coutre, Susanne Saussele, Andreas Hochhaus, Evin Tuere, Stephan K. Metzelder, Kim Pauck, Holger Garn, Hartmann Raifer, Magdalena Huber, Norbert Gattermann, Martina Crysandt, Philippe Schafhausen, Matthias Bormann, Markus P. Radsak, Agnès Guerci-Bresler, Thomas Illmer, Maria E. Goebeler, Peter Herhaus, Lino L. Teichmann, Georg-Nikolaus Franke, Fabian Lang, Stefan W. Krause, Robert Möhle, Martine Klausmann, Frank Stegelmann, Christoph Lutz, Gabriel Etienne, Andrea Stoltefuß, Joachim R. Göthert, Thomas Ernst, Maisun Abu-Samra, Heinz-Gert Höffkes, Andreas Neubauer, Ying Wang, Paul Weiland, Clara Otto, Lea Kiessler, Theresa Weber, Lea Kroning, Andrea Nist, Thorsten Stiewe, Rüdiger Hehlmann, Behnaz Aminossadati, Michael Wittenberg, Kerstin Winterstein, Thomas Oellerich, Marcus Lechner, Markus Pfirrmann, Carmen Schade-Brittinger, Paul Klemm, Christian Michel
Treatment-free remission (TFR) after discontinuation of ABL tyrosine kinase inhibitors (TKIs) is an important therapeutic goal in chronic myeloid leukemia (CML). Interferon-α (IFN) has been suggested to promote durable TFR. The phase 3 ENDURE trial (NCT03117816; EUDRA-CT 2016-001030-94) prospectively tested this hypothesis in patients with stable deep molecular remission after TKI therapy. A total of 203 patients were randomised 1:1 to receive ropeginterferon alfa-2b (ropeg-IFN; 100 µg subcutaneously every two weeks for 15 months, n = 95) or observation alone (n = 108) after TKI discontinuation. The primary endpoint was molecular relapse-free survival (MRFS), defined as time to loss of major molecular response (MMR) or death. At a median follow-up of 36 months, 25-month MRFS was 56% (95% confidence interval (CI), 45–66) with ropeg-IFN and 59% (95% CI, 49–68) with observation (hazard ratio (HR), 1.02; 95% CI, 0.68–1.55; P = 0.91). Among 83 patients with molecular data after TKI restart, 79 (95%) regained at least MMR, 78 within 12 months (median 3 months, interquartile range: 2-4 months). Ropeg-IFN was well tolerated (median administered dose of 92 µg, range 3–104), and no new safety signals were observed. Ropeg-IFN maintenance did not improve the probability of sustained TFR after TKI discontinuation.
{"title":"Randomized phase 3 trial of Ropeginterferon alfa-2b versus surveillance after tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia (ENDURE/CML-IX)","authors":"Andreas Burchert, Franck E. Nicolini, Philipp le Coutre, Susanne Saussele, Andreas Hochhaus, Evin Tuere, Stephan K. Metzelder, Kim Pauck, Holger Garn, Hartmann Raifer, Magdalena Huber, Norbert Gattermann, Martina Crysandt, Philippe Schafhausen, Matthias Bormann, Markus P. Radsak, Agnès Guerci-Bresler, Thomas Illmer, Maria E. Goebeler, Peter Herhaus, Lino L. Teichmann, Georg-Nikolaus Franke, Fabian Lang, Stefan W. Krause, Robert Möhle, Martine Klausmann, Frank Stegelmann, Christoph Lutz, Gabriel Etienne, Andrea Stoltefuß, Joachim R. Göthert, Thomas Ernst, Maisun Abu-Samra, Heinz-Gert Höffkes, Andreas Neubauer, Ying Wang, Paul Weiland, Clara Otto, Lea Kiessler, Theresa Weber, Lea Kroning, Andrea Nist, Thorsten Stiewe, Rüdiger Hehlmann, Behnaz Aminossadati, Michael Wittenberg, Kerstin Winterstein, Thomas Oellerich, Marcus Lechner, Markus Pfirrmann, Carmen Schade-Brittinger, Paul Klemm, Christian Michel","doi":"10.1038/s41375-025-02859-1","DOIUrl":"10.1038/s41375-025-02859-1","url":null,"abstract":"Treatment-free remission (TFR) after discontinuation of ABL tyrosine kinase inhibitors (TKIs) is an important therapeutic goal in chronic myeloid leukemia (CML). Interferon-α (IFN) has been suggested to promote durable TFR. The phase 3 ENDURE trial (NCT03117816; EUDRA-CT 2016-001030-94) prospectively tested this hypothesis in patients with stable deep molecular remission after TKI therapy. A total of 203 patients were randomised 1:1 to receive ropeginterferon alfa-2b (ropeg-IFN; 100 µg subcutaneously every two weeks for 15 months, n = 95) or observation alone (n = 108) after TKI discontinuation. The primary endpoint was molecular relapse-free survival (MRFS), defined as time to loss of major molecular response (MMR) or death. At a median follow-up of 36 months, 25-month MRFS was 56% (95% confidence interval (CI), 45–66) with ropeg-IFN and 59% (95% CI, 49–68) with observation (hazard ratio (HR), 1.02; 95% CI, 0.68–1.55; P = 0.91). Among 83 patients with molecular data after TKI restart, 79 (95%) regained at least MMR, 78 within 12 months (median 3 months, interquartile range: 2-4 months). Ropeg-IFN was well tolerated (median administered dose of 92 µg, range 3–104), and no new safety signals were observed. Ropeg-IFN maintenance did not improve the probability of sustained TFR after TKI discontinuation.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"410-417"},"PeriodicalIF":13.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02859-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s41375-025-02845-7
Fanny Gonzales, Constanze Schneider, Gabriela Alexe, Shan Lin, Delan Khalid, Montserrat Alvarez, Allen Basanthakumar, Jana M. Ellegast, Lucy Merickel, Silvi Salhotra, Audrey Taillon, Mariateresa Giaimo, Mark Wunderlich, Marc Ansari, Jennifer A. Perry, Barbara Degar, Yana Pikman, Kimberly Stegmaier
CBFA2T3::GLIS2-positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapy approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on JAK2 compared to other types of cancer. Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2-positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in CBFA2T3::GLIS2 AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, CBFA2T3::GLIS2 AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic NRAS mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.
CBFA2T3:: glis2阳性的儿童急性髓性白血病（AML）仍然是预后最差的AML亚群之一。为了发现这种疾病亚型的创新靶向治疗方法，我们进行了基因组规模的CRISPR-Cas9筛选，与其他类型的癌症相比，突出了对JAK2的强烈选择性依赖。利用强力霉素诱导的JAK2敲除（KO）系统，我们验证了CBFA2T3::GLIS2细胞系对JAK2的依赖性，观察了体外和体内增殖受损以及体外诱导凋亡的情况。I型（ruxolitinib）和II型（CHZ868） JAK2抑制剂在CBFA2T3:: glis2阳性AML模型中均显示选择性体外活性。为了确定对JAK2抑制剂的耐药和增敏机制，我们在CBFA2T3::GLIS2 AML中使用CRISPR-Cas9 ruxolitinib锚点筛选。靶向MAPK通路负调节因子的sgrna在ruxolitinib处理的细胞中富集。同样，CBFA2T3::GLIS2 AML亚群在慢性ruxolitinib治疗下产生耐药性，表达致病性NRAS突变。两种方法都将MAPK通路激活作为对ruxolitinib治疗的耐药机制。ruxolitinib联合MEK抑制剂在表达CBFA2T3::GLIS2 AML PDX的融合和体内活性的细胞系和患者来源的异种移植物（PDX）细胞中显示出协同作用，这表明在这种预后不良的AML亚型中靶向这种信号通路的潜在方法。
{"title":"Identifying targeted therapies for CBFA2T3::GLIS2 acute myeloid leukemia","authors":"Fanny Gonzales, Constanze Schneider, Gabriela Alexe, Shan Lin, Delan Khalid, Montserrat Alvarez, Allen Basanthakumar, Jana M. Ellegast, Lucy Merickel, Silvi Salhotra, Audrey Taillon, Mariateresa Giaimo, Mark Wunderlich, Marc Ansari, Jennifer A. Perry, Barbara Degar, Yana Pikman, Kimberly Stegmaier","doi":"10.1038/s41375-025-02845-7","DOIUrl":"10.1038/s41375-025-02845-7","url":null,"abstract":"CBFA2T3::GLIS2-positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapy approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on JAK2 compared to other types of cancer. Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2-positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in CBFA2T3::GLIS2 AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, CBFA2T3::GLIS2 AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic NRAS mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"383-396"},"PeriodicalIF":13.4,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02845-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41375-025-02853-7
S. D. Patterson, A. Gottschalk, C. Hayden, R. Young, A. Hair, H. G. Jørgensen, H. W. Wheadon, J. F. Apperley, I. Glauche, R. E. Clark, M. Copland, I. Roeder
{"title":"Sequential BCR::ABL1 evaluation during dose de-escalation in peripheral blood is more predictive of TFR success than single assessment at dose de-escalation in either peripheral blood or bone marrow","authors":"S. D. Patterson, A. Gottschalk, C. Hayden, R. Young, A. Hair, H. G. Jørgensen, H. W. Wheadon, J. F. Apperley, I. Glauche, R. E. Clark, M. Copland, I. Roeder","doi":"10.1038/s41375-025-02853-7","DOIUrl":"10.1038/s41375-025-02853-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"459-463"},"PeriodicalIF":13.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02853-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41375-025-02841-x
Noffar Bar, Thomas Martin, Craig C. Hofmeister, Maria-Victoria Mateos, Markus Hansson, Laura Paris, Swathi Namburi, Paz Ribas, Armando Santoro, Paula Rodriguez-Otero, Maria Creignou, Jinjie Chen, Cong Cao, Brian Kiesel, Allison Gaudy, Ethan G. Thompson, Ye Shen, Samah Zarif, Kevin Hsu, Suresh G. Shelat, Michael R. Burgess, Colin Godwin, Luciano J. Costa
B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.
{"title":"Alnuctamab, a bivalent B-cell maturation antigen-targeting T cell engager for patients with relapsed or refractory multiple myeloma: results from a phase 1, first-in-human study","authors":"Noffar Bar, Thomas Martin, Craig C. Hofmeister, Maria-Victoria Mateos, Markus Hansson, Laura Paris, Swathi Namburi, Paz Ribas, Armando Santoro, Paula Rodriguez-Otero, Maria Creignou, Jinjie Chen, Cong Cao, Brian Kiesel, Allison Gaudy, Ethan G. Thompson, Ye Shen, Samah Zarif, Kevin Hsu, Suresh G. Shelat, Michael R. Burgess, Colin Godwin, Luciano J. Costa","doi":"10.1038/s41375-025-02841-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02841-x","url":null,"abstract":"B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"57 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aggressive NK-cell leukemia (ANKL) is a rare NK-cell leukemia characterized by, an aggressive clinical course, and frequent Epstein–Barr virus association. We retrospectively collected 126 ANKL patients diagnosed between 2000 and 2021 from 71 institutes; 108 were evaluable for analysis to characterize the recent advances. The median age was 49 years (range: 17–90), and 63 patients were male. The median percentage of leukemic cells in the bone marrow and peripheral blood was 19.7% and 10.0%, respectively. The first-line regimens included SMILE (n = 38, 42%), CHOP(-like) (n = 26, 29%), DeVIC (n = 15, 17%), and other L-asparaginase-containing regimens (n = 8, 9%), with the overall response rates of 66%, 31%, 33%, and 50%, respectively. Median overall survival (OS) was 5.5 months, with a 2-year OS of 18.7%. Patients treated with SMILE had significantly better OS than others (2-year OS 30.1% vs. 7.0%; P < 0.001). Prognosis further improved with allogeneic hematopoietic stem cell transplantation (HSCT) (2-year OS 37.2% vs 3.5%; P < 0.001). Multivariate analysis confirmed treatment with SMILE [hazard ratio (HR) 0.53, 95% confidential interval (CI) 0.31–0.88] and allogeneic HSCT (HR 0.33, 95% CI 0.18–0.61) as independent favorable factors. In conclusion, SMILE chemotherapy followed by allogeneic HSCT may improve outcomes in ANKL.
侵袭性nk细胞白血病（ANKL）是一种罕见的nk细胞白血病，其特点是具有侵袭性的临床病程和频繁的爱泼斯坦-巴尔病毒关联。我们回顾性收集了2000年至2021年间从71个研究所诊断的126例ANKL患者；其中108项可用于分析，以描述最近的进展。中位年龄49岁（17-90岁），男性63例。骨髓和外周血中白血病细胞的中位数百分比分别为19.7%和10.0%。一线方案包括SMILE （n = 38, 42%）、CHOP(-like) （n = 26, 29%）、DeVIC （n = 15, 17%）和其他含l -天冬酰胺酶方案（n = 8, 9%），总有效率分别为66%、31%、33%和50%。中位总生存期（OS）为5.5个月，2年OS为18.7%。SMILE治疗患者的OS明显优于其他治疗组（2年OS 30.1% vs. 7.0%; P < 0.001）。同种异体造血干细胞移植（HSCT）的预后进一步改善（2年生存率37.2% vs 3.5%; P < 0.001）。多因素分析证实SMILE治疗[危险比（HR） 0.53, 95%可信区间（CI） 0.31-0.88]和异体造血干细胞移植（HR 0.33, 95% CI 0.18-0.61）是独立的有利因素。总之，SMILE化疗配合同种异体造血干细胞移植可能改善ANKL的预后。
{"title":"Advances in the treatment and prognosis of aggressive NK-cell leukemia: results from the ANKL22 study","authors":"Ayumi Fujimoto, Takeshi Maeda, Noriko Doki, Noriko Fukuhara, Noriko Iwaki, Nobuhiro Hiramoto, Hideki Goto, Takuya Miyazaki, Ikue Shiki, Kana Miyazaki, Motoko Yamaguchi, Fumihiro Ishida, Ritsuro Suzuki","doi":"10.1038/s41375-025-02854-6","DOIUrl":"10.1038/s41375-025-02854-6","url":null,"abstract":"Aggressive NK-cell leukemia (ANKL) is a rare NK-cell leukemia characterized by, an aggressive clinical course, and frequent Epstein–Barr virus association. We retrospectively collected 126 ANKL patients diagnosed between 2000 and 2021 from 71 institutes; 108 were evaluable for analysis to characterize the recent advances. The median age was 49 years (range: 17–90), and 63 patients were male. The median percentage of leukemic cells in the bone marrow and peripheral blood was 19.7% and 10.0%, respectively. The first-line regimens included SMILE (n = 38, 42%), CHOP(-like) (n = 26, 29%), DeVIC (n = 15, 17%), and other L-asparaginase-containing regimens (n = 8, 9%), with the overall response rates of 66%, 31%, 33%, and 50%, respectively. Median overall survival (OS) was 5.5 months, with a 2-year OS of 18.7%. Patients treated with SMILE had significantly better OS than others (2-year OS 30.1% vs. 7.0%; P < 0.001). Prognosis further improved with allogeneic hematopoietic stem cell transplantation (HSCT) (2-year OS 37.2% vs 3.5%; P < 0.001). Multivariate analysis confirmed treatment with SMILE [hazard ratio (HR) 0.53, 95% confidential interval (CI) 0.31–0.88] and allogeneic HSCT (HR 0.33, 95% CI 0.18–0.61) as independent favorable factors. In conclusion, SMILE chemotherapy followed by allogeneic HSCT may improve outcomes in ANKL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"373-382"},"PeriodicalIF":13.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：