LeukemiaPub Date : 2024-09-25DOI: 10.1038/s41375-024-02414-4
Farhad Ravandi, Jayastu Senapati, Nitin Jain, Nicholas J. Short, Tapan Kadia, Gautam Borthakur, Marina Konopleva, William Wierda, Xuelin Huang, Abhishek Maiti, Ghayas Issa, Hayley Balkin, Rebecca Garris, Alessandra Ferrajoli, Guillermo Garcia-Manero, Yesid Alvarado, Partow Kebriaei, Elias Jabbour, Hagop M. Kantarjian
{"title":"Longitudinal follow up of a phase 2 trial of venetoclax added to hyper-CVAD, nelarabine and pegylated asparaginase in patients with T-cell acute lymphoblastic leukemia and lymphoma","authors":"Farhad Ravandi, Jayastu Senapati, Nitin Jain, Nicholas J. Short, Tapan Kadia, Gautam Borthakur, Marina Konopleva, William Wierda, Xuelin Huang, Abhishek Maiti, Ghayas Issa, Hayley Balkin, Rebecca Garris, Alessandra Ferrajoli, Guillermo Garcia-Manero, Yesid Alvarado, Partow Kebriaei, Elias Jabbour, Hagop M. Kantarjian","doi":"10.1038/s41375-024-02414-4","DOIUrl":"https://doi.org/10.1038/s41375-024-02414-4","url":null,"abstract":"<p>Optimal frontline use of active agents in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is prudent to improve outcomes. We report the long-term follow-up of the phase 2 trial of HyperCVAD with nelarabine and pegylated asparaginase (Original cohort). In the latest protocol iteration venetoclax was added to the induction/consolidation regimen (Venetoclax cohort). Eligible patients were adults with untreated T-ALL/LBL or after minimal therapy and with adequate organ function. Primary endpoint of this analysis was improvement in 2-year progression free survival (PFS) and overall survival (OS) with venetoclax. From Aug 2007 to Dec 2024, 145 patients, at a median age of 35.4 years, were treated; 46 (33.8%) were in the venetoclax cohort. At median follow-up (mFU) of 62.4 months, 5-year PFS, duration of response (DOR), and OS were 63.7%, 72.0% and 66.2% respectively. In the venetoclax cohort (mFU 24.4 months) 2-year PFS (87.9% versus 64.1%, <i>p</i> = 0.03) and 2-year DOR (93.6% versus 69.2%, <i>p</i> = 0.005) were superior to the original cohort (mFU 89.4 months) and 2-year OS appeared better (87.8% versus 73.9%, <i>p</i> = 0.16). Febrile neutropenia was the most common serious adverse event, seen in 60% patients. The addition of venetoclax to HyperCVAD-nelarabine-pegylated asparaginase was tolerable and led to improvement in DOR and PFS.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317196","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}
LeukemiaPub Date : 2024-09-25DOI: 10.1038/s41375-024-02404-6
María-Victoria Mateos, Katja Weisel, Valerio De Stefano, Hartmut Goldschmidt, Michel Delforge, Mohamad Mohty, Dominik Dytfeld, Emanuele Angelucci, Laure Vincent, Aurore Perrot, Reuben Benjamin, Niels W. C. J. van de Donk, Enrique M. Ocio, Tito Roccia, Jordan M. Schecter, Silva Koskinen, Imène Haddad, Vadim Strulev, Lada Mitchell, Jozefien Buyze, Octavio Costa Filho, Hermann Einsele, Philippe Moreau
{"title":"LocoMMotion: a study of real-life current standards of care in triple-class exposed patients with relapsed/refractory multiple myeloma – 2-year follow-up (final analysis)","authors":"María-Victoria Mateos, Katja Weisel, Valerio De Stefano, Hartmut Goldschmidt, Michel Delforge, Mohamad Mohty, Dominik Dytfeld, Emanuele Angelucci, Laure Vincent, Aurore Perrot, Reuben Benjamin, Niels W. C. J. van de Donk, Enrique M. Ocio, Tito Roccia, Jordan M. Schecter, Silva Koskinen, Imène Haddad, Vadim Strulev, Lada Mitchell, Jozefien Buyze, Octavio Costa Filho, Hermann Einsele, Philippe Moreau","doi":"10.1038/s41375-024-02404-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02404-6","url":null,"abstract":"<p>Treatment of relapsed/refractory multiple myeloma (RRMM) is challenging as patients exhaust all available therapies and the disease becomes refractory to standard drug classes. Here we report the final results of LocoMMotion, the first prospective study of real-world clinical practice (RWCP) in triple-class exposed (TCE) patients with RRMM, with a median follow-up of 26.4 months (range, 0.1–35.0). Patients (<i>N</i> = 248) had received median 4 prior LOT (range, 2–13) at enrollment. 91 unique regimens were used in index LOT. Overall response rate was 31.9% (95% CI, 26.1–38.0), median progression-free survival (PFS) was 4.6 months (95% CI, 3.9–5.6) and median overall survival was 13.8 months (95% CI, 10.8–17.0). 152 patients (61.3%) had subsequent LOTs with 134 unique regimens, of which 78 were used in first subsequent LOT. Median PFS2 (from start of study through first subsequent LOT) was 10.8 months (95% CI, 8.4–13.0). 158 patients died on study, 67.7% due to progressive disease. Additional subgroup analyses and long-term safety summaries are reported. The high number of RWCP treatment regimens utilized and poor clinical outcomes confirm a lack of standardized treatment for TCE patients with RRMM, highlighting the need for new treatments with novel mechanisms.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317199","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}
LeukemiaPub Date : 2024-09-25DOI: 10.1038/s41375-024-02408-2
Justus M. Huelse, Swati S. Bhasin, Kristen M. Jacobsen, Juhye Yim, Beena E. Thomas, Gianna M. Branella, Mojtaba Bakhtiari, Madison L. Chimenti, Travon A. Baxter, Sunil S. Raikar, Xiaodong Wang, Stephen V. Frye, Curtis J. Henry, H. Shelton Earp, Manoj Bhasin, Deborah DeRyckere, Douglas K. Graham
{"title":"MERTK inhibition selectively activates a DC – T-cell axis to provide anti-leukemia immunity","authors":"Justus M. Huelse, Swati S. Bhasin, Kristen M. Jacobsen, Juhye Yim, Beena E. Thomas, Gianna M. Branella, Mojtaba Bakhtiari, Madison L. Chimenti, Travon A. Baxter, Sunil S. Raikar, Xiaodong Wang, Stephen V. Frye, Curtis J. Henry, H. Shelton Earp, Manoj Bhasin, Deborah DeRyckere, Douglas K. Graham","doi":"10.1038/s41375-024-02408-2","DOIUrl":"https://doi.org/10.1038/s41375-024-02408-2","url":null,"abstract":"<p>TAM-family tyrosine kinases (TYRO3, AXL and MERTK) are potential cancer therapeutic targets. In previous studies MERTK inhibition in the immune microenvironment was therapeutically effective in a B-cell acute leukemia (B-ALL) model. Here, we probed anti-leukemia immune mechanisms and evaluated roles for TYRO3 and AXL in the leukemia microenvironment. Host <i>Mertk</i> knock-out or MERTK inhibitor MRX-2843 increased CD8α<sup>+</sup> dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis. High <i>MERTK</i> or low DC gene expression were associated with poor prognosis in pediatric ALL patients, indicating the clinical relevance of these findings. MRX-2843 increased CD8<sup>+</sup> T-cell numbers and prevented induction of exhaustion markers, implicating a DC – T-cell axis. Indeed, combined depletion of CD8α<sup>+</sup> DCs and CD8<sup>+</sup> T-cells was required to abrogate anti-leukemia immunity in <i>Mertk</i><sup><i>–/–</i></sup> <i>mice</i>. <i>Tyro3</i><sup>–/–</sup> mice were also protected against B-ALL, implicating TYRO3 as an immunotherapeutic target. In contrast to <i>Mertk</i><sup><i>–/–</i></sup> mice, <i>Tyro3</i><sup>–/–</sup> did not increase CD8α<sup>+</sup> DCs with enhanced antigen-presentation capacity and therapeutic activity was less dependent on DCs, indicating a different immune mechanism. <i>Axl</i><sup>–/–</sup> did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317197","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}
LeukemiaPub Date : 2024-09-24DOI: 10.1038/s41375-024-02419-z
Laura Martinez-Verbo, Yoana Veselinova, Pere Llinàs-Arias, Carlos A. García-Prieto, Aleix Noguera-Castells, Miguel L. Pato, Alberto Bueno-Costa, Ignacio Campillo-Marcos, Lorea Villanueva, Aina Oliver-Caldes, Oriol Cardus, Sergi V. Salsench, Almudena García-Ortiz, Antonio Valeri, Elizabeta A. Rojas, Naroa Barrena, Norma C. Gutiérrez, Felipe Prósper, Xabier Agirre, Carlos Fernández de Larrea, Joaquín Martínez-López, Gerardo Ferrer, Manel Esteller
{"title":"PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma","authors":"Laura Martinez-Verbo, Yoana Veselinova, Pere Llinàs-Arias, Carlos A. García-Prieto, Aleix Noguera-Castells, Miguel L. Pato, Alberto Bueno-Costa, Ignacio Campillo-Marcos, Lorea Villanueva, Aina Oliver-Caldes, Oriol Cardus, Sergi V. Salsench, Almudena García-Ortiz, Antonio Valeri, Elizabeta A. Rojas, Naroa Barrena, Norma C. Gutiérrez, Felipe Prósper, Xabier Agirre, Carlos Fernández de Larrea, Joaquín Martínez-López, Gerardo Ferrer, Manel Esteller","doi":"10.1038/s41375-024-02419-z","DOIUrl":"https://doi.org/10.1038/s41375-024-02419-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317241","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}
{"title":"Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database.","authors":"Joachim Alexandre,Jonaz Font,Da-Silva Angélique,Baptiste Delapierre,Ghandi Damaj,Anne-Flore Plane,Damien Legallois,Paul Milliez,Charles Dolladille,Basile Chrétien","doi":"10.1038/s41375-024-02413-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02413-5","url":null,"abstract":"Whether ibrutinib-related atrial fibrillation (IRAF) is a dose-dependent adverse drug reaction (ADR) and whether ibrutinib should be discontinued or dose-reduced in case of IRAF occurrence remains unknown. Using the World Health Organization individual case safety report pharmacovigilance database, VigiBase®, we aimed to determine the association between ibrutinib dosing regimens and IRAF reporting. Ibrutinib daily dose was extracted from IRAF cases from VigiBase® and was divided into 5 ibrutinib dosing regimen (140-280-420-560 and >560 mg/day). Disproportionality analysis was used to evaluate the association between IRAF reporting and ibrutinib daily dose, through logistic regression. Single term deletions produced the ibrutinib daily dose global p-value. Then, a multivariable adjusted reporting odds-ratio with its 95% confidence interval was calculated for each ibrutinib dosing regimen, against the lowest dosing regimen (140 mg/day) as reference. A total of 1162 IRAF cases were identified in VigiBase® (n = 62 for ibrutinib 140 mg/day, 114 for ibrutinib 280 mg/day, 811 for ibrutinib 420 mg/day, 164 for ibrutinib 560 mg/day and 11 for ibrutinib >560 mg/day). After adjustment on several variables of interest, IRAF reporting was not significantly associated with ibrutinib dosing regimen (p = 0.09). Our results from Vigibase® do not support IRAF as a dose-dependent ADR (ClinicalTrial registration number: NCT06224452).","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273465","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}
LeukemiaPub Date : 2024-09-18DOI: 10.1038/s41375-024-02409-1
Laura Volta, Renier Myburgh, Christian Pellegrino, Christian Koch, Monique Maurer, Francesco Manfredi, Mara Hofstetter, Anne Kaiser, Florin Schneiter, Jan Müller, Marco M. Buehler, Roberto De Luca, Nicholas Favalli, Chiara F. Magnani, Timm Schroeder, Dario Neri, Markus G. Manz
{"title":"Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells","authors":"Laura Volta, Renier Myburgh, Christian Pellegrino, Christian Koch, Monique Maurer, Francesco Manfredi, Mara Hofstetter, Anne Kaiser, Florin Schneiter, Jan Müller, Marco M. Buehler, Roberto De Luca, Nicholas Favalli, Chiara F. Magnani, Timm Schroeder, Dario Neri, Markus G. Manz","doi":"10.1038/s41375-024-02409-1","DOIUrl":"https://doi.org/10.1038/s41375-024-02409-1","url":null,"abstract":"<p>CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245874","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}
LeukemiaPub Date : 2024-09-17DOI: 10.1038/s41375-024-02412-6
Ekaterina Chelysheva, Jane Apperley, Anna Turkina, Mohamed A Yassin, Delphine Rea, Franck E Nicolini, Daniela Barraco, Khamida Kazakbaeva, Sukhrob Saliev, Adi Shacham Abulafia, Salam Al-Kindi, Jennifer Byrne, Harry F Robertson, Marco Cerrano, Roman Shmakov, Evgenia Polushkina, Paolo de Fabritiis, Malgorzata Monika Trawinska, Elisabetta Abruzzese
{"title":"Correction: Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry.","authors":"Ekaterina Chelysheva, Jane Apperley, Anna Turkina, Mohamed A Yassin, Delphine Rea, Franck E Nicolini, Daniela Barraco, Khamida Kazakbaeva, Sukhrob Saliev, Adi Shacham Abulafia, Salam Al-Kindi, Jennifer Byrne, Harry F Robertson, Marco Cerrano, Roman Shmakov, Evgenia Polushkina, Paolo de Fabritiis, Malgorzata Monika Trawinska, Elisabetta Abruzzese","doi":"10.1038/s41375-024-02412-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02412-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290420","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}
LeukemiaPub Date : 2024-09-17DOI: 10.1038/s41375-024-02405-5
Melisa Halilovic, Mohamed Abdelsalam, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Matthias Schmidt, Walburgis Brenner, Sara Najafi, Ina Oehme, Christoph Hieber, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H. Krämer
{"title":"Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins","authors":"Melisa Halilovic, Mohamed Abdelsalam, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Matthias Schmidt, Walburgis Brenner, Sara Najafi, Ina Oehme, Christoph Hieber, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H. Krämer","doi":"10.1038/s41375-024-02405-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02405-5","url":null,"abstract":"<p>Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (<i>p</i> < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a <i>Danio rerio</i> model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (<i>p</i> < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (<i>p</i> < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245596","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}
LeukemiaPub Date : 2024-09-17DOI: 10.1038/s41375-024-02411-7
Andrew J. Innes, Chloe Hayden, Victoria Orovboni, Simone Claudiani, Fiona Fernando, Afzal Khan, David Rees, Jennifer Byrne, Paolo Gallipoli, Sebastian Francis, Mhairi Copland, Gillian Horne, Manoj Raghavan, Claire Arnold, Angela Collins, Tanya Cranfield, Nicholas Cunningham, Akila Danga, Peter Forsyth, Rebecca Frewin, Paula Garland, Guy Hannah, Daniele Avenoso, Sandra Hassan, Brian J. P. Huntly, Jissan Husain, Sudhakaran Makkuni, Kate Rothwell, Jamshid Khorashad, Jane F. Apperley, Dragana Milojkovic
{"title":"Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy","authors":"Andrew J. Innes, Chloe Hayden, Victoria Orovboni, Simone Claudiani, Fiona Fernando, Afzal Khan, David Rees, Jennifer Byrne, Paolo Gallipoli, Sebastian Francis, Mhairi Copland, Gillian Horne, Manoj Raghavan, Claire Arnold, Angela Collins, Tanya Cranfield, Nicholas Cunningham, Akila Danga, Peter Forsyth, Rebecca Frewin, Paula Garland, Guy Hannah, Daniele Avenoso, Sandra Hassan, Brian J. P. Huntly, Jissan Husain, Sudhakaran Makkuni, Kate Rothwell, Jamshid Khorashad, Jane F. Apperley, Dragana Milojkovic","doi":"10.1038/s41375-024-02411-7","DOIUrl":"https://doi.org/10.1038/s41375-024-02411-7","url":null,"abstract":"<p>Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-<i>BCR::ABL1</i> single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245598","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}
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