Article
Cell Biology
Emily Gruber, Joan So, Alexander C. Lewis, Rheana Franich, Rachel Cole, Luciano G. Martelotto, Amy J. Rogers, Eva Vidacs, Peter Fraser, Kym Stanley, Lisa Jones, Anna Trigos, Niko Thio, Jason Li, Brandon Nicolay, Scott Daigle, Adriana E. Tron, Marc L. Hyer, Jake Shortt, Ricky W. Johnstone, Lev M. Kats
Summary: A study found that the efficacy of the IDH1 inhibitor AG-120 in AML patients depends on the cell type. Although AG-120 as a single agent cannot completely eradicate the disease, it can increase the proliferation of leukemia stem cells and enhance sensitivity to azacitidine. Therefore, the combination therapy of AG-120 and azacitidine shows improved efficacy in patients.
Article
Oncology
Rana Gbyli, Yuanbin Song, Wei Liu, Yimeng Gao, Giulia Biancon, Namrata S. Chandhok, Xiaman Wang, Xiaoying Fu, Amisha Patel, Ranjini Sundaram, Toma Tebaldi, Padmavathi Mamillapalli, Amer M. Zeidan, Richard A. Flavell, Thomas Prebet, Ranjit S. Bindra, Stephanie Halene
Summary: Treatment options for relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients are limited. Our study demonstrates the effectiveness of the PARP inhibitor olaparib in IDH1/2-mutant AML/MDS patients, particularly those who are resistant to IDH(m)i treatment or have relapsed.
Article
Oncology
Hannah J. Uckelmann, Elena L. Haarer, Reina Takeda, Eric M. Wong, Charlie Hatton, Christian Marinaccio, Florian Perner, Masooma Rajput, Noa J. C. Antonissen, Yanhe Wen, Lu Yang, Lorenzo Brunetti, Chun -Wei Chen, Scott A. Armstrong
Summary: The dysregulation of developmental and stem cell-associated genes is a common phenomenon during cancer development. Most patients with acute myeloid leukemia (AML) express high levels of HOXA cluster genes and MEIS1, with an NPM1 mutation (NPM1c) being common in these cases. This study reveals that NPM1c directly binds to specific chromatin targets, collaborates with the MLL1 complex, and directly regulates oncogenic gene expression in AML.
Article
Medicine, General & Internal
Pau Montesinos, Christian Recher, Susana Vives, Ewa Zarzycka, Jianxiang Wang, Giambattista Bertani, Michael Heuser, Rodrigo T. Calado, Andre C. Schuh, Su-Peng Yeh, Scott R. Daigle, Jianan Hui, Shuchi S. Pandya, Diego A. Gianolio, Stephane de Botton, Hartmut Dohner
Summary: This study demonstrated that the combination therapy of oral ivosidenib and azacitidine showed better event-free survival and longer overall survival in patients with newly diagnosed IDH1-mutated acute myeloid leukemia.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Multidisciplinary Sciences
Mahmoud S. Alghamri, Brandon L. McClellan, Ruthvik P. Avvari, Rohit Thalla, Stephen Carney, Margaret S. Hartlage, Santiago Haase, Maria Ventosa, Ayman Taher, Neha Kamran, Li Zhang, Syed Mohd Faisal, Felipe J. Nunez, Maria Belen Garcia-Fabiani, Wajd N. Al-Holou, Daniel Orringer, Shawn Hervey-Jumper, Jason Heth, Parag G. Patil, Karen Eddy, Sofia D. Merajver, Peter J. Ulintz, Joshua Welch, Chao Gao, Jialin Liu, Gabriel Nunez, Dolores Hambardzumyan, Pedro R. Lowenstein, Maria G. Castro
Summary: The efficacy of immune-stimulatory gene therapy is enhanced in mIDH1 gliomas due to the reprogramming of infiltrating myeloid cells, mainly non-suppressive neutrophils and pre-neutrophils, in the tumor microenvironment. This reprogramming is triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells, leading to non-inhibitory myeloid cells within the tumor microenvironment and enhancing the therapy's effectiveness.
Article
Medicine, General & Internal
Ingo K. Mellinghoff, Martin J. van den Bent, Deborah T. Blumenthal, Mehdi Touat, Katherine B. Peters, Jennifer Clarke, Joe Mendez, Shlomit Yust-Katz, Liam Welsh, Warren P. Mason, Francois Ducray, Yoshie Umemura, Burt Nabors, Matthias Holdhoff, Andreas F. Hottinger, Yoshiki Arakawa, Juan M. Sepulveda, Wolfgang Wick, Riccardo Soffietti, James R. Perry, Pierre Giglio, Macarena de la Fuente, Elizabeth A. Maher, Steven Schoenfeld, Dan Zhao, Shuchi S. Pandya, Lori Steelman, Islam Hassan, Patrick Y. Wen, Timothy F. Cloughesy
Summary: In a phase 3 trial, vorasidenib showed significant improvement in progression-free survival and delay in the time to the next intervention for patients with grade 2 IDH-mutant glioma.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Hematology
Yu Gu, Risheng Yang, Ying Yang, Yuanlin Zhao, Andrew Wakeham, Wanda Y. Li, Alan Tseng, Julie Leca, Thorsten Berger, Mary Saunders, Jerome Fortin, Xing Gao, Yuan Yuan, Liming Xiao, Feng Zhang, Lijun Zhang, Guangxun Gao, Wenjing Zhou, Zhe Wang, Tak W. Mak, Jing Ye
Summary: IDH1 mutations disrupt normal erythropoiesis by inhibiting succinyl-CoA production, impairing heme biosynthesis, and inducing excessive reactive oxygen species, resulting in the cell death of mutant erythroid cells. Exogenous succinyl-CoA can rescue erythropoiesis in IDH1-mutant erythroid cells, providing potential therapeutic implications for IDH-mutant tumors.
Article
Hematology
Jingtao Lu, Meiyu Chen, Haiying Hua, Wei Qin, Ri Zhang, Xuzhang Lu, Hongying Chao
Summary: Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) frequently occur in acute myeloid leukemia (AML) patients, showing a complex coexistence with other mutated genes, particularly those involved in transcription regulation and DNA methylation. Different IDH mutations, such as IDH2 (R140Q) and IDH2 (R172K), exhibit distinct clinical features, including age-related platelet and white blood cell count abnormalities. Further research is needed to investigate the association between IDH mutations and other genetic abnormalities that may impact disease progression and prognosis.
INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY
(2021)
Article
Immunology
Lucille Stuani, Marie Sabatier, Estelle Saland, Guillaume Cognet, Nathalie Poupin, Claudie Bosc, Florence A. Castelli, Lara Gales, Evgenia Turtoi, Camille Montersino, Thomas Farge, Emeline Boet, Nicolas Broin, Clement Larrue, Natalia Baran, Madi Y. Cisse, Marc Conti, Sylvain Loric, Tony Kaoma, Alexis Hucteau, Aliki Zavoriti, Ambrine Sahal, Pierre-Luc Mouchel, Mathilde Gotanegre, Cedric Cassan, Laurent Fernando, Feng Wang, Mohsen Hosseini, Emeline Chu-Van, Laurent Le Cam, Martin Carroll, Mary A. Selak, Norbert Vey, Remy Castellano, Francois Fenaille, Andrei Turtoi, Guillaume Cazals, Pierre Bories, Yves Gibon, Brandon Nicolay, Sebastien Ronseaux, Joseph R. Marszalek, Koichi Takahashi, Courtney D. DiNardo, Marina Konopleva, Vera Pancaldi, Yves Collette, Floriant Bellvert, Fabien Jourdan, Laetitia K. Linares, Christian Recher, Jean-Charles Portais, Jean-Emmanuel Sarry
Summary: Mutations in IDH lead to enhanced mitochondrial oxidative metabolism in AML, involving increased electron transport chain activity and fatty acid oxidation. IDH1 mutant inhibitors reduce 2-HG levels and CEBPα methylation, but do not reverse fatty acid oxidation and OxPHOS. Targeting mitochondrial activities may improve anti-AML efficacy of IDH mutant inhibitors.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Oncology
Xue Qing David Wang, Dandan Fan, Qinyu Han, Yiman Liu, Hongzhi Miao, Xinyu Wang, Qinglan Li, Dong Chen, Haley Gore, Pamela Himadewi, Gerd P. Pfeifer, Tomasz Cierpicki, Jolanta Grembecka, Jianzhong Su, Shasha Chong, Liling Wan, Xiaotian Zhang
Summary: Nucleophosmin (NPM1) is a nucleolar protein with various functions, and its mutation is commonly found in acute myeloid leukemia (AML). This study shows that mutant NPM1 directly binds to active chromatin regions and controls the transcription of AML-driving genes. These findings provide insights into the mechanism behind AML caused by NPM1 mutation and suggest potential therapeutic interventions.
Article
Hematology
Stephane de Botton, Pierre Fenaux, Karen Yee, Christian Recher, Andrew H. Wei, Pau Montesinos, David C. Taussig, Arnaud Pigneux, Thorsten Braun, Antonio Curti, Carolyn Grove, Brian A. Jonas, Asim Khwaja, Ollivier Legrand, Pierre Peterlin, Montserrat Arnan, William Blum, Daniela Cilloni, Devendra K. Hiwase, Joseph G. Jurcic, Juergen Krauter, Xavier Thomas, Justin M. Watts, Jay Yang, Olga Polyanskaya, Julie Brevard, Jennifer Sweeney, Emma Barrett, Jorge Cortes
Summary: Olutasidenib (FT-2102) is an effective and selective oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). In a pivotal cohort study, olutasidenib monotherapy showed a complete remission (CR) plus CR with partial hematologic recovery (CRh) rate of 35% and an overall response rate of 48% in IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory acute myeloid leukemia (AML). The median duration of CR/CRh was 25.9 months, and the median overall survival was 11.6 months. Grade 3 or 4 adverse events included febrile neutropenia, anemia, thrombocytopenia, and neutropenia. Differentiation syndrome adverse events occurred in 14% of patients, with one fatal case reported. Olutasidenib provides a therapeutic advance in this poor-prognostic population of AML patients with mIDH1 R/R. This trial was registered at www.clinicaltrials.gov as #NCT02719574.
Review
Oncology
Claudio Cerchione, Alessandra Romano, Naval Daver, Courtney DiNardo, Elias Joseph Jabbour, Marina Konopleva, Farhad Ravandi-Kashani, Tapan Kadia, Maria Paola Martelli, Alessandro Isidori, Giovanni Martinelli, Hagop Kantarjian
Summary: The discovery of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2 has led to the development of individualized treatment strategy in approximately 20% of patients with acute myeloid leukemia (AML). Targeting IDH to promote differentiation and maturation of malignant clone is an emerging strategy in AML, and small molecule inhibitors have shown promising efficacy in phase I/II trials. The contribution of IDH1/IDH2 mutations in leukemogenesis and progress of targeted therapeutics in AML is highlighted in this review.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Daniel A. Pollyea, Courtney D. DiNardo, Martha L. Arellano, Arnaud Pigneux, Walter Fiedler, Marina Konopleva, David A. Rizzieri, B. Douglas Smith, Atsushi Shinagawa, Roberto M. Lemoli, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L. Miller, Hagop M. Kantarjian
Summary: The combination therapy of venetoclax and azacitidine shows high efficacy and safety in patients with IDH1/2-mutant acute myeloid leukemia (AML), leading to improved overall survival.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Elizabeth M. Corley, Moaath K. Mustafa Ali, Hanan Alharthy, Kathryn A. F. Kline, Danielle Sewell, Jennie Y. Law, Seung Tae Lee, Sandrine Niyongere, Vu H. Duong, Maria R. Baer, Ashkan Emadi
Summary: In this retrospective cohort study, we found that the IDH1 c.315C>T SNP does not have a worse prognosis for AML patients.
FRONTIERS IN ONCOLOGY
(2022)
Article
Chemistry, Medicinal
Bongki Ko, Yongsoo Jang, Min Ha Kim, Thai Thi Lam, Hye Kyung Seo, Pyeonghwa Jeong, Munkyung Choi, Keon Wook Kang, So-Deok Lee, Jin-Hee Park, Myungjin Kim, Sun-Young Han, Yong-Chul Kim
Summary: This study developed novel inhibitors targeting mutant FLT3 kinases through chemical moieties optimization. The optimized compound 22f exhibited potent inhibitory activities against FLT3 and FLT3/D835Y, as well as strong antiproliferative activity against AML cell line MV4-11 cells. It also showed single-digit nanomolar inhibitory values in mutant FLT kinase expressed cell lines.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Hematology
David H. Henry, John Glaspy, Rosemary Harrup, Moshe Mittelman, Amy Zhou, Hetty E. Carraway, Charles Bradley, Gopal Saha, Katharina Modelska, Pamela Bartels, Robert Leong, Kin-Hung P. Yu
Summary: The study confirmed that among the three starting doses of oral roxadustat, 2.5 mg/kg showed the best performance in treating anemia, facilitating transfusion independence and reducing the need for RBC transfusions. Roxadustat administered orally thrice weekly was well-tolerated, with no fatalities or progression to acute myeloid leukemia observed.
AMERICAN JOURNAL OF HEMATOLOGY
(2022)
Article
Oncology
Sridhar A. Malkaram, Aymen Shatnawi, Jun Fan, Hetty Carraway, James Denvir, Donald A. Primerano, Zakaria Y. Abd Elmageed, Tamer E. Fandy
Summary: The study compares the effects of 5-azacytidine (5AC) and decitabine (DAC) on histone acetylation and methylation. Both drugs were found to induce changes in histone posttranslational modifications, but with distinct differences. This highlights the importance of considering the drugs separately despite their structural and activity similarities.
Letter
Biophysics
Sanghee Hong, Lisa Rybicki, Carmelo Gurnari, Simona Pagliuca, Aiwen Zhang, Dawn Thomas, Valeria Visconte, Jibran Durrani, Ronald M. Sobecks, Matt Kalaycio, Aaron T. Gerds, Hetty E. Carraway, Sudipto Mukherjee, Mikkael A. Sekeres, Anjali S. Advani, Navneet S. Majhail, Betty K. Hamilton, Bhumika J. Patel, Jaroslaw P. Maciejewski
BONE MARROW TRANSPLANTATION
(2022)
Letter
Hematology
Rami S. Komrokji, Hetty E. Carraway, Ulrich Germing, Martin Wermke, Amer M. Zeidan, Eric Fu, Bjoern Rueter, Ute Burkard, Annika Osswald, James M. Foran
Article
Hematology
Courtney D. DiNardo, Sangeetha Venugopal, Curtis Lachowiez, Koichi Takahashi, Sanam Loghavi, Guillermo Montalban-Bravo, Xuemei Wang, Hetty Carraway, Mikkael Sekeres, Ameenah Sukkur, Danielle Hammond, Kelly Chien, Abhishek Maiti, Lucia Masarova, Koji Sasaki, Yesid Alvarado, Tapan Kadia, Nicholas J. Short, Naval Daver, Gautam Borthakur, Farhad Ravandi, Hagop M. Kantarjian, Bhumika Patel, Amy Dezern, Gail Roboz, Guillermo Garcia-Manero
Summary: The combination of enasidenib with azacitidine showed a 74% overall response rate in newly diagnosed mIDH2 MDS patients, while enasidenib monotherapy achieved a 35% response rate in patients after HMA failure. These findings demonstrate that enasidenib is an effective treatment option for mIDH2 MDS.
Letter
Oncology
Amer M. Zeidan, Jan Philipp Bewersdorf, Rena Buckstein, Mikkael A. Sekeres, David P. Steensma, Uwe Platzbecker, Sanam Loghavi, Jacqueline Boultwood, Rafael Bejar, John M. Bennett, Uma Borate, Andrew M. Brunner, Hetty Carraway, Jane E. Churpek, Naval G. Daver, Matteo Della Porta, Amy E. DeZern, Fabio Efficace, Pierre Fenaux, Maria E. Figueroa, Peter Greenberg, Elizabeth A. Griffiths, Stephanie Halene, Robert P. Hasserjian, Christopher S. Hourigan, Nina Kim, Tae Kon Kim, Rami S. Komrokji, Vijay Kutchroo, Alan F. List, Richard F. Little, Ravi Majeti, Aziz Nazha, Stephen D. Nimer, Olatoyosi Odenike, Eric Padron, Mrinal M. Patnaik, Gail J. Roboz, David A. Sallman, Guillermo Sanz, Maximilian Stahl, Daniel T. Starczynowski, Justin Taylor, Zhuoer Xie, Mina Xu, Michael R. Savona, Andrew H. Wei, Omar Abdel-Wahab, Valeria Santini
Letter
Hematology
Tariq Kewan, Waled Bahaj, Arda Durmaz, Mai Aly, Olisaemeka D. Ogbue, Hetty E. Carraway, Mikkael A. Sekeres, Valeria Visconte, Carmelo Gurnari, Jaroslaw P. Maciejewski
Article
Hematology
Amer M. Zeidan, Uwe Platzbecker, Jan Philipp Bewersdorf, Maximilian Stahl, Lionel Ades, Uma Borate, David Bowen, Rena Buckstein, Andrew Brunner, Hetty E. Carraway, Naval Daver, Maria Diez-Campelo, Theo de Witte, Amy E. DeZern, Fabio Efficace, Guillermo Garcia-Manero, Jacqueline S. Garcia, Ulrich Germing, Aristoteles Giagounidis, Elizabeth A. Griffiths, Robert P. Hasserjian, Eva Hellstrom-Lindberg, Marcelo Iastrebner, Rami Komrokji, Austin G. Kulasekararaj, Luca Malcovati, Yasushi Miyazaki, Olatoyosi Odenike, Valeria Santini, Guillermo Sanz, Phillip Scheinberg, Reinhard Stauder, Arjan A. van de Loosdrecht, Andrew H. Wei, Mikkael A. Sekeres, Pierre Fenaux
Summary: The initial response criteria developed by the International Working Group (IWG) in 2000 have limitations in their application to higher-risk MDS and their ability to fully capture the clinical benefits of novel investigational drugs. Therefore, an international panel of MDS experts used a modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results.
Meeting Abstract
Hematology
Julia H. Joo, Yanwen Chen, Aaron T. Gerds, Anjali Advani, Sophia R. Balderman, Hetty E. Carraway, Abhay Singh Singh, Sudipto Mukherjee
Meeting Abstract
Hematology
Tariq Kewan, Arda Durmaz, Waled Bahaj, Carmelo Gurnari, Hussein Awada, Olisaemeka Ogbue, Ramsha Ahmed, Simona Pagliuca, Hassan Awada, Yasuo Kubota, Minako Mori, Ben Ponvilawan, Bayan Al-Share, Bhumika J. Patel, Hetty E. Carraway, Jacob Scott, Suresh Kumar Balasubramanian, Taha Bat, Yazan F. Madanat, Mikkael A. Sekeres, Torsten Haferlach, Valeria Visconte, Jaroslaw P. Maciejewski
Meeting Abstract
Hematology
Teodora Kuzmanovic, Metis Hasipek, Samuel Li, Thomas Laframboise, Valeria Visconte, Sunisa Kongkiatkamon, Seth J. Corey, Sudipto Mukherjee, Anjali Advani, Aaron T. Gerds, Yogenthiran Saunthararajah, Sophia R. Balderman, Abhay Singh Singh, Hetty E. Carraway, Niroshan Nadarajah, Manja Meggendorfer, Jaroslaw P. Maciejewski, Bhumika J. Patel
Letter
Oncology
Mrinal M. Patnaik, Amer M. Zeidan, Eric Padron, Uwe Platzbecker, David A. Sallman, Amy E. DeZern, Rafael Bejar, Mikkael Sekeres, Justin Taylor, Richard F. Little, Jan P. Bewersdorf, Tae Kon. Kim, Nina Kim, Christopher S. Hourigan, Matteo G. Dela Porta, Maximilian Stahl, David Steensma, Mina L. Xu, Olatoyosi Odenike, Hetty Carraway, Pierre Fenaux, Aziz Nazha, Rami Komrokji, Sanam Loghavi, Zhuoer Xie, Robert Hasserjian, Michael Savona, John M. Bennett
Meeting Abstract
Oncology
Sudipto Mukherjee, Weichuan Dong, Aaron T. Gerds, Hetty E. Carraway, Abhay Singh, Anjali S. Advani, Siran M. Koroukian
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
(2023)
Meeting Abstract
Oncology
Farhad Ravandi, Ashwin Kishtagari, Hetty E. Carraway, Gary J. Schiller, Steve Morris, Alexandru Cacovean, Bhagyashree Kelshikar Yadav, Thomas Butler, Jeffrey E. Lancet
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Meeting Abstract
Oncology
Farhad Ravandi, Hetty E. Carraway, Lilia Taningco, Eric Laille, Jing Gong, Thomas Prebet, Daniel Lopes De Menezes, Andrew H. Wei
JOURNAL OF CLINICAL ONCOLOGY
(2022)