Review
Medicine, General & Internal
Cristina Negotei, Andrei Colita, Iuliana Mitu, Anca Roxana Lupu, Mihai-Emilian Lapadat, Constanta Elena Popovici, Madalina Crainicu, Oana Stanca, Nicoleta Mariana Berbec
Summary: Acute myeloid leukemia (AML) is an aggressive disease characterized by the accumulation of abnormal hematopoietic precursors. FLT3 gene mutations increase the risk of relapse and mortality. FLT3 mutation screening is mandatory for AML patients, and FLT3 inhibitors are crucial for treatment. FLT3-ITD is the most common mutation type, while FLT3-TKD affects a smaller percentage. FLT3 inhibitors are now vital in treating AML patients with FLT3 mutations.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Oncology
Jiao Wei, Ai-Min Hui, Nitika
Summary: This article is a summary of biomarkers for FLT3 inhibitors in acute myeloid leukemia (AML) and alternative approaches to overcome resistance to current therapies. AML is a type of leukemia where FLT3 gene mutations are common, making it an attractive target for treatment. However, the current inhibitors face challenges due to multiple mutations in the FLT3 gene. Therefore, the identification of biomarkers and finding alternative approaches are important.
Article
Pediatrics
Franziska Schmidt, Miriam Erlacher, Charlotte Niemeyer, Dirk Reinhardt, Jan-Henning Klusmann
Summary: This study reports four pediatric patients with FLT3-ITD-positive AML and hyperleukocytosis, who received sorafenib in combination with cytoreductive chemotherapy prior to the induction phase. The study showed that sorafenib rapidly reduced white blood cells and resulted in clinical stabilization of the patients. Adverse side effects were mild and chemotherapy could be initiated concurrently or subsequently.
FRONTIERS IN PEDIATRICS
(2022)
Article
Oncology
Shaowei Qiu, Harish Kumar, Chengcheng Yan, Hui Li, Andrew J. Paterson, Nicholas R. Anderson, Jianbo He, Jing Yang, Min Xie, David K. Crossman, Rui Lu, Robert S. Welner, Ravi Bhatia
Summary: The FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML). FLT3 tyrosine kinase inhibitors (TKIs) demonstrate clinical efficacy but fail to target leukemia stem cells (LSC) and do not generate sustained responses. Autophagy plays an important role in regulating FLT3-ITD AML stem cell function and response to TKI treatment. Autophagy inhibition reduces the quiescence and repopulating potential of FLT3-ITD AML LSC, while TKI treatment reduces mitochondrial respiration and counteracts the effects of autophagy inhibition on LSC. The targeting of AML LSC and progenitor cells by TKIs is p53-dependent, enhanced by autophagy inhibition in progenitors but reduced in LSC, suggesting a potential alternative approach to target AML LSC quiescence and regenerative potential.
Article
Oncology
Amin Huang, Peiting Zeng, Yinguang Li, Wenhua Lu, Yaoming Lai
Summary: This study discusses the resistance of AML patients with FLT3-ITD mutation to sorafenib, potentially due to the loss of the FLT3 target protein and sustained activation of the PI3K/Akt signaling pathway. The PI3K inhibitor, LY294002, can block this pathway and inhibit glycolysis, disrupting ATP production and inducing cell apoptosis.
FRONTIERS IN ONCOLOGY
(2021)
Article
Medicine, General & Internal
Xin Xu, Zhiping Fan, Yu Wang, Fen Huang, Yajing Xu, Jing Sun, Na Xu, Lan Deng, Xudong Li, Xinquan Liang, Xiaodan Luo, Pengcheng Shi, Hui Liu, Yan Chen, Sanfang Tu, Xiaojun Huang, Qifa Liu, Li Xuan
Summary: The study found that sorafenib maintenance post-transplantation does not increase the incidence and mortality of EBV and CMV infections in patients with FLT3-ITD acute myeloid leukemia, demonstrating a favorable safety profile.
Article
Cell Biology
Bogdan Popescu, Carlos Stahlhut, Theodore C. Tarver, Sydney Wishner, Bianca J. Lee, Cheryl A. C. Peretz, Cuyler Luck, Paul Phojanakong, Juan Antonio Camara Serrano, Henry Hongo, Jose M. Rivera, Simayijiang Xirenayi, John A. Chukinas, Veronica Steri, Sarah K. Tasian, Elliot Stieglitz, Catherine C. Smith
Summary: This study reports the preclinical efficacy of co-targeting the key node in MAPK signaling, SHP2, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses the proliferation of AML cell lines and increases apoptotic dependency on BCL2. RMC-4550 and venetoclax show synergistic lethality in AML cell lines.
CELL REPORTS MEDICINE
(2023)
Article
Immunology
Varvara Maiorova, Murad D. Mollaev, Polina Vikhreva, Elena Kulakovskaya, Dmitry Pershin, Dmitriy M. Chudakov, Alexey Kibardin, Michael A. Maschan, Sergey Larin
Summary: A CAR-T cell targeted at AML's full-length Flt3 ligand recognition module is shown to have specific killing effects on Flt3-positive leukemia cells without cytotoxicity towards Flt3-negative cells. The cytolytic capacity of T cells plays a crucial role in the killing, and the targeting authenticity is confirmed through competitive inhibition. The developed system, functioning as a non-immunogenic equivalent of scFv-mediated targeting, shows promising antitumor effects with low off-target cytotoxicity for AML treatment.
Article
Oncology
Jad Othman, Nicola Potter, Katya Mokretar, David Taussig, Anjum Khan, Pramila Krishnamurthy, Anne-Louise Latif, Paul Cahalin, James Aries, Mariam Amer, Edward Belsham, Eibhlin Conneally, Charles Craddock, Dominic Culligan, Mike Dennis, Caroline Duncan, Sylvie D. Freeman, Caroline Furness, Amanda Gilkes, Paraskevi Gkreka, Katherine Hodgson, Wendy Ingram, Manish Jain, Andrew King, Steven Knapper, Panagiotis Kottaridis, Mary Frances McMullin, Unmesh Mohite, Loretta Ngu, Jenny O'Nions, Katharine Patrick, Tom Rider, Wing Roberts, Marianne Tang Severinsen, Neill Storrar, Tom Taylor, Nigel H. Russell, Richard Dillon
Summary: Patients with FLT3-mutated AML are at high risk of relapse and poor outcomes. Monitoring measurable residual disease (MRD) can help identify patients destined to relapse, providing an opportunity for pre-emptive intervention. In this study, 56 patients with molecular failure were treated with FLT3 inhibitors (FLT3i), resulting in a molecular response rate of 60% and an overall survival rate of 80% at 2 years. High-sensitivity next-generation sequencing identified patients more likely to benefit from FLT3i monotherapy. Further prospective studies are warranted to evaluate this promising treatment strategy.
Article
Multidisciplinary Sciences
Jarno Kivioja, Disha Malani, Ashwini Kumar, Mika Kontro, Alun Parsons, Olli Kallioniemi, Caroline A. Heckman
Summary: The study demonstrated a significant association between FLT3 internal tandem duplication allelic ratio (ITD-AR) and ex vivo response to FLT3 inhibitors in adult AML, while ITD length showed no correlation. Patients with high HLF gene expression and ITD-AR had better clinical response to the FLT3 inhibitor sorafenib compared to those with low ITD-AR and HLF expression.
SCIENTIFIC REPORTS
(2021)
Article
Hematology
Mohammad Azhar, Zachary Kincaid, Meenu Kesarwani, Arhama Ahmed, Mark Wunderlich, Tahir Latif, Daniel Starczynowski, Mohammad Azam
Summary: The JAK2 inhibitor momelotinib is a potent type 1 FLT3 inhibitor that effectively suppresses FLT3 mutations and growth factor signaling, showing better efficacy in suppressing leukemia in a preclinical murine model of AML.
Article
Cell Biology
You-Liang Lai, Kai-Hung Wang, Hsing-Pang Hsieh, Wan-Ching Yen
Summary: DBPR114 showed activity against HCC tumor cell proliferation in vitro regardless of p53 alteration status and tumor grade. It induced growth inhibition in HCC cells through apoptosis induction, cell cycle arrest, and polyploidy formation. DBPR114 also exhibited anti-angiogenic effects and significantly inhibited tumor growth in multiple HCC tumor xenograft models.
JOURNAL OF BIOMEDICAL SCIENCE
(2022)
Article
Chemistry, Medicinal
Zhijie Wang, Donglin Wu, Xiaofei Zhao, Canlin Liu, Siming Jia, Qindi He, Fei Huang, Zitian Cheng, Tao Lu, Yadong Chen, Yun Chen, Pei Yang, Shuai Lu
Summary: AML patients need new therapies due to poor outcomes and relapse with single-target drugs. Inhibiting multiple oncogenic signals simultaneously is a promising strategy. This study developed novel dual FLT3/HDAC inhibitors through rational drug design and demonstrated their potential for AML treatment. The inhibitors blocked FLT3 and HDAC pathways, induced apoptosis, and arrested cell cycle.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Shai Shimony, Moshe Yeshurun, Ofir Wolach, Ron Ram, Uri Rozovski, Liat Shargian, Tsila Zukerman, Odelia Amit, Yael Bar-On, Baher Krayem, Batya Avni, Galit Peretz, Pia Raanani, Oren Pasvolsky
Summary: The study demonstrates that post-transplant use of TKIs is safe and effective in improving overall survival of patients with acute myeloid leukemia, especially in the era of widespread pre-transplant use of these agents. Most patients maintained complete remission after transplantation, with those receiving pre-transplant TKIs showing similar outcomes.
LEUKEMIA & LYMPHOMA
(2021)
Review
Biochemistry & Molecular Biology
Michael Loschi, Rinzine Sammut, Edmond Chiche, Thomas Cluzeau
Summary: FLT3-mutated acute myeloid leukemia, accounting for around 30% of AML cases, has seen improved prognosis with the emergence of tyrosine kinase inhibitors. However, challenges such as drug resistance still exist in the treatment of this disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Letter
Hematology
Michele Wieczorek, Myriam Labopin, Luca Castagna, Eolia Brissot, Gerard Socie, Anna Maria Raiola, Emanuele Angelucci, Arancha Bermudez Rodriguez, Ibrahim Yakoub-Agha, Mahmoud Aljurf, Charles Crawley, Jean Baptiste Mear, Maurizio Musso, Renato Fanin, Daniele Avenoso, Pascal Turlure, Cristina Tecchio, Jaime Sanz, Fabio Ciceri, Arnon Nagler, Mohamad Mohty
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Hematology
Sebastian Giebel, Myriam Labopin, Thomas Schroeder, Ryszard Swoboda, Johan Maertens, Jean Henri Bourhis, Giovanni Grillo, Urpu Salmenniemi, Inken Hilgendorf, Nicolaus Kroeger, Xavier Poire, Jan J. Cornelissen, Mutlu Arat, Bipin Savani, Alexandros Spyridonidis, Arnon Nagler, Mohamad Mohty
Summary: A comparison was made between two myeloablative regimens for acute myeloid leukemia (AML) patients, one involving cyclophosphamide and total body irradiation (CyTBI12Gy) and the other involving fludarabine and total body irradiation (FluTBI12Gy). The results showed that the two regimens had similar efficacy in terms of relapse rate, non-relapse mortality, and survival rate. However, the FluTBI12Gy regimen was associated with a lower incidence of acute graft-versus-host disease and better survival rates.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Editorial Material
Hematology
Jean-Luc Harousseau, Mohamad Mohty
Article
Biophysics
Riccardo Saccardi, Hein Putter, Dirk-Jan Eikema, Maria Paula Busto, Eoin McGrath, Bas Middelkoop, Gillian Adams, Marina Atlija, Francis Ayuketang Ayuk, Helen Baldomero, Yves Beguin, Rafael de la Camara, Angel Cedillo, Anna Maria Sureda Balari, Christian Chabannon, Selim Corbacioglu, Harry Dolstra, Rafael F. Duarte, Remy Dulery, Raffaella Greco, Andreu Gusi, Nada Hamad, Michelle Kenyon, Nicolaus Kroeger, Myriam Labopin, Julia Lee, Per Ljungman, Lynn Manson, Florence Mensil, Noel Milpied, Mohamad Mohty, Elena Oldani, Kim Orchard, Jakob Passweg, Rachel Pearce, Regis Peffault de Latour, Helene A. Poirel, Tuula Rintala, J. Douglas Rizzo, Annalisa Ruggeri, Carla Sanchez-Martinez, Fermin Sanchez-Guijo, Isabel Sanchez-Ortega, Marie Trnkova, David Valcarcel Ferreiras, Leonie Wilcox, Liesbeth C. de Wreede, John A. Snowden
Summary: From 2016, EBMT and JACIE developed an international risk-adapted benchmarking program for HSCT outcome. The program aims to assure quality and meet accreditation requirements for EBMT Centers. With input from previous experience, the program established criteria for patient and Center selection and a statistical model based on key clinical variables. The experience so far has shown the feasibility, acceptability, and reliability of the system, while also identifying limitations and future challenges.
BONE MARROW TRANSPLANTATION
(2023)
Review
Biophysics
Mohamad Mohty, Florent Malard, Ahmed S. Alaskar, Mahmoud Aljurf, Mutlu Arat, Peter Bader, Frederic Baron, Ali Bazarbachi, Didier Blaise, Eolia Brissot, Fabio Ciceri, Selim Corbacioglu, Jean-Hugues Dalle, Fiona Dignan, Anne Huynh, Michelle Kenyon, Arnon Nagler, Antonio Pagliuca, Zinaida Peric, Paul G. Richardson, Annalisa Ruggeri, Tapani Ruutu, Ibrahim Yakoub-Agha, Rafael F. Duarte, Enric Carreras
Summary: Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can occur after hematopoietic cell transplantation (HCT). The European Society for Blood and Marrow Transplantation (EBMT) has recently updated the definition and severity grading system for SOS/VOD in adult patients. The aim of this work is to provide an update on the diagnosis, severity assessment, pathophysiology, and treatment of SOS/VOD in adult patients.
BONE MARROW TRANSPLANTATION
(2023)
Article
Biophysics
Gesine Bug, Myriam Labopin, Riitta Niittyvuopio, Matthias Stelljes, Hans Christian Reinhardt, Inken Hilgendorf, Nicolaus Kroeger, Ain Kaare, Wolfgang Bethge, Kerstin Schaefer-Eckart, Mareike Verbeek, Stephan Mielke, Kristina Carlson, Ali Bazarbachi, Alexandros Spyridonidis, Bipin N. Savani, Arnon Nagler, Mohamad Mohty
Summary: Retrospective analysis compared two different conditioning regimens for AML patients undergoing HSCT and found that using FluTBI resulted in lower relapse probability but higher non-relapse mortality. There were no significant differences in overall survival and GRFS between the two groups. Therefore, FluTBI may be more suitable for younger patients below the age of 55.
BONE MARROW TRANSPLANTATION
(2023)
Article
Biophysics
Klaus Hirschbuehl, Myriam Labopin, Emmanuelle Polge, Didier Blaise, Jean Henri Bourhis, Gerard Socie, Edouard Forcade, Ibrahim Yakoub-Agha, Helene Labussiere-Wallet, Wolfgang Bethge, Patrice Chevallier, Sarah Bonnet, Matthias Stelljes, Alexandros Spyridonidis, Zinaida Peric, Eolia Brissot, Bipin Savani, Sebastian Giebel, Christoph Schmid, Fabio Ciceri, Arnon Nagler, Mohamad Mohty
Summary: Allogeneic hematopoietic cell transplantation is a curative treatment for high-risk acute lymphoblastic leukemia, and conditioning regimens based on 12 Gray total body irradiation are the standard for patients under 45 years old. However, elderly patients often receive intermediate intensity conditioning to reduce toxicity. A retrospective study compared the outcomes of different conditioning regimens in ALL patients over 45 years old.
BONE MARROW TRANSPLANTATION
(2023)
Article
Oncology
Arnon Nagler, Myriam Labopin, Didier Blaise, Anna Maria Raiola, Lucia Lopez Corral, Stefania Bramanti, Simona Sica, Mi Kwon, Yener Koc, Jiri Pavlu, Alexander Kulagin, Alessandro Busca, Arancha Bermudez Rodriguez, Peter Remenyi, Christoph Schmid, Eolia Brissot, Jaime Sanz, Ali Bazarbachi, Sebastian Giebel, Fabio Ciceri, Mohamad Mohty
Summary: Comparing outcomes of adult patients with secondary acute myeloid leukemia (sAML) and de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide, no significant difference was observed in transplantation outcomes between the two groups.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)
Review
Immunology
Mohammad Hassan Hodroj, Iman Abou Dalle, Nour Moukalled, Jean El Cheikh, Mohamad Mohty, Ali Bazarbachi
Summary: The outcome of B-cell acute lymphoblastic leukemia has improved with multi-agent chemotherapy and immunotherapeutic agents. However, relapse post-transplant is still common. This review discusses strategies such as tyrosine kinase inhibitors, innovative agents, and cellular therapy to prevent and overcome relapse post allo-HCT in ALL patients.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Hematology
Stephan A. Grupp, Selim Corbacioglu, Hyoung Jin Kang, Takanori Teshima, Seong Lin Khaw, Franco Locatelli, Johan Maertens, Matthias Stelljes, Polina Stepensky, Paty Lopez, Vian Amber, Antonio Pagliuca, Paul G. Richardson, Mohamad Mohty
Summary: This study compared defibrotide prophylaxis plus best supportive care to best supportive care alone for preventing sinusoidal obstruction syndrome after hematopoietic stem-cell transplantation. The results showed that defibrotide did not provide a benefit in preventing sinusoidal obstruction syndrome.
LANCET HAEMATOLOGY
(2023)
Article
Medicine, General & Internal
Florent Malard, Ernst Holler, Brenda M. Sandmaier, He Huang, Mohamad Mohty
Summary: Acute graft-versus-host disease (GVHD) is a common immune complication that can occur after allogeneic haematopoietic cell transplantation (alloHCT). This Primer summarizes the epidemiology, pathophysiology, diagnosis, prevention and treatment of this disorder. The article also reviews future research avenues and the effect this disorder has on patients' quality of life.
NATURE REVIEWS DISEASE PRIMERS
(2023)
Article
Oncology
Maria-Victoria Mateos, Sikander Ailawadhi, Luciano J. Costa, Shakira J. Grant, Lalit Kumar, Mohamad Mohty, Didem Aydin, Saad Z. Usmani
Summary: This study examined the influence of sociodemographic factors on disparities in outcomes for multiple myeloma patients. The results showed that increasing age and low socioeconomic status were associated with worse patient outcomes globally. In the US, men had worse outcomes while women and minority populations had poorer access to treatment.
BLOOD CANCER JOURNAL
(2023)
Article
Hematology
Molly C. Tokaz, Helen Baldomero, Andrew J. Cowan, Wael Saber, Hildegard Greinix, Mickey B. C. Koh, Nicolaus Kroeger, Mohamad Mohty, Sebastian Galeano, Shinichiro Okamoto, Naeem Chaudhri, Amado J. Karduss, Fabio Ciceri, Vergilio Antonio R. Colturato, Selim Corbacioglu, Alaa Elhaddad, Lisa M. Force, Cristobal Frutos, Andres Gomez-De Leon, Nada Hamad, Nelson Hamerschlak, Naya He, Aloysius Ho, Xiao-jun Huang, Ben Jacobs, Hee-Je Kim, Minako Iida, Leslie Lehmann, Regis Peffault de Latour, Mary-Elizabeth M. Percival, Martina Perdomo, Walid Rasheed, Kirk R. Schultz, Adriana Seber, Bor-Sheng Ko, Anderson Joao Simione, Alok Srivastava, Jeff Szer, William A. Wood, Yoshihisa Kodera, Arnon Nagler, John A. Snowden, Daniel Weisdorf, Jakob Passweg, Marcelo C. Pasquini, Anna Sureda, Yoshiko Atsuta, Mahmoud Aljurf, Dietger Niederwieser
Summary: Acute myeloid leukemia (AML) is a fast-progressing and historically challenging disease. Hematopoietic stem cell transplantation (HSCT) is the best treatment option for many patients, but access and utilization on a global scale are unclear. This study aimed to investigate the global use of HSCT in AML and identify areas of need. The study found that AML incidence has increased globally, as has the use of HSCT, particularly allogeneic HSCT. However, there are significant regional variations in HSCT utilization and practices, including differences in graft sources. Further research is needed to understand and address these disparities.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)
Article
Hematology
Thomas G. Martin, Marcelo Capra, Mohamad Mohty, Kenshi Suzuki, Hang Quach, Michele Cavo, Philippe Moreau, Meletios Dimopoulos, Kwee Yong, Christina Tekle, Meredith C. Foster, Yvonne Barnes, Marie-Laure Risse, Joseph Mikhael
Summary: The role, timing, and impact of transplantation on further therapy after relapse in multiple myeloma (MM) are still being debated in the era of highly active novel agents. The impact of prior transplantation on treatment benefit from monoclonal antibodies in patients with relapsed/refractory MM (RRMM) is largely unknown. This subgroup analysis examined efficacy and safety in patients from the Phase 3 IKEMA study with and without previous transplantation.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)
Article
Medicine, Research & Experimental
Vincent Jachiet, Laure Ricard, Pierre Hirsch, Florent Malard, Laurent Pascal, Odile Beyne-Rauzy, Pierre Peterlin, Alexandre Thibault Jacques Maria, Norbert Vey, Maud D'Aveni, Marie-Pierre Gourin, Sophie Dimicoli-Salazar, Anne Banos, Stefan Wickenhauser, Louis Terriou, Benoit De Renzis, Eric Durot, Shanti Natarajan-Ame, Anne Vekhoff, Laurent Voillat, Sophie Park, Julien Vinit, Celine Dieval, Azeddine Dellal, Vincent Grobost, Lise Willems, Julien Rossignol, Eric Solary, Olivier Kosmider, Nicolas Dulphy, Lin Pierre Zhao, Lionel Ades, Pierre Fenaux, Olivier Fain, Mohamad Mohty, Beatrice Gaugler, Arsene Mekinian
Summary: Background systemic inflammatory and autoimmune diseases (SIADs) occur in a significant proportion of myelodysplastic syndrome (MDS) patients. The recently identified VEXAS syndrome, associated with somatic mutations in UBA1, is characterized by severe inflammatory conditions and hematological abnormalities, including MDS. However, the mechanisms underlying the association between MDS and SIADs are largely unknown. This study aimed to evaluate myeloid immune cell subsets in MDS patients with and without SIAD and compare them to healthy controls.
CLINICAL AND EXPERIMENTAL MEDICINE
(2023)