Review
Biochemistry & Molecular Biology
Moo-Kon Song, Byeong-Bae Park, Ji-Eun Uhm
Summary: FLT3 mutations are the most common genetic alterations in AML and have a negative impact on clinical prognosis. The development of FLT3 inhibitors has shown promise in improving outcomes for AML patients with FLT3 mutations. Midostaurin and gilteritinib have recently been approved as frontline treatments for AML by the FDA. Clinical trials are ongoing to explore the use of FLT3 inhibitors in different treatment settings. The accumulation of data on FLT3 inhibitors will be important evidence for guiding the use of these inhibitors in AML patients with FLT3 mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Xinhong Fei, Shuqin Zhang, Jiangying Gu, Jingbo Wang
Summary: The meta-analysis reveals that post-transplant FLT3i maintenance therapy can improve survival and reduce relapse in FLT3-mutated AML patients, and it is well-tolerated.
Article
Oncology
Javier Bregante, Anna Schoenbichler, Daniel Poeloeske, Lina Degenfeld-Schonburg, Garazi Monzo Contreras, Emir Hadzijusufovic, Elvin D. de Araujo, Peter Valent, Richard Moriggl, Anna Orlova
Summary: FLT3-ITD mutations are common and detrimental in AML, with AML cells quickly developing resistance to FLT3 kinase inhibitors. Through a drug screen, new potential therapeutics like ispinesib, WS6, ponatinib, and cabozantinib have been identified for FLT3-ITD+ AML. Combination therapy with cabozantinib and ispinesib shows strong efficacy against FLT3-ITD+ AML, suggesting promising novel treatment options for this clinical challenge.
Article
Biochemistry & Molecular Biology
Fansheng Ran, Yun Liu, Jian Zhu, Xuexian Deng, Hongmei Wu, Weizhi Tao, Xudong Xie, Yirong Hu, Yanan Zhang, Yong Ling
Summary: A novel class of aminopyrimidine-based dual-target inhibitors, designed for the treatment acute myeloid leukemia, effectively inhibited the activities of BTK, FLT3, and FLT3(D835Y) mutant. These compounds showed potent antiproliferative activities against leukemia cells and induced autophagy and apoptosis. In vivo studies demonstrated that compound 14m significantly suppressed the growth of MV-4-11 cells without apparent toxicity. These dual-target inhibitors hold promise for further optimization and mechanism studies.
BIOORGANIC CHEMISTRY
(2023)
Article
Oncology
Jessica K. Altman, Alexander E. Perl, Jason E. Hill, Matt Rosales, Erkut Bahceci, Mark J. Levis
Summary: The FLT3 inhibitor gilteritinib shows clinical activity in FLT3-mutated relapsed/refractory AML patients, with FLT3 mutation clearance and the achievement of composite complete remission or complete remission/complete remission with partial hematologic recovery potentially prolonging overall survival.
Article
Biochemistry & Molecular Biology
Chukwuebuka Egbuna, Kingsley C. Patrick-Iwuanyanwu, Eugene N. Onyeike, Johra Khan, Bader Alshehri
Summary: Mutations in FLT3 account for over 30-35% of AML cases, with current treatments providing only a 5-year average survival rate. Research is ongoing to discover new drug targets that may offer better outcomes for patients.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemistry & Molecular Biology
Joshua J. Lara, Alfonso E. Bencomo-Alvarez, Mayra A. Gonzalez, Idaly M. Olivas, James E. Young, Jose L. Lopez, Vanessa V. Velazquez, Steven Glovier, Mehrshad Keivan, Andres J. Rubio, Sara K. K. Dang, Jonathan P. Solecki, Jesse C. Allen, Desiree N. Tapia, Boranai Tychhon, Gonzalo E. Astudillo, Connor Jordan, Darshan S. Chandrashekar, Anna M. Eiring
Summary: PSMD1 and PSMD3 were identified as prognostic biomarkers and potential therapeutic targets in chronic myeloid leukemia and multiple solid tumors. In this study, the expression of 19S proteasome subunits in acute myeloid leukemia patients with FLT3 gene mutations was analyzed. The results showed that high levels of PSMD3 expression were associated with worse overall survival. PSMD3 knockdown impaired colony formation of FLT3+ AML cell lines and increased overall survival in xenograft models. Proteomics analyses suggested a role for PSMD3 in neutrophil degranulation and energy metabolism.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Hematology
Nianci Chen, Jiajia Pan, Yile Zhou, Liping Mao, Yinjun Lou, Jiejing Qian, Gaixiang Xu, Juying Wei, De Zhou, Lihong Shou, Li Huang, Minchao Yan, Hui Zeng, Cuihua Fan, Gongqiang Wu, Weiying Feng, Hongyan Tong, Jie Jin, Huafeng Wang
Summary: This retrospective analysis investigated the efficacy and safety of different gilteritinib-based combination therapies in relapsed/refractory FLT3-mutated AML patients. The study found that gilteritinib plus hypomethylating agent and venetoclax combination therapy showed higher response rates and may serve as an effective bridge to transplantation.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
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)
Article
Biochemistry & Molecular Biology
Daria Monogiou Belik, Riccardo Bernasconi, Lifen Xu, Giacomo Della Verde, Vera Lorenz, Vivienne Gruterich, Melania Balzarolo, Michika Mochizuki, Otmar Pfister, Gabriela M. Kuster
Summary: This study aimed to test whether Flt3-targeting TKI treatment aggravates cardiac injury after myocardial infarction (MI). The results showed that quizartinib did not alter cardiac dimensions or function in healthy mice, but significantly enhanced ventricular dilatation and apoptotic cell death in MI mice. In vitro studies further confirmed that quizartinib increased cell death and apoptosis, potentially through a p38-dependent mechanism.
Article
Oncology
Mahran Shoukier, Tapan Kadia, Marina Konopleva, Ahmad S. Alotaibi, Mansour Alfayez, Sanam Loghavi, Keyur P. Patel, Rashmi Kanagal-Shamanna, Jorge Cortes, Bachar Samra, Elias Jabbour, Guillermo Garcia-Manero, Koichi Takahashi, Sherry Pierce, Nicholas J. Short, Musa Yilmaz, Koji Sasaki, Lucia Masarova, Naveen Pemmaraju, Gautam Borthakur, Hagop M. Kantarjian, Farhad Ravandi, Courtney D. DiNardo, Naval Daver
Summary: The combination of FLT3 inhibitor-based therapy with cytotoxic chemotherapy or low-intensity therapy appears to be effective in patients with FLT3-ITD/IDH co-mutated disease in both the frontline and recurrent and/or refractory settings. Fewer dual-mutated patients received cytotoxic chemotherapy or low-intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach.
Article
Chemistry, Medicinal
Qing-Xin Wang, Yi-Bo Wang, Jiu-Kai Sha, Hai Zhou, Jia-Chuan Liu, Jia-Zhen Wu, Zhen-Jiang Tong, Jiao Cai, Zi-Jun Chen, Chen-Qian Zhang, Xin-Rui Zheng, Jing-Jing Wang, Xiao-Long Wang, Xin Xue, Yan-Cheng Yu, Ning Ding, Xue-Jiao Leng, Wei-Chen Dai, Shan-Liang Sun, Liang Chang, Nian-Guang Li, Zhi-Hao Shi
Summary: A series of covalent derivatives were synthesized and optimized to overcome secondary resistance mutations of FLT3. Compound F15 exhibited potent inhibition activities against FLT3 and FLT3-ITD, as well as FLT3-dependent human AML cell lines and BaF3 cells with secondary mutations. Mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. F15 could be considered as a potential drug candidate for AML treatment.
DRUG DEVELOPMENT RESEARCH
(2023)
Article
Oncology
Yuta Kaito, Mitsuhito Hirano, Muneyoshi Futami, Masanori Nojima, Hideto Tamura, Arinobu Tojo, Yoichi Imai
Summary: Acute myeloid leukemia (AML) relapse is associated with escape from anti-tumor immunity. Changes in CD155 and CD112 expression affect tumor immunity and FLT3 inhibitors could be a potential solution for AML immunotherapy.
Article
Oncology
Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schoenberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Summary: The presence of internal tandem duplications (ITD) in FMS-like tyrosine kinase 3 (FLT3) combined with DNMT3A mutations in acute myeloid leukemia (AML) leads to poor prognosis. Studies have shown that GAB2 is essential for the development of Flt3-ITD driven AML, with Gab2 deficient mice displaying prolonged survival and reduced pathology. Gab2 increases signaling of receptor tyrosine kinases, promoting AML aggressiveness and drug resistance, making it a promising biomarker and therapeutic target in human AML.
Article
Oncology
Diego Carbonell, Maria Chicano, Alfonso J. Cardero, Ignacio Gomez-Centurion, Rebeca Bailen, Gillen Oarbeascoa, Diana Martinez-Senaris, Carolina Franco, Paula Muniz, Javier Anguita, Mi Kwon, Jose Luis Diez-Martin, Ismael Buno, Carolina Martinez-Laperche
Summary: FLT3-ITD cDNA analysis showed higher sensitivity than DNA analysis, detecting disease before relapse in patients undergoing allogeneic hematopoietic stem cell transplantation. It also evaluated the response to FLT3 inhibitors. FLT3-ITD expression could be a useful additional biomarker at diagnosis and for the assessment of measurable residual disease after transplantation and FLT3 inhibitor treatment.
Article
Hematology
Deepak Kumar, Thinh H. Nguyen, Carolyn M. Bennett, Chengyu Prince, Laura Lucas, Sunita Park, Taylor Lawrence, Karin Chappelle, Mariam Ishaq, Edmund K. Waller, Sampath Prahalad, Michael Briones, Shanmuganathan Chandrakasan
Summary: mTOR inhibitors like sirolimus are increasingly used to manage multilineage immune cytopenia (m-IC) in children. However, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC.
Article
Hematology
Jennifer Teichman, Michelle Geddes, Nancy Zhu, Mary-Margaret Keating, Mitchell Sabloff, Grace Christou, Brian Leber, Dina Khalaf, Eve St-Hilaire, Nicholas Finn, April Shamy, Karen W. L. Yee, John M. Storring, Thomas J. Nevill, Robert Delage, Mohamed Elemary, Versha Banerji, Brett Houston, Lee Mozessohn, Lisa Chodirker, Liying Zhang, Mohammed Siddiqui, Anne Parmentier, Heather A. Leitch, Rena J. Buckstein
Summary: Iron overload and elevated ferritin are associated with increased mortality in MDS, but ferritin is an imperfect metric. Elevated labile plasma iron is correlated with clinical outcomes and TSAT >80%, but is not easily measurable.
Review
Hematology
Michael R. Cook, C. Scott Dorris, Kepher H. Makambi, Yutong Luo, Pashna N. Munshi, Michelle Donato, Scott Rowley, Ayman Saad, Andre Goy, Kieron Dunleavy, Alaa Ali
Summary: Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) have limited treatment options and poor prognosis. This study conducted a systematic review and meta-analysis of CAR T-cell therapy in PCNSL and SCNSL. The results showed that CAR T-cell therapy had acceptable toxicity and promising efficacy in both PCNSL and SCNSL patients.
Article
Hematology
Ulrich Jaeger, Nina Worel, Joseph P. McGuirk, Peter A. Riedell, Isabelle Fleury, Yan Du, Xia Han, David Pearson, Santiago Redondo, Edmund K. Waller
Summary: In the PORTIA trial, it was feasible to add pembrolizumab to tisagenlecleucel for adult patients with r/r DLBCL who had& GE;2 prior lines of therapy and had an Eastern Cooperative Oncology Group performance status of& LE;1. The combination showed a manageable safety profile and had potential efficacy benefits when pembrolizumab was given the day before tisagenlecleucel.
Article
Oncology
David Bernard Miklos, Mohammad Abu Zaid, Julian P. Cooney, Joern C. Albring, Mary Flowers, Alan P. Skarbnik, Ibrahim Yakoub-Agha, Bor-Sheng Ko, Benedetto Bruno, Edmund K. Waller, Jean Yared, Sang Kyun Sohn, Claude-Eric Bulabois, Takanori Teshima, David Jacobsohn, Hildegard Greinix, Ahmad Mokatrin, Yihua Lee, Justin T. Wahlstrom, Lori Styles, Gerard Socie
Summary: In this study, the safety and efficacy of ibrutinib with prednisone in patients with chronic graft-versus-host disease were evaluated. The primary and secondary end points did not show a statistically significant difference between the two treatment groups.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Letter
Hematology
Bhavana Bhatnagar, Jessica Kohlschmidt, Shelley J. Orwick, Daelynn R. Buelow, Sydney Fobare, Christopher C. Oakes, Jonathan E. Kolitz, Geoff Uy, Wendy Stock, Bayard L. Powell, Deedra Nicolet, Erin K. Hertlein, Krzysztof Mrozek, James S. Blachly, Ann-Kathrin Eisfeld, Sharyn D. Baker, John C. Byrd
Article
Oncology
Lee Mozessohn, Qing Li, Ning Liu, Brian Leber, Dina Khalaf, Mitchell Sabloff, Grace Christou, Karen Yee, Lisa Chodirker, Anne Parmentier, Mohammed Siddiqui, Alexandre Mamedov, Liying Zhang, Ying Liu, Craig C. Earle, Matthew C. Cheung, Nicole Mittmann, Rena Buckstein
Summary: This study explores the impact of frailty on survival, healthcare resource utilization, and costs of care in patients with myelodysplastic syndromes. The results show a positive association between frailty and hospitalization rates and costs of care. The study suggests that assessing frailty can help inform patients and physicians about expected outcomes.
JCO ONCOLOGY PRACTICE
(2023)
Article
Oncology
Vijaya Raj Bhatt, Angela M. Ulrich, Geoffrey L. Uy, Richard M. Stone, Wendy Stock, Michael O. Ojelabi, Jun Yin, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Maria R. Baer, Selina Chow, Heidi Klepin, Jennifer Le-Rademacher, Aminah Jatoi
Summary: This study investigated the differences in outcomes of older patients with AML based on their participation in intensive chemotherapy trials at community versus academic cancer centers. The results showed no significant differences in severe adverse events, 1-month mortality, and overall survival between the two types of centers.
JCO ONCOLOGY PRACTICE
(2023)
Article
Hematology
Santosh Putta, Bradford A. Young, John E. Levine, Ran Reshef, Ryotaro Nakamura, Christopher Strouse, Miguel -Angel Perales, Alan Howard, Polly Pine, Ju Shi, Peixin Zhang, Vincent T. Ho, Wael Saber
Summary: This study aimed to determine blood biomarkers that could identify high-risk patients for hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) shortly after hematopoietic cell transplantation (HCT). The study found that a combination of up to 5 protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)
Letter
Hematology
Rajshekhar Chakraborty, Divaya Bhutani, Markus Mapara, Ran Reshef, Mathew S. Maurer, Jai Radhakrishnan, Suzanne Lentzsch
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Hematology
Muhammad Bilal Abid, Noel Estrada-Merly, Mei-Jie Zhang, Karen Chen, Christopher Bredeson, David Allan, Mitchell Sabloff, David I. Marks, Mark Litzow, Christopher Hourigan, Partow Kebriaei, Wael Saber
Summary: This retrospective study found that selecting younger unrelated donors can significantly reduce the risk of disease relapse in older ALL patients. However, younger unrelated donors also increase the risk of chronic GVHD and nonrelapse mortality.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)
Meeting Abstract
Oncology
Michael R. Savona, James K. McCloskey, Elizabeth A. Griffiths, Karen W. L. Yee, Amer M. Zeidan, Aref Al-Kali, H. Joachim Deeg, Prapti A. Patel, Mitchell Sabloff, Mary-Margaret Keating, Nancy Zhu, Nashat Gabrail, Salman Fazal, Joseph Maly, Olatoyosi Odenike, Hagop M. Kantarjian, Amy E. DeZern, Casey L. O'Connell, Gail J. Roboz, Lambert Busque, Rena Buckstein, Harshad Amin, Jasleen K. Randhawa, Brian Leber, Kim-Hien Dao, Yuri Sano, Beloo Mirakhur, Winny Chan, Aram Oganesian, Harold Keer, Guillermo Garcia-Manero
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Meeting Abstract
Oncology
Samer A. Srour, Amandeep Salhotra, Robert Lowsky, Rasmus T. Hoeg, Ayman Saad, Edmund K. Waller, Anna Pavlova, J. Scott McClellan, Nathaniel B. Fernhoff, Everett H. Meyer, Mehrdad Abedi
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Meeting Abstract
Oncology
Rajneesh Nath, Stuart Seropian, Hannah Choe, Mark R. Litzow, Camille Abboud, Nebu Koshy, Patrick J. Stiff, Benjamin Tomlinson, Sunil Abhyankar, James M. Foran, Parameswaran Hari, George L. Chen, Zaid S. Al-Kadhimi, Partow Kebriaei, Mitchell Sabloff, Johnnie J. Orozco, Katarzyna Jamieson, Margarida Magalhaes-Silverman, Koen Van Besien, Michael Schuster, Arjun Law, Sameem Abedin, Karilyn Larkin, Scott Rowley, Pashna Munshi, Rachel Cook, Sebastian Mayer, Moshe Yair Levy, Hillard M. Lazarus, Brenda M. Sandmaier, Vijay Reddy, Jennifer Spross, Kathleen McNamara, Elaina Haeuber, Madhuri Vusirikala, Akash Nahar, John M. Pagel, Sergio A. Giralt, Avinash Desai, Boglarka Gyurkocza
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Article
Hematology
Muhammad Bilal Abid, Noel Estrada-Merly, Mei-Jie Zhang, Karen Chen, David Allan, Christopher Bredeson, Mitchell Sabloff, Guru Subramanian Guru Murthy, Talha Badar, Shahrukh Hashmi, Mahmoud Aljurf, Mark R. Litzow, Partow Kebriaei, Christopher S. Hourigan, Wael Saber
Summary: For older patients with AML undergoing alloHCT, the use of younger MUDs is associated with decreased relapse risk and improved DFS compared with the use of older MSDs.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)