Review
Biochemistry & Molecular Biology
Ing S. Tiong, Sun Loo
Summary: Measurable residual disease (MRD) assessment plays an important role in prognostication and guiding treatment decisions in acute myeloid leukemia (AML). With the development of new therapeutics and the recent approval of NPM1 MRD as a regulatory endpoint, MRD-directed therapy and its potential application in clinical trials are being explored. This article reviews emerging molecular MRD markers, the impact of novel therapeutics on MRD endpoints, and the use of MRD as a predictive biomarker in guiding therapy in AML.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Elisa Meddi, Arianna Savi, Federico Moretti, Flavia Mallegni, Raffaele Palmieri, Giovangiacinto Paterno, Elisa Buzzatti, Maria Ilaria Del Principe, Francesco Buccisano, Adriano Venditti, Luca Maurillo
Summary: In acute myeloid leukemia (AML), many patients experience relapse despite achieving complete remission. Traditional morphologic criteria are inadequate for assessing treatment response. Quantification of measurable residual disease (MRD) is a strong prognostic marker in AML, with MRD-negative patients having lower relapse rates and better survival. Different techniques for detecting MRD are available, and their use in guiding post-remission therapy is being actively investigated. Despite controversy, the prognostic value of MRD shows promise in supporting drug development and potentially expediting regulatory approval of new agents.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Riana van der Linde, Prudence N. Gatt, Sandy Smith, Marian A. Fernandez, Lachlin Vaughan, Emily Blyth, Jennifer Curnow, David A. Brown, Elizabeth Tegg, Sarah C. Sasson
Summary: This study found divergent utilities of flow cytometry-measurable residual disease (FC-MRD) in adult B-ALL and AML. FC-MRD was strongly associated with relapse and survival in AML but not in B-ALL. Additionally, there was a moderate correlation between FC-MRD and corresponding Mol-MRD in B-ALL, while no correlation was found in AML.
Editorial Material
Hematology
Maria Teresa Voso, Francesco Buccisano
Summary: In this study, Li et al demonstrate that detection of leukemic stem cells (LSCs) using multiparameter flow cytometry (MFC) may be a better predictor of relapse and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) compared to classical measurable residual disease (MRD).
Article
Oncology
Nikhil Patkar, Chinmayee Kakirde, Anam Fatima Shaikh, Rakhi Salve, Prasanna Bhanshe, Gaurav Chatterjee, Sweta Rajpal, Swapnali Joshi, Shruti Chaudhary, Rohan Kodgule, Sitaram Ghoghale, Nilesh Deshpande, Dhanalaxmi Shetty, Syed Hasan Khizer, Hasmukh Jain, Bhausaheb Bagal, Hari Menon, Navin Khattry, Manju Sengar, Prashant Tembhare, Papagudi Subramanian, Sumeet Gujral
Summary: NGS-MRD is an effective tool for predicting relapse risk and prognosis in AML patients, particularly in those with intermediate cytogenetic risk and favorable cytogenetic risk. The kinetics of NGS-MRD clearance is crucial for patient survival. Combining NGS-MRD with FCM-MRD provides comprehensive information for better clinical management.
Review
Oncology
Marisa J. L. Aitken, Farhad Ravandi, Keyur P. Patel, Nicholas J. Short
Summary: Quantification of measurable residual disease (MRD) provides critical prognostic information in acute myeloid leukemia (AML), with different detection platforms having varying sensitivity and applicability. MRD negativity is associated with reduced risk of relapse in AML, but the therapeutic implications remain unclear and require further investigation.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Review
Oncology
Massimo Bernardi, Felicetto Ferrara, Matteo Giovanni Carrabba, Sara Mastaglio, Francesca Lorentino, Luca Vago, Fabio Ciceri
Summary: The prognosis of patients with acute myeloid leukemia remains poor, especially in those with adverse genetic risk or residual disease after complete remission. Genetic classification and measurable residual disease evaluation are important for predicting outcomes and guiding therapeutic interventions. New technologies such as multiparameter flow cytometry and next-generation sequencing play a critical role in detecting minimal residual disease. However, more research is needed for patients receiving low-intensity regimens.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Thomas Cluzeau, Roberto M. Lemoli, James McCloskey, Todd Cooper
Summary: Assessment of measurable residual disease (MRD) is important in predicting outcomes and managing high-risk acute myeloid leukemia (AML). However, there is currently no consensus on the best method for determining MRD negativity, making comparisons across studies difficult.
Review
Biochemistry & Molecular Biology
Annalisa Talami, Francesca Bettelli, Valeria Pioli, Davide Giusti, Andrea Gilioli, Corrado Colasante, Laura Galassi, Rachele Giubbolini, Hillary Catellani, Francesca Donatelli, Rossana Maffei, Silvia Martinelli, Patrizia Barozzi, Leonardo Potenza, Roberto Marasca, Tommaso Trenti, Enrico Tagliafico, Patrizia Comoli, Mario Luppi, Fabio Forghieri
Summary: Despite the favorable risk category of AML carrying inv(16)/t(16;16) with fusion transcript CBFB-MYH11, approximately 30% of cases eventually relapse after obtaining morphological complete remission after induction. Measurable residual disease (MRD) monitoring by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) has a significant independent prognostic impact, especially in predicting relapse, surpassing other prognostic factors. Controversies exist regarding the frequency of subsequent serial monitoring, significant MRD thresholds (most commonly 0.1%), and the best source to be analyzed (bone marrow or peripheral blood samples).
Editorial Material
Oncology
Tali Azenkot, Brian A. Jonas
Summary: Measurable residual disease (MRD) has become a primary marker of risk severity and prognosis in acute myeloid leukemia (AML). However, there is ongoing debate about the monitoring and treatment based on MRD. The identified literature has described the prognostic value of pre-transplant MRD and suggested optimal timing and techniques to quantify MRD. Several studies have addressed the implications of MRD on treatment selection and hematopoietic stem cell transplant, but more prospective, randomized studies are needed to guide the application of MRD in AML treatment, particularly in transplantation.
Article
Hematology
Michael Heuser, Sylvie D. Freeman, Gert J. Ossenkoppele, Francesco Buccisano, Christopher S. Hourigan, Lok Lam Ngai, Jesse M. Tettero, Costa Bachas, Constance Baer, Marie-Christine Bene, Veit Bucklein, Anna Czyz, Barbara Denys, Richard Dillon, Michaela Feuring-Buske, Monica L. Guzman, Torsten Haferlach, Lina Han, Julia K. Herzig, Jeffrey L. Jorgensen, Wolfgang Kern, Marina Y. Konopleva, Francis Lacombe, Marta Libura, Agata Majchrzak, Luca Maurillo, Yishai Ofran, Jan Philippe, Adriana Plesa, Claude Preudhomme, Farhad Ravandi, Christophe Roumier, Marion Subklewe, Felicitas Thol, Arjan A. van de Loosdrecht, Bert A. van der Reijden, Adriano Venditti, Agnieszka Wierzbowska, Peter J. M. Valk, Brent L. Wood, Roland B. Walter, Christian Thiede, Konstanze Dohner, Gail J. Roboz, Jacqueline Cloos
Summary: The European LeukemiaNet MRD Working Party updated the 2018 MRD recommendations, including technical specifications and integrative assessments. They also proposed the use of MRD as a prognostic and surrogate endpoint for drug testing, as well as the clinical implications of MRD assessment in AML. Recommendations include technical requirements for flow cytometry and molecular MRD analysis, as well as reporting methods for MRD results.
Review
Oncology
Noortje van Gils, Fedor Denkers, Linda Smit
Summary: Standard induction chemotherapy is the first-line therapy for AML, but many patients face relapse or refractory disease. AML relapse is caused by therapy-resistant leukemia cells, with LSCs being considered the origin. The different states of treatment persisters and LSCs can be exploited to achieve optimal therapy response.
FRONTIERS IN ONCOLOGY
(2021)
Review
Oncology
Kritika Srinivasan Rajsri, Nainita Roy, Sohini Chakraborty
Summary: Acute myeloid leukemia (AML) is a blood cancer characterized by immature blood cells called leukemic blasts. Leukemia stem cells (LSCs) are resistant to chemotherapy and can cause disease relapse. Understanding the molecular basis of LSCs is important in identifying and targeting these cells for more effective treatment.
Article
Oncology
Alban Canali, Ines Vergnolle, Sarah Bertoli, Laetitia Largeaud, Marie-Laure Nicolau, Jean-Baptiste Rieu, Suzanne Tavitian, Francoise Huguet, Muriel Picard, Pierre Bories, Jean Philippe Vial, Nicolas Lechevalier, Marie Christine Bene, Isabelle Luquet, Veronique Mansat-De Mas, Eric Delabesse, Christian Recher, Francois Vergez
Summary: This study aims to evaluate the predictive effect of clustering analysis on residual disease in patients with acute myeloid leukemia (AML). The results indicate that residual disease assessment using multiparametric flow cytometry in AML patients can predict patient survival, and the analysis of LSC MRD in the chemotherapy-resistant subpopulation is more clinically relevant.
CLINICAL CANCER RESEARCH
(2023)
Article
Hematology
Cheng-Hong Tsai, Jih-Luh Tang, Feng-Ming Tien, Yuan-Yeh Kuo, Dung-Chi Wu, Chien-Chin Lin, Mei-Hsuan Tseng, Yen-Ling Peng, Mei-Fang Hou, Yi-Kuang Chuang, Ming-Chih Liu, Chia-Wen Liu, Ming Yao, Liang-In Lin, Wen-Chien Chou, Chien-Yu Chen, Hsin-An Hou, Hwei-Fang Tien
Summary: This study demonstrated the clinical significance of measuring NGS MRD in AML patients, especially predicting clinical outcome after the first consolidation therapy. Patients with detectable MRD at both time points had poorer prognosis, while those with positive MRD1st but negative MRD2nd showed similar good prognosis as those with negative MRD at both time points. Incorporating NGS MRD testing, particularly after the first consolidation therapy, can help predict the clinical outcome of AML patients.
Review
Oncology
David G. J. Cucchi, Tobias B. Polak, Gert J. Ossenkoppele, Carin A. Uyl-De Groot, Jacqueline Cloos, Sonja Zweegman, Jeroen J. W. M. Janssen
Summary: Precision medicine is increasingly important in treating acute myeloid leukemia (AML). A comprehensive overview of phase II and phase III trials investigating targeted therapies in AML over the past two decades was provided, showing that drugs primarily designed for AML had more success in clinical development compared to repurposed drugs.
Article
Hematology
Bob Lowenberg, Thomas Pabst, Johan Maertens, Patrycja Gradowska, Bart J. Biemond, Olivier Spertini, Edo Vellenga, Laimonas Griskevicius, Lidwine W. Tick, Mojca Jongen-Lavrencic, Marinus van Marwijk Kooy, Marie-Christiane Vekemans, Walter J. F. M. van der Velden, Berna Beverloo, Lucienne Michaux, Carlos Graux, Dries Deeren, Okke de Weerdt, Joost W. J. van Esser, Mario Bargetzi, Saskia K. Klein, Alain Gadisseur, Peter E. Westerweel, Hendrik Veelken, Michael Gregor, Tobias Silzle, Danielle Van Lammeren-Venema, Ine Moors, Dimitri A. Breems, Mels Hoogendoorn, Marie-Cecile J. C. Legdeur, Thomas Fischer, Juergen Kuball, Jan Cornelissen, Kimmo Porkka, Gunnar Juliusson, Peter Meyer, Martin Hoglund, Bjorn T. Gjertsen, Jeroen J. W. M. Janssen, Gerwin Huls, Jakob Passweg, Jacqueline Cloos, Peter J. M. Valk, Catharina H. M. J. van Elssen, Markus G. Manz, Yngvar Floisand, Gert J. Ossenkoppele
Summary: The study compared two treatment regimens for AML and found that lenalidomide did not show significant benefit in overall outcome, but may have some advantage in AML patients with SRSF2 mutation. Additionally, the use of an MRD-guided treatment approach resulted in more favorable survival estimates compared to previous studies with similar regimens.
Article
Hematology
Diana Hanekamp, Lok Lam Ngai, Jeroen J. W. M. Janssen, Arjan van de Loosdrecht, Gert J. Ossenkoppele, Jacqueline Cloos
Article
Biochemical Research Methods
Carolien van Alphen, David G. J. Cucchi, Jacqueline Cloos, Tim Schelfhorst, Alexander A. Henneman, Sander R. Piersma, Thang Pham, Jaco C. Knol, Connie R. Jimenez, Jeroen J. W. M. Janssen
Summary: Delayed processing of acute myeloid leukemia samples beyond four hours leads to significant changes in phosphorylation profiles, especially in the phosphorylation of JNK and p38 kinases. Standardized processing within four hours is crucial for accurate phosphoproteomics analysis in AML research.
JOURNAL OF PROTEOMICS
(2021)
Letter
Oncology
Inge van der Werf, Anna Wojtuszkiewicz, Huilan Yao, Rocco Sciarrillo, Manja Meggendorfer, Stephan Hutter, Wencke Walter, Jeroen Janssen, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach, Gerrit Jansen, Gertjan J. L. Kaspers, Richard Groen, Gert Ossenkoppele, Jacqueline Cloos
Article
Cell Biology
Margot S. F. Roeten, Johan van Meerloo, Zinia J. Kwidama, Giovanna ter Huizen, Wouter H. Segerink, Sonja Zweegman, Gertjan J. L. Kaspers, Gerrit Jansen, Jacqueline Cloos
Summary: Ixazomib (IXA) is a promising orally available proteasome inhibitor with improved safety profile compared to Bortezomib (BTZ). In vitro and ex vivo studies showed that IXA has a similar mechanism of action as BTZ, but demonstrated anti-leukemic effects in primary leukemia cells, suggesting further pre-clinical evaluation.
Editorial Material
Hematology
J. Cloos, G. J. Ossenkoppele
Summary: The fate of FLT3-ITD clones in AML patients treated with midostaurin was described in the current issue of Blood by Schmalbrock et al.
Article
Biochemical Research Methods
Ittai B. Muller, Stijn Meijers, Peter Kampstra, Steven van Dijk, Michel van Elswijk, Marry Lin, Anna M. Wojtuszkiewicz, Gerrit Jansen, Robert de Jonge, Jacqueline Cloos
Summary: This study compared the computational performance of three splicing tools and found that rMATS outperformed MISO and SUPPA2 in terms of job times and CPU utilization. Despite high concordance between tool outputs, differences were observed in the analysis of retained intron events. Users should consider factors such as job time, replicates, and splice event type when choosing the optimal alternative splicing tool for RNA-seq analyses.
BMC BIOINFORMATICS
(2021)
Article
Oncology
Kim Klein, H. Berna Beverloo, Martin Zimmermann, Susana C. Raimondi, Christine von Neuhoff, Valerie Haas, Romy van Weelderen, Jacqueline Cloos, Jonas Abrahamsson, Yves Bertrand, Michael Dworzak, Alcira Fynn, Brenda Gibson, Shau-Yin Ha, Christine J. Harrison, Henrik Hasle, Sarah Elitzur, Guy Leverger, Alexei Maschan, Bassem Razzouk, Dirk Reinhardt, Carmelo Rizzari, Pter Smisek, Ursula Creutzig, Gertjan J. L. Kaspers
Summary: Cytogenetic profiles and karyotypic changes at relapse play a significant role in predicting survival outcomes for children with relapsed AML, with certain abnormalities associated with better or worse prognosis. Early treatment response, time to relapse, and cytogenetic profile at relapse are important prognostic factors, outweighing karyotypic instability per se.
PEDIATRIC BLOOD & CANCER
(2022)
Article
Hematology
Michael Heuser, Sylvie D. Freeman, Gert J. Ossenkoppele, Francesco Buccisano, Christopher S. Hourigan, Lok Lam Ngai, Jesse M. Tettero, Costa Bachas, Constance Baer, Marie-Christine Bene, Veit Bucklein, Anna Czyz, Barbara Denys, Richard Dillon, Michaela Feuring-Buske, Monica L. Guzman, Torsten Haferlach, Lina Han, Julia K. Herzig, Jeffrey L. Jorgensen, Wolfgang Kern, Marina Y. Konopleva, Francis Lacombe, Marta Libura, Agata Majchrzak, Luca Maurillo, Yishai Ofran, Jan Philippe, Adriana Plesa, Claude Preudhomme, Farhad Ravandi, Christophe Roumier, Marion Subklewe, Felicitas Thol, Arjan A. van de Loosdrecht, Bert A. van der Reijden, Adriano Venditti, Agnieszka Wierzbowska, Peter J. M. Valk, Brent L. Wood, Roland B. Walter, Christian Thiede, Konstanze Dohner, Gail J. Roboz, Jacqueline Cloos
Summary: The European LeukemiaNet MRD Working Party updated the 2018 MRD recommendations, including technical specifications and integrative assessments. They also proposed the use of MRD as a prognostic and surrogate endpoint for drug testing, as well as the clinical implications of MRD assessment in AML. Recommendations include technical requirements for flow cytometry and molecular MRD analysis, as well as reporting methods for MRD results.
Article
Oncology
Katerina Bakunina, Hein Putter, Jurjen Versluis, Eva A. S. Koster, Bronno van der Holt, Markus G. Manz, Dimitri A. Breems, Bjorn T. Gjertsen, Jacqueline Cloos, Peter J. M. Valk, Jakob Passweg, Thomas Pabst, Gert J. Ossenkoppele, Bob Lowenberg, Jan J. Cornelissen, Liesbeth C. de Wreede
Summary: The study found that using clofarabine treatment in patients with acute myeloid leukemia can reduce the risk of relapse, regardless of individual MRD status or subsequent treatment method. However, during the period from CR to receiving alloSCT, non-relapse mortality was higher in patients receiving clofarabine treatment. Overall, clofarabine treatment has been shown to be beneficial in terms of current leukemia-free survival.
Article
Hematology
Sabine Haggenburg, Birgit Lissenberg-Witte, Rob S. van Binnendijk, Gerco den Hartog, Michel S. Bhoekhan, Nienke J. E. Haverkate, Dennis M. de Rooij, Johan van Meerloo, Jacqueline Cloos, Neeltje A. Kootstra, Dorine Wouters, Suzanne S. Weijers, Ester M. M. van Leeuwen, Hetty J. Bontkes, Saida Tonouh-Aajoud, Mirjam H. M. Heemskerk, Rogier W. Sanders, Elianne Roelandse-Koop, Quincy Hofsink, Kazimierz Groen, Lucia Cetinel, Louis Schellekens, Yvonne M. den Hartog, Belle Toussaint, Iris M. J. Kant, Thecla Graas, Emma de Pater, Willem A. Dik, Marije D. Engel, Cheyenne R. N. Pierie, Suzanne R. Janssen, Edith van Dijkman, Meliawati Poniman, Judith A. Burger, Joey H. Bouhuijs, Gaby Smits, Nynke Y. Rots, Sonja Zweegman, Arnon P. Kater, Tom van Meerten, Pim G. N. J. Mutsaers, Jaap A. van Doesum, Annoek E. C. Broers, Marit J. van Gils, Abraham Goorhuis, Caroline E. Rutten, Mette D. Hazenberg, Inger S. Nijhof
Summary: Vaccination guidelines for hematological patients are typically conservative. However, this study shows that most patients, even those with compromised immune systems, can develop sufficient antibody concentrations after receiving the Moderna vaccine. However, certain treatments may affect the vaccine's efficacy.
Article
Medical Laboratory Technology
Costa Bachas, Carolien Duetz, Margot F. van Spronsen, Jan Verhoeff, Juan J. Garcia Vallejo, Joop H. Jansen, Jacqueline Cloos, Theresia M. Westers, Arjan A. van de Loosdrecht
Summary: Through mass cytometry and computational data analysis, we were able to characterize HSPC subsets in MDS and identify leukemia stem cell populations based on their immunophenotype. Stem cells in MDS that display leukemia-associated features may predict the risk of developing AML.
CYTOMETRY PART B-CLINICAL CYTOMETRY
(2023)
Article
Hematology
Jesse M. Tettero, Sylvie Freeman, Veit Buecklein, Adriano Venditti, Luca Maurillo, Wolfgang Kern, Roland B. Walter, Brent L. Wood, Christophe Roumier, Jan Philippe, Barbara Denys, Jeffrey L. Jorgensen, Marie C. Bene, Francis Lacombe, Adriana Plesa, Monica L. Guzman, Agnieszka Wierzbowska, Anna Czyz, Lok Lam Ngai, Adrian Schwarzer, Costa Bachas, Jacqueline Cloos, Marion Subklewe, Michaela Fuering-Buske, Francesco Buccisano
Summary: Experts from the MRD Working Party of the European LeukemiaNet evaluated the key factors for accurate MFC-MRD measurement in acute myeloid leukemia (AML) and provided recommendations to ensure quality and reproducibility of results. The recommendations were tested by comparing two 8-color MRD panels in multiple laboratories, confirming their feasibility.