Review
Hematology
Brunangelo Falini, Lorenzo Brunetti, Maria Paola Martelli
Summary: Mutations of the nucleophosmin (NPM1) gene play a crucial role in adult acute myeloid leukemia (AML), with unique molecular, pathological, and clinical features. Accurate diagnosis and distinction of NPM1-mutated AML from other entities is important for guiding treatment decisions and assessing relapse risk. Monitoring measurable residual disease (MRD) using NPM1 mutations can provide valuable insights for therapeutic management after remission.
Review
Oncology
Roberta Ranieri, Giulia Pianigiani, Sofia Sciabolacci, Vincenzo Maria Perriello, Andrea Marra, Valeria Cardinali, Sara Pierangeli, Francesca Milano, Ilaria Gionfriddo, Lorenzo Brunetti, Maria Paola Martelli, Brunangelo Falini
Summary: NPM1 mutations are the most common genetic alteration in AML, and NPM1-mutated AML is regarded as a distinct genetic entity. This study provides an overview of potential targeted therapies against NPM1-mutated AML, including strategies to interfere with oligomerization and abnormal traffic of NPM1, induce protein degradation, and target nucleolar structure integrity. Therapeutic results with BCL-2 inhibitor and menin inhibitors, as well as immunotherapeutic approaches, are also discussed.
Review
Oncology
Rong Wang, Pan Xu, Lin-Lin Chang, Shi-Zhong Zhang, Hong-Hu Zhu
Summary: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the malignant proliferation of myeloid hematopoietic stem/progenitor cells. The NPM1 gene is the most frequently mutated gene in AML, found in approximately 30% of AML cases. While NPM1 is considered a good prognostic marker, some patients still relapse or fail to respond to treatment. Therefore, finding optimal therapies for AML with NPM1 mutations is urgently needed.
FRONTIERS IN ONCOLOGY
(2022)
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
Oncology
Vincenzo Maria Perriello, Ilaria Gionfriddo, Roberta Rossi, Francesca Milano, Federica Mezzasoma, Andrea Marra, Orietta Spinelli, Alessandro Rambaldi, Ombretta Annibali, Giuseppe Avvisati, Francesco Di Raimondo, Stefano Ascani, Brunangelo Falini, Maria Paola Martelli, Lorenzo Brunetti
Summary: One-third of adult AML patients have NPM1 mutations, with high expression of CD123 identified as a potential target for therapy in NPM1-mutated leukemic cells, particularly in CD34(+)CD38(-) cells. Targeting CD123 may be effective for treating NPM1-mutated AML, especially in combination with FLT3 mutations.
Article
Oncology
Mael Heiblig, Nicolas Duployez, Alice Marceau, Delphine Lebon, Laure Goursaud, Isabelle Plantier, Laure Stalnikiewich, Nathalie Cambier, Marie Balsat, Gaelle Fossard, Helene Labussiere-Wallet, Fiorenza Barraco, Sophie Ducastelle-Lepretre, Pierre Sujobert, Sarah Huet, Sandrine Hayette, Herve Ghesquieres, Xavier Thomas, Claude Preudhomme
Summary: DNMT3A mutation is associated with adverse outcomes in AML patients, but a 4log reduction in NPM1 MRD can predict better survival. Post-induction NPM1 MRD1 reduction is a reliable tool to assess disease outcome in elderly AML patients, while the presence of DNMT3A also identifies a subgroup at high risk of relapse.
Article
Multidisciplinary Sciences
Arvind Singh Mer, Emily M. Heath, Seyed Ali Madani Tonekaboni, Nergiz Dogan-Artun, Sisira Kadambat Nair, Alex Murison, Laura Garcia-Prat, Liran Shlush, Rose Hurren, Veronique Voisin, Gary D. Bader, Corey Nislow, Mattias Rantalainen, Soren Lehmann, Mark Gower, Cynthia J. Guidos, Mathieu Lupien, John E. Dick, Mark D. Minden, Aaron D. Schimmer, Benjamin Haibe-Kains
Summary: The molecular heterogeneity of AML poses challenges for prognosis and therapy. NPM1 mutated AML is heterogeneous, with two subtypes exhibiting distinct molecular characteristics, differentiation state, patient survival, and drug response.
NATURE COMMUNICATIONS
(2021)
Article
Hematology
Jad Othman, Manja Meggendorfer, Enrico Tiacci, Christian Thiede, Richard Schlenk, Richard Dillon, Sebastian Stasik, Alessandra Venanzi, Sarah Bertoli, Eric Delabesse, Pierre-Yves Dumas, Arnaud Pigneux, Audrey Bidet, Amanda F. Gilkes, Ian Thomas, Maria Teresa Voso, Alessandro Rambaldi, Lorenzo Brunetti, Vincenzo M. Perriello, Vibeke Andresen, Bjorn T. Gjertsen, Maria Paola Martelli, Christian Recher, Christoph Roellig, Martin Bornhaeuser, Hubert Serve, Carsten Mueller-Tidow, Claudia D. Baldus, Tortsten Haferlach, Nigel Russell, Brunangelo Falini
Summary: The characteristics of therapy-related NPM1-mutated AML (t-NPM1 AML) were found to be similar to de novo NPM1-mutated AML (dn-NPM1 AML) in terms of genetics, transcriptional profile, and clinical outcomes. However, t-NPM1 AML showed better overall survival and relapse-free survival compared to t-AML.
Article
Oncology
Brunangelo Falini, Sofia Sciabolacci, Lorenza Falini, Lorenzo Brunetti, Maria Paola Martelli
Summary: Mutations of Nucleophosmin (NPM1) are common in adult AML and are recognized as a distinct entity. Evaluation of NPM1 and FLT3 status is important for risk stratification and monitoring of MRD. Combining MRD monitoring with the ELN prognostication model can help guide therapeutic decisions for NPM1-mutated AML.
Article
Biochemistry & Molecular Biology
Anette Lodvir Hemsing, Kristin Paulsen Rye, Kimberley Joanne Hatfield, Hakon Reikvam
Summary: Targeted therapy with Rac1 inhibitors could effectively inhibit cell proliferation, induce apoptosis, and reduce cytokine levels in AML cells. AML patients with NPM1 mutations showed increased vulnerability to Rac1 inhibitors.
Article
Oncology
Anna Wojtuszkiewicz, Inge van der Werf, Stephan Hutter, Wencke Walter, Constance Baer, Wolfgang Kern, Jeroen J. W. M. Janssen, Gert J. Ossenkoppele, Claudia Haferlach, Jacqueline Cloos, Torsten Haferlach
Summary: This study explored differential splicing profiles associated with two common aberrations in AML, FLT3-ITD and NPM1 mutations. The co-occurrence of FLT3-ITD and mutated NPM1 was found to be associated with differential splicing of gene sets specific to FAB types, affecting cell cycle control and DNA damage response. Interestingly, differential expression mainly impacted genes involved in hematopoietic differentiation, indicating potential oncogenic relevance in FLT3-ITD+/NPM1+ samples.
Article
Hematology
Sofia von Palffy, Hanna Thorsson, Pablo Pena-Martinez, Noelia Puente-Moncada, Carl Sanden, Anna M. Blom, Rasmus Henningsson, Gunnar Juliusson, Ben King, Niklas Landberg, Vladimir Lazarevic, Christina Orsmark-Pietras, Marianne Rissler, Vendela Rissler, Helena Agerstam, Marcus Jaras, Henrik Lilljebjorn, Thoas Fioretos
Summary: Mutations in the NPM1 gene are common in acute myeloid leukemia (AML), but relapse is still a significant concern. In this study, we identified the complement receptor C3AR as specifically expressed in NPM1-mutated AML cells, making it a potential target for antibody-based therapies. We also found that C3AR, in combination with GPR56, distinguishes leukemic stem cells from normal hematopoietic stem cells, and stimulation of C3AR-expressing cells leads to increased survival of AML cells. Furthermore, antibodies directed against C3AR effectively induce natural killer cell-mediated killing of primary AML cells, highlighting its potential as a therapeutic target in NPM1-mutated AML.
Article
Oncology
Claudia Tregnago, Maddalena Benetton, Davide Padrin, Katia Polato, Giulia Borella, Ambra Da Ros, Anna Marchetti, Elena Porcu, Francesca Del Bufalo, Cristina Mecucci, Franco Locatelli, Martina Pigazzi
Summary: In this study, NPM1 mutations in AML were classified into A-like and non-A-like mutations based on the loss of tryptophan residues, revealing different biological features and sensitivity to chemotherapy. The differential expression of HOXA and HOXB genes and cell death pathways between these two types of mutations suggests the potential for further sub-classification and personalized management of NPM1-mutated AML patients.
Article
Hematology
Giulia Pianigiani, Andrea Gagliardi, Federica Mezzasoma, Francesca Rocchio, Valentina Tini, Barbara Bigerna, Paolo Sportoletti, Simona Caruso, Andrea Marra, Sara Peruzzi, Eleonora Petito, Giulio Spinozzi, Sharon Shacham, Yosef Landesman, Concetta Quintarelli, Paolo Gresele, Franco Locatelli, Lorenzo Brunetti, Maria Paola Martelli, Brunangelo Falini
Summary: NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes high expression of homeobox (HOX) genes. However, the current dosing frequency and efficacy of drugs against NPM1-mutated AML are limited. The second-generation XPO1 inhibitor eltanexor, with a higher dosing frequency, can induce sustained downregulation of HOX genes, induce terminal AML differentiation, and prolong the survival of patients, providing important information for the design of clinical trials.
Article
Hematology
Gabrielle Paras, Linde M. Morsink, Megan Othus, Filippo Milano, Brenda M. Sandmaier, Lucas C. Zarling, Raffaele Palmieri, Gary Schoch, Chris Davis, Marie Bleakley, Mary E. D. Flowers, H. Joachim Deeg, Frederick R. Appelbaum, Rainer Storb, Roland B. Walter
Summary: In AML, assessing MRD status before and after allogeneic HCT is crucial for predicting patient outcomes. The dynamics of peri-HCT MRD can significantly impact relapse risk and survival probabilities across varying conditioning intensities, improving risk assessment in AML patients compared to isolated pre- or post-HCT MRD assessments.
Article
Hematology
Patrick Harrington, Richard Dillon, Deepti Radia, Philippe Rousselot, Donal P. McLornan, Mark Ong, Anna Green, Alessandro Verde, Farzana Hussain, Kavita Raj, Shahram Kordasti, Claire Harrison, Hugues de Lavallade
Summary: Dasatinib is a multi-kinase inhibitor that inhibits the SRC kinase LCK, resulting in inhibition of T-cell receptor signaling. It has been found to enhance tumor immunity and selectively deplete regulatory T cells (Tregs), leading to potential immunotherapeutic applications. This study compared the impact of dasatinib with other tyrosine kinase inhibitors (TKI) on chronic myeloid leukemia patients and found that dasatinib inhibits TCR and STAT5 signaling pathways, reduces pro-inflammatory cytokines, and preserves anti-tumor immunity by preventing T-cell exhaustion through TIM-3 signaling. These findings provide insights into the immunomodulatory effects of dasatinib and its potential use in immunotherapies.
Letter
Hematology
Shilpa Prabhu, Richard Dillon, Iara Maria Sequeiros, Caroline Besley FrcPath, David Ian Marks
INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION
(2023)
Article
Hematology
Eshrak Al-Shaibani, Shiyi Chen, Carol Chen, Ivan Pasic, Fotios V. V. Michelis, Wilson Lam, Arjun Law, Igor Novitzky-Basso, Armin Gerbitz, Dennis D. D. Kim, Auro Viswabandya, Jeffrey H. H. Lipton, Jonas Mattson, Rajat Kumar
Summary: This study retrospectively analyzed the outcomes of 332 patients who received hematopoietic cell transplantation and found that patients over the age of 70 had poorer event-free survival and higher non-relapse mortality. This may be attributed to a higher rate of re-hospitalization and infectious complications.
ANNALS OF HEMATOLOGY
(2023)
Article
Multidisciplinary Sciences
William Villiers, Audrey Kelly, Xiaohan He, James Kaufman-Cook, Abdurrahman Elbasir, Halima Bensmail, Paul Lavender, Richard Dillon, Borbala Mifsud, Cameron S. Osborne
Summary: The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.
NATURE COMMUNICATIONS
(2023)
Editorial Material
Hematology
Jad Othman, Richard Dillon
LANCET HAEMATOLOGY
(2023)
Article
Hematology
Stuart Scott, Richard Dillon, Christian Thiede, Sadia Sadiq, Ashley Cartwright, Hazel J. Clouston, Debbie Travis, Katya Mokretar, Nicola Potter, Andrew Chantry, Liam Whitby
Summary: The European LeukaemiaNet (ELN) MRD working group has published guidelines for standardizing molecular genetic MRD testing of certain markers. A study involving 29 international laboratories showed that most participants were able to accurately detect and interpret MRD testing results, although some errors were identified. False-positive results were reported in the NPM1 marker-negative samples, emphasizing the need for ongoing quality assessment and proficiency testing. The study also highlighted the need for revising the guidelines to address interpretive issues and improve dissemination.
Article
Hematology
Jad Othman, Charlotte Wilhelm-Benartzi, Richard Dillon, Steve Knapper, Sylvie D. Freeman, Leona M. Batten, Joanna Canham, Emily L. Hinson, Julie Wych, Sophie Betteridge, William Villiers, Michelle Kleeman, Amanda Gilkes, Nicola Potter, Ulrik Malthe Overgaard, Priyanka Mehta, Panagiotis Kottaridis, Jamie Cavenagh, Claire Hemmaway, Claire Arnold, Mike Dennis, Nigel H. Russell
Summary: This study compared the efficacy of CPX-351 and FLAG-Ida in younger patients, and found no significant difference in overall survival between the two treatments. However, the use of CPX-351 significantly prolonged relapse-free survival, particularly in patients with MDS-related gene mutations.
Article
Hematology
Justin Loke, Nicholas McCarthy, Aimee Jackson, Shamyla Siddique, Andrea Hodgkinson, John Mason, Charles Crawley, Maria Gilleece, Andrew Peniket, Rachel Protheroe, Rahuman Salim, Eleni Tholouli, Keith Wilson, Georgia Andrew, Richard Dillon, Naeem Khan, Victoria Potter, Pramila Krishnamurthy, Charles Craddock, Sylvie Freeman
Summary: This study reports the prognostic impact of biomarkers including MRD, T-cell chimerism, and blast HLA-DR expression in AML/MDS patients receiving allogeneic stem-cell transplant. MRD positivity is associated with reduced overall survival, while MRD is infrequent and does not affect the outcome in patients with full donor T-cell chimerism.
Article
Biophysics
Igor Novitzky-Basso, Swe Mar Linn, Jennifer White, Mohamed Elemary, Anargyros Xenocostas, Uday Deotare, Kate Kelly, Nada Hamad, Sui Tan, Samantha Culos, Arjun Law, Rajat Kumar, Jonas Mattsson, Dennis Dong Hwan Kim
Summary: The study compared the treatment outcomes of ruxolitinib (RUX) and the best available treatment (BAT) in 426 patients with chronic graft-versus-host disease (cGvHD). The results showed that RUX was superior to BAT as second-line therapy or beyond in terms of 12-month failure-free survival (FFS) rate. The RUX group also had higher rates of discontinuation of prednisone compared to the BAT group.
BONE MARROW TRANSPLANTATION
(2023)
Letter
Medicine, Research & Experimental
P. Sriskandarajah, D. P. McLornan, C. Oni, A. J. Wilson, C. Woodley, M. Ciesielska, K. Raj, R. Dillon, M. Ethell, J. Chacko, K. Orchard, D. H. Radia
Summary: Advanced systemic mastocytosis (AdvSM) is a rare, life-limiting mast cell (MC) neoplasm, which is often associated with a hematological neoplasm (AHN) in approximately 70% of patients. Avapritinib, a selective tyrosine kinase inhibitor, has shown potent activity in treating AdvSM and has successfully bridged three patients to allogeneic hematopoietic cell transplant (allo-HCT). Two cases also highlight the risk of clonal evolution within the AHN component and the necessity of close monitoring during targeted therapy.
CURRENT RESEARCH IN TRANSLATIONAL MEDICINE
(2023)
Article
Hematology
Soren Thorgaard Bonlokke, Christian Fenger-Eriksen, Hans Beier Ommen, Anne-Mette Hvas
Summary: This study investigated the dynamics of fibrinolysis in patients with hematological cancer and found that patients with lymphoma exhibited impaired fibrinolysis, while patients with acute promyelocytic leukemia and light-chain amyloidosis showed hyperfibrinolysis.
Article
Hematology
Jennifer White, Mohamed Elemary, Swe Mar Linn, Igor Novitzky-Basso, Samantha Culos, Sui Keat Tan, Kate Kelly, Uday Deotare, Anargyros Xenocostas, Nada Hamad, Arjun Law, Rajat Kumar, Dennis Dong Hwan Kim
Summary: This study evaluated the real-world efficacy and safety of ruxolitinib in heavily pretreated chronic graft versus host disease (cGVHD) patients who have failed previous systemic therapy. The overall response rate was 48.6% and the clinical benefit rate was 58.7%. Some patients were able to discontinue or reduce the use of steroids. The study demonstrates the therapeutic efficacy of ruxolitinib for cGVHD in a heavily pretreated real-world population.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)
Article
Hematology
Mariana Pinto Pereira, Mats Remberger, Carol Chen, Armin Gerbitz, Dennis Dong Hwan Kim, Rajat Kumar, Wilson Lam, Arjun Datt Law, Jeffrey H. Lipton, Fotios V. Michelis, Igor Novitzky-Basso, Auro Viswabandya, Jonas Mattsson, Ivan Pasic
Summary: The choice between an older matched sibling donor (MSD) and a younger matched unrelated donor (MUD) remains debated in allogeneic hematopoietic cell transplantation (HCT). In this study, researchers compared outcomes of patients who received grafts from MSDs age >60 years and MUDs age <30 years for AML and MDS, and found no significant differences in most measures.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)
Article
Hematology
Abel Santos Carreira, Maria Queralt Salas, Mats Remberger, Igor Novitzky-Basso, Arjun Datt Law, Wilson Lam, Ivan Pasic, Tony Mazzulli, Christine Cserti-Gazdewich, Dennis (Dong Hwan) Kim, Fotios Michelis, Auro Viswabandya, Armin Gerbitz, Jeffrey Howard Lipton, Rajat Kumar, Moustapha Hassan, Jonas Mattsson
Summary: This study investigates the incidence and predictors of hemorrhagic cystitis (HC) in adults undergoing allo-hematopoietic stem cell transplantation. The results suggest that certain conditioning regimens and prophylaxis treatments increase the risk of HC. Additionally, there is a correlation between HC and graft-versus-host disease and BK virus.
TRANSPLANTATION AND CELLULAR THERAPY
(2023)