334 results on '"Valk, Peter J M'
Search Results
2. Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study
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Hernández-Sánchez, Alberto, González, Teresa, Sobas, Marta, Sträng, Eric, Castellani, Gastone, Abáigar, María, Valk, Peter J. M., Villaverde Ramiro, Ángela, Benner, Axel, Metzeler, Klaus H., Azibeiro, Raúl, Tettero, Jesse M., Martínez-López, Joaquín, Pratcorona, Marta, Martínez Elicegui, Javier, Mills, Ken I., Thiede, Christian, Sanz, Guillermo, Döhner, Konstanze, Heuser, Michael, Haferlach, Torsten, Turki, Amin T., Reinhardt, Dirk, Schulze-Rath, Renate, Barbus, Martje, Hernández-Rivas, Jesús María, Huntly, Brian, Ossenkoppele, Gert, Döhner, Hartmut, and Bullinger, Lars
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- 2024
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3. Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients
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Adriane Halik, Marlon Tilgner, Patricia Silva, Natalia Estrada, Robert Altwasser, Ekaterina Jahn, Michael Heuser, Hsin-An Hou, Marta Pratcorona, Robert K. Hills, Klaus H. Metzeler, Laurene Fenwarth, Anna Dolnik, Christine Terre, Klara Kopp, Olga Blau, Martin Szyska, Friederike Christen, Jan Krönke, Loïc Vasseur, Bob Löwenberg, Jordi Esteve, Peter J. M. Valk, Matthieu Duchmann, Wen-Chien Chou, David C. Linch, Hartmut Döhner, Rosemary E. Gale, Konstanze Döhner, Lars Bullinger, Kenichi Yoshida, and Frederik Damm
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AML ,del(7q) ,Monosomy 7 ,Complex karyotype ,KMT2C ,TP53 ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood. Methods To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines. Results In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7—most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or −7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66–3.86]; P
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- 2024
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4. Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients
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Halik, Adriane, Tilgner, Marlon, Silva, Patricia, Estrada, Natalia, Altwasser, Robert, Jahn, Ekaterina, Heuser, Michael, Hou, Hsin-An, Pratcorona, Marta, Hills, Robert K., Metzeler, Klaus H., Fenwarth, Laurene, Dolnik, Anna, Terre, Christine, Kopp, Klara, Blau, Olga, Szyska, Martin, Christen, Friederike, Krönke, Jan, Vasseur, Loïc, Löwenberg, Bob, Esteve, Jordi, Valk, Peter J. M., Duchmann, Matthieu, Chou, Wen-Chien, Linch, David C., Döhner, Hartmut, Gale, Rosemary E., Döhner, Konstanze, Bullinger, Lars, Yoshida, Kenichi, and Damm, Frederik
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- 2024
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5. Long‐term genetic and clinical remissions after cessation of azacitidine treatment in patients with VEXAS syndrome
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Anna M. Aalbers, Paul L. A. vanDaele, Virgil A. S. H. Dalm, Peter J. M. Valk, and Marc H. G. P. Raaijmakers
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2024
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6. Prognostic relevance of molecular measurable residual disease detection in AML with mutated CEBPA
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Christian M. Vonk, Emma L. Boertjes, Francois G. Kavelaars, Melissa Rijken, Jolinda M. L. Konijnenburg, Roxanne E. Cromwell, Bob Löwenberg, Tim Grob, and Peter J. M. Valk
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2024
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7. Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia
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Koury, Luísa Corrêa de Araújo, Kim, Haesook T., Undurraga, Maria Soledad, Navarro-Cabrera, Juan Ramon, Salinas, Victor, Muxi, Pablo, Melo, Raul A. M., Glória, Ana Beatriz, Pagnano, Katia, Nunes, Elenaide C., Bittencourt, Rosane I., Rojas, Ninoska, Quintana, Shirley, Ayala-Lugo, Ana, Oliver, Ana Carolina, Figueiredo-Pontes, Lorena, Traina, Fabiola, Moreira, Frederico, Fagundes, Evandro M., Duarte, Bruno K. L., Mora-Alferez, Analí Pamela, Ortiz, Percy, Untama, Jose, Tallman, Martin, Ribeiro, Raul, Ganser, Arnold, Dillon, Richard, Valk, Peter J. M., Sanz, Miguel, Löwenberg, Bob, Berliner, Nancy, and Rego, Eduardo M.
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- 2024
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8. Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine
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Hilberink, Jacobien R., van Zeventer, Isabelle A., Chitu, Dana A., Pabst, Thomas, Klein, Saskia K., Stussi, Georg, Griskevicius, Laimonas, Valk, Peter J. M., Cloos, Jacqueline, van de Loosdrecht, Arjan A., Breems, Dimitri, van Lammeren-Venema, Danielle, Boersma, Rinske, Jongen-Lavrencic, Mojca, Fehr, Martin, Hoogendoorn, Mels, Manz, Markus G., Söhne, Maaike, van Marwijk Kooy, Rien, Deeren, Dries, van der Poel, Marjolein W. M., Legdeur, Marie Cecile, Tick, Lidwine, Chalandon, Yves, Ammatuna, Emanuele, Blum, Sabine, Löwenberg, Bob, Ossenkoppele, Gert J., and Huls, Gerwin
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- 2023
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9. Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine
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Jacobien R. Hilberink, Isabelle A. van Zeventer, Dana A. Chitu, Thomas Pabst, Saskia K. Klein, Georg Stussi, Laimonas Griskevicius, Peter J. M. Valk, Jacqueline Cloos, Arjan A. van de Loosdrecht, Dimitri Breems, Danielle van Lammeren-Venema, Rinske Boersma, Mojca Jongen-Lavrencic, Martin Fehr, Mels Hoogendoorn, Markus G. Manz, Maaike Söhne, Rien van Marwijk Kooy, Dries Deeren, Marjolein W. M. van der Poel, Marie Cecile Legdeur, Lidwine Tick, Yves Chalandon, Emanuele Ammatuna, Sabine Blum, Bob Löwenberg, Gert J. Ossenkoppele, Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON), Swiss Group for Clinical Cancer Research (SAKK), and Gerwin Huls
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.
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- 2023
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10. The added value of multi‐state modelling in a randomized controlled trial: The HOVON 102 study re‐analyzed
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Katerina Bakunina, Hein Putter, Jurjen Versluis, Eva A. S. Koster, Bronno van derHolt, Markus G. Manz, Dimitri A. Breems, Bjorn T. Gjertsen, Jacqueline Cloos, Peter J. M. Valk, Jakob Passweg, Thomas Pabst, Gert J. Ossenkoppele, Bob Löwenberg, Jan J. Cornelissen, and Liesbeth C. deWreede
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AML ,clofarabine ,current leukemia‐free survival ,HSCT ,multi‐state model ,RCT ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi‐state models can provide additional insights to supplement the original intention‐to‐treat analysis of randomized controlled trials (RCT). We re‐analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi‐state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post‐remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post‐remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post‐remission treatment with alloSCT, non‐relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia‐free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi‐state models further detail the effect of treatment on competing and series of events.
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- 2022
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11. Long‐term genetic and clinical remissions after cessation of azacitidine treatment in patients with VEXAS syndrome.
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Aalbers, Anna M., van Daele, Paul L. A., Dalm, Virgil A. S. H., Valk, Peter J. M., and Raaijmakers, Marc H. G. P.
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- 2024
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12. BCR::ABL1 digital PCR for treatment‐free remission prediction in chronic myeloid leukemia patients: An individual participant data meta‐analysis.
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Kockerols, Camille, Valk, Peter J. M., Dulucq, Stéphanie, Nicolini, Franck‐Emmanuel, Mahon, François‐Xavier, Atallah, Ehab, Mauro, Michael J., Radich, Jerald P., Bernardi, Simona, Russo, Domenico, Farina, Mirko, Mori, Silvia, Gambacorti‐Passerini, Carlo, Civettini, Ivan, Lu, Liu, Yeung, David, Branford, Susan, Colafigli, Gioia, Breccia, Massimo, and Hogenbirk, Pauline
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- 2024
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13. Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis
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Monica Hellesøy, Caroline Engen, Tim Grob, Bob Löwenberg, Peter J. M. Valk, and Bjørn T. Gjertsen
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acute myeloid leukaemia ,context‐dependency ,FLT3 ,FLT3‐ITD ,sex disparity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex‐related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3‐ITD) mutation and co‐mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3‐ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML‐TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex‐associated molecular differences. Co‐occurrence of FLT3‐ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3‐ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia‐associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3‐ITD‐mutated AML. Thus, we suggest optimization of FLT3‐ITD mutation status as a clinical tool in a sex‐adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex‐specific considerations.
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- 2021
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14. FLT3‐ITD mutations in acute myeloid leukaemia – molecular characteristics, distribution and numerical variation
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Caroline Engen, Monica Hellesøy, Tim Grob, Adil Al Hinai, Atle Brendehaug, Line Wergeland, Siv Lise Bedringaas, Randi Hovland, Peter J. M. Valk, and Bjørn T. Gjertsen
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acute myeloid leukaemia ,FLT3‐ITD ,length mutation ,outcome ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Recurrent somatic internal tandem duplications (ITD) in the FMS‐like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3‐ITD mutation status guides risk‐adapted treatment strategies. The aim of this work was to characterise FLT3‐ITD variant distribution in relation to molecular and clinical features, and overall survival in adult AML patients. We performed two parallel retrospective cohort studies investigating FLT3‐ITD length and expression by cDNA fragment analysis, followed by Sanger sequencing in a subset of samples. In the two cohorts, a total of 139 and 172 mutant alleles were identified in 111 and 123 patients, respectively, with 22% and 28% of patients presenting with more than one mutated allele. Further, 15% and 32% of samples had a FLT3‐ITD total variant allele frequency (VAF)
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- 2021
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15. Genomic and evolutionary portraits of disease relapse in acute myeloid leukemia
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Rapaport, Franck, Neelamraju, Yaseswini, Baslan, Timour, Hassane, Duane, Gruszczynska, Agata, Robert de Massy, Marc, Farnoud, Noushin, Haddox, Samuel, Lee, Tak, Medina-Martinez, Juan, Sheridan, Caroline, Thurmond, Alexis, Becker, Michael, Bekiranov, Stefan, Carroll, Martin, Moses Murdock, Heardly, Valk, Peter J. M., Bullinger, Lars, D’Andrea, Richard, Lowe, Scott W., Neuberg, Donna, Levine, Ross L., Melnick, Ari, and Garrett-Bakelman, Francine E.
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- 2021
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16. PPM1D mutations appear in complete remission after exposure to chemotherapy without predicting emerging AML relapse
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Al Hinai, Adil S. A., Grob, Tim, Rijken, Melissa, Kavelaars, François G., Zeilemaker, Annelieke, Erpelinck-Verschueren, Claudia A. J., Sanders, Mathijs A., Löwenberg, Bob, Jongen-Lavrencic, Mojca, and Valk, Peter J. M.
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- 2021
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17. Prediction of sustained remission after tyrosine kinase inhibitor discontinuation with BCR::ABL1 digital PCR in chronic myeloid leukemia patients.
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Kockerols, Camille, Valk, Peter J. M., Janssen, Jeroen J. W. M., Hogenbirk, Pauline, Cornelissen, Jan J., Saussele, Susanne, Spiess, Birgit, Perusini, Maria Agustina, Kim, Dennis, and Westerweel, Peter E.
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CHRONIC myeloid leukemia , *PROTEIN-tyrosine kinase inhibitors , *IMATINIB , *TREATMENT duration , *PROBABILITY theory - Abstract
Precise and reliable predictive parameters to accurately identify chronic myeloid leukemia (CML) patients who can successfully discontinue their tyrosine kinase inhibitor (TKI) treatment are lacking. One promising parameter is depth of molecular response measured by BCR::ABL1 digital PCR (dPCR). The aim of this study was to validate a previously described prediction cutoff of 0.0023%IS and to assess the value of dPCR for treatment‐free remission (TFR) prediction in relation to other clinical parameters. A droplet‐based dPCR assay assessed BCR::ABL1 %IS prior to TKI discontinuation. The primary endpoint was molecular recurrence (MolR) by 36 months. A total of 186 patients from Canada, Germany, and the Netherlands were included. In patients with a first TKI discontinuation attempt (n = 163), a BCR::ABL1 dPCR < and ≥0.0023%IS had a MolR probability of 33% and 70%, respectively. Patients treated less than 6 years with a BCR::ABL1 dPCR <0.0023%IS had a MolR probability of 31%. After correction for treatment duration, both high dPCR value and the use of imatinib (vs. second‐generation TKI) were significantly associated with a higher risk of MolR (HR of 3.66, 95%CI 2.06–6.51, p <.001; and 2.85, 95%CI 1.25–6.46, p =.013, respectively). BCR::ABL1 dPCR was not associated with TFR outcome after second TKI discontinuation, however, with the limitation of a small number of patients analyzed (n = 23). In conclusion, BCR::ABL1 digital PCR based on the cutoff of 0.0023%IS is a valuable predictive tool to identify CML patients with a high probability of TFR success after first TKI discontinuation, including patients treated for less than 6 years. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing
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Arindrarto, Wibowo, Borràs, Daniel M., de Groen, Ruben A. L., van den Berg, Redmar R., Locher, Irene J., van Diessen, Saskia A. M. E., van der Holst, Rosalie, van der Meijden, Edith D., Honders, M. Willy, de Leeuw, Rick H., Verlaat, Wina, Jedema, Inge, Kroes, Wilma G. M., Knijnenburg, Jeroen, van Wezel, Tom, Vermaat, Joost S. P., Valk, Peter J. M., Janssen, Bart, de Knijff, Peter, van Bergen, Cornelis A. M., van den Akker, Erik B., Hoen, Peter A. C. ’t, Kiełbasa, Szymon M., Laros, Jeroen F. J., Griffioen, Marieke, and Veelken, Hendrik
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- 2021
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19. Prognostic relevance of molecular measurable residual disease detection in AML with mutated CEBPA.
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Vonk, Christian M., Boertjes, Emma L., Kavelaars, Francois G., Rijken, Melissa, Konijnenburg, Jolinda M. L., Cromwell, Roxanne E., Löwenberg, Bob, Grob, Tim, and Valk, Peter J. M.
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- 2024
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20. Azacytidine Treatment for VEXAS Syndrome
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Marc H. G. P. Raaijmakers, Maud Hermans, Anna Aalbers, Melissa Rijken, Virgil A. S. H. Dalm, Paul van Daele, and Peter J. M. Valk
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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21. Archived bone marrow smears are an excellent source for NGS-based mutation detection in acute myeloid leukemia
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Al Hinai, Adil S. A., Grob, Tim, Kavelaars, François G., Rijken, Melissa, Zeilemaker, Annelieke, Erpelinck-Verschueren, Claudia A. J., Gussinklo, Kirsten J., Sanders, Mathijs A., van Lom, Kirsten, and Valk, Peter J. M.
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- 2020
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22. The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia
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Angenendt, Linus, Bormann, Eike, Pabst, Caroline, Alla, Vijay, Görlich, Dennis, Braun, Leonie, Dohlich, Kim, Schwöppe, Christian, Bohlander, Stefan K., Arteaga, Maria Francisca, Wethmar, Klaus, Hartmann, Wolfgang, Angenendt, Adrian, Kessler, Torsten, Mesters, Rolf M., Stelljes, Matthias, Rothenberg-Thurley, Maja, Spiekermann, Karsten, Hébert, Josée, Sauvageau, Guy, Valk, Peter J. M., Löwenberg, Bob, Serve, Hubert, Müller-Tidow, Carsten, Lenz, Georg, Wörmann, Bernhard J., Sauerland, M. Christina, Hiddemann, Wolfgang, Berdel, Wolfgang E., Krug, Utz, Metzeler, Klaus H., Mikesch, Jan-Henrik, Herold, Tobias, and Schliemann, Christoph
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- 2019
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23. Prospective validation of the prognostic relevance of CD34+CD38– AML stem cell frequency in the HOVON-SAKK132 trial
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Ngai, Lok Lam, Hanekamp, Diana, Janssen, Fleur, Carbaat-Ham, Jannemieke, Hofland, Maaike A M, Fayed, Mona M H E, Kelder, Angèle, Oudshoorn-van Marsbergen, Laura, Scholten, Willemijn J, Snel, Alexander N, Bachas, Costa, Tettero, Jesse M, Breems, Dimitri A, Fischer, Thomas, Gjertsen, Bjorn T, Griskevicius, Laimonas, Juliusson, Gunnar, van de Loosdrecht, Arjan A, Maertens, Johan A, Manz, Markus G, Pabst, Thomas, Passweg, Jakob R, Porkka, Kimmo, Valk, Peter J M, Gradowska, Patrycja, Löwenberg, Bob, de Leeuw, David C, Janssen, Jeroen J W M, Ossenkoppele, Gert J, Cloos, Jacqueline, Hematology laboratory, VU University medical center, Hematology, AII - Cancer immunology, AII - Inflammatory diseases, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, and CCA - Cancer Treatment and quality of life
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All institutes and research themes of the Radboud University Medical Center ,Immunology ,Cell Biology ,Hematology ,610 Medicine & health ,Biochemistry ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
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- 2023
24. CD34+CD38− leukemic stem cell frequency to predict outcome in acute myeloid leukemia
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Zeijlemaker, Wendelien, Grob, Tim, Meijer, Rosa, Hanekamp, Diana, Kelder, Angèle, Carbaat-Ham, Jannemieke C., Oussoren-Brockhoff, Yvonne J. M., Snel, Alexander N., Veldhuizen, Dennis, Scholten, Willemijn J., Maertens, Johan, Breems, Dimitri A., Pabst, Thomas, Manz, Markus G., van der Velden, Vincent H. J., Slomp, Jennichjen, Preijers, Frank, Cloos, Jacqueline, van de Loosdrecht, Arjan A., Löwenberg, Bob, Valk, Peter J. M., Jongen-Lavrencic, Mojca, Ossenkoppele, Gert J., and Schuurhuis, Gerrit J.
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- 2019
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25. Molecular Minimal Residual Disease Detection in Acute Myeloid Leukemia
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Christian M. Vonk, Adil S. A. Al Hinai, Diana Hanekamp, and Peter J. M. Valk
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acute myeloid leukemia ,minimal/measurable residual disease ,MRD ,next generation sequencing ,clonal hematopoiesis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Initial induction chemotherapy to eradicate the bulk of acute myeloid leukemia (AML) cells results in complete remission (CR) in the majority of patients. However, leukemic cells persisting in the bone marrow below the morphologic threshold remain unaffected and have the potential to proliferate and re-emerge as AML relapse. Detection of minimal/measurable residual disease (MRD) is a promising prognostic marker for AML relapse as it can assess an individual patients’ risk profile and evaluate their response to treatment. With the emergence of molecular techniques, such as next generation sequencing (NGS), a more sensitive assessment of molecular MRD markers is available. In recent years, the detection of MRD by molecular assays and its association with AML relapse and survival has been explored and verified in multiple studies. Although most studies show that the presence of MRD leads to a worse clinical outcome, molecular-based methods face several challenges including limited sensitivity/specificity, and a difficult distinction between mutations that are representative of AML rather than clonal hematopoiesis. This review describes the studies that have been performed using molecular-based assays for MRD detection in the context of other MRD detection approaches in AML, and discusses limitations, challenges and opportunities.
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- 2021
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26. BCR::ABL1 kinase domain mutation testing and clinical outcome in a nationwide chronic myeloid leukemia patient population.
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Kockerols, Camille, Valk, Peter J. M., Blijlevens, Nicole M. A., Cornelissen, Jan J., Dinmohamed, Avinash G., Geelen, Inge, Hoogendoorn, Mels, Janssen, Jeroen J. W. M., Daenen, Laura G. M., Reijden, Bert A. van der, and Westerweel, Peter E.
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CHRONIC myeloid leukemia , *GENETIC mutation , *CHRONIC leukemia , *PROTEIN-tyrosine kinase inhibitors , *MISSENSE mutation , *TREATMENT failure - Abstract
Objectives: Acquired missense mutations in the BCR::ABL1 kinase domain (KD) may cause tyrosine kinase inhibitor (TKI) treatment failure. Based on mutation‐specific in vitro derived IC50‐values, alternative TKI may be selected. We assessed clinical practice of BCR::ABL1 KD mutation testing, clinical response in relation to IC50‐values, and clinical outcome of tested patients. Methods: Patients from six Dutch CML reference centers and a national registry were included once a mutational analysis was performed. Reasons for testing were categorized as suboptimal TKI response, and primary or secondary TKI resistance. Results: Four hundred twenty analyses were performed in 275 patients. Sixty‐nine patients harbored at least one mutation. Most analyses were performed because of suboptimal TKI response but with low mutation incidence (4%), while most mutations were found in primary and secondary resistant patients (21% and 51%, respectively). Harboring a BCR::ABL1 mutation was associated with inferior overall survival (HR 3.2 [95% CI, 1.7–6.1; p <.001]). Clinically observed responses to TKI usually corresponded with the predicted TKI sensitivity based on the IC50‐values, but a high IC50‐value did not preclude a good clinical response per se. Conclusions: We recommend BCR::ABL1 KD mutation testing in particular in the context of primary or secondary resistance. IC50‐values can direct the TKI choice for CML patients, but clinical efficacy can be seen despite adverse in vitro resistance. [ABSTRACT FROM AUTHOR]
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- 2023
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27. Measurable residual disease monitoring in patients with acute myeloid leukemia treated with lower‐intensity therapy: Roadmap from an ELN‐DAVID expert panel.
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Ravandi, Farhad, Cloos, Jacqueline, Buccisano, Francesco, Dillon, Richard, Döhner, Konstanze, Freeman, Sylvie D., Hourigan, Christopher S., Ossenkoppele, Gerrit J., Roboz, Gail J., Subklewe, Marion, Thiede, Christian, Arnhardt, Isabell, Valk, Peter J. M., Venditti, Adriano, Wei, Andrew H., Walter, Roland B., and Heuser, Michael
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- 2023
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28. Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine
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Hilberink, Jacobien R, van Zeventer, Isabelle A, Chitu, Dana A, Pabst, Thomas, Klein, Saskia K, Stussi, Georg, Griskevicius, Laimonas, Valk, Peter J M, Cloos, Jacqueline, van de Loosdrecht, Arjan A, Breems, Dimitri, van Lammeren-Venema, Danielle, Boersma, Rinske, Jongen-Lavrencic, Mojca, Fehr, Martin, Hoogendoorn, Mels, Manz, Markus G, Söhne, Maaike, van Marwijk Kooy, Rien, Deeren, Dries, van der Poel, Marjolein W M, Legdeur, Marie Cecile, Tick, Lidwine, Chalandon, Yves, Ammatuna, Emanuele, Blum, Sabine, Löwenberg, Bob, Ossenkoppele, Gert J, and Huls, Gerwin
- Subjects
610 Medicine & health - Abstract
Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.
- Published
- 2023
29. Measurable residual disease-guided therapy in intermediate-risk acute myeloid leukemia patients is a valuable strategy in reducing allogeneic transplantation without negatively affecting survival
- Author
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Tettero, Jesse M, Ngai, Lok Lam, Bachas, Costa, Breems, Dimitri A, Fischer, Thomas, Gjertsen, Bjorn T, Gradowska, Patrycja, Griskevicius, Laimonas, Janssen, Jeroen J W M, Juliusson, Gunnar, Maertens, Johan, Manz, Markus G, Pabst, Thomas, Passweg, Jakob, Porkka, Kimmo, Valk, Peter J M, Löwenberg, Bob, Ossenkoppele, Gert J, and Cloos, Jacqueline
- Subjects
610 Medicine & health ,Hematology - Abstract
Not available.
- Published
- 2023
30. EXABS-100-AML Is TP53 Mutated AML the Same Disease as TP53 Mutated MDS?
- Author
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Peter J M, Valk and Hematology
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Leukemia, Myeloid, Acute ,Cancer Research ,Oncology ,SDG 3 - Good Health and Well-being ,Myelodysplastic Syndromes ,Mutation ,Humans ,Hematology ,Tumor Suppressor Protein p53 - Published
- 2022
31. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome
- Author
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Tim Grob, Adil S. A. Al Hinai, Mathijs A. Sanders, François G. Kavelaars, Melissa Rijken, Patrycja L. Gradowska, Bart J. Biemond, Dimitri A. Breems, Johan Maertens, Marinus van Marwijk Kooy, Thomas Pabst, Okke de Weerdt, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Gerwin A. Huls, Jan J. Cornelissen, H. Berna Beverloo, Bob Löwenberg, Mojca Jongen-Lavrencic, Peter J. M. Valk, Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Hematology, Clinical Haematology, CCA - Cancer biology and immunology, and Hematology laboratory
- Subjects
OUTCOMES ,endocrine system diseases ,ALLELE FREQUENCY ,MUTATIONS ,Immunology ,CLONAL HEMATOPOIESIS ,Cell Biology ,Hematology ,Biochemistry ,Cytogenetics ,Leukemia, Myeloid, Acute ,stomatognathic system ,Myelodysplastic Syndromes ,hemic and lymphatic diseases ,Mutation ,Humans ,Tumor Suppressor Protein p53 ,610 Medicine & health ,neoplasms - Abstract
Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity. ispartof: BLOOD vol:139 issue:15 pages:2347-2354 ispartof: location:United States status: published
- Published
- 2022
32. CEBPA mutations in 4708 patients with acute myeloid leukemia
- Author
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Christoph Schliemann, Sylvia Herold, Friedrich Stölzel, Claudia D. Baldus, Sebastian Scholl, Richard Noppeney, Michael Kramer, Martin Bornhäuser, Martin Kaufmann, Julia Annabell Georgi, Tim H. Brümmendorf, Uwe Platzbecker, Hubert Serve, Carsten Müller-Tidow, Bjoern Steffen, Wolfgang E. Berdel, Stefan W. Krause, Sebastian Stasik, Malte von Bonin, Ralph Naumann, Andreas Petzold, Kerstin Schäfer-Eckart, Andreas Neubauer, Gerhard Ehninger, Mathias Hänel, Alwin Krämer, Roger Mulet-Lazaro, Hermann Einsele, Utz Krug, Markus Schaich, Andreas Hochhaus, Johannes Schetelig, Peter J. M. Valk, Christian Thiede, Christoph Röllig, Andreas Burchert, Franziska Taube, Jan Moritz Middeke, Katja Sockel, Ulrich Kaiser, and Hematology
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Immunology ,Medizin ,Favorable prognosis ,Biochemistry ,Transactivation ,Internal medicine ,CEBPA ,medicine ,Basic Leucine Zipper ,Humans ,Differential impact ,Aged ,Retrospective Studies ,business.industry ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Leukemia ,Leukemia, Myeloid, Acute ,Basic-Leucine Zipper Transcription Factors ,Mutation ,CCAAT-Enhancer-Binding Proteins ,Female ,business ,Protein Binding - Abstract
Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.
- Published
- 2022
33. A 17-gene stemness score for rapid determination of risk in acute leukaemia
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Ng, Stanley W. K., Mitchell, Amanda, Kennedy, James A., Chen, Weihsu C., McLeod, Jessica, Ibrahimova, Narmin, Arruda, Andrea, Popescu, Andreea, Gupta, Vikas, Schimmer, Aaron D., Schuh, Andre C., Yee, Karen W., Bullinger, Lars, Herold, Tobias, Görlich, Dennis, Büchner, Thomas, Hiddemann, Wolfgang, Berdel, Wolfgang E., Wörmann, Bernhard, Cheok, Meyling, Preudhomme, Claude, Dombret, Hervé, Metzeler, Klaus, Buske, Christian, Löwenberg, Bob, Valk, Peter J. M., Zandstra, Peter W., Minden, Mark D., Dick, John E., and Wang, Jean C. Y.
- Published
- 2016
- Full Text
- View/download PDF
34. Next-Generation Sequencing Analysis of the Human TCRγδ+ T-Cell Repertoire Reveals Shifts in Vγ- and Vδ-Usage in Memory Populations upon Aging
- Author
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Martine J. Kallemeijn, François G. Kavelaars, Michèle Y. van der Klift, Ingrid L. M. Wolvers-Tettero, Peter J. M. Valk, Jacques J. M. van Dongen, and Anton W. Langerak
- Subjects
TCRγδ+ ,development ,aging ,repertoire ,next-generation sequencing ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Immunological aging remodels the immune system at several levels. This has been documented in particular for the T-cell receptor (TCR)αβ+ T-cell compartment, showing reduced naive T-cell outputs and an accumulation of terminally differentiated clonally expanding effector T-cells, leading to increased proneness to autoimmunity and cancer development at older age. Even though TCRαβ+ and TCRγδ+ T-cells follow similar paths of development involving V(D)J-recombination of TCR genes in the thymus, TCRγδ+ T-cells tend to be more subjected to peripheral rather than central selection. However, the impact of aging in shaping of the peripheral TRG/TRD repertoire remains largely elusive. Next-generation sequencing analysis methods were optimized based on a spike-in method using plasmid vector DNA-samples for accurate TRG/TRD receptor diversity quantification, resulting in optimally defined primer concentrations, annealing temperatures and cycle numbers. Next, TRG/TRD repertoire diversity was evaluated during TCRγδ+ T-cell ontogeny, showing a broad, diverse repertoire in thymic and cord blood samples with Gaussian CDR3-length distributions, in contrast to the more skewed repertoire in mature circulating TCRγδ+ T-cells in adult peripheral blood. During aging the naive repertoire maintained its diversity with Gaussian CDR3-length distributions, while in the central and effector memory populations a clear shift from young (Vγ9/Vδ2 dominance) to elderly (Vγ2/Vδ1 dominance) was observed. Together with less clear Gaussian CDR3-length distributions, this would be highly suggestive of differentially heavily selected repertoires. Despite the apparent age-related shift from Vγ9/Vδ2 to Vγ2/Vδ1, no clear aging effect was observed on the Vδ2 invariant T nucleotide and canonical Vγ9–Jγ1.2 selection determinants. A more detailed look into the healthy TRG/TRD repertoire revealed known cytomegalovirus-specific TRG/TRD clonotypes in a few donors, albeit without a significant aging-effect, while Mycobacterium tuberculosis-specific clonotypes were absent. Notably, in effector subsets of elderly individuals, we could identify reported TRG and TRD receptor chains from TCRγδ+ T-cell large granular lymphocyte leukemia proliferations, which typically present in the elderly population. Collectively, our results point to relatively subtle age-related changes in the human TRG/TRD repertoire, with a clear shift in Vγ/Vδ usage in memory cells upon aging.
- Published
- 2018
- Full Text
- View/download PDF
35. Splicing factor gene mutations in acute myeloid leukemia offer additive value if incorporated in current risk classification
- Author
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Manja Meggendorfer, Torsten Haferlach, Martijn W. Heymans, Anna Wojtuszkiewicz, Stephan Hutter, Inge van der Werf, Peter J. M. Valk, Jeroen Janssen, Wolfgang Kern, Constance Baer, Claudia Haferlach, Gert J. Ossenkoppele, Jacqueline Cloos, Hematology, VU University medical center, Hematology laboratory, CCA - Cancer biology and immunology, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, and CCA - Cancer Treatment and quality of life
- Subjects
Oncology ,medicine.medical_specialty ,Myeloid ,Gene mutation ,Pathogenesis ,European LeukemiaNet ,chemistry.chemical_compound ,Splicing factor ,Risk Factors ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Aged ,Myeloid Neoplasia ,business.industry ,Myeloid leukemia ,Hematology ,Prognosis ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,RUNX1 ,chemistry ,Concomitant ,Mutation ,RNA Splicing Factors ,business - Abstract
Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clinical features, cytogenetic and molecular abnormalities, and clinical outcome in a large cohort of 1447 patients with AML and high-risk myelodysplastic syndrome. SF mutations were identified in 22% of patients and were associated with multiple unfavorable clinical features, such as older age, antecedent myeloid disorders, and adverse risk factors (mutations in RUNX1 and ASXL1). Furthermore, they had significantly shorter event-free and overall survival. Notably, in European LeukemiaNet (ELN) 2017 favorable- and intermediate-risk groups, SF3B1 mutations were indicative of relatively poor prognosis. In addition, patients carrying concomitant SF mutations and RUNX1 mutations had a particularly adverse prognosis. In patients without any of the 4 most common SF mutations, RUNX1 mutations were associated with relatively good outcome, which was comparable to that of intermediate-risk patients. In this study, we propose that SF mutations be considered for incorporation into prognostic classification systems. First, SF3B1 mutations could be considered an intermediate prognostic factor when co-occurring with favorable risk features and as an adverse prognostic factor for patients currently categorized as having intermediate risk, according to the ELN 2017 classification. Second, the prognostic value of the current adverse factor RUNX1 mutations seems to be limited to its co-occurrence with SF mutations.
- Published
- 2021
36. FLT3-ITD mutations in acute myeloid leukaemia – molecular characteristics, distribution and numerical variation
- Author
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Line Wergeland, Siv Lise Bedringaas, Peter J. M. Valk, Adil Al Hinai, Atle Brendehaug, Monica Hellesøy, Caroline Engen, Tim Grob, Bjørn Tore Gjertsen, Randi Hovland, and Hematology
- Subjects
Male ,0301 basic medicine ,Oncology ,FLT3‐ITD ,Cancer Research ,medicine.disease_cause ,0302 clinical medicine ,Gene Frequency ,Gene Duplication ,hemic and lymphatic diseases ,Research Articles ,RC254-282 ,Aged, 80 and over ,Sanger sequencing ,Mutation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,hemic and immune systems ,General Medicine ,Middle Aged ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cohort ,embryonic structures ,symbols ,outcome ,Molecular Medicine ,Female ,psychological phenomena and processes ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Young Adult ,03 medical and health sciences ,symbols.namesake ,SDG 3 - Good Health and Well-being ,Internal medicine ,White blood cell ,Genetics ,medicine ,Humans ,acute myeloid leukaemia ,Allele ,Gene ,Aged ,Retrospective Studies ,length mutation ,business.industry ,Retrospective cohort study ,Molecular diagnostics ,Survival Analysis ,body regions ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,prognosis ,business - Abstract
Recurrent somatic internal tandem duplications (ITD) in the FMS‐like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3‐ITD mutation status guides risk‐adapted treatment strategies. The aim of this work was to characterise FLT3‐ITD variant distribution in relation to molecular and clinical features, and overall survival in adult AML patients. We performed two parallel retrospective cohort studies investigating FLT3‐ITD length and expression by cDNA fragment analysis, followed by Sanger sequencing in a subset of samples. In the two cohorts, a total of 139 and 172 mutant alleles were identified in 111 and 123 patients, respectively, with 22% and 28% of patients presenting with more than one mutated allele. Further, 15% and 32% of samples had a FLT3‐ITD total variant allele frequency (VAF), Internal tandem duplications (ITD) in the FMS‐like tyrosine kinase 3 (FLT3) gene is present in 20–30% of acute myeloid leukaemia (AML) patients. Here, we perform molecular profiling of FLT3‐ITD mutations in 263 AML patients. We provide a comprehensive overview of the heterogeneity and impact of FLT3‐ITD mutations by assessing various molecular features and the relationship with clinical features and overall survival.
- Published
- 2021
37. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML
- Author
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Ibrahim Aldoss, Ivana Gojo, Tung On Yau, Anbarasu Lourdusamy, Anjali S. Advani, Catherine Lai, Martin Bornhäuser, John F. DiPersio, Heidi Altmann, Martha Arellano, Michael P. Rettig, Bob Löwenberg, Stephen Reeder, Peter J. M. Valk, Jan K Davidson-Moncada, John E. Godwin, Sarah E. Church, Kendra Sweet, Jan Moritz Middeke, Tressa Hood, Friedrich Stölzel, John Muth, Gemma A. Foulds, Sergio Rutella, Farhad Ravandi, Jayakumar Vadakekolathu, Matthew J. Wieduwilt, Antonio Curti, Marilena Ciciarello, Hematology, Vadakekolathu, Jayakumar, Lai, Catherine, Reeder, Stephen, Church, Sarah E, Hood, Tressa, Lourdusamy, Anbarasu, Rettig, Michael P, Aldoss, Ibrahim, Advani, Anjali S, Godwin, John, Wieduwilt, Matthew J, Arellano, Martha, Muth, John, Yau, Tung On, Ravandi, Farhad, Sweet, Kendra, Altmann, Heidi, Foulds, Gemma A, Stölzel, Friedrich, Middeke, Jan Moritz, Ciciarello, Marilena, Curti, Antonio, Valk, Peter J M, Löwenberg, Bob, Gojo, Ivana, Bornhäuser, Martin, DiPersio, John F, Davidson-Moncada, Jan K, and Rutella, Sergio
- Subjects
Oncology ,medicine.medical_specialty ,Chemokine ,AML, TP53, immunotherapy ,endocrine system diseases ,Immunobiology and Immunotherapy ,medicine.medical_treatment ,Interleukin-3 Receptor alpha Subunit ,Cytogenetics ,Immune system ,Internal medicine ,Antibodies, Bispecific ,medicine ,Humans ,neoplasms ,biology ,business.industry ,Myeloid leukemia ,FOXP3 ,Hematology ,Immunotherapy ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,biology.protein ,Interleukin-3 receptor ,Bone marrow ,Antibody ,Tumor Suppressor Protein p53 ,business - Abstract
Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (
- Published
- 2020
38. Lack of splice factor and cohesin complex mutations in pediatric myelodysplastic syndrome
- Author
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Julia C. Obenauer, François G. Kavelaars, Mathijs A. Sanders, Remco M. Hoogenboezem, Andrica C. H. de Vries, Paulina M. H. van Strien, Valerie de Haas, Franco Locatelli, Henrik Hasle, Peter J. M. Valk, Ivo P. Touw, and Marry M. van den Heuvel-Eibrink
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2016
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39. Genomic and evolutionary portraits of disease relapse in acute myeloid leukemia
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Richard J D'Andrea, Caroline Sheridan, Noushin Farnoud, Yaseswini Neelamraju, Agata Gruszczynska, Timour Baslan, Ross L. Levine, Donna Neuberg, Peter J. M. Valk, Martin Carroll, Franck Rapaport, Stefan Bekiranov, Tak C. Lee, Michael W. Becker, Samuel Haddox, Duane C. Hassane, Alexis Thurmond, Juan S. Medina-Martinez, Ari Melnick, Scott W. Lowe, Marc Robert de Massy, Lars Bullinger, Francine E. Garrett-Bakelman, Heardly Moses Murdock, Hematology, Rapaport, Franck, Neelamraju, Yaseswini, Baslan, Timour, Hassane, Duane, D'Andrea, Richard, and Garrett-Bakelman, Francine E
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Letter ,business.industry ,MEDLINE ,Myeloid leukemia ,Hematology ,Genomics ,Prognosis ,Evolution, Molecular ,Gene Expression Regulation, Neoplastic ,Leukemia, Myeloid, Acute ,Text mining ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Neoplasm Recurrence, Local ,business ,DISEASE RELAPSE ,Cancer genetics - Abstract
Refereed/Peer-reviewed
- Published
- 2021
40. miR-15a-5p and miR-21-5p contribute to chemoresistance in cytogenetically normal acute myeloid leukaemia by targeting PDCD4, ARL2 and BTG2
- Author
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Hélène Schoemans, Lucienne Michaux, Pascale Saussoy, Sandrine Lenglez, Emeline Bollaert, Violaine Havelange, Virginie Vandewalle, Ahmed Essaghir, Carlos Graux, Peter J. M. Valk, Jean-Baptiste Demoulin, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de biologie hématologique, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de thérapie tissulaire et cellulaire, UCL - (MGD) Service d'hématologie, and Hematology
- Subjects
0301 basic medicine ,Research & Experimental Medicine ,RECOMMENDATIONS ,0302 clinical medicine ,AML ,CHEMOSENSITIVITY ,hemic and lymphatic diseases ,RNA, Small Interfering ,Principal Component Analysis ,Cytarabine ,apoptosis ,Nuclear Proteins ,chemoresistance ,microRNAs ,Leukemia, Myeloid, Acute ,Medicine, Research & Experimental ,030220 oncology & carcinogenesis ,Molecular Medicine ,Original Article ,Nucleophosmin ,Life Sciences & Biomedicine ,medicine.drug ,medicine.medical_specialty ,NPM1 ,Daunorubicin ,Blotting, Western ,DIAGNOSIS ,03 medical and health sciences ,CISPLATIN ,Cell Line, Tumor ,microRNA ,MICRORNA-21 INDUCES RESISTANCE ,medicine ,MANAGEMENT ,Humans ,acute myeloid leukaemia ,Gene ,BTG2 ,Science & Technology ,IDENTIFICATION ,business.industry ,Cytogenetics ,Original Articles ,Cell Biology ,target genes ,030104 developmental biology ,Drug Resistance, Neoplasm ,Apoptosis ,Mutation ,CELLS ,Cancer research ,business - Abstract
Cytarabine and daunorubicin are old drugs commonly used in the treatment of acute myeloid leukaemia (AML). Refractory or relapsed disease because of chemotherapy resistance is a major issue. microRNAs (miRNAs) were incriminated in resistance. This study aimed to identify miRNAs involved in chemoresistance in AML patients and to define their target genes. We focused on cytogenetically normal AML patients with wild-type NPM1 without FLT3-ITD as the treatment of this subset of patients with intermediate-risk cytogenetics is not well established. We analysed baseline AML samples by small RNA sequencing and compared the profile of chemoresistant to chemosensitive AML patients. Among the miRNAs significantly overexpressed in chemoresistant patients, we revealed miR-15a-5p and miR-21-5p as miRNAs with a major role in chemoresistance in AML. We showed that miR-15a-5p and miR-21-5p overexpression decreased apoptosis induced by cytarabine and/or daunorubicin. PDCD4, ARL2 and BTG2 genes were found to be targeted by miR-15a-5p, as well as PDCD4 and BTG2 by miR-21-5p. Inhibition experiments of the three target genes reproduced the functional effect of both miRNAs on chemosensitivity. Our study demonstrates that miR-15a-5p and miR-21-5p are overexpressed in a subgroup of chemoresistant AML patients. Both miRNAs induce chemoresistance by targeting three pro-apoptotic genes PDCD4, ARL2 and BTG2. ispartof: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE vol:25 issue:1 pages:575-585 ispartof: location:England status: published
- Published
- 2021
41. A congenital CSF3R mutation in chronic neutropenia reveals a vital role for a cytokine receptor extracellular hinge motif in the response to granulocyte colony‐stimulating factor.
- Author
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Feyen, Jacqueline, Ernst, Martijn P. T., van der Velden, Vincent H. J., Valk, Peter J. M., Broeders, Lianne, Touw, Ivo P., and Raaijmakers, Marc H. G. P.
- Published
- 2023
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42. Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes
- Author
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Alexandar Tzankov, Pontus Lundberg, Martina Kleber, Jakob Passweg, Mario Uhr, Joerg Halter, Ivo P. Touw, Laurent Schmied, Beatrice Drexler, Patricia A. Olofsen, Peter J. M. Valk, and Hematology
- Subjects
Neutropenia ,Clinical Trials and Observations ,Chronic neutrophilic leukemia ,Transcriptome ,chemistry.chemical_compound ,hemic and lymphatic diseases ,medicine ,Congenital Bone Marrow Failure Syndromes ,Humans ,Progenitor cell ,Congenital Neutropenia ,business.industry ,Anemia, Aplastic ,Myeloid leukemia ,Hematology ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,medicine.anatomical_structure ,nervous system ,RUNX1 ,chemistry ,Mutation ,Cancer research ,Bone marrow ,business - Abstract
Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.
- Published
- 2020
43. Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia
- Author
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Marije Havermans, Eric M.J. Bindels, Leonie Smeenk, Peter J. M. Valk, Stanley van Herk, Claudia Erpelinck, Roger Mulet-Lazaro, H. Berna Beverloo, Ruud Delwel, Robert van der Helm, Sophie Ottema, Torsten Haferlach, Claudia Haferlach, Tim Grob, Hematology, and Clinical Genetics
- Subjects
Male ,Myeloid ,MECOM ,Immunology ,Chromosomal translocation ,Biology ,Biochemistry ,Translocation, Genetic ,Genocopy ,hemic and lymphatic diseases ,medicine ,Humans ,Allele ,Gene Expression Regulation, Leukemic ,GATA2 ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,MDS1 and EVI1 Complex Locus Protein ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Enhancer Elements, Genetic ,Chromosome Inversion ,Cancer research ,Female ,Chromosomes, Human, Pair 3 - Abstract
Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct World Health Organization recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML. Here, we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOM involvement with EVI1 overexpression but no or low MDS1-EVI1 levels. Moreover, the 3q26 translocations in these AML patients often involve superenhancers of genes active in myeloid development (eg, CD164, PROM1, CDK6, or MYC). In >50% of these cases, allele-specific GATA2 expression was observed, either by copy-number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1 overexpression driven by enhancer hijacking, absent MDS1-EVI1 expression and potential GATA2 involvement. Therefore, we conclude that both atypical 3q26/MECOM and inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOM rearrangements and EVI1 and MDS1-EVI1 expression are required to recognize 3q-rearranged AML cases.
- Published
- 2020
44. The added value of multi-state modelling in a randomized controlled trial
- Author
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Katerina Bakunina, Hein Putter, Jurjen Versluis, Eva A. S. Koster, Bronno Holt, Markus G. Manz, Dimitri A. Breems, Bjorn T. Gjertsen, Jacqueline Cloos, Peter J. M. Valk, Jakob Passweg, Thomas Pabst, Gert J. Ossenkoppele, Bob Löwenberg, Jan J. Cornelissen, Liesbeth C. Wreede, Hematology, Hematology laboratory, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, CCA - Cancer Treatment and quality of life, University of Zurich, and Bakunina, Katerina
- Subjects
Cancer Research ,multi‐state model ,current leukemia‐free survival ,610 Medicine & health ,multi-state model ,SDG 3 - Good Health and Well-being ,AML ,Recurrence ,2741 Radiology, Nuclear Medicine and Imaging ,Humans ,Radiology, Nuclear Medicine and imaging ,1306 Cancer Research ,RC254-282 ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,current leukemia-free survival ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,clofarabine ,10032 Clinic for Oncology and Hematology ,HSCT ,2730 Oncology ,RCT - Abstract
Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events. publishedVersion
- Published
- 2021
45. Azacytidine Treatment for VEXAS Syndrome
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Peter J. M. Valk, Virgil A. S. H. Dalm, Marc H.G.P. Raaijmakers, Anna Aalbers, Melissa Rijken, Paul L A van Daele, Maud A.W. Hermans, Hematology, Internal Medicine, and Immunology
- Subjects
Letter ,business.industry ,Medicine ,Diseases of the blood and blood-forming organs ,Hematology ,RC633-647.5 ,business - Published
- 2021
46. DNA vs cDNA FLT3-ITD allelic ratio and length measurements in adult acute myeloid leukemia
- Author
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François G. Kavelaars, Elvira Verhoef, Bianca Venniker-Punt, Peter J. M. Valk, Christian M. Vonk, Pauline A. Merle, Zinia J. Kwidama, Jacqueline Cloos, Patrycja L Gradowska, Jeroen Janssen, David G. J. Cucchi, Bob Löwenberg, Melissa Rijken, Hematology, VU University medical center, Elderly care medicine, Hematology laboratory, and CCA - Cancer biology and immunology
- Subjects
Adult ,DNA, Complementary ,business.industry ,Adult Acute Myeloid Leukemia ,Hematology ,Allelic ratio ,Molecular biology ,chemistry.chemical_compound ,Leukemia, Myeloid, Acute ,chemistry ,fms-Like Tyrosine Kinase 3 ,Complementary DNA ,Research Letter ,Medicine ,Humans ,business ,DNA ,Alleles ,Flt3 itd - Published
- 2021
47. Molecular Minimal Residual Disease Detection in Acute Myeloid Leukemia
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Adil Al Hinai, Diana Hanekamp, Peter J. M. Valk, and Christian M. Vonk
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Oncology ,Cancer Research ,medicine.medical_specialty ,Context (language use) ,Review ,Disease ,acute myeloid leukemia ,SDG 3 - Good Health and Well-being ,Internal medicine ,hemic and lymphatic diseases ,clonal hematopoiesis ,Medicine ,RC254-282 ,next generation sequencing ,business.industry ,Clonal hematopoiesis ,Myeloid leukemia ,Induction chemotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Response to treatment ,Minimal residual disease ,body regions ,medicine.anatomical_structure ,minimal/measurable residual disease ,MRD ,Bone marrow ,business - Abstract
Simple Summary Although the majority of patients with acute myeloid leukemia (AML) reach a morphologic complete remission after high-dose chemotherapy, the majority of them face a relapse within a few years. Detection of residual cells, persisting in a considerably small amount, has shown to be predictive of impending relapse in multiple studies. Whereas the gold standard in minimal residual disease (MRD) detection in AML is currently based on immunophenotypic approaches, the use of molecular MRD testing to predict AML relapse has been explored extensively in recent years. This review aims to provide an overview of the different studies that improve molecular MRD detection in AML, and to describe the limitations and challenges it faces. Abstract Initial induction chemotherapy to eradicate the bulk of acute myeloid leukemia (AML) cells results in complete remission (CR) in the majority of patients. However, leukemic cells persisting in the bone marrow below the morphologic threshold remain unaffected and have the potential to proliferate and re-emerge as AML relapse. Detection of minimal/measurable residual disease (MRD) is a promising prognostic marker for AML relapse as it can assess an individual patients’ risk profile and evaluate their response to treatment. With the emergence of molecular techniques, such as next generation sequencing (NGS), a more sensitive assessment of molecular MRD markers is available. In recent years, the detection of MRD by molecular assays and its association with AML relapse and survival has been explored and verified in multiple studies. Although most studies show that the presence of MRD leads to a worse clinical outcome, molecular-based methods face several challenges including limited sensitivity/specificity, and a difficult distinction between mutations that are representative of AML rather than clonal hematopoiesis. This review describes the studies that have been performed using molecular-based assays for MRD detection in the context of other MRD detection approaches in AML, and discusses limitations, challenges and opportunities.
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- 2021
48. PPM1D mutations appear in complete remission after exposure to chemotherapy without predicting emerging AML relapse
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Tim Grob, Peter J. M. Valk, Mojca Jongen-Lavrencic, Annelieke Zeilemaker, Mathijs A. Sanders, Claudia A.J. Erpelinck-Verschueren, Melissa Rijken, François G. Kavelaars, Bob Löwenberg, Adil Al Hinai, and Hematology
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,MEDLINE ,Complete remission ,Hematology ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,business - Published
- 2021
49. Review: Aberrant EVI1 expression in acute myeloid leukaemia
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Hinai, Adil A. and Valk, Peter J. M.
- Published
- 2016
- Full Text
- View/download PDF
50. A 4-gene expression score associated with high levels of Wilms Tumor-1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia
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Niavarani, Ahmadreza, Herold, Tobias, Reyal, Yasmin, Sauerland, Maria C., Buchner, Thomas, Hiddemann, Wolfgang, Bohlander, Stefan K., Valk, Peter J. M., and Bonnet, Dominique
- Published
- 2016
- Full Text
- View/download PDF
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