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1. Midostaurin added to 10-day decitabine, for patients unfit for intensive chemotherapy with AML and higher risk MDS, irrespective of FLT3 mutational status, does not improve outcome

Author

Huls, Gerwin, Chitu, Dana A., Tick, Lidwine, Boersma, Rinske, Breems, Dimitri, Herbers, Alexandra, Klein, Saskia K., de Jonge, Suzan, Westerweel, Peter E., Cruijsen, Marjan, Hoogendoorn, Mels, Cuijpers, Marlous, Deeren, Dries, Bailly, Benjamin, Visser, Otto, van Rhenen, Anna, Posthuma, Eduard F. M., Valk, Peter J. M., Cloos, Jacqueline, Ammatuna, Emanuele, Refos, Jeannine M., Fakkert, R., Löwenberg, Bob, and Ossenkoppele, Gert J.

Published
2024
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4. Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial

Author

van der Maas, Niek G., Versluis, Jurjen, Nasserinejad, Kazem, van Rosmalen, Joost, Pabst, Thomas, Maertens, Johan, Breems, Dimitri, Manz, Markus, Cloos, Jacqueline, Ossenkoppele, Gert J., Floisand, Yngvar, Gradowska, Patrycja, Löwenberg, Bob, Huls, Gerwin, Postmus, Douwe, Pignatti, Francesco, and Cornelissen, Jan J.

Published
2024
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6. Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells

Author

van der Werf, Inge, Mondala, Phoebe K, Steel, S Kathleen, Balaian, Larisa, Ladel, Luisa, Mason, Cayla N, Diep, Raymond H, Pham, Jessica, Cloos, Jacqueline, Kaspers, Gertjan JL, Chan, Warren C, Mark, Adam, La Clair, James J, Wentworth, Peggy, Fisch, Kathleen M, Crews, Leslie A, Whisenant, Thomas C, Burkart, Michael D, Donohoe, Mary E, and Jamieson, Catriona HM

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Stem Cell Research - Nonembryonic - Human, Regenerative Medicine, Rare Diseases, Stem Cell Research, Cancer, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Human Genome, Hematology, Pediatric, Pediatric Cancer, Adult, Child, Humans, Stem Cells, RNA Splicing, Leukemia, Myeloid, Acute, Protein Isoforms, Mutation, RNA Splicing Factors, Repressor Proteins, CD47, RBFOX2, SF3B1, embryonic stem cells, hematopoietic stem cells, pediatric AML, pre-mRNA splicing, splicing modulation, Biomedical and clinical sciences
Abstract

Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy.

Published
2023

7. Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Author

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

Published
2023
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8. Bimodal expression of potential drug target CLL-1 (CLEC12A) on CD34+ blasts of AML patients.

Author

Ngai, Lok, Ma, Connie, Maguire, Orla, Do, An, Robert, Alberto, Logan, Aaron, Griffiths, Elizabeth, Nemeth, Michael, Green, Cherie, Pourmohamad, Tony, van Kuijk, Bo, Snel, Alexander, Kwidama, Zinia, Venniker-Punt, Bianca, Cooper, James, Manz, Markus, Gjertsen, Bjørn, Smit, Linda, Ossenkoppele, Gert, Janssen, Jeroen, Cloos, Jacqueline, and Sumiyoshi, Teiko

Subjects
CD34+ blasts, CLL-1, acute myeloid leukemia, bimodality, bone marrow aspirates, flow cytometry, Antigens, CD34, Biomarkers, Tumor, Bone Marrow Cells, Cytogenetic Analysis, Female, Flow Cytometry, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Humans, Immunophenotyping, Lectins, C-Type, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Myeloid Cells, Precursor Cells, B-Lymphoid, Primary Cell Culture, Receptors, Mitogen
Abstract

OBJECTIVES: This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics. METHODS: Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL-1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL-1-negative subpopulation of CLL-1 bimodal AML samples. RESULTS: The frequency of a bimodal pattern of CLL-1 expression of CD34+ blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL-1 expression was most prevalent in patients with MDS-related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia-associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL-1- subpopulation may consist of pre-B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)-leukemic mutations were detected in both CLL-1+ and CLL-1- subfractions of bimodal samples (N = 3). CONCLUSIONS: C-lectin-like molecule 1 bimodality occurs in about 25% of AML patients and the CLL-1- cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL-1-targeted therapies and warrant further investigation.

Published
2021

9. Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI): a cohort study

Author

Kant, Iris M.J., Graas, Thecla, Toussaint, Belle, de Jong, Sterre, Darwesh, Shahan, Mahes, Sandjiv S., Kamminga, Dora, Koelewijn, Matthijs, Faber, Gino, Beaumont, Guus, Engel, Marije D., Pierie, R. Cheyenne N., Janssen, Suzanne R., van Dijkman, Edith, Heijmans, Jarom, Witte, Yara Y., Nahui Palomino, Rogers A., Omar, Said Z., Zweegman, Sonja, Kater, Arnon P., van den Vegt, Caya, Arends-Halbesma, Ilonka, de Pater, Emma, Dijkstra, Margriet J., Rots, Nynke Y., Rijnstra, Esther Siteur-van, de Rooij, Dennis M., Sanders, Rogier W., Poniman, Meliawati, Olijhoek, Wouter, van Rijswijk, Jacqueline, Beaumont, Tim, Çetinel, Lusia, Schellekens, Louis, den Hartogh, Yvonne M., Cloos, Jacqueline, Weijers, Suzanne S., Tonouh-Aajoud, Saïda, Avci, Selime, Roelandse-Koop, Elianne, Dik, Willem A., Hofsink, Quincy, Haggenburg, Sabine, Lissenberg-Witte, Birgit I., Broers, Annoek E.C., van Doesum, Jaap A., van Binnendijk, Rob S., den Hartog, Gerco, Bhoekhan, Michel S., Haverkate, Nienke J.E., van Meerloo, Johan, Burger, Judith A., Bouhuijs, Joey H., Smits, Gaby P., Wouters, Dorine, van Leeuwen, Ester M.M., Bontkes, Hetty J., Kootstra, Neeltje A., Vogels-Nooijen, Sandra, Rots, Nynke, van Beek, Josine, Heemskerk, Mirjam H.M., Groen, Kazimierz, van Meerten, Tom, Mutsaers, Pim G.N.J., van Gils, Marit J., Goorhuis, Abraham, Rutten, Caroline E., Hazenberg, Mette D., and Nijhof, Inger S.

Published
2023
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10. Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients

Author

Haggenburg, Sabine, Lissenberg-Witte, Birgit I., van Binnendijk, Rob S., den Hartog, Gerco, Bhoekhan, Michel S., Haverkate, Nienke J.E., de Rooij, Dennis M., van Meerloo, Johan, Cloos, Jacqueline, Kootstra, Neeltje A., Wouters, Dorine, Weijers, Suzanne S., van Leeuwen, Ester M.M., Bontkes, Hetty J., Tonouh-Aajoud, Saïda, Heemskerk, Mirjam H.M., Sanders, Rogier W., Roelandse-Koop, Elianne, Hofsink, Quincy, Groen, Kazimierz, Çetinel, Lucia, Schellekens, Louis, den Hartog, Yvonne M., Toussaint, Belle, Kant, Iris M.J., Graas, Thecla, de Pater, Emma, Dik, Willem A., Engel, Marije D., Pierie, Cheyenne R.N., Janssen, Suzanne R., van Dijkman, Edith, Poniman, Meliawati, Burger, Judith A., Bouhuijs, Joey H., Smits, Gaby, Rots, Nynke Y., Zweegman, Sonja, Kater, Arnon P., van Meerten, Tom, Mutsaers, Pim G.N.J., van Doesum, Jaap A., Broers, Annoek E.C., van Gils, Marit J., Goorhuis, Abraham, Rutten, Caroline E., Hazenberg, Mette D., and Nijhof, Inger S.

Published
2022
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11. Immunophenotypic features of early haematopoietic and leukaemia stem cells.

Author

Reuvekamp, Tom, Bachas, Costa, and Cloos, Jacqueline

Abstract

Many tumours are organised in a hierarchical structure with at its apex a cell that can maintain, establish, and repopulate the tumour—the cancer stem cell. The haematopoietic stem cell (HSC) is the founder cell for all functional blood cells. Like HSCs, the leukaemia stem cells (LSC) are hypothesised to be the leukaemia‐initiating cells, which have features of stemness such as self‐renewal, quiescence, and resistance to cytotoxic drugs. Immunophenotypically, CD34+CD38− defines HSCs by adding lineage negativity and CD90+CD45RA−. At which stage of maturation the further differentiation is blocked, determines the type of leukaemia, and determines the immunophenotype of the LSC specific to the leukaemia type. No apparent LSC phenotype has been described in lymphoid leukaemia, and it is debated if a specific acute lymphocytic leukaemia‐initiating cell is present, as all cells are capable of engraftment in a secondary mouse model. In chronic lymphocytic leukaemia, a B‐cell clone is responsible for uncontrolled proliferation, not a specific LSC. In chronic and acute myeloid leukaemia, LSC is described as CD34+CD38− with the expression of a marker that is aberrantly expressed (LSC marker), such as CD45RA, CD123 or in the case of chronic myeloid leukaemia CD26. In acute myeloid leukaemia, the LSC load had prognostic relevance and might be a biomarker that can be used for monitoring and as an addition to measurable residual disease. However, challenges such as the CD34‐negative immunophenotype need to be explored. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial

Author

Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J., Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W., Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J.F.M., Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W.J., Bargetzi, Mario, Klein, Saskia K., Gadisseur, Alain, Westerweel, Peter E., Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A., Hoogendoorn, Mels, Legdeur, Marie-Cecile J.C., Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T., Janssen, Jeroen J.W.M., Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J.M., van Elssen, Catharina H.M.J., Manz, Markus G., Floisand, Yngvar, and Ossenkoppele, Gert J.

Published
2021
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16. The role of the primitive marker CD133 in CD34-negative acute myeloid leukemia for the detection of leukemia stem cells

Author

Reuvekamp, Tom, Janssen, Luca L. G., Ngai, Lok Lam, Carbaat-Ham, Jannemieke, den Hartog, Daphne, Scholten, Willemijn J., Kelder, Angele, Hanekamp, Diana, Wensink, Eliza, van Gils, Noortje, Gradowska, Patrycja, Lowenberg, Bob, Ossenkoppele, Gert J., van de Loosdrecht, Arjan A., Westers, Theresia M., Smit, Linda, Bachas, Costa, Cloos, Jacqueline, Reuvekamp, Tom, Janssen, Luca L. G., Ngai, Lok Lam, Carbaat-Ham, Jannemieke, den Hartog, Daphne, Scholten, Willemijn J., Kelder, Angele, Hanekamp, Diana, Wensink, Eliza, van Gils, Noortje, Gradowska, Patrycja, Lowenberg, Bob, Ossenkoppele, Gert J., van de Loosdrecht, Arjan A., Westers, Theresia M., Smit, Linda, Bachas, Costa, and Cloos, Jacqueline

Abstract

The most important reason for dismal outcomes in acute myeloid leukemia (AML) is the development of relapse. Leukemia stem cells (LSCs) are hypothesized to initiate relapse, and high CD34+CD38- LSC load is associated with poor prognosis. In 10% of AML patients, CD34 is not or is low expressed on the leukemic cells (<1%), and CD34+CD38- LSCs are absent. These patients are classified as CD34-negative. We aimed to determine whether the primitive marker CD133 can detect LSCs in CD34-negative AML. We retrospectively quantified 148 CD34-negative patients for proportions of CD34-CD133+ and CD133+CD38- cell fractions in the diagnostic samples of CD34-negative patients in the HOVON102 and HOVON132 trials. No prognostic difference was found between patients with high or low proportions of CD34-CD133+, which is found to be aberrantly expressed in AML. A high level of CD133+CD38- cells was not associated with poor overall survival, and expression in AML was similar to normal bone marrow. To conclude, CD133 is useful as an additional primitive marker for the detection of leukemic blast cells in CD34-negative AML. However, CD133+CD38 alone is not suitable for the detection of LSCs at diagnosis.

Published
2024

17. Bayesian interim analysis for prospective randomized studies:reanalysis of the acute myeloid leukemia HOVON 132 clinical trial

Author

van der Maas, Niek G., Versluis, Jurjen, Nasserinejad, Kazem, van Rosmalen, Joost, Pabst, Thomas, Maertens, Johan, Breems, Dimitri, Manz, Markus, Cloos, Jacqueline, Ossenkoppele, Gert J., Floisand, Yngvar, Gradowska, Patrycja, Löwenberg, Bob, Huls, Gerwin, Postmus, Douwe, Pignatti, Francesco, Cornelissen, Jan J., van der Maas, Niek G., Versluis, Jurjen, Nasserinejad, Kazem, van Rosmalen, Joost, Pabst, Thomas, Maertens, Johan, Breems, Dimitri, Manz, Markus, Cloos, Jacqueline, Ossenkoppele, Gert J., Floisand, Yngvar, Gradowska, Patrycja, Löwenberg, Bob, Huls, Gerwin, Postmus, Douwe, Pignatti, Francesco, and Cornelissen, Jan J.

Abstract

Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a “7 + 3” induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81–1.69), 1.05 (95% CI 0.86–1.30), 1.00 (95% CI 0.84–1.19), and 1.02 (95% CI 0.87–1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.

Published
2024

20. Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target.

Author

Sciarrillo, Rocco, Terrana, Francesca, Comandatore, Annalisa, Supadmanaba, I. Gede Putu, Bing Wang, El Hassouni, Btissame, Mantini, Giulia, Jansen, Gerrit, Avan, Amir, Carbone, Daniela, Diana, Patrizia, Peters, Godefridus J., Morelli, Luca, Cloos, Jacqueline, Assaraf, Yehuda G., and Giovannetti, Elisa

Published
2024
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21. Optimal Prognostic Threshold for Acute Myeloid Leukemia (AML) Measurable Residual Disease (MRD) Positivity By Multiparameter Flow Cytometry: A Report of 2,051 Patients from MRC/NCRI, Gimema, HOVON, and Seattle

Author

Rodríguez-Arbolí, Eduardo, primary, Othus, Megan, additional, Freeman, Sylvie, additional, Buccisano, Francesco, additional, Ngai, Lok Lam, additional, Thomas, Ian, additional, Palmieri, Raffaele, additional, Cloos, Jacqueline, additional, Johnson, Sean, additional, Meddi, Elisa, additional, Russell, Nigel H., additional, Venditti, Adriano, additional, Gradowska, Patrycja, additional, Ossenkoppele, Gert J., additional, Lowenberg, Bob, additional, and Walter, Roland B., additional

Published
2024
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24. Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds

Author

Li Petri, Giovanna, El Hassouni, Btissame, Sciarrillo, Rocco, Funel, Niccola, Mantini, Giulia, Zeeuw van der Laan, Eveline A., Cascioferro, Stella, Avan, Amir, Zucali, Paolo Andrea, Zaffaroni, Nadia, Lagerweij, Tonny, Parrino, Barbara, Smid, Kees, Deraco, Marcello, Granchi, Carlotta, Braczko, Alicja, Smolenski, Ryszard T., Matherly, Larry H., Jansen, Gerrit, Assaraf, Yehuda G., Diana, Patrizia, Cloos, Jacqueline, Peters, Godefridus J., Minutolo, Filippo, and Giovannetti, Elisa

Published
2020
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28. Prognostic Significance of Measurable Residual Disease Detection by Flow Cytometry in Autologous Stem Cell Apheresis Products in AML

Author

Tettero, Jesse M., primary, Buisman, Yara, additional, Ngai, Lok Lam, additional, Bachas, Costa, additional, Gjertsen, Bjorn T., additional, Kelder, Angèle, additional, van de Loosdrecht, Arjan A., additional, Manz, Markus G., additional, Pabst, Thomas, additional, Scholten, Willemijn, additional, Ossenkoppele, Gert J., additional, Cloos, Jacqueline, additional, and de Leeuw, David C., additional

Published
2023
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30. Analytical assay validation for acute myeloid leukemia measurable residual disease assessment by multiparametric flow cytometry

Author

Tettero, Jesse M., primary, Dakappagari, Naveen, additional, Heidinga, Maaike E., additional, Oussoren‐Brockhoff, Yvonne, additional, Hanekamp, Diana, additional, Pahuja, Anil, additional, Burns, Kerri, additional, Kaur, Pavinder, additional, Alfonso, Zeni, additional, van der Velden, Vincent H. J., additional, te Marvelde, Jeroen G., additional, Hobo, Willemijn, additional, Slomp, Jennichjen, additional, Bachas, Costa, additional, Kelder, Angele, additional, Nguyen, Kevin, additional, and Cloos, Jacqueline, additional

Published
2023
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31. Measurable residual disease monitoring in patients with acute myeloid leukemia treated with lower‐intensity therapy: Roadmap from an ELN‐DAVID expert panel

Author

Ravandi, Farhad, primary, Cloos, Jacqueline, additional, Buccisano, Francesco, additional, Dillon, Richard, additional, Döhner, Konstanze, additional, Freeman, Sylvie D., additional, Hourigan, Christopher S., additional, Ossenkoppele, Gerrit J., additional, Roboz, Gail J., additional, Subklewe, Marion, additional, Thiede, Christian, additional, Arnhardt, Isabell, additional, Valk, Peter J. M., additional, Venditti, Adriano, additional, Wei, Andrew H., additional, Walter, Roland B., additional, and Heuser, Michael, additional

Published
2023
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32. Prospective validation of the prognostic relevance of CD34+CD38– AML stem cell frequency in the HOVON-SAKK132 trial

Author

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

Subjects
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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Published
2023

34. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party

Author

Schuurhuis, Gerrit J., Heuser, Michael, Freeman, Sylvie, Béné, Marie-Christine, Buccisano, Francesco, Cloos, Jacqueline, Grimwade, David, Haferlach, Torsten, Hills, Robert K., Hourigan, Christopher S., Jorgensen, Jeffrey L., Kern, Wolfgang, Lacombe, Francis, Maurillo, Luca, Preudhomme, Claude, van der Reijden, Bert A., Thiede, Christian, Venditti, Adriano, Vyas, Paresh, Wood, Brent L., Walter, Roland B., Döhner, Konstanze, Roboz, Gail J., and Ossenkoppele, Gert J.

Published
2018
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35. CD34+CD38− leukemic stem cell frequency to predict outcome in acute myeloid leukemia

Author

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.

Published
2019
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36. P432: VALIDATION OF LIMIT OF QUANTIFICATION APPROACH BASED FLOW CYTOMETRY FOR MEASURABLE RESIDUAL DISEASE ASSESSMENT IN ACUTE MYELOID LEUKEMIA IN THE HOVON-SAKK-132 TRIAL

Author

Tettero, Jesse, primary, Palmieri, Raffaele, additional, Lam Ngai, Lok, additional, Bachas, Costa, additional, Arena, Valentina, additional, Breems, Dimitri, additional, Fischer, Thomas, additional, Tore Gjertsen, Bjorn, additional, Griškevičius, Laimonas, additional, Juliusson, Gunnar, additional, Maertens, Johan, additional, Manz, Markus, additional, Maurillo, Luca, additional, Pabst, Thomas, additional, Passweg, Jakob, additional, Piciocchi, Alfonso, additional, Porkka, Kimmo, additional, Löwenberg, Bob, additional, Venditti, Adriano, additional, Ossenkoppele, Gert, additional, Buccisano, Francesco, additional, and Cloos, Jacqueline, additional

Published
2023
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37. P475: EMERGING LEUKEMIA ASSOCIATED IMMUNOPHENOTYPES (LAIPS) IN BONE MARROW OF ACUTE MYELOID LEUKEMIA PATIENTS AFTER INTENSIVE CHEMOTHERAPY.

Author

Lam Ngai, Lok, primary, Hanekamp, Diana, additional, Kelder, Angèle, additional, Scholten, Willemijn J., additional, Carbaat - Ham, Jannemieke, additional, Snel, Alexander N., additional, Bachas, Costa, additional, Tettero, Jesse, additional, van der Velden, Vincent, additional, Slomp, Jennichjen, additional, Hobo, Willemijn, additional, Breems, Dimitri, additional, Fischer, Thomas, additional, Tore Gjertsen, Bjorn, additional, Griškevičius, Laimonas, additional, Juliusson, Gunnar, additional, Maertens, Johan, additional, Manz, Markus, additional, Pabst, Thomas, additional, Passweg, Jakob, additional, Porkka, Kimmo, additional, Valk, Peter, additional, Gradowska, Patrycja, additional, Löwenberg, Bob, additional, de Leeuw, David, additional, van de Loosdrecht, Arjan, additional, Ossenkoppele, Gert, additional, and Cloos, Jacqueline, additional

Published
2023
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38. P329: HIGH IMMUNOPROTEASOME ACTIVITY AS NOVEL INDICATOR FOR SENSITIVITY TO BORTEZOMIB-CONTAINING CHEMOTHERAPY IN ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS FROM CHILDREN’S ONCOLOGY GROUP TRIAL AALL1231

Author

Roeten, Margot, primary, van Dijk, Suzanne, additional, van Meerloo, Johan, additional, Kwidama, Zinia, additional, Jenkins, Gaya, additional, Teachey, David, additional, Devidas, Meenakshi, additional, Loh, Mignon, additional, Kaspers, Gertjan, additional, Zweegman, Sonja, additional, Jansen, Gerrit, additional, Horton, Terzah, additional, and Cloos, Jacqueline, additional

Published
2023
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39. P448: PROGNOSTIC SIGNIFICANCE OF MEASURABLE RESIDUAL DISEASE DETECTION BY FLOW CYTOMETRY IN AUTOLOGOUS STEM CELL APHERESIS PRODUCTS OF PATIENTS WITH AML

Author

Tettero, Jesse, primary, Buisman, Yara, additional, Lam Ngai, Lok, additional, Bachas, Costa, additional, Tore Gjertsen, Bjorn, additional, Kelder, Angèle, additional, van de Loosdrecht, Arjan, additional, Manz, Markus, additional, Pabst, Thomas, additional, Scholten, Willemijn, additional, Ossenkoppele, Gert, additional, Cloos, Jacqueline, additional, and de Leeuw, David, additional

Published
2023
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40. Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI): a cohort study

Author

Hofsink, Quincy, primary, Haggenburg, Sabine, additional, Lissenberg-Witte, Birgit I., additional, Broers, Annoek E.C., additional, van Doesum, Jaap A., additional, van Binnendijk, Rob S., additional, den Hartog, Gerco, additional, Bhoekhan, Michel S., additional, Haverkate, Nienke J.E., additional, van Meerloo, Johan, additional, Burger, Judith A., additional, Bouhuijs, Joey H., additional, Smits, Gaby P., additional, Wouters, Dorine, additional, van Leeuwen, Ester M.M., additional, Bontkes, Hetty J., additional, Kootstra, Neeltje A., additional, Vogels-Nooijen, Sandra, additional, Rots, Nynke, additional, van Beek, Josine, additional, Heemskerk, Mirjam H.M., additional, Groen, Kazimierz, additional, van Meerten, Tom, additional, Mutsaers, Pim G.N.J., additional, van Gils, Marit J., additional, Goorhuis, Abraham, additional, Rutten, Caroline E., additional, Hazenberg, Mette D., additional, Nijhof, Inger S., additional, Kant, Iris M.J., additional, Graas, Thecla, additional, Toussaint, Belle, additional, de Jong, Sterre, additional, Darwesh, Shahan, additional, Mahes, Sandjiv S., additional, Kamminga, Dora, additional, Koelewijn, Matthijs, additional, Faber, Gino, additional, Beaumont, Guus, additional, Engel, Marije D., additional, Pierie, R. Cheyenne N., additional, Janssen, Suzanne R., additional, van Dijkman, Edith, additional, Heijmans, Jarom, additional, Witte, Yara Y., additional, Nahui Palomino, Rogers A., additional, Omar, Said Z., additional, Zweegman, Sonja, additional, Kater, Arnon P., additional, van den Vegt, Caya, additional, Arends-Halbesma, Ilonka, additional, de Pater, Emma, additional, Dijkstra, Margriet J., additional, Rots, Nynke Y., additional, Rijnstra, Esther Siteur-van, additional, de Rooij, Dennis M., additional, Sanders, Rogier W., additional, Poniman, Meliawati, additional, Olijhoek, Wouter, additional, van Rijswijk, Jacqueline, additional, Beaumont, Tim, additional, Çetinel, Lusia, additional, Schellekens, Louis, additional, den Hartogh, Yvonne M., additional, Cloos, Jacqueline, additional, Weijers, Suzanne S., additional, Tonouh-Aajoud, Saïda, additional, Avci, Selime, additional, Roelandse-Koop, Elianne, additional, and Dik, Willem A., additional

Published
2023
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42. Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Author

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

43. Methotrexate Provokes Disparate Folate Metabolism Gene Expression and Alternative Splicing in Ex Vivo Monocytes and GM-CSF- and M-CSF-Polarized Macrophages

Author

Muller, Ittai B., Lin, Marry, Jonge, Robert de, Will, Nico, López-Navarro, Baltasar, Laken, Conny van der, Struys, Eduard A., Oudejans, Cees B. M., Assaraf, Yehuda G., Cloos, Jacqueline, Puig-Kröger, Amaya, and Jansen, Gerrit

Abstract

Macrophages constitute important immune cell targets of the antifolate methotrexate (MTX) in autoimmune diseases, including rheumatoid arthritis. Regulation of folate/MTX metabolism remains poorly understood upon pro-inflammatory (M1-type/GM-CSF-polarized) and anti-inflammatory (M2-type/M-CSF-polarized) macrophages. MTX activity strictly relies on the folylpolyglutamate synthetase (FPGS) dependent intracellular conversion and hence retention to MTX-polyglutamate (MTX-PG) forms. Here, we determined FPGS pre-mRNA splicing, FPGS enzyme activity and MTX-polyglutamylation in human monocyte-derived M1- and M2-macrophages exposed to 50 nmol/L MTX ex vivo. Moreover, RNA-sequencing analysis was used to investigate global splicing profiles and differential gene expression in monocytic and MTX-exposed macrophages. Monocytes displayed six–eight-fold higher ratios of alternatively-spliced/wild type FPGS transcripts than M1- and M2-macrophages. These ratios were inversely associated with a six–ten-fold increase in FPGS activity in M1- and M2-macrophages versus monocytes. Total MTX-PG accumulation was four-fold higher in M1- versus M2-macrophages. Differential splicing after MTX-exposure was particularly apparent in M2-macrophages for histone methylation/modification genes. MTX predominantly induced differential gene expression in M1-macrophages, involving folate metabolic pathway genes, signaling pathways, chemokines/cytokines and energy metabolism. Collectively, macrophage polarization-related differences in folate/MTX metabolism and downstream pathways at the level of pre-mRNA splicing and gene expression may account for variable accumulation of MTX-PGs, hence possibly impacting MTX treatment efficacy.

Published
2023

45. 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

Tettero, Jesse M., primary, Ngai, Lok Lam, additional, Bachas, Costa, additional, Breems, Dimitri A., additional, Fischer, Thomas, additional, Gjertsen, Bjorn T., additional, Gradowska, Patrycja, additional, Griskevicius, Laimonas, additional, Janssen, Jeroen J.W.M., additional, Juliusson, Gunnar, additional, Maertens, Johan, additional, Manz, Markus G., additional, Pabst, Thomas, additional, Passweg, Jakob, additional, Porkka, Kimmo, additional, Valk, Peter J.M., additional, Löwenberg, Bob, additional, Ossenkoppele, Gert J., additional, and Cloos, Jacqueline, additional

Published
2023
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49. 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

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., Cloos, Jacqueline, 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

Published
2023

50. Analytical assay validation for acute myeloid leukemia measurable residual disease assessment by multiparametric flow cytometry

Author

Tettero, Jesse M., Dakappagari, Naveen, Heidinga, Maaike E., Oussoren-Brockhoff, Yvonne, Hanekamp, Diana, Pahuja, Anil, Burns, Kerri, Kaur, Pavinder, Alfonso, Zeni, van der Velden, Vincent H.J., te Marvelde, Jeroen G., Hobo, Willemijn, Slomp, Jennichjen, Bachas, Costa, Kelder, Angele, Nguyen, Kevin, Cloos, Jacqueline, Tettero, Jesse M., Dakappagari, Naveen, Heidinga, Maaike E., Oussoren-Brockhoff, Yvonne, Hanekamp, Diana, Pahuja, Anil, Burns, Kerri, Kaur, Pavinder, Alfonso, Zeni, van der Velden, Vincent H.J., te Marvelde, Jeroen G., Hobo, Willemijn, Slomp, Jennichjen, Bachas, Costa, Kelder, Angele, Nguyen, Kevin, and Cloos, Jacqueline

Abstract

Background: Measurable residual disease (MRD) assessed by multiparametric flow cytometry (MFC) has gained importance in clinical decision-making for acute myeloid leukemia (AML) patients. However, complying with the recent In Vitro Diagnostic Regulations (IVDR) in Europe and Food and Drug Administration (FDA) guidance in the United States requires rigorous validation prior to their use in investigational clinical trials and diagnostics. Validating AML MRD-MFC assays poses challenges due to the unique underlying disease biology and paucity of patient specimens. In this study, we describe an experimental framework for validation that meets regulatory expectations. Methods: Our validation efforts focused on evaluating assay accuracy, analytical specificity, analytical and functional sensitivity (limit of blank (LoB), detection (LLoD) and quantitation (LLoQ)), precision, linearity, sample/reagent stability and establishing the assay background frequencies. Results: Correlation between different MFC methods was highly significant (r = 0.99 for %blasts and r = 0.93 for %LAIPs). The analysis of LAIP specificity accurately discriminated from negative control cells. The assay demonstrated a LoB of 0.03, LLoD of 0.04, and LLoQ of 0.1%. Precision experiments yielded highly reproducible results (Coefficient of Variation <20%). Stability experiments demonstrated reliable measurement of samples up to 96 h from collection. Furthermore, the reference range of LAIP frequencies in non-AML patients was below 0.1%, ranging from 0.0% to 0.04%.Conclusion: In this manuscript, we present the validation of an AML MFC-MRD assay using BM/PB patient specimens, adhering to best practices. Our approach is expected to assist other laboratories in expediting their validation activities to fulfill recent health authority guidelines.

Published
2023

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