260 results on '"C. Michel Zwaan"'
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2. Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms
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Eline J. M. Bertrums, Jurrian K. de Kanter, Lucca L. M. Derks, Mark Verheul, Laurianne Trabut, Markus J. van Roosmalen, Henrik Hasle, Evangelia Antoniou, Dirk Reinhardt, Michael N. Dworzak, Nora Mühlegger, Marry M. van den Heuvel-Eibrink, C. Michel Zwaan, Bianca F. Goemans, and Ruben van Boxtel
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Science - Abstract
Abstract Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.
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- 2024
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3. Oncogenic and immunological targets for matched therapy of pediatric blood cancer patients: Dutch iTHER study experience
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Judith M. Boer, Uri Ilan, Aurélie Boeree, Karin P. S. Langenberg, Jan Koster, Marco J. Koudijs, Jayne Y. Hehir‐Kwa, Stefan Nierkens, Corinne Rossi, Jan J. Molenaar, Bianca F. Goemans, Monique L. denBoer, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Over the past 10 years, institutional and national molecular tumor boards have been implemented for relapsed or refractory pediatric cancer to prioritize targeted drugs for individualized treatment based on actionable oncogenic lesions, including the Dutch iTHER platform. Hematological malignancies form a minority in precision medicine studies. Here, we report on 56 iTHER leukemia/lymphoma patients for which we considered cell surface markers and oncogenic aberrations as actionable events, supplemented with ex vivo drug sensitivity for six patients. Prior to iTHER registration, 34% of the patients had received allogeneic hematopoietic cell transplantation (HCT) and 18% CAR‐T therapy. For 51 patients (91%), a sample with sufficient tumor percentage (≥20%) required for comprehensive diagnostic testing was obtained. Up to 10 oncogenic actionable events were prioritized in 49/51 patients, and immunotherapy targets were identified in all profiled patients. Targeted treatment(s) based on the iTHER advice was given to 24 of 51 patients (47%), including immunotherapy in 17 patients, a targeted drug matching an oncogenic aberration in 12 patients, and a drug based on ex vivo drug sensitivity in one patient, resulting in objective responses and a bridge to HCT in the majority of the patients. In conclusion, comprehensive profiling of relapsed/refractory hematological malignancies showed multiple oncogenic and immunotherapy targets for a precision medicine approach, which requires multidisciplinary expertise to prioritize the best treatment options for this rare, heavily pretreated pediatric population.
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- 2024
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4. Targeted treatment options for paediatric B-cell precursor acute lymphoblastic leukaemia patients with constitutional or somatic chromosome 21 alterations
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Naomi Michels, Femke M. Hormann, Aurélie Boeree, Edwin Sonneveld, Anthony V. Moorman, Gabriele Escherich, Rosemary Sutton, H. Berna Beverloo, Rob Pieters, C. Michel Zwaan, Monique L. den Boer, and Judith M. Boer
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Acute lymphoblastic leukemia ,RAS ,JAK ,Paediatric ,Chromosome 21 ,Down syndrome ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Chromosome 21 is affected in ∼60% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients and includes somatic and constitutional gains, intrachromosomal amplification of chromosome 21 (iAMP21), and the translocation t(12;21) resulting in the ETV6::RUNX1 gene fusion. Methods: Since these numeric and structural chromosome 21 alterations are not targetable, we studied the type and frequency of yet-proven targetable events co-occurring with chromosome 21 alterations. Results: Among 307 primary paediatric BCP-ALL cases, JAK/STAT pathway lesions were most frequent in patients with constitutional gain of chromosome 21 (Down syndrome ALL; 35/71, 49%) and iAMP21 (9/22, 41%). RAS pathway lesions were most frequent in high hyperdiploidy (62/108, 57%) and FLT3 lesions were most frequent in iAMP21 (7/22, 32%). Virtually all cases expressed CD19 and CD22 at the cell surface. Positivity for CD20 surface expression ranged from 67% in iAMP21 (8/12) to 20% in ETV6::RUNX1 (26/129). Conclusion: Activated JAK/STAT, RAS or FLT3 signalling, and CD marker surface expression may provide targetable treatment options for the majority of chromosome 21-altered BCP-ALL cases.
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- 2024
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5. Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia
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Erica Brivio, Francisco Bautista, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The treatment of childhood acute lymphoblastic leukemia (ALL) has reached overall survival rates exceeding 90%. The present and future challenges are to cure the remainder of patients still dying from disease, and to reduce morbidity and mortality in those who can be cured with standard-of-care chemotherapy by replacing toxic chemotherapy elements while retaining cure rates. With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes. For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody, has established its role in the consolidation treatment for both high- and standard-risk first relapse of ALL, in the presence of bone marrow involvement, and may also have an impact on the outcome of high-risk subsets such as infant ALL and Philadelphia chromosome-positive ALL. Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has demonstrated high efficacy in inducing complete remission in relapsed ALL, even in the presence of high tumor burden, but randomized phase III trials are still ongoing. For T-ALL the role of CD38-directed treatment, such as daratumumab, is gaining interest, but randomized data are needed to assess its specific benefit. These antibodies are currently being tested in patients with newly diagnosed ALL and may lead to major changes in the present paradigm of treatment of pediatric ALL. Unlike the past, lessons may be learned from innovations in adult ALL, in which more drastic changes are piloted that may need to be translated to pediatrics.
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- 2024
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6. Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia
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Fabienne R. S. Adriaanse, Pauline Schneider, Susan T. C. J. M. Arentsen-Peters, Ana M. Neves da Fonseca, Janine Stutterheim, Rob Pieters, C. Michel Zwaan, and Ronald W. Stam
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KMT2A-rearranged ,pediatric ,AML ,infant ,ALL ,revumenib ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating KMT2A-rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in KMT2A-rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in KMT2A-rearranged ALL cells can occur either through the acquisition of MEN1 mutations or independently of mutations in MEN1. Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.
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- 2024
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7. Case Report: Immune dysregulation associated with long-lasting regression of a (pre)leukemic clone
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Joost B. Koedijk, Thomas B. van Beek, Marijn A. Vermeulen, Lennart A. Kester, Elizabeth K. Schweighart, Stefan Nierkens, Mirjam E. Belderbos, C. Michel Zwaan, Katja M. J. Heitink-Pollé, and Olaf Heidenreich
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spontaneous remission ,acute myeloid leukemia ,childhood ,immune-mediated ,case report ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Regression of leukemia in the absence of disease-modifying therapy remains poorly understood, although immunological mechanisms are thought to play a role. Here, we present a unique case of a 17-year-old boy with immune dysregulation and long-lasting regression of a (pre)leukemic clone in the absence of disease-modifying therapy. Using molecular and immunological analyses, we identified bone marrow features associated with disease control and loss thereof. In addition, our case reveals that detection of certain fusion genes with hardly any blasts in the bone marrow may be indicative of an accompanying oncogenic fusion gene, with implications for disease surveillance- and management in future patients.
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- 2023
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8. P494: A FIRST-IN-HUMAN STUDY OF CD123 NK CELL ENGAGER SAR443579 IN RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA, B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA OR HIGH RISK-MYELODYSPLASIA
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Anthony Selwyn Stein, Mojca Jongen-Lavrencic, Sylvain Garciaz, Gerwin A Huls, Abhishek Maiti, Nicolas Boissel, Stephane De Botton, Shaun Fleming, C. Michel Zwaan, David C. de Leeuw, Pinkal Desai, Martha Lucia Arellano, David Avigan, Saskia Langemeijer, Kyle Jensen, Timothy Wagenaar, Gu MI, Giovanni Abbadessa, and Ashish Bajel
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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9. P561: REVUMENIB IN PATIENTS WITH ACUTE LEUKEMIAS: COMPASSIONATE USE PROGRAM EXPERIENCE
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Jeffrey Rubnitz, Ghayas C. Issa, Eytan M. Stein, Neerav Shukla, Wendy Stock, Andrius Žučenka, Sajad Khazal, Nandita Khera, Elliot Stieglitz, Jeremy Rubinstein, Galit Rosen, Rachel Ghiraldi, Huy Van Nguyen, Nicole Mcneer, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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10. The MLL–Menin Interaction is a Therapeutic Vulnerability in NUP98-rearranged AML
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Milad Rasouli, Helen Blair, Selina Troester, Katarzyna Szoltysek, Rachel Cameron, Minoo Ashtiani, Anja Krippner-Heidenreich, Florian Grebien, Gerard McGeehan, C. Michel Zwaan, and Olaf Heidenreich
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin–MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL–Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors.
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- 2023
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11. Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia
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Eline J.M. Bertrums, Jenny L. Smith, Lauren Harmon, Rhonda E. Ries, Yi-Cheng J. Wang, Todd A. Alonzo, Andrew J. Menssen, Karen M. Chisholm, Amanda R. Leonti, Katherine Tarlock, Fabiana Ostronoff, Era L. Pogosova-Agadjanyan, Gertjan J.L. Kaspers, Henrik Hasle, Michael Dworzak, Christiane Walter, Nora Muhlegger, Cristina Morerio, Laura Pardo, Betsy Hirsch, Susana Raimondi, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Jason E. Farrar, Derek Stirewalt, Xiaotu Ma, Tim I. Shaw, Scott N. Furlan, Lisa Eidenschink Brodersen, Michael R. Loken, Marry M. van den Heuvel-Eibrink, C. Michel Zwaan, Timothy J. Triche, Bianca F. Goemans, and Soheil Meshinchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not cryptic. Furthermore, NUP98-X cases are associated with WT1 mutations, and have epigenomic profiles that resemble either NUP98-NSD1 or NUP98-KDM5A. Cooperating FLT3-ITD and WT1 mutations define NUP98-NSD1, and chromosome 13 aberrations are highly enriched in NUP98-KDM5A. Importantly, we demonstrate that NUP98 fusions portend dismal overall survival, with the noteworthy exception of patients bearing abnormal chromosome 13 (clinicaltrials gov. Identifiers: NCT00002798, NCT00070174, NCT00372593, NCT01371981).
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- 2023
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12. Outcome of children with relapsed acute myeloid leukemia improved over time in the Netherlands between 1998 and 2018
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Jasper J. van de Pol, Maya Schulpen, Bianca F. Goemans, Gertjan Kaspers, Henrike E. Karim-Kos, and C. Michel Zwaan
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Acute myeloid leukemia ,Relapse ,Pediatrics ,Survival ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Relapse is a major cause of treatment failure in children with acute myeloid leukemia (AML). The prognosis of children with relapsed AML is poor. Population-based data for this patient group are scarce. The aim of this study was to gain insight into the outcome of Dutch pediatric patients with relapsed AML by describing trends in survival against the background of first-line treatment protocols: ANLL-97 and AML 15 (1998–2009) versus DB AML-01 and NOPHO-DBH-AML-2012 (2010–2018). Material and methods: We retrospectively analyzed outcome and clinical data of all pediatric patients (1 year) was an independent favorable prognostic factor of (event-free) survival. Conclusion: Survival of Dutch pediatric patients with relapsed AML has improved significantly between 1998 and 2018, but remains dismal. Treatment during the period 2010–2018 and late relapse were favorable prognostic factors for OS and EFS.
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- 2023
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13. Combination therapy with crizotinib and vinblastine for relapsed or refractory pediatric ALK-positive anaplastic large cell lymphoma
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Fabian Knörr, Kim P.J. Schellekens, Reineke A. Schoot, Judith Landman-Parker, Heiko-Manuel Teltschik, Jan Förster, Amambay Riquelme, Alwin D.R. Huitema, Natasha K.A. van Eijkelenburg, Auke Beishuizen, C. Michel Zwaan, Wilhelm Woessmann, and Jasper van der Lugt
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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14. Analysis of rare driving events in pediatric acute myeloid leukemia
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Sanne Noort, Jolieke van Oosterwijk, Jing Ma, Elizabeth A.R. Garfinkle, Stephanie Nance, Michael Walsh, Guangchun Song, Dirk Reinhardt, Martina Pigazzi, Franco Locatelli, Henrik Hasle, Jonas Abrahamsson, Marie Jarosova, Charikleia Kelaidi, Sophia Polychronopoulou, Marry M. van den Heuvel-Eibrink, Maarten Fornerod, Tanja A. Gruber, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.
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- 2022
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15. Silent cerebral infarcts in patients with sickle cell disease: a systematic review and meta-analysis
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Maite E. Houwing, Rowena L. Grohssteiner, Marjolein H. G. Dremmen, Ferdows Atiq, Wichor M. Bramer, Anne P. J. de Pagter, C. Michel Zwaan, Tonya J. H. White, Meike W. Vernooij, and Marjon H. Cnossen
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Sickle cell disease ,Silent cerebral infarction ,Stroke ,Magnetic resonance imaging ,Medicine - Abstract
Abstract Background and purpose Silent cerebral infarcts (SCIs) are the most common neurological complication in children and adults with sickle cell disease (SCD). In this systematic review, we provide an overview of studies that have detected SCIs in patients with SCD by cerebral magnetic resonance imaging (MRI). We focus on the frequency of SCIs, the risk factors involved in their development and their clinical consequences. Methods The databases of Embase, MEDLINE ALL via Ovid, Web of Science Core Collection, Cochrane Central Register of Trials via Wiley and Google Scholar were searched from inception to June 1, 2019. Results The search yielded 651 results of which 69 studies met the eligibility criteria. The prevalence of SCIs in patients with SCD ranges from 5.6 to 80.6% with most studies reported in the 20 to 50% range. The pooled prevalence of SCIs in HbSS and HbSβ0 SCD patients is 29.5%. SCIs occur more often in patients with the HbSS and HbSβ0 genotype in comparison with other SCD genotypes, as SCIs are found in 9.2% of HbSC and HbSβ+ patients. Control subjects showed a mean pooled prevalence of SCIs of 9.8%. Data from included studies showed a statistically significant association between increasing mean age of the study population and mean SCI prevalence. Thirty-three studies examined the risk factors for SCIs. The majority of the risk factors show no clear association with prevalence, since more or less equal numbers of studies give evidence for and against the causal association. Conclusions This systematic review and meta-analysis shows SCIs are common in patients with SCD. No clear risk factors for their development were identified. Larger, prospective and controlled clinical, neuropsychological and neuroimaging studies are needed to understand how SCD and SCIs affect cognition.
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- 2020
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16. Guideline for management of non-Down syndrome neonates with a myeloproliferative disease on behalf of the I-BFM AML Study Group and EWOG-MDS
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Eline J.M. Bertrums, C. Michel Zwaan, Daisuke Hasegawa, Valerie de Haas, Dirk N. Reinhardt, Franco Locatelli, Barbara de Moerloose, Michael Dworzak, Arjan Buijs, Petr Smisek, Alexandra Kolenova, Cornelis Jan Pronk, Jan-Henning Klusmann, Ana Carboné, Alina Ferster, Evangelia Antoniou, Soheil Meshinchi, Susana C. Raimondi, Charlotte M. Niemeyer, Henrik Hasle, Marry M. van den Heuvel-Eibrink, and Bianca F. Goemans
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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17. High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia
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Priscilla Wander, Susan T.C.J.M. Arentsen-Peters, Sandra S. Pinhanҫos, Bianca Koopmans, M.Emmy M. Dolman, Rijndert Ariese, Frank L. Bos, Patricia Garrido Castro, Luke Jones, Pauline Schneider, Miriam Guillen Navarro, Jan J. Molenaar, Anne C. Rios, C. Michel Zwaan, and Ronald W. Stam
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High-throughput drug library screen ,Pyrvinium pamoate ,MLL-rearranged AML ,Pediatric acute myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Pediatric MLL-rearranged acute myeloid leukemia (AML) has a generally unfavorable outcome, primarily due to relapse and drug resistance. To overcome these difficulties, new therapeutic agents are urgently needed. Yet, implementing novel drugs for clinical use is a time-consuming, laborious, costly and high-risk process. Therefore, we applied a drug-repositioning strategy by screening drug libraries, comprised of >4000 compounds that are mostly FDA-approved, in a high-throughput format on primary MLL-rearranged AML cells. Here we identified pyrvinium pamoate (pyrvinium) as a novel candidate drug effective against MLL-rearranged AML, eliminating all cell viability at
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- 2021
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18. Ibrutinib is not an effective drug in primografts of TCF3-PBX1
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Cesca van de Ven, Aurélie Boeree, Femke Stalpers, C. Michel Zwaan, and Monique L. Den Boer
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Aim: The Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib (PCI-32765) is effective in patients with multiple myeloma, non-Hodgkin lymphoma and chronic lymphoblastic leukemia. We previously showed that primary cells of children with TCF3-PBX1 positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) express BTK and are sensitive to ibrutinib in vitro. However, preclinical studies in mice are lacking that justify clinical implementation. Methods: Immunocompromised NSG mice were engrafted with a luciferase-positive TCF3-PBX1 leukemic cell line or primary leukemic cells and treated with ibrutinib or placebo. Additionally, primary cells were exposed in vitro to 4 main induction drugs as monotherapy and in combination with ibrutinib. Results: Treatment with ibrutinib of mice engrafted with a TCF3-PBX1 cell line, TCF3-PBX1 positive or TCF3-PBX1 negative primary leukemic cells did not result in prolonged life span compared to placebo treated mice. In vitro sensitivity to ibrutinib was unaltered in leukemic cells obtained from engrafted mice compared to the original material. However, ibrutinib treatment did not affect leukemic cell viability and tumor outgrowth, nor could lymphocytosis be detected. Ibrutinib was biologically active, since hCD19+ cells harvested from ibrutinib treated mice had no detectable levels of phospho-BTK at tyrosine 223 (pBTK Y223), whereas pBTK Y223 was still detectable in placebo treated cases. In combination tests, we noticed an antagonistic effect of ibrutinib on vincristine sensitivity, which was not observed for prednisolone, L-asparaginase and daunorubicin. Conclusions: We conclude that ibrutinib is not the precision medicine of choice for TCF3-PBX1 positive BCP-ALL.
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- 2020
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19. The clinical and biological characteristics of NUP98-KDM5A in pediatric acute myeloid leukemia
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Sanne Noort, Priscilla Wander, Todd A. Alonzo, Jenny Smith, Rhonda E. Ries, Robert B. Gerbing, M. Emmy M. Dolman, Franco Locatelli, Dirk Reinhardt, Andre Baruchel, Jan Stary, Jan J. Molenaar, Ronald W. Stam, Marry M. van den Heuvel-Eibrink, C. Michel Zwaan, and Soheil Meshinchi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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20. Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study
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Marius Flasinski, Kira Scheibke, Martin Zimmermann, Ursula Creutzig, Katarina Reinhardt, Femke Verwer, Valerie de Haas, Vincent H.J. van der Velden, Christine von Neuhoff, C. Michel Zwaan, Dirk Reinhardt, and Jan-Henning Klusmann
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1.5 mg/kg for 7 days) in case of TMD-related symptoms at diagnosis (high white blood cell count, ascites, liver dysfunction, hydrops fetalis) or detection of minimal residual disease (MRD) 8 weeks after diagnosis. The 5-year probability of event-free and overall survival of 102 enrolled TMD patients was 72 ± 5% and 91 ± 3%, respectively. In patients eligible for treatment because of symptoms (n = 43), we observed a significantly lower cumulative incidence (CI) of early death as compared with symptomatic patients in the historical control (n = 45) (12 ± 5% vs 33 ± 7%, PGray = .02). None of the asymptomatic patients in the current study suffered early death. However, the treatment of symptomatic or MRD-positive patients did not result in a significantly lower CI of ML-DS (25 ± 7% [treated] vs 14 ± 7% [untreated], PGray = .34 [per protocol analysis]; historical control: 22 ± 4%, PGray = .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS. This trial was registered at EudraCT as #2006-002962-20.
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- 2018
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21. TropicALL study: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin: a multicenter randomized controlled trial
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Irene L. M. Klaassen, Mandy N. Lauw, Marianne D. van de Wetering, Bart J. Biemond, Saskia Middeldorp, Floor C. H. Abbink, Marc Bierings, D. Maroeska M. W. te Loo, Rob Pieters, Inge M. van der Sluis, Wim J. E. Tissing, C. Michel Zwaan, and C. Heleen van Ommen
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Acute lymphoblastic leukemia ,Low molecular weight heparin ,Venous thromboembolic disease ,Asparaginase ,Pediatric ,Pediatrics ,RJ1-570 - Abstract
Abstract Background Venous thromboembolism (VTE) is a common and severe complication during treatment of acute lymphoblastic leukemia (ALL). An important cause is the intensive use of asparaginase. Prospective cohort studies in which prophylactic low-molecular-weight heparin (LMWH) was used to prevent VTE showed lower VTE risk than in historic control cohorts, with a negligible bleeding risk. However, the efficacy of thromboprophylaxis with LMWH during ALL treatment has never been investigated in a randomized design. Here, we present the protocol of a randomized controlled trial in which the efficacy and safety of thromboprophylaxis with high prophylactic dose LMWH versus no thromboprophylaxis will be assessed in children treated for primary ALL with asparaginase. Methods/Design Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin (TropicALL) is a multicenter, randomized controlled open-label trial conducted in the Netherlands. Patients between 1 and 19 years of age with primary ALL, who are treated within the Dutch Childhood Oncology Group (DCOG) ALL-11 or 12 study will be randomized to thromboprophylaxis with LMWH once daily, (dose of 85 IU/kg (intervention arm A)), or to no thromboprophylaxis (arm B, standard of care) during asparaginase courses of ALL treatment. Primary efficacy endpoint is symptomatic objectified VTE during ALL treatment; secondary efficacy endpoints are overall survival and the composite of symptomatic and asymptomatic objectified VTE. Primary safety endpoints are major bleeding, clinically relevant non-major bleeding and minor bleeding. A total of 324 patients will be included to obtain a relative risk reduction of 75% with a power of 80%, using a two-sided test with significance level α = 0.05. Discussion This trial will be the first to assess efficacy and safety of thromboprophylaxis with LMWH during asparaginase treatment for ALL in children in a randomized design. Trail registration Nederlands Trial Register NTR4707 . Registered 30 July 2014.
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- 2017
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22. Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study
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Natasha K.A. van Eijkelenburg, Mareike Rasche, Essam Ghazaly, Michael N. Dworzak, Thomas Klingebiel, Claudia Rossig, Guy Leverger, Jan Stary, Eveline S.J.M. De Bont, Dana A. Chitu, Yves Bertrand, Benoit Brethon, Brigitte Strahm, Inge M. van der Sluis, Gertjan J.L. Kaspers, Dirk Reinhardt, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m2/day × 5 days) and liposomal daunorubicin (40–80 mg/m2/day) were administered with cytarabine (2 g/m2/day × 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2nd relapse (n=8). Dose level 3 (30 mg/m2clofarabine; 60 mg/m2liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m2 clofarabine with 60 mg/m2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub) clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.
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- 2018
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23. Pediatric AML: From Biology to Clinical Management
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Jasmijn D. E. de Rooij, C. Michel Zwaan, and Marry van den Heuvel-Eibrink
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pediatric AML ,clinical management ,cytogenetics ,molecular aberrations ,Medicine - Abstract
Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine-containing chemotherapy and stem cell transplantation in selected genetic high-risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%–10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity.
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- 2015
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24. Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia
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Jasmijn D.E. de Rooij, Eva Beuling, Marry M. van den Heuvel-Eibrink, Askar Obulkasim, André Baruchel, Jan Trka, Dirk Reinhardt, Edwin Sonneveld, Brenda E.S. Gibson, Rob Pieters, Martin Zimmermann, C. Michel Zwaan, and Maarten Fornerod
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1–0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1–4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7
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- 2015
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25. BCOR and BCORL1 mutations in pediatric acute myeloid leukemia
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Jasmijn D.E. de Rooij, Marry M. van den Heuvel-Eibrink, Malou C.H. Hermkens, Lonneke J. Verboon, Susan T.C.J.M. Arentsen-Peters, Maarten Fornerod, Andre Baruchel, Jan Stary, Dirk Reinhardt, Valerie de Haas, Rob Pieters, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2015
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26. Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood
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Anna M. Aalbers, Marry M. van den Heuvel-Eibrink, Irith Baumann, Michael Dworzak, Henrik Hasle, Franco Locatelli, Barbara De Moerloose, Markus Schmugge, Ester Mejstrikova, Michaela Nováková, Marco Zecca, C. Michel Zwaan, Jeroen G. te Marvelde, Anton W. Langerak, Jacques J.M. van Dongen, Rob Pieters, Charlotte M. Niemeyer, and Vincent H.J. van der Velden
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Refractory cytopenia of childhood is the most common type of childhood myelodysplastic syndrome. Because the majority of children with refractory cytopenia have a normal karyotype and a hypocellular bone marrow, differentiating refractory cytopenia from the immune-mediated bone marrow failure syndrome (very) severe aplastic anemia can be challenging. Flow cytometric immunophenotyping of bone marrow has been shown to be a valuable diagnostic tool in differentiating myelodysplastic syndrome from non-clonal cytopenias in adults. Here, we performed the first comprehensive flow cytometric analysis of immature myeloid, lymphoid cells and erythroid cells, and granulocytes, monocytes, and lymphoid cells in bone marrow obtained from a large prospective cohort of 81 children with refractory cytopenia. Children with refractory cyotopenia had a strongly reduced myeloid compartment, but not as severe as children with aplastic anemia. Furthermore, the number of flow cytometric abnormalities was significantly higher in children with refractory cytopenia than in healthy controls and in children with aplastic anemia, but lower than in advanced myelodysplastic syndrome. We conclude that flow cytometric immunophenotyping could be a relevant addition to histopathology in the diagnosis of refractory cytopenia of childhood. (The multi-center studies EWOG-MDS RC06 and EWOG-MDS 2006 are registered at clinicaltrials.gov identifiers 00499070 and 00662090, respectively).
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- 2015
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27. Mapping epigenetic regulator gene mutations in cytogenetically normal pediatric acute myeloid leukemia
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Daria G. Valerio, Jenny E. Katsman-Kuipers, Joop H. Jansen, Lonneke J. Verboon, Valerie de Haas, Jan Stary, André Baruchel, Martin Zimmermann, Rob Pieters, Dirk Reinhardt, Marry M. van den Heuvel-Eibrink, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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28. t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients
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Julie Damgaard Sandahl, Eva A. Coenen, Erik Forestier, Jochen Harbott, Bertil Johansson, Gitte Kerndrup, Souichi Adachi, Anne Auvrignon, H. Berna Beverloo, Jean-Michel Cayuela, Lucy Chilton, Maarten Fornerod, Valérie de Haas, Christine J. Harrison, Hiroto Inaba, Gertjan J.L. Kaspers, Der-Cherng Liang, Franco Locatelli, Riccardo Masetti, Christine Perot, Susana C. Raimondi, Katarina Reinhardt, Daisuke Tomizawa, Nils von Neuhoff, Marco Zecca, C. Michel Zwaan, Marry M. van den Heuvel-Eibrink, and Henrik Hasle
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing
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- 2014
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29. Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study
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Marjolein Blink, Martin Zimmermann, Christine von Neuhoff, Dirk Reinhardt, Valerie de Haas, Henrik Hasle, Maureen M. O’Brien, Batia Stark, Julie Tandonnet, Andrea Pession, Katerina Tousovska, Daniel K.L. Cheuk, Kazuko Kudo, Takashi Taga, Jeffrey E. Rubnitz, Iren Haltrich, Walentyna Balwierz, Rob Pieters, Erik Forestier, Bertil Johansson, Marry M. van den Heuvel-Eibrink, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (±2%), with the overall survival rate being 79% (±2%), the cumulative incidence of relapse 12% (±2%), and the cumulative incidence of toxic death 7% (±1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%±4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (±2%) (P=0.004). Multivariate analyses revealed that white blood cell count ≥20×109/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols.
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- 2014
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30. Low frequency of type-I and type-II aberrations in myeloid leukemia of Down syndrome, underscoring the unique entity of this disease
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Marjolein Blink, Marry M. van den Heuvel-Eibrink, Valerie de Haas, Jan-Henning Klusmann, Henrik Hasle, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2012
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31. Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia
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Brian V. Balgobind, Iris H.I.M. Hollink, Susan T.C.J.M. Arentsen-Peters, Martin Zimmermann, Jochen Harbott, H. Berna Beverloo, Anne R.M. von Bergh, Jacqueline Cloos, Gertjan J.L. Kaspers, Valerie de Haas, Zuzana Zemanova, Jan Stary, Jean-Michel Cayuela, Andre Baruchel, Ursula Creutzig, Dirk Reinhardt, Rob Pieters, C. Michel Zwaan, and Marry M. van den Heuvel-Eibrink
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Several studies of pediatric acute myeloid leukemia have described the various type-I or type-II aberrations and their relationship with clinical outcome. However, there has been no recent comprehensive overview of these genetic aberrations in one large pediatric acute myeloid leukemia cohort.Design and Methods We studied the different genetic aberrations, their associations and their impact on prognosis in a large pediatric acute myeloid leukemia series (n=506). Karyotypes were studied, and hotspot regions of NPM1, CEPBA, MLL, WT1, FLT3, N-RAS, K-RAS, PTPN11 and KIT were screened for mutations of available samples. The mutational status of all type-I and type-II aberrations was available in 330 and 263 cases, respectively. Survival analysis was performed in a subset (n=385) treated on consecutive acute myeloid leukemia Berlin-Frankfurt-Munster Study Group and Dutch Childhood Oncology Group treatment protocols.Results Genetic aberrations were associated with specific clinical characteristics, e.g. significantly higher diagnostic white blood cell counts in MLL-rearranged, WT1-mutated and FLT3-ITD-positive acute myeloid leukemia. Furthermore, there was a significant difference in the distribution of these aberrations between children below and above the age of two years. Non-random associations, e.g. KIT mutations with core-binding factor acute myeloid leukemia, and FLT3-ITD with t(15;17)(q22;q21), NPM1- and WT1-mutated acute myeloid leukemia, respectively, were observed. Multivariate analysis revealed a ‘favorable karyotype’, i.e. t(15;17)(q22;q21), t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22). NPM1 and CEBPA double mutations were independent factors for favorable event-free survival. WT1 mutations combined with FLT3-ITD showed the worst outcome for 5-year overall survival (22±14%) and 5-year event-free survival (20±13%), although it was not an independent factor in multivariate analysis.Conclusions Integrative analysis of type-I and type-II aberrations provides an insight into the frequencies, non-random associations and prognostic impact of the various aberrations, reflecting the heterogeneity of pediatric acute myeloid leukemia. These aberrations are likely to guide the stratification of pediatric acute myeloid leukemia and may direct the development of targeted therapies.
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- 2011
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32. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia
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Iris H.I.M. Hollink, Marry M. van den Heuvel-Eibrink, Susan T.C.J.M. Arentsen-Peters, Martin Zimmermann, Justine K. Peeters, Peter J.M. Valk, Brian V. Balgobind, Edwin Sonneveld, Gertjan J.L. Kaspers, Eveline S.J.M. de Bont, Jan Trka, Andre Baruchel, Ursula Creutzig, Rob Pieters, Dirk Reinhardt, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Dysfunctioning of CCAAT/enhancer binding protein α (C/EBPα) in acute myeloid leukemia can be caused, amongst others, by mutations in the encoding gene (CEBPA) and by promoter hypermethylation. CEBPA-mutated acute myeloid leukemia is associated with a favorable outcome, but this may be restricted to the case of double mutations in CEBPA in adult acute myeloid leukemia. In pediatric acute myeloid leukemia, data on the impact of these mutations are limited to one series, and data on promoter hypermethylation are lacking. Our objective was to investigate the characteristics, gene expression profiles and prognostic impact of the different CEBPA aberrations in pediatric acute myeloid leukemia.Design and Methods We screened a large pediatric cohort (n=252) for CEBPA single and double mutations by direct sequencing, and for promoter hypermethylation by methylation-specific polymerase chain reaction. Furthermore, we determined the gene-expression profiles (Affymetrix HGU133 plus 2.0 arrays) of this cohort (n=237).Results Thirty-four mutations were identified in 20 out of the 252 cases (7.9%), including 14 double-mutant and 6 single-mutant cases. CEBPA double mutations conferred a significantly better 5-year overall survival compared with single mutations (79% versus 25%, respectively; P=0.04), and compared with CEBPA wild-type acute myeloid leukemia excluding core-binding factor cases (47%; P=0.07). Multivariate analysis confirmed that the double mutations were an independent favorable prognostic factor for survival (hazard ratio 0.23, P=0.04). The combination of screening for promoter hypermethylation and gene expression profiling identified five patients with silenced CEBPA, of whom four cases relapsed. All cases characteristically expressed T-lymphoid markers. Moreover, unsupervised clustering of gene expression profiles showed a clustering of CEBPA double-mutant and silenced cases, pointing towards a common hallmark of abrogated C/EBPα-functioning in these acute myeloid leukemias.Conclusions We showed the independent favorable outcome of patients with CEBPA double-mutant acute myeloid leukemia in a large pediatric series. This molecular marker may, therefore, improve risk-group stratification in pediatric acute myeloid leukemia. For the first time, CEBPA-silenced cases are suggested to confer a poor outcome in pediatric acute myeloid leukemia, indicating that further investigation of this aberration is needed. Furthermore, clustering of gene expression profiles provided insight into the biological similarities and diversities of the different aberrations in CEBPA in pediatric acute myeloid leukemia.
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- 2011
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33. Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia
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Brian V. Balgobind, Marry M. Van den Heuvel-Eibrink, Renee X. De Menezes, Dirk Reinhardt, Iris H.I.M. Hollink, Susan T.J.C.M. Arentsen-Peters, Elisabeth R. van Wering, Gertjan J.L. Kaspers, Jacqueline Cloos, Evelien S.J.M. de Bont, Jean-Michel Cayuela, Andre Baruchel, Claus Meyer, Rolf Marschalek, Jan Trka, Jan Stary, H. Berna Beverloo, Rob Pieters, C. Michel Zwaan, and Monique L. den Boer
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity.Design and Methods We examined the potential of gene expression profiles to classify pediatric acute myeloid leukemia. Gene expression microarray data of 237 children with acute myeloid leukemia were collected and a double-loop cross validation approach was used to generate a subtype-predictive gene expression profile in the discovery cohort (n=157) which was then tested for its true predictive value in the independent validation cohort (n=80). The classifier consisted of 75 probe sets, representing the top 15 discriminating probe sets for MLL-rearranged, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q21;q22) and t(7;12)(q36;p13)-positive acute myeloid leukemia.Results These cytogenetic subtypes represent approximately 40% of cases of pediatric acute myeloid leukemia and were predicted with 92% and 99% accuracy in the discovery and independent validation cohort, respectively. However, for NPM1, CEBPA, MLL(-PTD), FLT3(-ITD), KIT, PTPN11 and N/K-RAS gene expression signatures had limited predictive value. This may be caused by a limited frequency of these mutations and by underlying cytogenetics. This latter is exemplified by the fact that different gene expression signatures were discovered for FLT3-ITD in patients with normal cytogenetics and in those with t(15;17)(q21;q22)-positive acute myeloid leukemia, which pointed to HOXB-upregulation being specific for FLT3-ITD+ cytogenetically normal acute myeloid leukemia.Conclusions In conclusion, gene expression profiling correctly predicted the most prevalent cytogenetic subtypes of pediatric acute myeloid leukemia with high accuracy. In clinical practice, this gene expression signature may replace multiple diagnostic tests for approximately 40% of pediatric acute myeloid leukemia cases whereas only for the remaining cases (predicted as ‘acute myeloid leukemia-other’) are additional tests indicated. Moreover, the discriminative genes reveal new insights into the biology of acute myeloid leukemia subtypes that warrants follow-up as potential targets for new therapies.
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- 2011
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34. Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia
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Trudy D. Buitenkamp, Ron A.A. Mathôt, Valerie de Haas, Rob Pieters, and C. Michel Zwaan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Children with Down syndrome have an increased risk of developing acute lymphoblastic leukemia and a poor tolerance of methotrexate. This latter problem is assumed to be caused by a higher cellular sensitivity of tissues in children with Down syndrome. However, whether differences in pharmacokinetics play a role is unknown.Design and Methods We compared methotrexate-induced toxicity and pharmacokinetics in a retrospective case-control study between patients with acute lymphoblastic leukemia who did or did not have Down syndrome. Population pharmacokinetic models were fitted to data from all individuals simultaneously, using non-linear mixed effect modeling.Results Overall, 468 courses of methotrexate (1–5 g/m2) were given to 44 acute lymphoblastic leukemia patients with Down syndrome and to 87 acute lymphoblastic leukemia patients without Down syndrome. Grade 3–4 gastrointestinal toxicity was significantly more frequent in the children with Down syndrome than in those without (25.5% versus 3.9%; P=0.001). The occurrence of grade 3–4 gastrointestinal toxicity was not related to plasma methotrexate area under the curve. Methotrexate clearance was 5% lower in the acute lymphoblastic leukemia patients with Down syndrome (P=0.001); however, this small difference is probably clinically not relevant, because no significant differences in methotrexate plasma levels were detected at 24 and 48 hours.Conclusions We did not find evidence of differences in the pharmacokinetics of methotrexate between patients with and without Down syndrome which could explain the higher frequency of gastrointestinal toxicity and the greater need for methotrexate dose reductions in patients with Down syndrome. Hence, these problems are most likely explained by differential pharmaco-dynamic effects in the tissues between children with and without Down syndrome. Although the number of patients was limited to draw conclusions, we feel that it may be safe in children with Down syndrome to start with intermediate dosages of methotrexate (1–3 g/m2) and monitor the patients carefully.
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- 2010
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35. NRIP3: a novel translocation partner of MLL detected in a pediatric acute myeloid leukemia with complex chromosome 11 rearrangements
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Brian V. Balgobind, C. Michel Zwaan, Claus Meyer, Rolf Marschalek, Rob Pieters, H. Berna Beverloo, and Marry M. Van den Heuvel-Eibrink
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2009
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36. Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia
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Romy E. van Weelderen, Kim Klein, Christine J. Harrison, Yilin Jiang, Jonas Abrahamsson, Nira Arad-Cohen, Emmanuelle Bart-Delabesse, Barbara Buldini, Barbara De Moerloose, Michael N. Dworzak, Sarah Elitzur, José M. Fernández Navarro, Robert B. Gerbing, Bianca F. Goemans, Hester A. de Groot-Kruseman, Erin Guest, Shau-Yin Ha, Henrik Hasle, Charikleia Kelaidi, Hélène Lapillonne, Guy Leverger, Franco Locatelli, Riccardo Masetti, Takako Miyamura, Ulrika Norén-Nyström, Sophia Polychronopoulou, Mareike Rasche, Jeffrey E. Rubnitz, Jan Stary, Anne Tierens, Daisuke Tomizawa, C. Michel Zwaan, Gertjan J.L. Kaspers, Pediatrics, CCA - Cancer Treatment and quality of life, and CCA - Cancer biology and immunology
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Cancer och onkologi ,Cancer Research ,Oncology ,SDG 3 - Good Health and Well-being ,Cancer and Oncology ,Minimal residual disease ,Medicine and Health Sciences ,Pediatrik ,Minimal residual disease, myeloid leukemia, stem cell transplantation ,Pediatrics ,stem cell transplantation ,myeloid leukemia - Abstract
PURPOSE A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged ( KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non–high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (RESULTS The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non–high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.
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- 2023
37. Treating CD33-Positive de novo Acute Myeloid Leukemia in Pediatric Patients
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Noa E Wijnen, Joost B Koedijk, Kim Klein, Maaike Luesink, Bianca F Goemans, C Michel Zwaan, and Gertjan JL Kaspers
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Oncology ,Pharmacology (medical) - Abstract
Although survival in pediatric acute myeloid leukemia (AML) has increased considerably over the past decades, refractory disease and relapse rates remain high. Refractory and relapsed disease are difficult to treat, with overall survival rates less than 40–50%. Preventing relapse should, therefore, be one of the highest priorities. Current conventional chemotherapy regimens are hard to intensify due to associated toxic complications, hence more effective therapies that do not increase toxicity are needed. A promising targeted agent is the CD33-directed antibody–drug conjugate gemtuzumab ozogamicin (GO). Because CD33 is highly expressed on leukemic cells in the majority of AML patients, GO can be useful for a broad range of patients. Better relapse-free survival (RFS) after therapy including GO has been reported in several pediatric clinical trials; however, ambiguity about the clinical value of GO in newly diagnosed children remains. Treatment with GO in de novo AML patients aged ≥1 month, in combination with standard chemotherapy is approved in the United States, whereas in Europe, GO is only approved for newly diagnosed patients aged ≥15 years. In this review, we aimed to clarify the clinical value of GO for treatment of newly diagnosed pediatric AML patients. Based on current literature, GO seems to have additional value, in terms of RFS, and acceptable toxicity when used in addition to chemotherapy during initial treatment. Moreover, in KMT2A-rearranged patients, the clinical value of GO was even more evident. Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.
- Published
- 2023
38. Limited sampling strategies for individualized BAX 855 prophylaxis in severe hemophilia A
- Author
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Laura H. Bukkems, Tine M.H.J. Goedhart, C. Michel Zwaan, Marjon H. Cnossen, Ron A.A. Mathôt, Pharmacy, Other Research, AII - Infectious diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Pediatrics
- Subjects
factor VIII ,limited sampling strategy ,hemophilia A ,Hematology ,General Medicine ,extended half-life ,pharmacokinetics - Abstract
OBJECTIVE: Limited sampling strategies (LSS) lower the burden of pharmacokinetic (PK)-guided dosing, but an extensive evaluation of LSS for BAX 855 (Adynovi) is currently lacking. This study aimed to develop a LSS for BAX 855 and combine this with a LSS of a standard half-life (SHL) factor VIII (FVIII) concentrate in a clinical setting. METHODS: Individual PK parameters of BAX 855 were estimated for 10 000 virtual patients with severe hemophilia A using Monte Carlo simulations. Several LSS consisting of 2-6 samples were examined based on patient burden, bias and accuracy of clearance, elimination half-life, volume of distribution and trough levels at 72 h (C72). Analyses were performed separately for adults and children
- Published
- 2023
39. A CRISPR/Cas9 engineered MplS504N mouse model recapitulates human myelofibrosis
- Author
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Fabienne R. S. Adriaanse, Jennifer L. Kamens, Peter Vogel, Sadie M. Sakurada, Shondra M. Pruett-Miller, Ronald W. Stam, C. Michel Zwaan, Tanja A. Gruber, and Pediatrics
- Subjects
Cancer Research ,Oncology ,SDG 3 - Good Health and Well-being ,Hematology - Abstract
To the Editor:The genetic etiology of clonal hematopoiesis characterizing >90% of all myeloproliferative neoplasms (MPNs) involve somatic mutations that induce signaling downstream of cytokine receptors and demonstrate significant overlap in clinical phenotype. Among these mutated genes is MPL, encoding for the thrombopoietin receptor which plays a central role in the regulation of megakaryopoiesis, HSC maintenance, and proliferation of progenitors. The most frequent MPL mutations, MPL S505N and MPL W515K/L/R/S/A, reside in exon 10 encoding for the transmembrane domain and lead to TPO-independent receptor activation. MPL W515K/L/R/S/A occurs at a much higher frequency in MPN, comprising 82% of MPL mutant cases in one study. These somatic mutations are often found in the heterozygous state, but homozygous mutations do occur in primary myelofibrosis (PMF), typically through acquired copy-neutral loss of heterozygosity. Both MPLS505N and MPLW515 mutations are also found as heterozygous autosomal dominant germline mutations with incomplete penetrance in hereditary thrombocytosis. To date, two studies have generated retroviral overexpression murine models to investigate the impact of human MPLW515 mutations on murine hematopoietic cells, both resulting in rapid onset of disease. However, the ability of the MPLS505N mutation has not yet been evaluated for its ability to perturb hematopoiesis, induce an MPN phenotype and recapitulate the pathology found in patients with MPL mutations. Herein, we describe a CRISPR/Cas9 engineered mouse model harboring a germline MplS504N mutation that can aid further investigation into the complex etiology of MPNs and essential thrombocythemia. [...]
- Published
- 2022
40. A Population Pharmacokinetic Modelling Approach to Unravel the Complex Pharmacokinetics of Vincristine in Children
- Author
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A. Laura Nijstad, Wan-Yu Chu, Evelien de Vos-Kerkhof, Catherine F. Enters-Weijnen, Mirjam E. van de Velde, Gertjan J. L. Kaspers, Shelby Barnett, Gareth J. Veal, Arief Lalmohamed, C. Michel Zwaan, Alwin D. R. Huitema, Pediatrics, and CCA - Cancer biology and immunology
- Subjects
Pharmacology ,Organic Chemistry ,Pharmaceutical Science ,Molecular Medicine ,Pharmacology (medical) ,Biotechnology - Abstract
Background Vincristine, a chemotherapeutic agent that extensively binds to β-tubulin, is commonly dosed at 1.4–2.0 mg/m2 capped at 2 mg. For infants, doses vary from 0.025–0.05 mg/kg or 50–80% of the mg/m2 dose. However, evidence for lower doses in infants compared to older children is lacking. This study was conducted to unravel the complex pharmacokinetics of vincristine, including the effects of age, to assist optimal dosing in this population. Methods 206 patients (0.04–33.9 years; 25 patients Results A three-compartment model, with one saturable compartment resembling saturable binding to β-tubulin and thus, saturable distribution, best described vincristine pharmacokinetics. Body weight and age were covariates significantly influencing the maximal binding capacity to β-tubulin, which increased with increasing body weight and decreased with increasing age. Vincristine clearance (CL) was estimated as 30.6 L/h (95% confidence interval (CI) 27.6–33.0), intercompartmental CL (Q) as 63.2 L/h (95%CI 57.2–70.1), volume of distribution of the central compartment as 5.39 L (95%CI 4.23–6.46) and of the peripheral compartment as 400 L (95%CI 357–463) (all parameters correspond to a patient of 70 kg). The maximal binding capacity was 0.525 mg (95%CI 0.479–0.602) (for an 18 year old patient of 70 kg), with a high association rate constant, fixed at 1300 /h and a dissociation constant of 11.5 /h. Interpretation A decrease of vincristine β-tubulin binding capacity with increasing age suggests that young children tolerate higher doses of vincristine.
- Published
- 2022
41. Data from Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms
- Author
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Ruben van Boxtel, Bianca F. Goemans, C. Michel Zwaan, Hester A. de Groot-Kruseman, Markus J. van Roosmalen, Rurika Oka, Marry M. van den Heuvel-Eibrink, Mark Verheul, Anaïs J.C.N. van Leeuwen, Arianne M. Brandsma, Jurrian K. de Kanter, Axel K.M. Rosendahl Huber, and Eline J.M. Bertrums
- Abstract
Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure.Significance:Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging.This article is highlighted in the In This Issue feature, p. 1825
- Published
- 2023
42. Supplementary Excel Tables from Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators
- Author
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Tanja A. Gruber, C. Michel Zwaan, Stanley Pounds, Jinghui Zhang, James R. Downing, Jeffery M. Klco, Henrik Hasle, Franco Locatelli, Marry M. van den Heuvel-Eibrink, Dirk Reinhardt, Jeffrey E. Rubnitz, Sharyn D. Baker, Jatinder K. Lamba, Sophia Polychronopoulou, Charikleia Kelaidi, Marie Jarosova, Martina Pigazzi, Esther A. Obeng, Jennifer L. Kamens, Jacquelyn Myers, Donald Yergeau, Heather L. Mulder, John Easton, Tamara Lamprecht, Guangchun Song, Yuanyuan Wang, Yanling Liu, Stephanie Nance, Lei Shi, Michael P. Walsh, Yu Liu, Sanne Noort, Jing Ma, and Maarten Fornerod
- Abstract
Supplementary Excel Tables
- Published
- 2023
43. Supplementary Figure from Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms
- Author
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Ruben van Boxtel, Bianca F. Goemans, C. Michel Zwaan, Hester A. de Groot-Kruseman, Markus J. van Roosmalen, Rurika Oka, Marry M. van den Heuvel-Eibrink, Mark Verheul, Anaïs J.C.N. van Leeuwen, Arianne M. Brandsma, Jurrian K. de Kanter, Axel K.M. Rosendahl Huber, and Eline J.M. Bertrums
- Abstract
Supplementary Figure from Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms
- Published
- 2023
44. Supplementary Tables and Figures from Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators
- Author
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Tanja A. Gruber, C. Michel Zwaan, Stanley Pounds, Jinghui Zhang, James R. Downing, Jeffery M. Klco, Henrik Hasle, Franco Locatelli, Marry M. van den Heuvel-Eibrink, Dirk Reinhardt, Jeffrey E. Rubnitz, Sharyn D. Baker, Jatinder K. Lamba, Sophia Polychronopoulou, Charikleia Kelaidi, Marie Jarosova, Martina Pigazzi, Esther A. Obeng, Jennifer L. Kamens, Jacquelyn Myers, Donald Yergeau, Heather L. Mulder, John Easton, Tamara Lamprecht, Guangchun Song, Yuanyuan Wang, Yanling Liu, Stephanie Nance, Lei Shi, Michael P. Walsh, Yu Liu, Sanne Noort, Jing Ma, and Maarten Fornerod
- Abstract
Supplementary Tables and Figures
- Published
- 2023
45. Data from Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators
- Author
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Tanja A. Gruber, C. Michel Zwaan, Stanley Pounds, Jinghui Zhang, James R. Downing, Jeffery M. Klco, Henrik Hasle, Franco Locatelli, Marry M. van den Heuvel-Eibrink, Dirk Reinhardt, Jeffrey E. Rubnitz, Sharyn D. Baker, Jatinder K. Lamba, Sophia Polychronopoulou, Charikleia Kelaidi, Marie Jarosova, Martina Pigazzi, Esther A. Obeng, Jennifer L. Kamens, Jacquelyn Myers, Donald Yergeau, Heather L. Mulder, John Easton, Tamara Lamprecht, Guangchun Song, Yuanyuan Wang, Yanling Liu, Stephanie Nance, Lei Shi, Michael P. Walsh, Yu Liu, Sanne Noort, Jing Ma, and Maarten Fornerod
- Abstract
Genomic characterization of pediatric patients with acute myeloid leukemia (AML) has led to the discovery of somatic mutations with prognostic implications. Although gene-expression profiling can differentiate subsets of pediatric AML, its clinical utility in risk stratification remains limited. Here, we evaluate gene expression, pathogenic somatic mutations, and outcome in a cohort of 435 pediatric patients with a spectrum of pediatric myeloid-related acute leukemias for biological subtype discovery. This analysis revealed 63 patients with varying immunophenotypes that span a T-lineage and myeloid continuum designated as acute myeloid/T-lymphoblastic leukemia (AMTL). Within AMTL, two patient subgroups distinguished by FLT3-ITD and PRC2 mutations have different outcomes, demonstrating the impact of mutational composition on survival. Across the cohort, variability in outcomes of patients within isomutational subsets is influenced by transcriptional identity and the presence of a stem cell–like gene-expression signature. Integration of gene expression and somatic mutations leads to improved risk stratification.Significance:Immunophenotype and somatic mutations play a significant role in treatment approach and risk stratification of acute leukemia. We conducted an integrated genomic analysis of pediatric myeloid malignancies and found that a combination of genetic and transcriptional readouts was superior to immunophenotype and genomic mutations in identifying biological subtypes and predicting outcomes.This article is highlighted in the In This Issue feature, p. 549
- Published
- 2023
46. Data from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets
- Author
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Olaf Witt, Stefan M. Pfister, David Capper, Jan J. Molenaar, David T.W. Jones, Annette Kopp-Schneider, Peter Lichter, Ruth Witt, Angelika Freitag, Uta Dirksen, Andreas von Deimling, Felix Sahm, David Reuss, Stephan Wolf, Natalie Jäger, Till Milde, C. Michel Zwaan, Bianca Goemans, Maria Filippidou, Antonis Kattamis, Bernarda Kazanowska, Olli Lohi, Nicolas U. Gerber, Caroline Hutter, Ingrid Øra, Roman Tremmel, Matthias Schwab, Simone Hettmer, Monika Scheer, Michael T. Meister, Ewa Koscielniak, Simone Fulda, Petra Ketteler, Ines B. Brecht, Dominik T. Schneider, Michael C. Frühwald, Stefanie Hecker-Nolting, Michaela Nathrath, Wilhelm Wößmann, Birgit Burkhardt, Angelika Eggert, Matthias Fischer, Frank Westermann, Norbert Graf, Peter Vorwerk, Gabriele Calaminus, André O. von Bueren, Christof M. Kramm, Irene Schmid, Dietrich von Schweinitz, Stephan Tippelt, Gudrun Fleischhack, Jan-Henning Klusmann, Dirk Reinhardt, Roland Meisel, Arndt Borkhardt, Andrej Lissat, Andreas E. Kulozik, Arend von Stackelberg, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Kathrin Schramm, Mirjam Blattner-Johnson, Pascal D. Johann, Sebastian Stark, Gnana Prakash Balasubramanian, Barbara C. Jones, Petra Fiesel, Karin P.S. Langenberg, Kristian W. Pajtler, Elke Pfaff, and Cornelis M. van Tilburg
- Abstract
INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.Significance:The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659
- Published
- 2023
47. Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets
- Author
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Olaf Witt, Stefan M. Pfister, David Capper, Jan J. Molenaar, David T.W. Jones, Annette Kopp-Schneider, Peter Lichter, Ruth Witt, Angelika Freitag, Uta Dirksen, Andreas von Deimling, Felix Sahm, David Reuss, Stephan Wolf, Natalie Jäger, Till Milde, C. Michel Zwaan, Bianca Goemans, Maria Filippidou, Antonis Kattamis, Bernarda Kazanowska, Olli Lohi, Nicolas U. Gerber, Caroline Hutter, Ingrid Øra, Roman Tremmel, Matthias Schwab, Simone Hettmer, Monika Scheer, Michael T. Meister, Ewa Koscielniak, Simone Fulda, Petra Ketteler, Ines B. Brecht, Dominik T. Schneider, Michael C. Frühwald, Stefanie Hecker-Nolting, Michaela Nathrath, Wilhelm Wößmann, Birgit Burkhardt, Angelika Eggert, Matthias Fischer, Frank Westermann, Norbert Graf, Peter Vorwerk, Gabriele Calaminus, André O. von Bueren, Christof M. Kramm, Irene Schmid, Dietrich von Schweinitz, Stephan Tippelt, Gudrun Fleischhack, Jan-Henning Klusmann, Dirk Reinhardt, Roland Meisel, Arndt Borkhardt, Andrej Lissat, Andreas E. Kulozik, Arend von Stackelberg, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Kathrin Schramm, Mirjam Blattner-Johnson, Pascal D. Johann, Sebastian Stark, Gnana Prakash Balasubramanian, Barbara C. Jones, Petra Fiesel, Karin P.S. Langenberg, Kristian W. Pajtler, Elke Pfaff, and Cornelis M. van Tilburg
- Abstract
Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets
- Published
- 2023
48. Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets
- Author
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Olaf Witt, Stefan M. Pfister, David Capper, Jan J. Molenaar, David T.W. Jones, Annette Kopp-Schneider, Peter Lichter, Ruth Witt, Angelika Freitag, Uta Dirksen, Andreas von Deimling, Felix Sahm, David Reuss, Stephan Wolf, Natalie Jäger, Till Milde, C. Michel Zwaan, Bianca Goemans, Maria Filippidou, Antonis Kattamis, Bernarda Kazanowska, Olli Lohi, Nicolas U. Gerber, Caroline Hutter, Ingrid Øra, Roman Tremmel, Matthias Schwab, Simone Hettmer, Monika Scheer, Michael T. Meister, Ewa Koscielniak, Simone Fulda, Petra Ketteler, Ines B. Brecht, Dominik T. Schneider, Michael C. Frühwald, Stefanie Hecker-Nolting, Michaela Nathrath, Wilhelm Wößmann, Birgit Burkhardt, Angelika Eggert, Matthias Fischer, Frank Westermann, Norbert Graf, Peter Vorwerk, Gabriele Calaminus, André O. von Bueren, Christof M. Kramm, Irene Schmid, Dietrich von Schweinitz, Stephan Tippelt, Gudrun Fleischhack, Jan-Henning Klusmann, Dirk Reinhardt, Roland Meisel, Arndt Borkhardt, Andrej Lissat, Andreas E. Kulozik, Arend von Stackelberg, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Kathrin Schramm, Mirjam Blattner-Johnson, Pascal D. Johann, Sebastian Stark, Gnana Prakash Balasubramanian, Barbara C. Jones, Petra Fiesel, Karin P.S. Langenberg, Kristian W. Pajtler, Elke Pfaff, and Cornelis M. van Tilburg
- Abstract
Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets
- Published
- 2023
49. Clinical outcomes of second relapsed and refractory first relapsed paediatric AML
- Author
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Tara White, Gertjan Kaspers, Jonas Abrahamsson, Nira Arad‐Cohen, Daniela Cianci, Jose Fernandez, Shau‐Yin Ha, Henrik Hasle, Barbara De Moerloose, C. Michel Zwaan, Bianca F. Goemans, Pediatrics, Pediatric surgery, and CCA - Cancer Treatment and quality of life
- Subjects
relapse ,therapy ,paediatric acute myeloid leukaemia ,CHILDREN ,ACUTE MYELOID-LEUKEMIA ,Hematology ,Prognosis ,GEMTUZUMAB OZOGAMICIN ,survival ,FLT3 MUTATIONS ,Leukemia, Myeloid, Acute ,refractory disease ,Treatment Outcome ,Recurrence ,Medicine and Health Sciences ,Humans ,Neoplasm Recurrence, Local ,Child ,Retrospective Studies - Abstract
As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third-line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO-DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5-year pOS were 22 ± 3% and 14 ± 3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third-line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third-line therapy can be cured.
- Published
- 2022
50. Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype
- Author
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Vijay G. Sankaran, Deepa Bhojwani, C. Michel Zwaan, Nik F Nik-Abdul-Rashid, Josefine Palle, Jeffrey M Verboon, Stephanie DiTroia, Klas Raaschou-Jensen, Charlotte Guldborg Nyvold, Alan B. Cantor, Katherine R. Chao, Ronald M Kline, Henrik Hasle, Eigil Kjeldsen, and Pediatrics
- Subjects
Male ,Down syndrome ,Immunology ,Trisomy ,Biochemistry ,Germline ,Acute megakaryoblastic leukemia ,Leukemia, Megakaryoblastic, Acute ,hemic and lymphatic diseases ,medicine ,Humans ,GATA1 Transcription Factor ,Germ-Line Mutation ,Myeloid Neoplasia ,business.industry ,Myeloid leukemia ,GATA1 ,Cell Biology ,Hematology ,medicine.disease ,Leukemia ,Phenotype ,Leukemia, Myeloid ,Child, Preschool ,Tetrasomy ,Mutation ,Cancer research ,Down Syndrome ,business - Abstract
Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.
- Published
- 2022
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