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2. A 14-year-old girl with premature ovarian insufficiency but with a positive pregnancy test

Author

Endocrinologie patientenzorg, CDL Poli WKZ, CDL Cluster Speciële Diagnostiek, Other research (not in main researchprogram), Pathologie Groep Van Diest, Pathologie patiënten zorg, Brain, Cancer, Child Health, Touwslager, Robbert N.H., Michel Zwaan, C., Bakker, Boudewijn, Lentjes, Eef G.W.M., Looijenga, Leendert H.J., van Santen, Hanneke M., Endocrinologie patientenzorg, CDL Poli WKZ, CDL Cluster Speciële Diagnostiek, Other research (not in main researchprogram), Pathologie Groep Van Diest, Pathologie patiënten zorg, Brain, Cancer, Child Health, Touwslager, Robbert N.H., Michel Zwaan, C., Bakker, Boudewijn, Lentjes, Eef G.W.M., Looijenga, Leendert H.J., and van Santen, Hanneke M.

Published
2024

3. 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

Author

Selwyn Stein, Anthony, primary, Jongen-Lavrencic, Mojca, additional, Garciaz, Sylvain, additional, A Huls, Gerwin, additional, Maiti, Abhishek, additional, Boissel, Nicolas, additional, De Botton, Stephane, additional, Fleming, Shaun, additional, Michel Zwaan, C., additional, C. de Leeuw, David, additional, Desai, Pinkal, additional, Lucia Arellano, Martha, additional, Avigan, David, additional, Langemeijer, Saskia, additional, Jensen, Kyle, additional, Wagenaar, Timothy, additional, MI, Gu, additional, Abbadessa, Giovanni, additional, and Bajel, Ashish, additional

Published
2023
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5. Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to TherapyRelated Myeloid Neoplasms

Author

Bertrums, Eline J.M., Rosendahl Huber, Axel K.M., de Kanter, Jurrian K., Brandsma, Arianne M., van Leeuwen, Anaïs J.C.N., Verheul, Mark, van den Heuvel-Eibrink, Marry M., Oka, Rurika, van Roosmalen, Markus J., de Groot-Kruseman, Hester A., Michel Zwaan, C., Goemans, Bianca F., van Boxtel, Ruben, Bertrums, Eline J.M., Rosendahl Huber, Axel K.M., de Kanter, Jurrian K., Brandsma, Arianne M., van Leeuwen, Anaïs J.C.N., Verheul, Mark, van den Heuvel-Eibrink, Marry M., Oka, Rurika, van Roosmalen, Markus J., de Groot-Kruseman, Hester A., Michel Zwaan, C., Goemans, Bianca F., and van Boxtel, Ruben

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.

Published
2022

6. Somatic thrombopoietin (THPO) gene mutations in childhood myeloid leukemias

Author

Houwing, Maite E., Koopman-Coenen, Eva A., Kersseboom, Rogier, Gooskens, Saskia, Appel, Inge M., Arentsen-Peters, Susan T. C. J. M., de Vries, Andrica C. H., Reinhardt, Dirk, Stary, Jan, Baruchel, André, de Haas, Valerie, Blink, Marjolein, Lopes Cardozo, Rob H., Pieters, Rob, Michel Zwaan, C., and van den Heuvel-Eibrink, Marry M.

Published
2015
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8. The clinical and biological characteristics of NUP98-KDM5A pediatric acute myeloid leukemia

Author

Noort, S., Wander, P., Alonzo, T. A., Smith, J., Ries, R. E., Gerbing, R. B., Dolman, E. M. M., Locatelli, Franco, Reinhardt, D., Baruchel, A., Stary, J., Molenaar, J. J., Stam, R. W., van den Heuvel-Eibrink, M. M., Michel Zwaan, C., Meshinchi, S., Locatelli F. (ORCID:0000-0002-7976-3654), Noort, S., Wander, P., Alonzo, T. A., Smith, J., Ries, R. E., Gerbing, R. B., Dolman, E. M. M., Locatelli, Franco, Reinhardt, D., Baruchel, A., Stary, J., Molenaar, J. J., Stam, R. W., van den Heuvel-Eibrink, M. M., Michel Zwaan, C., Meshinchi, S., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2021

10. Pharmacokinetics of nilotinib in pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia or acute lymphoblastic leukemia

Author

Hijiya, N, Michel Zwaan, C, Rizzari, C, Foà, R, Abbink, F, Lancaster, D, Landman-Parker, J, Millot, F, Moppett, J, Nelken, B, Putti, M, Xianbin, T, Sinclair, K, Santanastasio, H, Buchbinder, A, Kearns, P, Michel Zwaan,CM, Putti, MC, Hijiya, N, Michel Zwaan, C, Rizzari, C, Foà, R, Abbink, F, Lancaster, D, Landman-Parker, J, Millot, F, Moppett, J, Nelken, B, Putti, M, Xianbin, T, Sinclair, K, Santanastasio, H, Buchbinder, A, Kearns, P, Michel Zwaan,CM, and Putti, MC

Abstract

Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Phþ) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Patients and Methods: Fifteen patients (aged 1–<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n 1⁄4 11) or Phþ ALL relapsed on or refractory to standard therapy (n 1⁄4 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. Results: The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Phþ ALL achieved complete remission. Conclusions: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Phþ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.

Published
2020

11. Contributors

Author

Abdel-Wahab, Omar, Abrahm, Janet L., Abutalib, Syed A., Adams, Sharon, Al Hadidi, Samer, Alcaide, Pilar, Allen, Carl E., Ambinder, Richard F., Amonoo, Hermioni L., Anderson, Julia A.M., Antin, Joseph H., Antony, Aśok C., Araten, David J., Arnold, Donald M., Awan, Farrukh T., Ayers, Emily C., Barth, Peter, Bates, Shannon M., Benz, Edward J., Berliner, Nancy, Bhardwaj, Nina, Bhatia, Smita, Bhatt, Mihir D., Bollard, Catherine M., Bowman, Mackenzie, Boyle, Eileen M., Braun, Benjamin S., Brenner, Malcolm K., Broccoli, Alessandro, Brodsky, Robert A., Brown, Myles, Broxmeyer, Hal E., Brummel-Ziedins, Kathleen, Brunner, Andrew M., Brunstein, Claudio G., Buadi, Francis K., Burkhardt, Birgit, Burns, Melissa A., Bussel, James B., Byrd, John C., Caimi, Paolo F., Camaschella, Clara, Canavan, Michelle, Cantor, Alan B., Capitano, Maegan L., Carcao, Manuel, Carrillo-Farga, Joaquin, Carroll, Michael C., Carson, William E., Carty, Shannon A., Castillo, Jorge J., Chakrabarti, Priyasmita, Chan, Anthony K.C., Chan, Noel C., Chhabra, Saurabh, Chute, John P., Cimen Bozkus, Cansu, Ciurea, Stefan O., Coates, Thomas D., Collins, Graham, Creager, Mark A., Cromwell, Caroline, Crowder, Lauren A., Cushing, Melissa M., Cutler, Corey, Dabaja, Bouthaina, Dave, Sandeep S., De, Caprio, James A., De, Carli, Kathryn, Deininger, Michael W., De, Simone, Robert A., Dinauer, Mary C., Dinner, Shira, Dixit, Karan S., Dogan, Ahmet, Dorshkind, Kenneth, Dotti, Gianpietro, Dror, Yigal, Dunleavy, Kieron, Dvorak, Christopher C., Ebert, Benjamin L., Eck, Michael J., Eckstein, Olive S., Eikelboom, John W., El Jamal, Siraj M., El-Jurdi, Najla, Kim El-Mallawany, Nader, Erba, Harry P., Evans, William E., Feld, Jonathan, Feldman, Alexander, Ferrara, James L., Fischer, Martin, Forbes, Lisa R., Franco, Idalid, Fredenburgh, James C., Frey, Noelle V., Friedman, Kenneth D., Fuller, Stephen J., Gabe, Caroline, Gailani, David, Gallagher, Patrick G., Gallardo-Grajeda, Andrea, Ganz, Tomas, Gee, Adrian P., George, Gemlyn, Gerson, Stanton L., Gertz, Morie A., Ghosh, Nilanjan, Gibson, Christopher J., Ginzburg, Yelena Z., Gomez, Keith, Gotlib, Jason, Grant, Shakira J., Graubert, Timothy A., Gregg, Xylina T., Gribben, John G., Gross, Peter L., Gulati, Nitya, Gurbuxani, Sandeep, Gutierrez, Alejandro, de Haan, Gerald, Haas-Kogan, Daphne, Haddad, Montaser, Halene, Stephanie, Hamadani, Mehdi, Hammond, Rebecca M., Hari, Parameswaran N., Hayman, Suzanne R., Hayward, Catherine, Hebbel, Robert P., Heidenreich, Olaf, Henkin, Stanislav, Hensch, Lisa, Hillis, Christopher, Hillyer, Christopher D., Hoffman, Ronald, Horny, Hans-Peter, Horowitz, Mia, Hsu, Katharine, Hub, Elin, Iancu-Rubin, Camelia, Isenman, David E., Israels, Sara J., Italiano, Joseph E., Jaffe, Elaine S., Jaffer, Iqbal H., Jäger, Ulrich, Jain, Nitin, James, Paula, Jimenez, Alexandra, Jordan, Michael B., Jung, Moonjung, Kager, Leo, Kanakry, Jennifer A., Kanate, Abraham S., Kelly, Kara M., Khandoga, Alexander G., Karsan, Aly, Kaufman, Richard M., Keyzner, Alla, Khanna-Gupta, Arati, Kharchenko, Evgeniya, Klein, Harvey G., Klepin, Heidi D., Anders Kolb, E., Kollet, Orit, Konopleva, Marina, Kontoyiannis, Dimitrios P., Koreth, John, Koretzky, Gary A., Kozieł-Siołkowska, Monika, Kremyanskaya, Marina, Kucine, Nicole, Kumar, Shaji, Küppers, Ralf, Lacy, Martha Q., Ola Landgren, C., Landier, Wendy, Lane, Andrew A., Lane, William J., Langer, Arielle L., Lapidot, Tsvee, Laureano, Marissa, Leblanc, Francis R., Le, Blanc, Thomas W., La, Casce, Ann S., Lee, Daniel W., Lee, Kathleen A., Leung, Wingchi, Levi, Marcel, Lewis, Russell E., Lichtman, Eben I., Lin, Judith C., Lin, Richard J., Lip, Gregory, Poh Loh, Kah, López, José A., Zoref Lorenz, Adi, Loughran, Thomas P., Lu, Sydney X., Lukas, Rimas V., Lulla, Premal, Luscinskas, Francis W., Ma, Alice D., Maakaron, Joseph E., Machlus, Kellie R., Maciejewski, Jaroslaw P., Magenau, John, Majhail, Navneet, Malek, Ehsan, Manis, John P., Mann, Kenneth G., Manno, Catherine S., Marcellino, Bridget K., Marcogliese, Andrea N., Marincola, Francesco M., Mascarenhas, John, Massberg, Steffen, Matino, Davide, Mc, Ever, Rodger P., Mc, Grath, Emer, Mc, Guire, Hilary, S. Mc, Kinney, Matthew, Mehta, Atul, A. Menapace, Laurel, Mentzer, William C., Michel, Marc, Rita Migliaccio, Anna, Mims, Martha P., Moffat, Karen A., Morgan, Gareth J., Najfeld, Vesna, Naymagon, Leonard, Ness, Paul M., Ng, Andrea K., Ning, Shuoyan, Notarangelo, Luigi D., O'Donnell, Martin, Ollila, Thomas A., Ordonez-Moreno, Alejandra, Own, Maryam, Pai, Menaka, Pai, Sung-Yun, Paidas, Michael, Papa, Luena, Papayannopoulou, Thalia, Peng, Cynthia S., Wang Petersdorf, Effie, Pickard, Lucy, Pierce, Glenn F., Pittaluga, Stefania, Porteus, Matthew, Potpara, Tatjana S., Prchal, Josef T., Puigserver, Pere, Vincent Rajkumar, S., Rak, Janusz, Ramos, Carlos A., Rand, Jacob H., Rand, Margaret L., Rao, Dinesh S., Rappazzo, Katherine C., Rau, Rachel E., Ravandi, Farhad, Rawley, Orla, Rawlings, David J., Reddy, Pavan, Reiter, Andreas, Reville, Barbara, Rice, Lawrence, Riese, Matthew J., Rippel, Noa, Riwes, Mary, Roberts, David J., Rodrigue, Bentley B., Rojek, Alexandra E., Roman, Elizabeth, Rossmann, Marlies P., Rot, Antal, Rouce, Rayne H., Rowley, Scott D., Rustad, Even H., Sahni, Gagan, Sahoo, Daisy, Salama, Mohamed E., Samji, Nasrin, Scadden, David, Schiffman, Fred J., Schipperus, Martin R., Schrier, Stanley L., Shaz, Beth H., Shelburne, Samuel A., Sheth, Sujit, Sholevar, Roxanne, Silberstein, Lev, Silverman, Lewis B., Silverstein, Roy L., Skeith, Leslie, Sloan, Steven R., Douglas Smith, Stephen, Steensma, David P., Steinberg, Martin H., Stieglitz, Elliot, Stock, Wendy, Storry, Jill R., Stramer, Susan L., Strati, Paolo, Stroncek, David F., Flohr Svendsen, Arthur, Sweetenham, John W., Tebaldi, Toma, Teegavarapu, Sravanti P., Tewari, Alok, Lay Thein, Swee, Tillman, Benjamin F., Tomlinson, Benjamin, Tremblay, Douglas, Treon, Steven P., Tsai, Frederick D., Tsang, Mazie, Tzannou, Ifigeneia, Usmani, Saad Z., Valent, Peter, Venkataraman, Girish, Venugopal, Sangeetha, M. Vercellotti, Gregory, Viero, Gabriella, von Andrian, Ulrich H., Vose, Julie M., Wagner, Andrew J., Wang, Ena, Wang, Jia-huai, Warkentin, Theodore E., Weitz, Jeffrey I., West, Kamille A., Westhoff, Connie M., Wheeler, Allison P., Wierda, William, Wiersum-Osselton, Johanna C., Wiley, James S., Williams, David A., Wolgast, Lucia R., Yang, Daozheng, Yang, Moua, Younes, Anas, Young, Neal S., Zayac, Adam S., Zeller, Michelle P., Zieske, Arthur W., Zimran, Ari, Luigi Zinzani, Pier, C. Zubair, Abba, and Michel Zwaan, C.

Published
2023
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13. Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: A retrospective study by the I-BFM study group

Author

Noort, S., Zimmermann, M., Reinhardt, D., Cuccuini, W., Pigazzi, M., Smith, J., Ries, R. E., Alonzo, T. A., Hirsch, B., Tomizawa, D., Locatelli, Franco, Gruber, T. A., Raimondi, S., Sonneveld, E., Cheuk, D. K., Dworzak, M., Stary, J., Abrahamsson, J., Arad-Cohen, N., Czogala, M., De Moerloose, B., Hasle, H., Meshinchi, S., Van Den Heuvel-Eibrink, M., Michel Zwaan, C., Locatelli F. (ORCID:0000-0002-7976-3654), Noort, S., Zimmermann, M., Reinhardt, D., Cuccuini, W., Pigazzi, M., Smith, J., Ries, R. E., Alonzo, T. A., Hirsch, B., Tomizawa, D., Locatelli, Franco, Gruber, T. A., Raimondi, S., Sonneveld, E., Cheuk, D. K., Dworzak, M., Stary, J., Abrahamsson, J., Arad-Cohen, N., Czogala, M., De Moerloose, B., Hasle, H., Meshinchi, S., Van Den Heuvel-Eibrink, M., Michel Zwaan, C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n 5 23) had significantly lower median white blood cell count (12.5 3 109/L, P 5 .03) compared with the reference cohort. FUS-ERG rearranged AML (n 5 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P 5 .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] 5 5%), significantly lower compared with the reference cohort (51%, SE 5 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE 5 8%, P 5 .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE 5 8%) in FUS-ERG, 0% (SE 5 0%) in RUNX1-CBFA2T3, compared with 32% (SE 5 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P 5 .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.

Published
2018

14. TropicALL study: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin: a multicenter randomized controlled trial

Author

Klaassen, Irene L. M., primary, Lauw, Mandy N., additional, van de Wetering, Marianne D., additional, Biemond, Bart J., additional, Middeldorp, Saskia, additional, Abbink, Floor C. H., additional, Bierings, Marc, additional, te Loo, D. Maroeska M. W., additional, Pieters, Rob, additional, van der Sluis, Inge M., additional, Tissing, Wim J. E., additional, Michel Zwaan, C., additional, and Heleen van Ommen, C., additional

Published
2017
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15. Bone marrow immunophenotyping by flow cytometry in refractory cytopenia of childhood

Author

Aalbers, A. M., Van Den Heuvel-Eibrink, M. M., Baumann, I., Dworzak, M., Hasle, H., Locatelli, Franco, De Moerloose, B., Schmugge, M., Mejstrikova, E., Novakova, M., Zecca, M., Michel Zwaan, C., Te Marvelde, J. G., Langerak, A. W., Van Dongen, J. J., Pieters, R., Niemeyer, C. M., Van Der Velden, V. H., Locatelli F. (ORCID:0000-0002-7976-3654), Aalbers, A. M., Van Den Heuvel-Eibrink, M. M., Baumann, I., Dworzak, M., Hasle, H., Locatelli, Franco, De Moerloose, B., Schmugge, M., Mejstrikova, E., Novakova, M., Zecca, M., Michel Zwaan, C., Te Marvelde, J. G., Langerak, A. W., Van Dongen, J. J., Pieters, R., Niemeyer, C. M., Van Der Velden, V. H., and Locatelli F. (ORCID:0000-0002-7976-3654)

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 and00662090, respectively).

Published
2015

16. miR-139-5p controls translation in myeloid leukemia through EIF4G2

Author

Emmrich, S, primary, Engeland, F, additional, El-Khatib, M, additional, Henke, K, additional, Obulkasim, A, additional, Schöning, J, additional, Katsman-Kuipers, J E, additional, Michel Zwaan, C, additional, Pich, A, additional, Stary, J, additional, Baruchel, A, additional, de Haas, V, additional, Reinhardt, D, additional, Fornerod, M, additional, van den Heuvel-Eibrink, M M, additional, and Klusmann, J H, additional

Published
2015
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17. CBLmutations do not frequently occur in paediatric acute myeloid leukaemia

Author

Coenen, Eva A., primary, Driessen, Emma M. C., additional, Michel Zwaan, C., additional, Stary, Jan, additional, Baruchel, Andre, additional, de Haas, Valerie, additional, de Bont, Eveline S. J. M., additional, Reinhardt, Dirk, additional, Kaspers, Gertjan J. L., additional, Arentsen-Peters, Susan T. C. J. M., additional, Meyer, Claus, additional, Marschalek, Rolf, additional, Pieters, Rob, additional, Stam, Ronald W., additional, and van den Heuvel-Eibrink, Marry M., additional

Published
2012
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18. Analysis of NUP98/NSD1 translocations in adult AML and MDS patients

Author

Thol, F, primary, Kölking, B, additional, Hollink, I H I, additional, Damm, F, additional, van den Heuvel-Eibrink, M M, additional, Michel Zwaan, C, additional, Bug, G, additional, Ottmann, O, additional, Wagner, K, additional, Morgan, M, additional, Hofmann, W K, additional, Göhring, G, additional, Schlegelberger, B, additional, Krauter, J, additional, Ganser, A, additional, and Heuser, M, additional

Published
2012
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19. Differentially expressed miRNAs in cytogenetic and molecular subtypes of pediatric acute myeloid leukemia

Author

Danen-van Oorschot, Astrid A., primary, Kuipers, Jenny E., additional, Arentsen-Peters, Susan, additional, Schotte, Diana, additional, de Haas, Valerie, additional, Trka, Jan, additional, Baruchel, André, additional, Reinhardt, Dirk, additional, Pieters, Rob, additional, Michel Zwaan, C., additional, and van den Heuvel-Eibrink, Marry M., additional

Published
2011
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21. Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Münster AML-study group.

Author

Coenen, Eva A., Michel Zwaan, C., Reinhardt, Dirk, Harrison, Christine J., Haas, Oskar A., de Haas, Valerie, Mihál, Vladimir, De Moerloose, Barbara, Jeison, Marta, Rubnitz, Jeffrey E., Tomizawa, Daisuke, Johnston, Donna, Alonzo, Todd A., Hasle, Henrik, Auvrignon, Anne, Dworzak, Michael, Pession, Andrea, van der Velden, Vincent H. J., Swansbury, John, and Kit-fai Wong

Subjects
*ACUTE myeloid leukemia in children, *DISSEMINATED intravascular coagulation, *GENE expression, *ACUTE myeloid leukemia treatment, *GENE expression profiling, *PROGNOSIS
Abstract

In pediatric acute myeloid leukemia (AML), cytogenetic abnormalities are strong indicators of prognosis. Some recurrent cytogenetic abnormalities, such as t(8;16)(p11;p13), are so rare that collaborative studies are required to define their prognostic impact. We collected the clinical characteristics, morphology, and immunophenotypes of 62 pediatric AML patients with t(8;16)(p11;p13) from 18 countries participating in the International Berlin-Frankfurt-Münster (I-BFM) AML study group. We used the AML-BFM cohort diagnosed from 1995-2005 (n = 543) as a reference cohort. Median age of the pediatric t(8;16)(p11;p13) AML patients was significantly lower (1.2 years). The majority (97%) had M4-M5 French-American-British type, significantly different from the reference cohort. Erythrophagocytosis (70%), leukemia cutis (58%), and disseminated intravascular coagulation (39%) occurred frequently. Strikingly, spontaneous remissions occurred in 7 neonates with t(8;16)(p11;p13), of whom 3 remain in continuous remission. The 5-year overall survival of patients diagnosed after 1993 was 59%, similar to the reference cohort (P = .14). Gene expression profiles of t(8;16)(p11;p13) pediatric AML cases clustered close to, but distinct from, MLL-rearranged AML. Highly expressed genes included HOXA11, HOXA10, RET, PERP, and GGA2. In conclusion, pediatric t(8;16)(p11;p13) AML is a rare entity defined by a unique gene expression signature and distinct clinical features in whom spontaneous remissions occur in a subset of neonatal cases. [ABSTRACT FROM AUTHOR]

Published
2013
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23. Pharmacokinetics of nilotinib in pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia or acute lymphoblastic leukemia

Author

Xianbin Tian, Aby Buchbinder, Helene Santanastasio, Maria Caterina Putti, Karen Sinclair, Floor Abbink, John Moppett, Carmelo Rizzari, Pamela Kearns, Judith Landman-Parker, Nobuko Hijiya, Brigitte Nelken, Donna Lancaster, C. Michel Zwaan, Robin Foà, Frédéric Millot, Pediatric surgery, CCA - Cancer Treatment and quality of life, Hijiya, N, Michel Zwaan, C, Rizzari, C, Foà, R, Abbink, F, Lancaster, D, Landman-Parker, J, Millot, F, Moppett, J, Nelken, B, Putti, M, Xianbin, T, Sinclair, K, Santanastasio, H, Buchbinder, A, Kearns, P, and Pediatrics

Subjects
0301 basic medicine, Male, Cancer Research, medicine.medical_specialty, Adolescent, Fusion Proteins, bcr-abl, Protein Kinase Inhibitor, Gastroenterology, Drug Administration Schedule, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, Humans, Tissue Distribution, Adverse effect, Child, Protein Kinase Inhibitors, business.industry, Myeloid leukemia, Imatinib, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Rash, Dasatinib, Leukemia, 030104 developmental biology, Pyrimidines, Oncology, Nilotinib, Pyrimidine, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Child, Preschool, Female, medicine.symptom, business, medicine.drug, Human
Abstract

Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Patients and Methods: Fifteen patients (aged 1– Results: The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph+ ALL achieved complete remission. Conclusions: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.

Published
2020

24. Classification of pediatric acute myeloid leukemia based on miRNA expression profiles.

Author

Obulkasim A, Katsman-Kuipers JE, Verboon L, Sanders M, Touw I, Jongen-Lavrencic M, Pieters R, Klusmann JH, Michel Zwaan C, van den Heuvel-Eibrink MM, and Fornerod M

Subjects
CCAAT-Enhancer-Binding Proteins genetics, Child, Chromosome Inversion, Female, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myeloid, Acute genetics, Male, Mutation, Nuclear Proteins genetics, Nucleophosmin, Translocation, Genetic, Gene Expression Profiling methods, Gene Regulatory Networks, Leukemia, Myeloid, Acute classification, MicroRNAs genetics
Abstract

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with respect to biology as well as outcome. In this study, we investigated whether known biological subgroups of pediatric AML are reflected by a common microRNA (miRNA) expression pattern. We assayed 665 miRNAs on 165 pediatric AML samples. First, unsupervised clustering was performed to identify patient clusters with common miRNA expression profiles. Our analysis unraveled 14 clusters, seven of which had a known (cyto-)genetic denominator. Finally, a robust classifier was constructed to discriminate six molecular aberration groups: 11q23-rearrangements, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17) (q21;q22), NPM1 and CEBPA mutations. The classifier achieved accuracies of 89%, 95%, 95%, 98%, 91% and 96%, respectively. Although lower sensitivities were obtained for the NPM1 and CEBPA (32% and 66%), relatively high sensitivities (84%-94%) were attained for the rest. Specificity was high in all groups (87%-100%). Due to a robust double-loop cross validation procedure employed, the classifier only employed 47 miRNAs to achieve the aforementioned accuracies. To validate the 47 miRNA signatures, we applied them to a publicly available adult AML dataset. Albeit partial overlap of the array platforms and molecular differences between pediatric and adult AML, the signatures performed reasonably well. This corroborates our claim that the identified miRNA signatures are not dominated by sample size bias in the pediatric AML dataset. In conclusion, cytogenetic subtypes of pediatric AML have distinct miRNA expression patterns. Reproducibility of the miRNA signatures in adult dataset suggests that the respective aberrations have a similar biology both in pediatric and adult AML.

Published
2017
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