Group leader: Prof.dr. Michel Zwaan, pediatric oncologist
and decrease toxicity" Prof. dr. Michel Zwaan - Group leader
As a pediatric oncologist, I am mainly concerned with the treatment of children with acute myeloid leukemia (AML) and related pre-clinical and clinical research, and with leukemia in children with Down syndrome.
In addition, I head the Trial and Data Center of the Princess Máxima Center, together with Dr. Harm van Tinteren, where I provide the medical expertise. I am general chair of the medical ethics review committee (METC) NedMec and of the NVMETC. I also chair the hematological malignancies committee of ITCC (phase 1-2 pediatric oncology network in Europe), for which the Maxima implements many studies.
Pre-clinical research
The research program on myeloid leukemias is done in close collaboration with group leaders in the Princess Máxima Center, including the Stam group, the Van Boxtel group and the Heidenreich group. The program focuses on identifying determinants of clinical outcome to improve risk-group stratification, and to identify novel options for targeted treatment. Down ALL projects are performed in close collaboration with the Den Boer group.
Close collaboration exists with Dr. Soheil Meshinchi from the Children’s Oncology Group (Seattle, USA), and Prof. Dirk Reinhardt from the AML-BFM Group (Essen, Germany), as well as with the International-BFM Study Group AML committee.
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Clinical Research
The early clinical trial program includes clinical studies of promising novel agents for children with cancer, and in addition focuses on therapeutic drug monitoring, bioequivalence studies of pediatric-friendly formulations, and age-dependent pharmacokinetics/dynamics.
This includes looking at new drugs developed under a Pediatric Investigational Plan of the EMA or under a commitment to the FDA. The following studies, involving Prof. Dr. Michel Zwaan as principal investigator, are currently ongoing in this context:
- Inotuzumab ozogamicin (phase 1 and 2 studies in children with ALL)
- Bosutinib (phase 1 and 2 studies in children with CML)
- Crizotinib (a phase 4 study of dosing and toxicity of this drug as part of a registration requirement)
- Brigatinib (a phase 1/2 study in children with solid tumors and large cell anaplastic lymphoma)
- Venetoclax (a phase 3 study in children with relapsed AML)
- Ziftomenib (a phase 1 study in children with relapsed AML)
Based on the first two studies, the FDA recently approved bosutinib for the treatment of newly diagnosed and resistant/intolerant children over 1 year of age with CML (September 2023), and inotuzumab ozogamicin for the treatment of children over one year of age with relapsed/refractory CD22-positive ALL (March 2024). These approvals were obtained after transfer of the data obtained in these intent-to-file academic studies to the pharma company, who submitted the dossier to the regulatory authorities for assessment. Approval for inotuzumab ozogamicin was also obtained from the Japanese health authorities (March 2024). The opinion of the European health authorities is awaited.
In addition, the Trial and Data Center is closely involved in two new leukemia studies initiated from the Máxima:
- The CHIP-AML study for newly diagnosed children with AML. As a subtrial, this involves studying quizartinib in FLT3 mutated patients as part of a pediatric investigational plan (principal investigator Prof. Dr. Gertjan Kaspers).
- The Interfant-21 study, studying blinatumomab (principal investigators Dr. Janine Stutterheim and Prof. Dr. Rob Pieters).
Research (clinical scientists) into pediatric drug development
- Erica Brivio
- Sae Ishimaru
- Paco Bautista
Hematological malignancies Unit
- Inge van der Sluis
- Britta Vormoor
- Auke Beishuizen (lymphoma)
- Caroline Lindemans (SCT)
- Maaike Luesink
Solid tumor Unit
- Natasha van Eijkelenburg
- Miranda Dierselhuis (fellow pediatric oncology)
Brain tumor Unit - Jasper van der Lugt
- Eveline de Vos
PhD students
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Brivio E, Pennesi E, Willemse ME, Huitema ADR, Jiang Y, van Tinteren HDR, van der Velden VHJ, Beverloo BH, den Boer ML, Rammeloo LAJ, Hudson C, Heerema N, Kowalski K, Zhao H, Kuttschreuter L, Bautista Sirvent FJ, Bukowinski A, Rizzari C, Pollard J, Murillo-Sanjuán L, Kutny M, Zarnegar-Lumley S, Redell M, Cooper S, Bertrand Y, Petit A, Krystal J, Metzler M, Lancaster D, Bourquin JP, Motwani J, van der Sluis IM, Locatelli F, Roth ME, Hijiya N, Zwaan CM. Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921. J Clin Oncol. 2024 Mar 1;42(7):821-831. PubMed PMID: 38033284
Van Weelderen RE, Klein K, Harrison CJ, Jiang Y, Abrahamsson J, Arad-Cohen N, Bart-Delabesse E, Buldini B, De Moerloose B, Dworzak MN, Elitzur S, Fernández Navarro JM, Gerbing RB, Goemans BF, de Groot-Kruseman HA, Guest E, Ha SY, Hasle H, Kelaidi C, Lapillonne H, Leverger G, Locatelli F, Masetti R, Miyamura T, Norén-Nyström U, Polychronopoulou S, Rasche M, Rubnitz JE, Stary J, Tierens A, Tomizawa D, Zwaan CM, Kaspers GJL. Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group. J Clin Oncol. 2023 Jun 1;41(16):2963-2974. PubMed PMID: 36996387
Langenberg KPS, Meister MT, Bakhuizen JJ, Boer JM, van Eijkelenburg NKA, Hulleman E, Ilan U, Looze EJ, Dierselhuis MP, van der Lugt J, Breunis W, Schild LG, Ober K, van Hooff SR, Scheijde-Vermeulen MA, Hiemcke-Jiwa LS, Flucke UE, Kranendonk MEG, Wesseling P, Sonneveld E, Punt S, Boltjes A, van Dijk F, Verwiel ETP, Volckmann R, Hehir-Kwa JY, Kester LA, Koudijs MMJ, Waanders E, Holstege FCP, Vormoor HJ, Hoving EW, van Noesel MM, Pieters R, Kool M, Stumpf M, Blattner-Johnson M, Balasubramanian GP, Van Tilburg CM, Jones BC, Jones DTW, Witt O, Pfister SM, Jongmans MCJ, Kuiper RP, de Krijger RR, Wijnen MHW, den Boer ML, Zwaan CM, Kemmeren P, Koster J, Tops BBJ, Goemans BF, Molenaar JJ. Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program 'iTHER'. Eur J Cancer. 2022 Sep 28;175:311-325. PubMed PMID: 36182817
Bertrums EJM, Rosendahl Huber AKM, de Kanter JK, Brandsma AM, van Leeuwen AJCN, Verheul M, van den Heuvel-Eibrink MM, Oka R, van Roosmalen MJ, de Groot-Kruseman HA, Zwaan CM, Goemans BF, van Boxtel R. Elevated mutational age in blood of children treated for cancer contributes to therapy-related myeloid neoplasms. Cancer Discov. 2022 Aug 5;12(8):1860-1872. PubMed PMID: 35678530
Pennesi E, Michels N, Brivio E, van der Velden VHJ, Jiang Y, Thano A, Ammerlaan AJC, Boer JM, Beverloo HB, Sleight B, Chen Y, Vormoor-Bürger B, Rives S, Bielorai B, Rössig C, Petit A, Rizzari C, Engstler G, Starý J, Bautista Sirvent FJ, Chen-Santel C, Bruno B, Bertrand Y, Rialland F, Plat G, Reinhardt D, Vinti L, Von Stackelberg A, Locatelli F, Zwaan CM. Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial. Leukemia. 2022 Jun;36(6):1516-1524. PubMed PMID: 35468945
Admiraal R, Nierkens S, Bierings MB, Bredius RGM, van Vliet I, Jiang Y, Lopez-Yurda M, Versluijs AB, Zwaan CM, Lindemans CA, Boelens JJ. Individualised dosing of anti-thymocyte globulin in paediatric unrelated allogeneic haematopoietic stem-cell transplantation (PARACHUTE): a single-arm, phase 2 clinical trial. Lancet Haematol. 2022 Feb;9(2):e111-e120. PubMed PMID: 35114150
Pearson AD, Rossig C, Mackall C, Shah NN, Baruchel A, Reaman G, Ricafort R, Heenen D, Bassan A, Berntgen M, Bird N, Bleickardt E, Bouchkouj N, Bross P, Brownstein C, Cohen SB, de Rojas T, Ehrlich L, Fox E, Gottschalk S, Hanssens L, Hawkins DS, Horak ID, Taylor DH, Johnson C, Karres D, Ligas F, Ludwinski D, Mamonkin M, Marshall L, Masouleh BK, Matloub Y, Maude S, McDonough J, Minard-Colin V, Norga K, Nysom K, Pappo A, Pearce L, Pieters R, Pule M, Quintás-Cardama A, Richardson N, Schüßler-Lenz M, Scobie N, Sersch MA, Smith MA, Sterba J, Tasian SK, Weigel B, Weiner SL, Zwaan CM, Lesa G, Vassal G.Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration. Eur J Cancer. 2022 Jan;160:112-133. PubMed PMID: 34840026
Michels N, Boer JM, Enshaei A, Sutton R, Heyman M, Ebert S, Fiocco M, de Groot-Kruseman HA, van der Velden VHJ, Barbany G, Escherich G, Vora A, Trahair T, Dalla-Pozza L, Pieters R, Zur Stadt U, Schmiegelow K, Moorman AV, Zwaan CM, den Boer ML. Minimal residual disease, long-term outcome, and IKZF1 deletions in children and adolescents with Down syndrome and acute lymphocytic leukaemia: a matched cohort study. Lancet Haematol. 2021 Oct;8(10):e700-e710. PubMed PMID: 34560013
Goemans BF, Noort S, Blink M, Wang YD, Peters STCJ, van Wouwe JP, Kaspers G, de Haas V, Kollen WJ, van der Velden VHJ, Gruber TA, Zwaan CM. Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia. Leukemia. 2021 Aug;35(8):2403-2406. PubMed PMID: 33483616
Brivio E, Locatelli F, Lopez-Yurda M, Malone A, Diaz de Heredia C, Bielorai B, Rossig C, van der Velden VHJ, Ammerlaan AC, Thano A, van der Sluis IM, Den Boer ML, Chen Y, Sleight B, Brethon B, Nysom K, Sramkova L, Øra I, Vinti L, Chen-Santel C, Zwaan CM. A Phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood. 2021 Mar 25;137(12):1582-1590. PubMed PMID: 33067614
Pearson ADJ, Zwaan CM, Kolb EA, Karres D, Guillot J, Kim SY, Marshall L, Tasian SK, Smith M, Cooper T, Adamson PC, Barry E, Benettaib B, Binlich F, Borgman A, Brivio E, Capdeville R, Delgado D, Faller DV, Fogelstrand L, Fraenkel PG, Hasle H, Heenen D, Kaspers G, Kieran M, Klusmann JH, Lesa G, Ligas F, Mappa S, Mohamed H, Moore A, Morris J, Nottage K, Reinhardt D, Scobie N, Simko S, Winkler T, Norga K, Reaman G, Vassal G. Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration. Eur J Cancer. 2020 Jul 17;136:116-129. PubMed PMID: 32688206
Hijiya N, Maschan A, Rizzari C, Shimada H, Dufour C, Goto H, Kang HJ, Guinipero T, Karakas Z, Bautista F, Ducassou S, Yoo KH, Zwaan CM, Millot F, Aimone P, Allepuz A, Quenet S, Hourcade-Potelleret F, Hertle S, Sosothikul D. Phase 2 Study of Nilotinib in Pediatric Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia. Blood. 2019 Dec 5;134(23):2036-2045. PubMed PMID: 31511239
Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, O'Brien MM, McNeer JL, Quereshi A, Cabannes A, Schlegel P, Rossig C, Dalla-Pozza L, August K, Alexander S, Bourquin JP, Zwaan M, Raetz EA, Loh ML, Rheingold SR. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019 Apr;33(4):1061-1062. Pub Med PMID: 30842605
Noort S, Zimmermann M, Reinhardt D, Cuccuini W, Pigazzi M, Smith J, Ries RE, Alonzo TA, Hirsch B, Tomizawa D, Locatelli F, Gruber TA, Raimondi S, Sonneveld E, Cheuk DK, Dworzak M, Stary J, Abrahamsson J, Arad-Cohen N, Czogala M, De Moerloose B, Hasle H, Meshinchi S, van den Heuvel-Eibrink M, Zwaan CM. 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. Blood. 2018 Oct 11;132(15):1584-1592. Pub Med PMID: 30150206
Gore L, Kearns PR, de Martino Lee ML, De Souza CA, Bertrand Y, Hijiya N, Stork LC, Chung NG, Cardos RC, Saikia T, Fagioli F, Seo JJ, Landman-Parker J, Lancaster D, Place AE, Rabin KR, Sacchi M, Swanink R, Zwaan CM. Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial. J Clin Oncol. 2018 May 1;36(13):1330-1338PubMed PMID: 29498925
Van Eijkelenburg NKA, Rasche M, Ghazaly E, Dworzak MN, Klingebiel T, Rossig C, Leverger G, Stary J, de Bont ESJM, Chitu DA, Bertrand Y, Brethon B, Strahm B, van der Sluis IM, Kaspers GJL, Reinhardt D, Zwaan CM. Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study. Haematologica. 2018 Sep;103(9):1484-1492 PubMed PMID: 29773602
Bolouri H, Farrar JE, Triche T Jr, Ries RE, Lim EL, Alonzo TA, Ma Y, Moore R, Mungall AJ, Marra MA, Zhang J, Ma X, Liu Y, Liu Y, Auvil JMG, Davidsen TM, Gesuwan P, Hermida LC, Salhia B, Capone S, Ramsingh G, Zwaan CM, Noort S, Piccolo SR, Kolb EA, Gamis AS, Smith MA, Gerhard DS, Meshinchi S. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018:Jan 24(1):103-112 PubMed PMID: 29227476
Moreno L, Pearson ADJ, Paoletti X, Jimenez I, Geoerger B, Kearns PR, Zwaan CM, Doz F, Baruchel A, Vormoor J, Casanova M, Pfister SM, Morland B, Vassal G; Innovative Therapies for Children with Cancer (ITCC) Consortium. Early phase clinical trials of anticancer agents in children and adolescents - an ITCC perspective. Nat Rev Clin Oncol. 2017 Aug;14(8):497-507 PubMed PMID: 28508875
Pearson ADJ, Pfister SM, Baruchel A, Bourquin JP, Casanova M, Chesler L, Doz F, Eggert A, Geoerger B, Jones DTW, Kearns PR, Molenaar JJ, Morland B, Schleiermacher G, Schulte JH, Vormoor J, Marshall LV, Zwaan CM, Vassal G; Executive and Biology Committees of the Innovative Therapies for Children with Cancer European Consortium. From class waivers to precision medicine in paediatric oncology. Lancet Oncol. 2017 Jul;18(7):e394-e404 PubMed PMID: 28677575
Madita Uffmann, Mareike Rasche, Martin Zimmermann, Christine von Neuhoff, Ursula Creutzig, Michael Dworzak, Lenie Scheffers, Henrik Hasle, C. Michel Zwaan, Dirk Reinhardt, and Jan-Henning Klusmann. Therapy reduction in patients with Down Syndrome Myeloid Leukemia: The international ML-DS 2006 trial. Blood 2017 Jun 22;129(25):3314-3321 PubMed PMID: 28400376
De Rooij JD, Branstetter C, Ma J, Li Y, Walsh MP, Cheng J, Obulkasim A, Dang J, Easton J, Verboon LJ, Mulder HL, Zimmermann M, Koss C, Gupta P, Edmonson M, Rusch M, Lim JY, Reinhardt K, Pigazzi M, Song G, Yeoh AE, Shih LY, Liang DC, Halene S, Krause DS, Zhang J, Downing JR, Locatelli F, Reinhardt D, van den Heuvel-Eibrink MM, Zwaan CM, Fornerod M, Gruber TA. Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet. 2017 Mar;49(3):451-456 PubMed PMID: 28112737
Arend von Stackelberg, Franco Locatelli, Gerhard Zugmaier, Rupert Handgretinger, Tanya M. Trippett, Carmelo Rizzari, Peter Bader, Maureen M. O’Brien, Benoˆıt Brethon, Deepa Bhojwani, Paul Gerhardt Schlegel, Arndt Borkhardt, Susan R. Rheingold, Todd Michael Cooper, Christian M. Zwaan, Phillip Barnette, Chiara Messina, Gerard Michel, Steven G. DuBois, Kuolung Hu, Min Zhu, James A. Whitlock, and Lia Gore. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389 PubMed PMID: 27998223
Zwaan CM, Kolb EA, Reinhardt D, Abrahamsson J, Adachi S, Aplenc R, De Bont ES, De Moerloose B, Dworzak M, Gibson BE, Hasle H, Leverger G, Locatelli F, Ragu C, Ribeiro RC, Rizzari C, Rubnitz JE, Smith OP, Sung L, Tomizawa D, van den Heuvel-Eibrink MM, Creutzig U, Kaspers GJ. Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia. J Clin Oncol. 2015 Sep 20;33(27):2949-62 PubMed PMID: 26304895
Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):385-94 PubMed PMID: 25770814
Buitenkamp TD, Izraeli S, Zimmermann M, Forestier E, Heerema NA, van den Heuvel-Eibrink MM, Pieters R, Korbijn CM, Silverman LB, Schmiegelow K, Liang DC, Horibe K, Arico M, Biondi A, Basso G, Rabin KR, Schrappe M, Cario G, Mann G, Morak M, Panzer-Grümayer R, Mondelaers V, Lammens T, Cavé H, Stark B, Ganmore I, Moorman AV, Vora A, Hunger SP, Pui CH, Mullighan CG, Manabe A, Escherich G, Kowalczyk JR, Whitlock JA, Zwaan CM. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. 2014 Jan 2;123(1):70-7 PubMed PMID: 24222333
Prof. Dr. Michel Zwaan's publications can be found on PubMed.
