Download PDF
Klin Padiatr 2021; 233(06): 267-277
DOI: 10.1055/a-1532-2016
Diagnostic and Treatment Recommendation

Recommendations for Diagnosis and Treatment of Children with Transient Abnormal Myelopoiesis (TAM) and Myeloid Leukemia in Down Syndrome (ML-DS)

Empfehlungen für die Diagnose und Behandlung von Kindern mit transienter abnormer Myelopoese (TAM) und myeloischer Leukämie bei Down Syndrom (ML-DS)
Sina Al-Kershi
1   Clinic for Pediatrics, University Hospital Frankfurt, Frankfurt, Germany
2   Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Richard Golnik 
1   Clinic for Pediatrics, University Hospital Frankfurt, Frankfurt, Germany
,
Marius Flasinski
3   Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Hospital Tauberbischofsheim, Tauberbischofsheim, Germany
,
Katharina Waack
4   Pediatrics III, Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
,
Mareike Rasche
4   Pediatrics III, Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
,
Ursula Creutzig
5   Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
,
Michael Dworzak
6   Department of Pediatrics, St. Anna Children’s Hospital and Children’s Cancer Research Institute, Wien, Austria
,
Dirk Reinhardt
4   Pediatrics III, Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
,
Jan-Henning Klusmann 
1   Clinic for Pediatrics, University Hospital Frankfurt, Frankfurt, Germany
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Children with Down syndrome are at a high risk of developing transient abnormal myelopoiesis (TAM; synonym: TMD) or myeloid leukemia (ML-DS). While most patients with TAM are asymptomatic and go into spontaneous remission without a need for therapy, around 20% of patients die within the first six months due to TAM-related complications. Another 20–30% of patients progress from TAM to ML-DS. ML-DS patients are particularly vulnerable to therapy-associated toxicity, but the prognosis of relapsed ML-DS is extremely poor – thus, ML-DS therapy schemata must strive for a balance between appropriate efficacy (to avoid relapses) and treatment-related toxicity. This guideline presents diagnostic and therapeutic strategies for TAM and ML-DS based on the experience and results of previous clinical studies from the BFM working group, which have helped reduce the risk of early death in symptomatic TAM patients using low-dose cytarabine, and which have achieved excellent cure rates for ML-DS using intensity-reduced treatment protocols.

Zusammenfassung

Kinder mit Down-Syndrom haben ein hohes Risiko, eine transiente abnorme Myelopoese (TAM; Synonym: TMD) oder myeloische Leukämie (ML-DS) zu entwickeln. Während die meisten Patienten mit TAM asymptomatisch bleiben und ohne Therapie eine Spontanremission erreichen, sterben ca. 20% der Patienten innerhalb der ersten sechs Monate an TAM-bedingten Komplikationen. Weitere 20–30% der Patienten zeigen einen Progress von TAM zu ML-DS. Patienten mit ML-DS sind besonders durch therapieassoziierte Toxizität gefährdet. Gleichzeitig ist die Prognose nach einem Rückfall sehr schlecht. Daher muss die Therapieintensität so gewählt werden, dass einerseits Rückfälle verhindert und andererseits therapiebedingte Komplikationen minimiert werden. Diese Richtlinie präsentiert diagnostische und therapeutische Maßnahmen für Patienten mit TAM und ML-DS, die auf den Erfahrungen und Ergebnissen früherer klinischer Studien der BFM-Arbeitsgruppe basieren, welche dazu beigetragen haben, das frühe Mortalitätsrisiko von symptomatischen TAM Patienten unter Einsatz von niedrig dosiertem Cytarabin zu reduzieren und mit intensitätsreduzierten Chemotherapieprotokollen hervorragende Heilungsraten für ML-DS Patienten zu erzielen.

Key words

down syndrome - trisomy 21 - leukemia - transient abnormal myelopoiesis - treatment recommendation - guideline

Schlüsselwörter

Down Syndrom - Trisomie 21 - Leukämie - transiente abnorme Myelopoese - Therapieempfehlung - Richtlinie

Supplementary Material



Publication History

Article published online:
18 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Abildgaard L, Ellebaek E, Gustafsson G. et al Optimal treatment intensity in children with Down syndrome and myeloid leukaemia: data from 56 children treated on NOPHO-AML protocols and a review of the literature. Ann Hematol 2006; 85: 275-280
    CrossrefPubMedSearch in Google Scholar
  • 2 Ahmed M, Sternberg A, Hall G. et al Natural history of GATA1 mutations in Down syndrome. Blood 2004; 103: 2480-2489
    CrossrefPubMedSearch in Google Scholar
  • 3 Al-Ahmari A, Shah N, Sung L. et al Long-term results of an ultra low-dose cytarabine-based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome. Br J Haematol 2006; 133: 646-648
    CrossrefPubMedSearch in Google Scholar
  • 4 Alford KA, Reinhardt K, Garnett C. et al Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood 2011; 118: 2222-2238
    CrossrefPubMedSearch in Google Scholar
  • 5 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften. S2k-Leitlinie: Down-Syndrom im Kindes- und Jugendalter. 07/2016; Available at https://www.awmf.org/uploads/tx_szleitlinien/027-051l_S2k_Down-Syndrom-Kinder-Jugendliche_2016-09.pdf
  • 6 Arber DA, Orazi A, Hasserjian R. et al The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391-2405
    CrossrefPubMedSearch in Google Scholar
  • 7 Bhatnagar N, Nizery L, Tunstall O. et al Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update. Curr Hematol Malig Rep 2016; 11: 333-341
    CrossrefPubMedSearch in Google Scholar
  • 8 Boztug H, Schumich A, Pötschger U. et al Blast cell deficiency of CD11a as a marker of acute megakaryoblastic leukemia and transient myeloproliferative disease in children with and without Down syndrome. Cytometry B Clin Cytom 2013; 84: 370-378
    CrossrefPubMedSearch in Google Scholar
  • 9 Caldwell JT, Edwards H, Buck SA. et al Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia. Pediatr Blood Cancer 2014; 61: 1767-1773
    CrossrefPubMedSearch in Google Scholar
  • 10 Cooper TM, Absalon MJ, Alonzo TA. et al Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children’s Oncology Group. J Clin Oncol 2020; 38: 2170-2177
    CrossrefPubMedSearch in Google Scholar
  • 11 Craze JL, Harrison G, Wheatley K. et al Improved outcome of acute myeloid leukaemia in Down’s syndrome. Arch Dis Child 1014; 81: 32-37
    CrossrefPubMedSearch in Google Scholar
  • 12 Creutzig U, Dworzak M, Reinhardt D. Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie - Akute myeloische Leukämie - AML - im Kindesalter. AWMF online. 2013
    Search in Google Scholar
  • 13 Creutzig U, Reinhardt D, Diekamp S. et al AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 2005; 19: 1355-1360
    CrossrefPubMedSearch in Google Scholar
  • 14 Creutzig U, Reinhardt D, Diekamp S. et al AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 2005; 19: 1355-1360
    CrossrefPubMedSearch in Google Scholar
  • 15 Creutzig U, Zimmermann M, Ritter J. et al Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials. Leukemia 2005; 19: 2030-2042
    CrossrefPubMedSearch in Google Scholar
  • 16 Cruz Hernandez D, Metzner M, de Groot A. et al Sensitive, rapid diagnostic test for transient abnormal myelopoiesis and myeloid leukemia of Down syndrome. Blood 2020; 136: 1460-1465
    CrossrefPubMedSearch in Google Scholar
  • 17 Flasinski M, Scheibke K, Zimmermann M. et al Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study. Blood Adv 2018; 2: 1532-1540
    CrossrefPubMedSearch in Google Scholar
  • 18 Forestier E, Izraeli S, Beverloo B. et al Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. Blood 2008; 111: 1575-1583
    CrossrefPubMedSearch in Google Scholar
  • 19 Gamis AS, Alonzo TA, Gerbing RB. et al Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children’s Oncology Group Study A2971. Blood 2011; 118: 6752-6759
    CrossrefPubMedSearch in Google Scholar
  • 20 Gamis AS, Woods WG, Alonzo TA. et al Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children’s Cancer Group Study 2891. J Clin Oncol 2003; 21: 3415-3422
    CrossrefPubMedSearch in Google Scholar
  • 21 Girodon F, Favre B, Couillaud G. et al Immunophenotype of a transient myeloproliferative disorder in a newborn with trisomy 21. Cytometry 2000; 42: 118-122
    CrossrefPubMedSearch in Google Scholar
  • 22 Goemans BF, Noort S, Blink M. et al Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia. Leukemia. 2021
    Search in Google Scholar
  • 23 Hasle H, Abrahamsson J, Arola M. et al Myeloid leukemia in children 4 years or older with Down syndrome often lacks GATA1 mutation and cytogenetics and risk of relapse are more akin to sporadic AML. Leukemia 2008; 22: 1428-1430
    CrossrefPubMedSearch in Google Scholar
  • 24 Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet 2000; 355: 165-169
    CrossrefPubMedSearch in Google Scholar
  • 25 Hitzler JK, He W, Doyle J. et al Outcome of transplantation for acute myelogenous leukemia in children with Down syndrome. Biol Blood Marrow Transplant 2013; 19: 893-897
    CrossrefPubMedSearch in Google Scholar
  • 26 Karandikar NJ, Aquino DB, McKenna RW. et al Transient myeloproliferative disorder and acute myeloid leukemia in Down syndrome. An immunophenotypic analysis. Am J Clin Pathol 2001; 116: 204-210
    CrossrefPubMedSearch in Google Scholar
  • 27 Klusmann JH, Creutzig U, Zimmermann M. et al Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008; 111: 2991-2998
    CrossrefPubMedSearch in Google Scholar
  • 28 Kudo K, Kojima S, Tabuchi K. et al Prospective study of a pirarubicin, intermediate-dose cytarabine, and etoposide regimen in children with Down syndrome and acute myeloid leukemia: the Japanese Childhood AML Cooperative Study Group. J Clin Oncol 2007; 25: 5442-5447
    CrossrefPubMedSearch in Google Scholar
  • 29 Labuhn M, Perkins K, Matzk S. et al Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome. Cancer Cell 2019; 36: 123-138.e10
    CrossrefPubMedSearch in Google Scholar
  • 30 Lange BJ, Kobrinsky N, Barnard DR. et al Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group Studies 2861 and 2891. Blood 1998; 91: 608-615
    PubMedSearch in Google Scholar
  • 31 Langebrake C, Creutzig U, Reinhardt D. Immunophenotype of down syndrome acute myeloid leukemia and transient myeloproliferative disease differs significantly from other diseases with morphologically identical or similar blasts. Klin Padiatr 2005; 217: 126-134
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Massey GV, Zipursky A, Chang MN. et al A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children’s Oncology Group (COG) study POG-9481. Blood 2006; 107: 4606-4613
    CrossrefPubMedSearch in Google Scholar
  • 33 Muntean AG, Ge Y, Taub JW. et al Transcription factor GATA-1 and Down syndrome leukemogenesis. Leuk Lymphoma 2006; 47: 986-997
    CrossrefPubMedSearch in Google Scholar
  • 34 Muramatsu H, Kato K, Watanabe N. et al Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 2008; 142: 610-615
    CrossrefPubMedSearch in Google Scholar
  • 35 Nikolaev SI, Santoni F, Vannier A. et al Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome. Blood 2013; 122: 554-561
    CrossrefPubMedSearch in Google Scholar
  • 36 Park MJ, Sotomatsu M, Ohki K. et al Liver disease is frequently observed in Down syndrome patients with transient abnormal myelopoiesis. Int J Hematol 2014; 99: 154-161
    CrossrefPubMedSearch in Google Scholar
  • 37 Prudowsky Z, Han H, Stevens A. Transient Abnormal Myelopoeisis and Mosaic Down Syndrome in a Phenotypically Normal Newborn. Children (Basel) 2020; 7: 52
    CrossrefPubMedSearch in Google Scholar
  • 38 Rainis L, Bercovich D, Strehl S. et al Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 2003; 102: 981-986
    CrossrefPubMedSearch in Google Scholar
  • 39 Rao A, Hills RK, Stiller C. et al Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. Br J Haematol 2006; 132: 576-583
    CrossrefPubMedSearch in Google Scholar
  • 40 Ravindranath Y, Abella E, Krischer JP. et al Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 1992; 80: 2210-2214
    CrossrefPubMedSearch in Google Scholar
  • 41 Roberts I, Alford K, Hall G. et al GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood 2013; 122: 3908-3917
    CrossrefPubMedSearch in Google Scholar
  • 42 Roy A, Cowan G, Mead AJ. et al Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proc Natl Acad Sci U S A 2012; 109: 17579-17584
    CrossrefPubMedSearch in Google Scholar
  • 43 Scheer C, Kratz C, Witt O. et al Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome. Pediatr Blood Cancer 2016; 63: 1677-1679
    CrossrefPubMedSearch in Google Scholar
  • 44 Schweitzer J, Zimmermann M, Rasche M. et al Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial. Ann Hematol 2015; 94: 1327-1336
    CrossrefPubMedSearch in Google Scholar
  • 45 Sorrell AD, Alonzo TA, Hilden JM. et al Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children’s Oncology Group trial A2971: a report from the Children’s Oncology Group. Cancer 2012; 118: 4806-4814
    CrossrefPubMedSearch in Google Scholar
  • 46 Taga T, Tanaka S, Hasegawa D. et al. Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome. Leukemia 2021
  • 47 Taga T, Saito AM, Kudo K. et al Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood 2012; 120: 1810-1815
    CrossrefPubMedSearch in Google Scholar
  • 48 Taga T, Watanabe T, Tomizawa D. et al Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan. Pediatr Blood Cancer 2016; 63: 248-254
    CrossrefPubMedSearch in Google Scholar
  • 49 Tandonnet J, Clavel J, Baruchel A. et al Myeloid leukaemia in children with Down syndrome: report of the registry-based French experience between 1990 and 2003. Pediatr Blood Cancer 2010; 54: 927-933
    CrossrefPubMedSearch in Google Scholar
  • 50 Taub JW, Berman JN, Hitzler JK. et al Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children’s Oncology Group AAML0431 trial. Blood 2017; 129: 3304-3313
    CrossrefPubMedSearch in Google Scholar
  • 51 Taub JW, Matherly LH, Stout ML. et al Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 1996; 87: 3395-3403
    CrossrefPubMedSearch in Google Scholar
  • 52 Tunstall-Pedoe O, Roy A, Karadimitris A. et al Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 2008; 112: 4507-4511
    CrossrefPubMedSearch in Google Scholar
  • 53 Uffmann M, Rasche M, Zimmermann M. et al Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 2017; 129: 3314-3321
    CrossrefPubMedSearch in Google Scholar
  • 54 Wechsler J, Greene M, McDevitt MA. et al Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 2002; 32: 148-152
    CrossrefPubMedSearch in Google Scholar
  • 55 Yoshida K, Toki T, Okuno Y. et al The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet 2013; 45: 1293-1299
    CrossrefPubMedSearch in Google Scholar
  • 56 Yumura-Yagi K, Hara J, Tawa A. et al Phenotypic characteristics of acute megakaryocytic leukemia and transient abnormal myelopoiesis. Leuk Lymphoma 1994; 13: 393-400
    CrossrefPubMedSearch in Google Scholar
  • 57 Zeller B, Gustafsson G, Forestier E. et al Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 2005; 128: 797-804
    CrossrefPubMedSearch in Google Scholar
  • 58 Zipursky A, Brown E, Christensen H. et al Leukemia and/or myeloproliferative syndrome in neonates with Down syndrome. Semin Perinatol 1997; 21: 97-101
    CrossrefPubMedSearch in Google Scholar
  • 59 Zipursky A, Thorner P, De Harven E. et al Myelodysplasia and acute megakaryoblastic leukemia in Down’s syndrome. Leuk Res 1994; 18: 163-171
    CrossrefPubMedSearch in Google Scholar
  • 60 Zwaan CM, Kaspers GJ, Pieters R. et al Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 2002; 99: 245-251
    CrossrefPubMedSearch in Google Scholar