Elemination of the preleukemic clone in children with Down syndrome and transient myeloproliferative disorder (TMD) to prevent AML - Model of Leukemia prevention

• Applicant: Professor Dr. Dirk Reinhardt
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2007 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34181068

Final Report Abstract

The clinical trial registered 139 infants. According to inclusion and exclusion criteria 108 infants were eligible for the protocol. Diagnosis of TMD have been confirmed in all cases by morphology and immunophenotyping and/or molecular detection of the mutated GATA1 transcription factor. Monitoring of the expected spontaneous remission was performed by morphology, immunophenotyping and quantitative measurement of the GATA1s (mutated GATA1). Inventions according to the protocol in order to treat residual disease in those patients with positive MRD levels at week 8 and/or week 12 have been recommended and applied in just 14 patients. All patients achieved complete morphological and immunological remission. The event-free and overall survival of the protocol patients were 72±5% and 90±3%, respectively. The cumulative incidence of ML-DS was 19±4%. In patients who received cytarabine-treatment due to persistent disease (trial intervention), no death or severe adverse event (SAE) > grade 3 occurred. Reported side effects were a transient elevation of liver enzymes (max. grade 3 2 pat. /14 pats; drop of platelets (2/14). Other toxicities have not been reported in this small patient group. In children with TMD and severe symptoms, the treatment of low cytarabine (1 to 1.5 mg/kgBW) was recommended. In total, 31 children have been treated with one or two course of low dose cytarabine. Early deaths due to multiorgan failure, cardiac defects or infections occurred in 4 patients in this group, another two death were reported in patients without treatment either because death occurred prior to treatment start or the general condition at birth was already moribund. Two children experienced liver fibrosis within the 1st 4 month post TMD. One girl finally received liver transplantation and is alive, a 2nd child died. The hypothesis of the trial to prevent development myeloid-leukemia in Down syndrome have not been achieved. Neither in the non-treated nor in the treated group, ML-DS could be prevented.

Publications

• Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Down's syndrome. Leukemia 2007;21:1584-7
  Klusmann JH, Reinhardt D, Hasle H, et al.
  
• Activating mutations in human acute megakaryoblastic leukemia. Blood 2008;112:4220-6
  Malinge S, Ragu C, Della-Valle V, et al.
  
• Acute Leukemias in children with Down syndrome. Pediatric Clinics of North America 2008;55:53
  Zwaan MC, Reinhardt D, Hitzler J, Vyas P
  
• 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;22:1428-30
  Hasle H, Abrahamsson J, Arola M, et al.
  
• Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008;111:2991-8
  Klusmann JH, Creutzig U, Zimmermann M, et al.
  
• Acute Leukemias in Children with Down Syndrome. Hematology-Oncology Clinics of North America 2010;24:19
  Zwaan CM, Reinhardt D, Hitzler J, Vyas P
  
• Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. Genes & Development 2010;24:1659-72
  Klusmann JH, Godinho FJ, Heitmann K, et al.
  
• miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. Genes & Development 2010;24:478-90
  Klusmann JH, Li Z, Bohmer K, et al.
  
• Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood 2011;118:2222-38
  Alford KA, Reinhardt K, Garnett C, et al.
  
• A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL. Br J Haematol 2012;157:180-7
  Haemmerling S, Behnisch W, Doerks T, et al.
  
• Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. Journal of Experimental Medicine 2012;209:2017-31
  Thiollier C, Lopez CK, Gerby B, et al.
  
• GATA1-Mutation Associated Leukemia in Children with Trisomy 21 Mosaic. Klinische Padiatrie 2012;224:153-5
  Reinhardt D, Reinhardt K, Neuhoff C, et al.
  
• High frequency of copy number alterations in myeloid leukaemia of Down syndrome. Br J Haematol 2012;158:800-3
  Blink M, van den Heuvel-Eibrink MM, Aalbers AM, et al.
  
• GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia. Leukemia 2014;28:1259-70
  Maroz A, Stachorski L, Emmrich S, et al.
  
• Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. Haematologica 2014;99:299-307
  Blink M, Zimmermann M, von Neuhoff C, et al.
  
• Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood 2015;126:1575-84
  Inaba H, Zhou Y, Abla O, et al.
  
• Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial. Annals of Hematology 2015;94:1327-36
  Schweitzer J, Zimmermann M, Rasche M, et al.
  
• Infectious Complications in Children With Acute Myeloid Leukemia and Down Syndrome: Analysis of the Prospective Multicenter Trial AML-BFM 2004. Pediatric Blood & Cancer 2016;63:1070-4
  Hassler A, Bochennek K, Gilfert J, et al.
  
• Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet 2017
  de Rooij JD, Branstetter C, Ma J, et al.