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DNA HYPERMETHYLATION EMERGES AS THE STRONGEST PREDICTOR FOR POOR OUTCOME AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML)

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Niemeyer, C. M.1; Flotho, C.1; Lipka, D. B.2; Buechner, J.3; Catala, A.4; De Haas, V.5; De Moerloose, B.6; Dworzak, M.7; Fabri, O.8; Hasle, H.9; Jahnukainen, K.10; Kállay, K.11; Masetti, R.12; Schmugge, M.13; Smith, O. P.14; Stary, J.15; Turkiewicz, D.16; Ussowicz, M.17; Schoenung, M.18; Erlacher, M.1; Yoshimi, A.1; Bierings, M.19; Bordon, V.6; Diaz-de-Heredia, C.20; Horakova, J.21; Lankaster, A. C.22; Masmas, T.23; Meisel, R.24; O'Marcaigh, A.14; Roessig, C.25; Peters, A.1; Pichler, H.7; Sauer, M.27; Sedlacek, P.15; Zecca, M.28; Noellke, P.1; Strahm, B.1; Locatelli, F.29

doi: 10.1097/01.HS9.0000560992.44507.cc
Poster Session I: Myeloproliferative neoplasms - Clinical
Free

1Department of Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg

2Regulation of Cellular Differentiation Group, Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

3Dept. of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway

4Department of Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Spain

5Diagnostic Laboratory / DCOG Laboratory, Princess Maxima Center, Utrecht, Netherlands

6Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

7St. Anna Children's Hospital and Cancer Research Institute, Pediatric Clinic, Medical University of Vienna, Vienna, Austria

8Department of Haematology and Transfusiology, National Institute of Children′s Diseases, Faculty of Medicine, Comenius University, Bratislava, Slovakia

9Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark

10Division of Hematology-Oncology and Stem Cell Transplantation, Children′s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

11Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases, Budapest, Hungary

12Department of Pediatric Oncology and Hematology, University of Bologna, Bologna, Italy

13Department of Hematology and Oncology, University Children's Hospital, Zurich, Switzerland

14Paediatric Oncology and Haematology, Our Lady′s Children′s Hospital Crumlin, Dublin, Ireland

15Department of Pediatric Hematology/ Oncology, Charles University and Univ Hospital Motol, Prague, Czech Republic

16Department of Pediatric Oncology/Hematology, Skåne University Hospital, Lund, Sweden

17Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wroclaw Medical University, Wroclaw, Poland

18Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany

19Department of Hematology, University Hospital for Children, Medical Center, Utrecht, Netherlands

20Pediatric Hematology and Oncology Department, HSCT Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain

21Department of Paediatric Haematology and Oncology, National Institute of Children's Diseases, Medical Faculty, Comenius University, Bratislava, Slovakia

22Department of Pediatrics Stem Cell Transplantation, Leiden University Medical Centre, Leiden, Netherlands

23Pediatric hematopoietic stem cell transplantation and immunodeficiency, The Child and Adolescent Clinic, Copenhagen University Hospital, Copenhagen, Denmark

24Division of Pediatric Stem Cell Therapy, Clinic for Pediatric Oncology, Hematology and Clin. Immunology, Duesseldorf

25Pediatric Hematology and Oncology, University Children′s Hospital Muenster, Muenster, Germany

27Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany

28Department of Pediatrics, IRCCS Policlinic San Matteo, University of Pavia, Pavia

29Department of Pediatric Hematology and Oncology, Bambino Gesu' Children's Hospital, Sapienza, University of Rome, Rome, Italy

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Background:

JMML is a childhood hematopoietic malignancy characterized by hyperactive RAS signaling. For most patients early allogeneic hematopoietic stem cell transplantation (HSCT) is the therapy of choice. Risk factors for early death and relapse following HSCT are represented by age ≥ 2 yrs, low platelet count and HbF elevated for age. Most recently, genome-wide DNA methylation profiles (Lipka, Nat Comm 2017) identified distinct methylation signatures predictive for outcome.

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Aims:

This study evaluates the clinical significance of these epigenetic changes in a large cohort of uniformly transplanted children registered to the European Working Group of MDS in Childhood (EWOG-MDS).

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Methods:

We analyzed the outcome of 153 children with JMML (96 males, 57 females; median age at HSCT 2.7 yrs [0.3-11.5]) given a HSCT after a preparative regimen consisting of busulfan, cyclophosphamide, and melphalan.

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Results:

Thirty-seven patients (pts) were transplanted from an HLA-identical sibling donor (MSD) and 116 from a matched unrelated donor (UD). Stem cell source was bone marrow (n = 122) or peripheral blood (n = 31). GVHD prophylaxis was CSA only in 25 (68%) MSD procedures, CSA/MTX/ATG was administered in 88 (76%) of UD-HSCT recipients. All but 9 pts engrafted. The cumulative incidence of grades II-IV acute GVHD was 44% (37-52). Thirty-three of the 133 pts at risk developed chronic GVHD, which was limited in 20 and extensive in 13 pts. With a median follow-up of 3.7 years (0.1-17.5), the 5-year leukemia-free survival (LFS) was 61% (53-69), while the cumulative incidence of non-relapse mortality (NRM) and relapse (CIR) were 13% (8-20) and 26% (20-35), respectively. There was no difference in outcome between MSD and UD-HSCT recipients. Of the 153 pts, 76 had a somatic PTPN11 mutation, 21 had neurofibromatosis type 1, 22 belonged to the NRAS- and 18 to the KRAS-mutated subgroup, while RAS pathway alterations were absent in 16 pts (“all negative”). 5-year CIR was higher in PTPN11-mutated JMML (35%) compared to that of the NF1 (24%), NRAS (23%), KRAS (11%) or all negative subtypes (14%). Methylation status was high (HM), intermediate (IM) or low (LM) in 61, 52 or 40 pts, respectively. 5-year LFS and CIR of pts of the LM class was similar to that noted in the IM class with 76% vs 69%, and 8% vs 13%, respectively. In contrast, children of the HM class had a significantly inferior LFS (44%, 31-57, p < 0.01) due to a high CIR (50%, 38-65, p < 0.01). NRM in the 3 methylation groups (LM 16%, IM 19%, HM 6%) did not differ. There was a clear correlation between methylation class and molecular genetic subtype: PTPN11-mutated JMML was less common in the LM class and the proportion of KRAS-mutated pts was highest in the LM class. Also, patients in the HM class had a higher median age at HSCT (3.8 yrs) than pts in the IM (2.1 yrs) or LM class (1.1 yrs). Multivariate analysis identified methylation class (HM vs IM: RR 5.3 [1.8-15.3], HM vs LM RR 7.6 [1.6 - 37.3]) as the only independent variable predicting relapse when analyzed with age at HSCT, platelet count and molecular genetic type (PTPN11-mutated vs others).

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Summary/Conclusion:

Patient outcome in genome-wide methylation classes nicely recapitulated earlier data applying a DNA methylation score of candidate gene regions (Olk-Batz, Blood 2011). Thus, DNA methylation classifiers are exceptionally consistent allowing prospective assignment of DNA methylation categories for molecularly-driven risk stratification. Future research needs to be directed at better understanding the mechanistic link of epigenetic dysregulation and resistance to treatment.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.