Published Ahead of Print on August 1, 2014, as doi: /haematol Copyright 2014 Ferrata Storti Foundation.

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1 Published Ahead of Print on August 1, 2014, as doi: /haematol Copyright 2014 Ferrata Storti Foundation. Outcome of Aplastic Anemia in adolescence. A survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation by Carlo Dufour, Marta Pillon, Jakob Passweg, Gerard Socié, Andrea Bacigalupo, Genny Franceschetto, Elisa Carraro, Rosi Oneto, Antonio Maria Risitano, Regis Peffault de Latour, Andre' Tichelli, Alicia Rovo, Christina Peters, Britta Hoechsmann, Sujith Samarasinghe, Austin G. Kulasekararaj, Hubert Schrezenmeier, Mahmoud Aljurf, and Judith Marsh Haematologica 2014 [Epub ahead of print] Citation: Dufour C, Pillon M, Passweg J, Socié G, Bacigalupo A, Franceschetto G, Carraro E, Oneto R, Risitano AM, Peffault de Latour R, Tichelli A, Rovo A, Peters C, Hoechsmann B, Samarasinghe S, Kulasekararaj AG, Schrezenmeier H, Aljurf M, and Marsh J. Outcome of Aplastic Anemia in adolescence. A survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2014; 99:xxx doi: /haematol Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.

2 Outcome of Aplastic Anemia in adolescence. A survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation Running title: aplastic anemia in adolescence Carlo Dufour 1, Marta Pillon 2, Jakob Passweg 3, Gerard Socié 4, Andrea Bacigalupo 5, Genny Franceschetto 2, Elisa Carraro 2, Rosi Oneto 5, Antonio Maria Risitano 6, Regis Peffault de Latour 4, André Tichelli 3, Alicia Rovo 3, Christina Peters 7, Britta Hoechsmann 8, Sujith Samarasinghe 9, Austin G. Kulasekararaj 10, Hubert Schrezenmeier 8, Mahmoud Aljurf 11 and Judith Marsh 10 1 Clinical and Experimental Hematology Unit. G Gaslini Childrens Hospital; Genova, Italy 2 Pediatric Hemato- Oncology Clinic, University of Padova, Padova, Italy 3 Basel University Hospital, Switzerland 4 Department of Hematology, Hospital St Louis, Paris, France 5 Second Division of Hematology, San Martino Hospital, Genova, Italy 6 Hematology, Department of Clinical Medicine and Surgery, Federico II University of Naples, Italy 7 Pediatric Heamtopoietic Stem Cell Transplantation, St Anna Kinderspital, Vienna, Austria 8 Institut for Clinical Transfusion Medicine and Immunogenetics, and Department of Transfusion Medicine University of Ulm, Germany. 9 Department of Paediatric and Adolescent Haematology and Oncology, Great North Children s Hospital, Newcastle upon Tyne Hospitals NHS. Current address: Great Ormod Street Children s Hospital, London UK 10. Department t of Haematological Medicine, King's College Hospital/King s College London, London, UK 11. King Faisal Specialist Hospital & Research Center, Saudi Arabia Key words: aplastic anemia, outcome, adolescents 1

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22 & Fig1a. Probability of 3-years OS (Kaplan-Meier method) for the whole population of 537 patients stratified by treatment. IST means patients receiving IST front line including subjects who were transplanted after IST failure. Fig1b. Probability of 3-years EFS (Kaplan-Meier method) for the whole population of 537 patients stratified by treatment. IST means patients receiving IST front line including subjects who were transplanted after IST failure. Figure 2a. Probability of 3-years OS (Kaplan-Meier method) for the whole population of 537 patients stratified by treatment. IST alone means patients receiving IST upfront with the exclusion of those subsequently transplanted. Figure 2b. Probability of 3-years EFS (Kaplan-Meier method) for the whole population of 537 patients stratified by treatment. IST alone means patients receiving IST up front with the exclusion of those subsequently transplanted. Subgroup analysis: First line MFD HSCT vs IST alone: p= First line MFD HSCT vs HSCT post- failed IST: p= IST alone vs HSCT post -failed IST: p=0.17. Fig 3a. Cumulative Incidence of rejection in patients receiving MFD HSCT vs those receiving HSCT post failed IST Fig 3b. Cumulative Incidence of Acute GVHD grade II-III-IV in patients transplanted front-line from MSD and after failed IST. Most of HSCT post failed IST were from MM(13%) and MUD (64%) donors. FIG 3c. Cumulative Incidence of Chronic GVHD in patients transplanted front-line from MSD and after failed IST. Most of HSCT post failed IST were from MM(13%) and MUD (64%) donors. Fig 3d. Cumulative Incidence of secondary malignancies in patients receiving IST alone front-line, MDF HSCT front line and HSCT post failed IST. It is of note that secondary tumors only occurred in patients who has have rejected. dd

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27 Supplementary Table 1a Events in the population undergoing Front-Line IST * N 143 Death 24 (17 %) Lack of response 0 Relapse 16 (11 %) Clinical PNH 4 (3 %) Post-therapy malignancies 8 (5.6%) Transplants 79 (55%) Alive at Follow up after transplant 60 (42 %)** Supplementary Table 1b. Causes of death MFD HSCT HSCT post IST IST alone N TRM 13(3.3%) 7(8.7%) n.ap Sepsis 27 (6.8%) 10 (12.7%) 0 Disease recurrence 4 (1%) 0 5 (7.8%) n.a. 2 (2.5%) 0 * In some patient more than a single event occurred (e.g. relapse and post therapy malignancy). ** These are the patients who survived after HST post failed IST. Percentage refers to the initial N of patients offered IST as a first option (143). The percentage of subjects (N 79) who failed initial IST and survived after rescue transplant is (N 60) 76%. MFD HSCT= matched family donor hematopoietic stem cell transplantation; HSCT post IST= hematopoietic stem cell transplantation after failed immunosuppressive therapy IST alone= immunosuppressive therapy without subsequent HSCT; TRM = transplant-related-mortality; n.ap.= not applicable; n.a. = not available 1

28 Supplementary Figure 1 Supplementary Figure 1a. Probability of 3-years OS ( Kaplan-Meier method), stratified by centre as identified by Jacie-based criteria in 472 transplanted patients (one missing value). P= pediatric centre, A=adult centre, M= mixed entre 2

29 Supplementari Figure 1 b. Probability of 3-years EFS calculated (Kaplan-Meier method) stratified by centre as identified by Jacie-based criteria in 472 transplanted patients (one missing value). P= pediatric centre, A=adult centre, M= mixed entre 3

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