Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols
Gunnar Cario,
Veronica Leoni,
Valentino Conter,
Andishe Attarbaschi,
Marketa Zaliova,
Lucie Sramkova,
Gianni Cazzaniga,
Grazia Fazio,
Rosemary Sutton,
Sarah Elitzur,
Shai Izraeli,
Melchior Lauten,
Franco Locatelli,
Giuseppe Basso,
Barbara Buldini,
Anke K. Bergmann,
Jana Lentes,
Doris Steinemann,
Gudrun Göhring,
Brigitte Schlegelberger,
Oskar A. Haas,
Denis Schewe,
Swantje Buchmann,
Anja Moericke,
Deborah White,
Tamas Revesz,
Martin Stanulla,
Georg Mann,
Nicole Bodmer,
Nira Arad-Cohen,
Jan Zuna,
Maria Grazia Valsecchi,
Martin Zimmermann,
Martin Schrappe,
Andrea Biondi
Affiliations
Gunnar Cario
Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Veronica Leoni
Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy
Valentino Conter
Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy
Andishe Attarbaschi
St. Anna Kinderspital and Children’s Cancer Research Institute, Vienna, Austria
Marketa Zaliova
CLIP, Department of Pediatric Hematology and Oncology, 2ndFaculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Lucie Sramkova
CLIP, Department of Pediatric Hematology and Oncology, 2ndFaculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Gianni Cazzaniga
Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy
Grazia Fazio
Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy
Rosemary Sutton
Molecular Diagnostics, Children’s Cancer Institute, University of NSW, Sydney, NSW, Australia
Sarah Elitzur
Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Shai Izraeli
Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Israel
Melchior Lauten
Pediatrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
Franco Locatelli
Department of Pediatric Hematology and Oncology, Scientific Institute for Research and Healthcare (IRCCS) Childrens' Hospital Bambino Gesù, Sapienza, University of Rome, Rome, Italy
Giuseppe Basso
IIGM Torino and Pediatric Hemato-Oncology, SDB Departiment, University of Padova, Padova, Italy
Barbara Buldini
IIGM Torino and Pediatric Hemato-Oncology, SDB Departiment, University of Padova, Padova, Italy
Anke K. Bergmann
Department of Human Genetics, Medical School Hannover, Hannover, Germany
Jana Lentes
Department of Human Genetics, Medical School Hannover, Hannover, Germany
Doris Steinemann
Department of Human Genetics, Medical School Hannover, Hannover, Germany
Gudrun Göhring
Department of Human Genetics, Medical School Hannover, Hannover, Germany
Brigitte Schlegelberger
Department of Human Genetics, Medical School Hannover, Hannover, Germany
Oskar A. Haas
St. Anna Kinderspital and Children’s Cancer Research Institute, Vienna, Austria
Denis Schewe
Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Swantje Buchmann
Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Anja Moericke
Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Deborah White
Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
Tamas Revesz
Women’s and Children’s Hospital, SA Pathology, University of Adelaide, Adelaide, Australia
Martin Stanulla
Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany
Georg Mann
St. Anna Kinderspital and Children’s Cancer Research Institute, Vienna, Austria
Nicole Bodmer
University Children’s Hospital Zurich, Zurich, Switzerland
Nira Arad-Cohen
Pediatric Hematology-Oncology Department, Ruth Rappaport Children’s Hospital, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Jan Zuna
CLIP, Department of Pediatric Hematology and Oncology, 2ndFaculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Maria Grazia Valsecchi
Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy
Martin Zimmermann
Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany
Martin Schrappe
Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Andrea Biondi
Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy
ABL-class fusions other than BCR-ABL1 characterize around 2–3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10−4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).