Monique L den Boer1, Gunnar Cario2, Anthony V Moorman3, Judith M Boer1, Hester A de Groot-Kruseman1, Marta Fiocco4, Gabriele Escherich5, Toshihiko Imamura6, Allen Yeoh7, Rosemary Sutton8, Luciano Dalla-Pozza8, Nobutaka Kiyokawa9, Martin Schrappe2, Kathryn G Roberts10, Charles G Mullighan10, Stephen P Hunger11, Ajay Vora12, Andishe Attarbaschi13, Marketa Zaliova14, Sara Elitzur15, Giovanni Cazzaniga16, Andrea Biondi16, Mignon L Loh17, Rob Pieters18. 1. Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands. 2. Department of Paediatrics, University Hospital Schleswig-Holstein, Kiel, Germany. 3. Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. 4. Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands; Institute of Mathematics, Leiden University, Leiden, Netherlands. 5. Department of Paediatric Haematology and Oncology, University Medical Center Hamburg Eppendorf, Germany. 6. Department of Pediatrics, Graduate School of Medical Science, Kyoto, Japan. 7. Khoo Teck Puat, National University Children's Medical Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 8. Children's Cancer Institute, University of New South Wales and Cancer Centre for Children, Children's Hospital at Westmead, Sydney, NSW, Australia. 9. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child and Development, Tokyo, Japan. 10. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA. 11. Children's Oncology Group, Monrovia, CA, USA; Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, PA, USA. 12. Department of Haematology, Great Ormond Street Hospital, London, UK. 13. Department of Paediatric Haematology and Oncology, St Anna Kinderspital, Vienna, Austria. 14. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic. 15. The Rina Zaizov Division of Haematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel. 16. Universtà di Milano-Bicocca, S Gerardo Hospital, Monza, Italy. 17. Children's Oncology Group, Monrovia, CA, USA; Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. 18. Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands. Electronic address: r.pieters@prinsesmaximacentrum.nl.
Abstract
BACKGROUND: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. METHODS: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. FINDINGS: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups. INTERPRETATION: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. FUNDING: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.
BACKGROUND: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. METHODS: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. FINDINGS: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups. INTERPRETATION: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. FUNDING: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.
Authors: Martin Dreyling; Marc André; Nicola Gökbuget; Hervé Tilly; Mats Jerkeman; John Gribben; Andrés Ferreri; Pierre Morel; Stephan Stilgenbauer; Christopher Fox; José Maria Ribera; Sonja Zweegman; Igor Aurer; Csaba Bödör; Birgit Burkhardt; Christian Buske; Maria Dollores Caballero; Elias Campo; Bjoern Chapuy; Andrew Davies; Laurence de Leval; Jeanette Doorduijn; Massimo Federico; Philippe Gaulard; Francesca Gay; Paolo Ghia; Kirsten Grønbæk; Hartmut Goldschmidt; Marie-Jose Kersten; Barbara Kiesewetter; Judith Landman-Parker; Steven Le Gouill; Georg Lenz; Sirpa Leppä; Armando Lopez-Guillermo; Elizabeth Macintyre; Maria Victoria Mateos Mantega; Philippe Moreau; Carol Moreno; Bertrand Nadel; Jessica Okosun; Roger Owen; Sarka Pospisilova; Christiane Pott; Tadeusz Robak; Michelle Spina; Kostas Stamatopoulos; Jan Stary; Karin Tarte; Allessandra Tedeschi; Catherine Thieblemont; Ralf Ulrich Trappe; Lorenz H Trümper; Gilles Salles Journal: Hemasphere Date: 2022-05-19
Authors: Thai Hoa Tran; Jonathan V Nguyen; Adrian Stecula; Jon Akutagawa; Anthony V Moorman; Benjamin S Braun; Andrej Sali; Charles G Mullighan; Neil P Shah; Yunfeng Dai; Meenakshi Devidas; Kathryn G Roberts; Catherine C Smith; Mignon L Loh Journal: Haematologica Date: 2021-08-01 Impact factor: 9.941