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).

Cancer Theme South Australian Health and Medical Research Institute Adelaide Australia

Clinica Pediatrica and Centro Ricerca Tettamanti Università di Milano Bicocca Fondazione MBBM S Gerardo Hospital Monza Italy

CLIP Department of Pediatric Hematology and Oncology 2Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Human Genetics Medical School Hannover Hannover Germany

Department of Pediatric Hematology and Oncology Scientific Institute for Research and Healthcare Childrens' Hospital Bambino Gesù Sapienza University of Rome Rome Italy

Department of Pediatric Hematology Oncology Hannover Medical School Hannover Germany

IIGM Torino and Pediatric Hemato Oncology SDB Departiment University of Padova Padova Italy

Molecular Diagnostics Children's Cancer Institute University of NSW Sydney NSW Australia

Pediatric Hematology Oncology Department Ruth Rappaport Children's Hospital Rambam Health Care Campus Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

Pediatric Hematology Oncology Schneider Children's Medical Center Petah Tikva and Sackler Faculty of Medicine Tel Aviv University Israel

Pediatrics University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Pediatrics University Hospital Schleswig Holstein Campus Lübeck Lübeck Germany

St Anna Kinderspital and Children's Cancer Research Institute Vienna Austria

University Children's Hospital Zurich Zurich Switzerland

Women's and Children's Hospital SA Pathology University of Adelaide Adelaide Australia

Haematologica. 2020 Jul;105(7):1754-1757. doi: 10.3324/haematol.2020.252916. PubMed

Zobrazit více v PubMed

Hunger SP, Mullighan CG. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood. 2015;125(26):3977–3987. PubMed PMC

Conter V, Aricò M, Valsecchi MG, et al. Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Acute Lymphoblastic Leukemia Studies, 1982–1995. Leukemia. 2000; 14(12):2196–2204. PubMed

Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Leukemia. 2000;14(12):2205–2222. PubMed

Möricke A, Reiter A, Zimmermann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111(9):4477–4489. PubMed

Pui CH, Evans WE. Treatment of acute lymphoblastic leukaemia. N Engl J Med. 2006;354(2):166–178. PubMed

Moghrabi A, Levy DE, Asselin B, et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood. 2007;109(3):896–904. PubMed PMC

Carroll WL, Bhojwani D, Min DJ, et al. Pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2003:102–113. PubMed

Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115(16):3206–3214. PubMed

Schrappe M, Valsecchi MG, Bartram CR, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118(8):2077-2084. PubMed

Bernt KM, Hunger SP. Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia. Front Oncol. 2014;4:54. PubMed PMC

Fielding AK. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: a broader range of options, improved outcomes, and more therapeutic dilemmas. Am Soc Clin Oncol Educ Book. 2015:e352–359. PubMed

Aricò M, Schrappe M, Hunger SP, et al. Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol. 2010;28(31):4755–4761. PubMed PMC

Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012; 13(9):936–945. PubMed PMC

Biondi A, Cario G, De Lorenzo P, et al. Long-term follow up of pediatric Philadelphia positive acute lymphoblastic leukemia treated with the EsPhALL2004 study: high white blood cell count at diagnosis is the strongest prognostic factor. Haematologica. 2019;104(1):13–16. PubMed PMC

Biondi A, Gandemer V, De Lorenzo P, et al. Imatinib treatment of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010): a prospective, intergroup, open-label, single-arm clinical trial. Lancet Haematol. 2018; 5(12):641–652. PubMed

Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. 2009;27(31):5175–5181. PubMed PMC

Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group Study AALL0031. Leukemia. 2014;28(7):1467–1471. PubMed PMC

Slayton WB, Schultz KR, Kairalla JA, et al. Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with philadelphia chromosome-positive acute lymphoblastic leukemia: results of Children’s Oncology Group Trial AALL0622. J Clin Oncol. 2018;36(22):2306–2314. PubMed PMC

Roberts KG, Yang Y, Turner DP, et al. Oncogenic role and therapeutic targeting of ABL-class and JAK-STAT activating kinase alterations in Ph-like ALL. Blood Adv. 2017;1(20):1657–1671. PubMed PMC

Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–134. PubMed PMC

Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph- like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005–1015. PubMed PMC

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405. PubMed

Boer JM, Koenders JE, van der Holt B, et al. Expression profiling of adult acute lymphoblastic leukemia identifies a BCR-ABL1-like subgroup characterized by high non-response and relapse rates. Haematologica. 2015;100(7):261–264. PubMed PMC

Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010; 116(23):4874–4884. PubMed PMC

van der Veer A, Waanders E, Pieters R, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013;122(15):2622–2629. PubMed PMC

Roberts KG, Pei D, Campana D, et al. Outcomes of children with BCR-ABL1–like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32(27):3012–3020. PubMed PMC

Boer JM, Steeghs EM, Marchante JR, et al. Tyrosine kinase fusion genes in pediatric BCRABL1-like acute lymphoblastic leukemia. Oncotarget. 2017;8(3):4618–4628. PubMed PMC

Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group. Blood. 2017; 129(25):3352–3361. PubMed PMC

Dworzak MN, Buldini B, Gaipa G, et al. AIEOP-BFM consensus guidelines 2016 for flow cytometric immunophenotyping of Pediatric acute lymphoblastic leukemia. Cytometry B Clin Cytom. 2018;94(1):82–93. PubMed

van der Velden VH, Cazzaniga G, Schrauder A, et al. European Study Group on MRD detection in ALL (ESG-MRD-ALL). Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21(4):604–611. PubMed

van der Does-van den Berg A, Bartram CR, Basso G, et al. Minimal requirements for the diagnosis, classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the “BFM Family” Cooperative Group. Med Pediatr Oncol. 1992;20(6):497–505. PubMed

Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group. Blood. 2017; 129(25):3352–3361. PubMed PMC

Basso G, Veltroni M, Valsecchi MG, et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol. 2009;27(31):5168–5174. PubMed

Möricke A, Zimmermann M, Valsecchi MG, et al. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016;127(17):2101–2112. PubMed

Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457–481.

Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50(3):163–170. PubMed

Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data (ed 1). New York: John Wiley and sons; 1980:163–188.

Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16(3):1141–1154.

Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31(25):413–416. PubMed

Lengline E, Beldjord K, Dombret H, Soulier J, Boissel N, Clappier E. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion. Haematologica. 2013;98(11):146–148. PubMed PMC

Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia

Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study

Zobrazit více v PubMed

ClinicalTrials.gov
NCT00613457, NCT01117441