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Ferrata Storti Foundation
Haematologica 2020 Volume 105(9):2200-2204
BCR-ABL1-like acute lymphoblastic leukemia in childhood and targeted therapy
Gunnar Cario,1* Veronica Leoni,2* Valentino Conter,2* André Baruchel,3# Martin Schrappe1# and Andrea Biondi2#
1Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 2Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Hospital S.Gerardo, Monza, Italy and 3Hôpital Universitaire Robert Debré (APHP) and Université de Paris, Paris, France
*GC, VL and VC contributed equally to this work as co-first authors. #AB, MS and AB contributed equally as co-senior authors.
Acute lymphoblastic leukemia (ALL) is a constellation of diseases driven by genetic alterations commonly derived from structural chromosome rearrange- ments, aneuploidy and co-operating mutations in genes that encode for tran- scription factors regulating lymphoid development, tumor suppressors, proteins reg- ulating cell cycle progression, and epigenetic modifiers.1
Recent years have witnessed dramatic progress in ALL classification. Subtypes of ALL can be defined according to the nature of specific sentinel genetic aberrations that confer distinct biological and clinical characteristics. Some of them represent a therapeutic target for specific treatments, which may contribute to a further increase in cure rates, to reduce the intensity of conventional chemotherapy and/or the need for hematopoietic stem cell transplantation (HSCT).
One of the first genetic aberrations identified was the Philadelphia chromosome (Ph), characterized by the t(9;22)(q34;q11) translocation that produces the BCR-ABL1 gene, and, in turn, a constitutively active tyrosine kinase. BCR-ABL1 fusion is present in 3-5% of pediatric ALL and in 25% of adult ALL patients. The evidence of this genetic aberration allowed the introduction of targeted therapy with tyrosine kinase inhibitors (TKI), which has dramatically improved the outcome of this subset of ALL.2-10 The pediatric COG AALL1131 and AALL0622 studies, and the contemporary EsPhALL2004 and subsequent EsPhALL2010 trials, in fact, showed a clear advantage in Ph positive (Ph+) ALL from early, continuous and protracted exposure to TKI com- bined with chemotherapy, challenging the indications for HSCT.5-10 Of note, however, the combination of chemotherapy and TKI may also be associated with increased toxicity, as shown in the EsPhALL2010 study.6,7
With advanced technologies, such as whole genome and transcriptome sequenc- ing, novel genetic subtypes have recently been discovered. In 2009, among the so called “B-other”, a subgroup of B-cell precursor (BCP)-ALL lacking the known sentinel BCP-ALL genetic aberrations, a new category of ALL has been described by Mullighan11 and by den Boer12, and termed Philadelphia chromosome (Ph)-like and BCR-ABL1-like ALL, respectively. The second term is used in this paper. The two sig- natures are based on the prediction analysis of microarrays (PAM) classifier consisting of 257 gene probe sets trained on Ph+ ALL cases (Mullighan11) or on hierarchical clus- tering of 110 gene probe sets identified to predict the major pediatric ALL subtypes (den Boer), with only nine overlapping probe sets.12 BCR-ABL1-like ALL, defined by a gene expression profile greatly similar to that of Ph+ ALL, presents a high frequency of deletions of IKZF1, which encodes the lymphoid transcription factor IKAROS, and of other lymphoid transcription factor genes.11,13 BCR-ABL1–like ALL has been recog- nized as a provisional entity in the 2016 World Health Organization classification of myeloid neoplasms and acute leukemia;14 the prevalence varies with age from 12% in children to 21% in adolescents, 27% in young adults, and 20-24% in older adults with BCP-ALL. In addition to older age at diagnosis, BCR-ABL1–like ALL is associated with other high-risk clinical features, such as elevated leukocyte count at diagnosis and poor treatment response, i.e. high levels of end-induction minimal residual dis- ease (MRD), increased risk of induction failure and of relapse.11,13,15-30
Importantly, BCR-ABL1-like ALL is not defined by a single unifying sentinel molec- ular aberration; but rather, it is characterized by a variety of genomic alterations that activate kinases and deregulate cytokine receptor signaling. Fusion genes involving at least 17 cytokine receptors or tyrosine kinases have been identified.23,29,31,32 These alter- ations can be grouped into several major subclasses: approximately 50% of BCR-
Correspondence:
ANDREA BIONDI
abiondi.unimib@gmail.com
Received: March 7, 2019. Accepted: May 8, 2020. Pre-published: May 15, 2020.
doi:10.3324/haematol.2018.207019 ©2020 Ferrata Storti Foundation
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