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BMC Cancer
Published in: BMC Cancer 1/2021

01-12-2021 | Acute Lymphoblastic Leukemia | Research article

Low incidence of ABL-class and JAK-STAT signaling pathway alterations in uniformly treated pediatric and adult B-cell acute lymphoblastic leukemia patients using MRD risk-directed approach – a population-based study

Authors: Rimvydas Norvilas, Vaidas Dirse, Ruta Semaskeviciene, Orinta Mickeviciute, Egle Gineikiene, Mindaugas Stoskus, Goda Vaitkeviciene, Jelena Rascon, Laimonas Griskevicius

Published in: BMC Cancer | Issue 1/2021

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Abstract

Background

ABL-class and JAK-STAT signaling pathway activating alterations have been associated with both a poor post-induction minimal residual disease (MRD) response and an inferior outcome in B-cell acute lymphoblastic leukemia (B-ALL). However, in most of the studies patients received non-uniform treatment.

Methods

We performed a population-based analysis of 160 (122 pediatric and 38 adult) Lithuanian BCR-ABL1-negative B-ALL patients who had been uniformly treated according to MRD-directed NOPHO ALL-2008 protocol. Targeted RNA sequencing and FISH analysis were performed in cases without canonical B-ALL genomic alterations (high hyperdiploids and low hypodiploids included).

Results

We identified ABL-class fusions in 3/160 (1.9%) B-ALL patients, and exclusively in adults (p = 0.003). JAK-STAT pathway fusions were present in 4/160 (2.5%) cases. Of note, P2RY8-CRLF2 fusion was absent in both pediatric and adult B-ALL cases. Patients with ABL-class or JAK-STAT pathway fusions had a poor MRD response and were assigned to the higher risk groups, and had an inferior event-free survival (EFS) / overall survival (OS) compared to patients without these fusions. In a multivariate analysis, positivity for ABL-class and JAK-STAT fusions was a risk factor for worse EFS (p = 0.046) but not for OS (p = 0.278) in adults.

Conclusions

We report a low overall frequency of ABL-class and JAK-STAT fusions and the absence of P2RY8-CRLF2 gene fusion in the Lithuanian BCR-ABL1 negative B-ALL cohort. Future (larger) studies are warranted to confirm an inferior event-free survival of ABL-class/JAK-STAT fusion-positive adult patients in MRD-directed protocols.
Appendix
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Literature
1.
Mullighan CG. The molecular genetic makeup of acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program. 2012;2012:389–96.CrossRef
2.
Toft N, Birgens H, Abrahamsson J, Griškevičius L, Hallböök H, Heyman M, et al. Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Leukemia. 2018;32(3):606–15.PubMedCrossRef
3.
Moorman AV. New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2016;101(4):407–16.PubMedPubMedCentralCrossRef
4.
Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–34.CrossRef
5.
Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80.PubMedPubMedCentralCrossRef
6.
Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153–66.PubMedPubMedCentralCrossRef
7.
Weston BW, Hayden MA, Roberts KG, Bowyer S, Hsu J, Fedoriw G, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31(25):e413–6.PubMedCrossRef
8.
Roberts KG, Yang YL, Payne-Turner D, Lin W, Files JK, Dickerson K, 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):1657–71.PubMedPubMedCentral
9.
Ding YY, Stern JW, Jubelirer TF, Wertheim GB, Lin F, Chang F, et al. Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure. Haematologica. 2018;103(9):e427–31.PubMedPubMedCentralCrossRef
10.
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):e146–8.PubMedPubMedCentralCrossRef
11.
O'Connor D, Moorman AV, Wade R, Hancock J, Tan RM, Bartram J, et al. Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2017;35(6):660–7.PubMedCrossRef
12.
Moorman A, Schwab C, Kirkwood A, Winterman E, Hancock J, Kearns P, et al. Improved outcome for patients with acute lymphoblastic leukemia (ALL) and an ABL-class fusion following treatment with a tyrosine kinase inhibitor: preliminary data from UKALL2011. EHA Library. 2020;1:294937.
13.
Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's oncology group. Blood. 2017;129(25):3352–61.PubMedPubMedCentralCrossRef
14.
Boer JM, Steeghs EM, Marchante JR, Boeree A, Beaudoin JJ, Beverloo HB, et al. Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget. 2017;8(3):4618–28.PubMedCrossRef
15.
Kotb A, El Fakih R, Hanbali A, Hawsawi Y, Alfraih F, Hashmi S, et al. Philadelphia-like acute lymphoblastic leukemia: diagnostic dilemma and management perspectives. Exp Hematol. 2018;67:1–9.PubMedCrossRef
16.
Lilljebjörn H, Henningsson R, Hyrenius-Wittsten A, Olsson L, Orsmark-Pietras C, von Palffy S, et al. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nat Commun. 2016;7:11790.PubMedPubMedCentralCrossRef
17.
Chiaretti S, Brugnoletti F, Messina M, Paoloni F, Fedullo AL, Piciocchi A, et al. CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities. Leuk Res. 2016;41:36–42.PubMedCrossRef
18.
Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005–15.PubMedPubMedCentralCrossRef
19.
Jain N, Roberts KG, Jabbour E, Patel K, Eterovic AK, Chen K, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572–81.PubMedPubMedCentralCrossRef
20.
Herold T, Schneider S, Metzeler KH, Neumann M, Hartmann L, Roberts KG, et al. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica. 2017;102(1):130–8.PubMedPubMedCentralCrossRef
21.
Roberts KG, Pei D, Campana D, Payne-Turner D, Li Y, Cheng C, 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):3012–20.PubMedPubMedCentralCrossRef
22.
Pui CH, Pei D, Raimondi SC, Coustan-Smith E, Jeha S, Cheng C, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with response-adapted therapy. Leukemia. 2017;31(2):333–9.PubMedCrossRef
23.
Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, et al. The genomic landscape of Hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45(3):242–52.PubMedPubMedCentralCrossRef
24.
Paulsson K, Lilljebjörn H, Biloglav A, Olsson L, Rissler M, Castor A, et al. The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Nat Genet. 2015;47(6):672–6.PubMedCrossRef
25.
van Dongen J, Macintyre E, Gabert J, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia. 1999;13:1901–28.PubMedCrossRef
26.
Zaliova M, Moorman AV, Cazzaniga G, Stanulla M, Harvey RC, Roberts KG, et al. Characterization of leukemias with ETV6-ABL1 fusion. Haematologica. 2016;101(9):1082–93.PubMedPubMedCentralCrossRef
27.
Zaliova M, Stuchly J, Winkowska L, Musilova A, Fiser K, Slamova M, et al. Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort. Haematologica. 2019;104(7):1396–406.PubMedPubMedCentralCrossRef
28.
Heatley SL, Mayne B, McClure BJ, Kok C, Sadras T, Dang P, et al. Exploring the genomic diversity of AYA and adult high-risk B-ALL cases by mRNA sequencing. EHA learning center; 2018.
29.
Garrido T, Soares MJ, Barbosa A, Amorim ML, Gomes P, Trigo F, et al. Tirosine kinase rearrangements in Ph-negative acute lymphoblastic leukemia - a FISH approach. EHA learning center; 2018. 216176 Abstract.
30.
Moorman A, Barretta E, Kirkwood A, Schwab C, Creasey T, Patrick P, et al. Comprehensive screening of B-other adult ALL patients treated on UKALL14 estimates frequency and prognostic impact of gene alterations and identifies JAK-STAT abnormalities as markers of poor outcome. EHA learning center; 2018. 214532 Abstract.
31.
Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. 2009;114(13):2688–98.PubMedCrossRef
32.
Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JP, Beverloo HB, et al. Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia. 2012;26(10):2204–11.PubMedCrossRef
33.
Ferrari A, Vitali S, Ghelli Luserna Di Rora A, Baldazzi C, Testoni N, Robustelli V, et al. Unexpected high rate of known and unknown rearrangements in adult triple negative acute lymphoblastic leukemia identified thanks to a efficient transcriptome four tool pipeline analysis. EHA library; 2020. 294277 abstract.
34.
Chen IM, Harvey RC, Mullighan CG, Gastier-Foster J, Wharton W, Kang H, et al. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's oncology group study. Blood. 2012;119(15):3512–22.PubMedPubMedCentralCrossRef
35.
Harvey RC, Mullighan CG, Chen IM, Wharton W, Mikhail FM, Carroll AJ, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood. 2010;115(26):5312–21.PubMedPubMedCentralCrossRef
36.
Konoplev S, Lu X, Konopleva M, Jain N, Ouyang J, Goswami M, et al. CRLF2-positive B-cell acute lymphoblastic leukemia in adult patients: a single-institution experience. Am J Clin Pathol. 2017;147(4):357–63.PubMedCrossRef
37.
Yoda A, Yoda Y, Chiaretti S, Bar-Natan M, Mani K, Rodig SJ, et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2010;107(1):252–7.PubMedCrossRef
38.
Parsa C, Thompson A, Orlando R, Rupani R, Guo J. Novel KMT2A-ATP5L gene fusion in a young adult with rapidly progressive Ph-like t(9;12) acute B lymphoblastic leukemia. Hum Pathol. 2020;20:200359.
39.
Heatley SL, Sadras T, Kok CH, Nievergall E, Quek K, Dang P, et al. High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment. Haematologica. 2017;102(12):e490–3.PubMedPubMedCentralCrossRef
40.
Goekbuget N, Beck J, Brueggemann M, Burmeister T, Buss EC, Frickhofen N, et al. Moderate intensive chemotherapy including CNS-prophylaxis with liposomal Cytarabine is feasible and effective in older patients with Ph-negative acute lymphoblastic leukemia (ALL): results of a prospective trial from the German multicenter study Group for Adult ALL (GMALL). Blood. 2012;120:1493.CrossRef
41.
Roberts KG, Gu Z, Payne-Turner D, McCastlain K, Harvey RC, Chen IM, et al. High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults. J Clin Oncol. 2017;35(4):394–401.PubMedCrossRef
42.
Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019;133(14):1548–59.PubMedPubMedCentralCrossRef
43.
Cario G, Leoni V, Conter V, Attarbaschi A, Zaliova M, Sramkova L. 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. Haematologica. 2020;105(7):1887–94.PubMedPubMedCentralCrossRef
Metadata
Title
Low incidence of ABL-class and JAK-STAT signaling pathway alterations in uniformly treated pediatric and adult B-cell acute lymphoblastic leukemia patients using MRD risk-directed approach – a population-based study
Authors
Rimvydas Norvilas
Vaidas Dirse
Ruta Semaskeviciene
Orinta Mickeviciute
Egle Gineikiene
Mindaugas Stoskus
Goda Vaitkeviciene
Jelena Rascon
Laimonas Griskevicius
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-020-07781-6

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