KINASE AND CYTOKINE RECEPTOR SIGNALING PATHWAY ACTIVATING ALTERATIONS IN UNIFORMLY TREATED B-ALL
Author(s): ,
Rimvydas Norvilas
Affiliations:
Hematology, Oncology and Transfusion Medicine Center,Vilnius University Hospital Santaros Klinikos,Vilnius,Lithuania;Department of experimental, preventive and clinical medicine,State Research Institute Centre for Innovative Medicine,Vilnius,Lithuania
,
Vaidas Dirsė
Affiliations:
Hematology, Oncology and Transfusion Medicine Center,Vilnius University Hospital Santaros Klinikos,Vilnius,Lithuania;Institute of Clinical Medicine,Vilnius University,Vilnius,Lithuania
,
Rūta Semaškevičienė
Affiliations:
Hematology, Oncology and Transfusion Medicine Center,Vilnius University Hospital Santaros Klinikos,Vilnius,Lithuania
,
Orinta Mickevičiūtė
Affiliations:
Hematology, Oncology and Transfusion Medicine Center,Vilnius University Hospital Santaros Klinikos,Vilnius,Lithuania
,
Goda Vaitkevičienė
Affiliations:
Center for Pediatric Oncology and Hematology,Children's Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos,Vilnius,Lithuania
,
Jelena Rascon
Affiliations:
Center for Pediatric Oncology and Hematology,Children's Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos,Vilnius,Lithuania
Laimonas Griškevičius
Affiliations:
Hematology, Oncology and Transfusion Medicine Center,Vilnius University Hospital Santaros Klinikos,Vilnius,Lithuania;Institute of Clinical Medicine,Vilnius University,Vilnius,Lithuania
EHA Library. Norvilas R. Jun 14, 2019; 265958; PF168
Mr. Rimvydas Norvilas
Mr. Rimvydas Norvilas
Contributions
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Abstract

Abstract: PF168

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background

Recent B-acute lymphoblastic leukemia (B-ALL) studies revealed a new subgroup of patients with ABL-class and JAK-STAT fusions which can be targeted using small-molecule inhibitors (Roberts et al., 2017). Positivity for ABL-class or JAK-STAT fusions was associated with positive post-induction minimal residual disease (MRD) (Pui et al., 2017) and inferior outcome (Boer et al, 2017) but most studies were conducted in non-uniformly treated patient populations. 

Aims
To identify kinase and cytokine receptor pathway activating alterations and determine their clinical significance in uniformly treated B-ALL.

Methods
The study includes 160 BCR-ABL1-negative B-ALL (122 pediatric, 38 adults (≥18 y/o)) patients treated according to MRD-driven pediatric-adult NOPHO ALL-2008 protocol. 101 B-ALL cases (including high hyperdyploids and low hipodyploids) without canonical B-ALL aberrations were selected for targeted RNA-Sequencing (RNA-Seq). Sequencing was performed using TruSight Pan-Cancer sequencing panel (Illumina Inc., CA). FISH analysis was used to identify CRLF2-IGH gene rearrangements.

Results
Of 101 B-ALL patients (75 pediatric, 26 adults), RNR-Seq and FISH analysis identified three (3%) cases with ABL-class (ABL1-ETV6, ABL2-ZC3HAV1, PDGFRB-EBF1) fusions and four (4%) cases with JAK-STAT fusions (JAK2-BCR, n=1; CRLF2-IGH, n=3). Five of seven ABL-class and JAK-STAT mutually exclusive fusions were detected in adults. Remaining ten (9.9%) gene fusions were identified in the pediatric group, of which five cases had PAX5 gene and three had ZNF384 gene rearrangements.

Gene mutation analysis detected Ras pathway mutations in a total of 48 (47.5%) cases: NRAS (n=28), KRAS (n=17), PTPN11 (n=7). Other JAK-STAT and FLT3-TKD gene mutations were present in 10 (9.9%) and 8 (7.9%) cases, respectively. Thirty-seven (36.6 %) patients harbored other gene variants (n=23) or had no recurrent gene variants/fusions (n=14) detected by RNA-Seq.

ABL-class and JAK-STAT fusions were more frequent among adults than pediatric patients (19.2% vs. 2.7%) while ABL-class fusions were exclusive to adults (p=0.032). The prognostic analysis was restricted to the adult group. More adult patients with ABL-class or JAK-STAT fusions had positive post-induction day 29 MRD values compared to negative patients (p<0.001) and were more frequently assigned to NOPHO-2008 high-risk groups or had induction failure (80% vs 30.3%, p=0.05). 75th percentile event-free (EFS) and overall survival (OS) were 5 vs. 35 (p=0.008) and 15 vs. 37 (p=0.07) months in ABL-class or JAK-STAT fusion positive vs. negative adult groups, respectively.

In multivariate analysis, the positivity for ABL-class or JAK-STAT fusions was an independent risk factor for worse EFS (p=0.032) but not for OS (p=0.242).

Conclusion
Overall, ABL-class and JAK-STAT fusions were infrequent and were more often detectable in adults compared to children. Adult patients with ABL-class or JAK-STAT fusions had higher post-induction MRD values and were more frequently assigned to high-risk disease groups or had induction failure resulting in lower event-free survival. 

Session topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): B cell acute lymphoblastic leukemia, Mutation analysis

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