PF168 KINASE AND CYTOKINE RECEPTOR SIGNALING PATHWAY ACTIVATING ALTERATIONS IN UNIFORMLY TREATED B‐ALL
Authors: Norvilas R. , Dirsė V. , Sema‐kevičienė R. , Mickevičiūtė O. , Vaitkevičienė G. , Rascon J. , Griškevičius L. 
Published: June 2019

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).

Summary/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.