Poster Session I: Acute lymphoblastic leukemia - Biology & translational research
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.
To identify kinase and cytokine receptor pathway activating alterations and determine their clinical significance in uniformly treated B-ALL.
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.
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).
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.