Pediatric B-lineage acute lymphoblastic leukemia with CRLF2 rearrangements. Own experience in molecular genetic diagnostics and patient monitoring

B-lineage acute lymphoblastic leukemia (ALL) with CRLF2 rearrangements is characterized by high genetic heterogeneity and can be accompanied with mutations in the JAK-STAT signaling pathway, intrachromosomal amplification of chromosome 21 (iAMP21), dic (9;20), as well as IKZF1 deletions and has an unfavorable outome. Purpose. To characterize clinical, immunological and molecular genetic features of children with B-lineage ALL with CRLF2 rearrangements. Materials and methods. The study included 958 children aged 1-18 years with primarily diagnosed B-lineage ALL. Among them, a search for CRLF2 rearrangements was carried out using the fluorescence in situ hybridization, and the spectrum of genetic aberrations was analyzed using multiplex ligase-dependent probe amplification (MLPA) and targeted next-generation sequencing of RNA. Results. CRLF2 rearrangements were detected in 58 (6.1%) patients, including 42 with P2RY8::CRLF2 (72.4%) and 16 with IGH::CRLF2 (27.6%). Patients with IGH::CRLF2 fusion gene were significantly older, more often had an initial WBC ≥50×109/L and were significantly more often classified as high-risk according to the criteria of the US National Cancer Institute, however no significant differences in survival and cumulative incidence of relapse between these groups were found. JAK1/2 mutations were detected in 14.0% of CRLF2-rearranged patients, RAS family gene mutations in 23.3% and PAX5 alterations (both point mutations and fusion genes) in 18.6%. Seventeen patients (37.7%) with IKZF1 deletions were identified, while 10 of them (22.2%) had the IKZF1plus profile. With a median follow-up time of 5.3 years, the event-free survival of patients with ALL and CRLF2 rearrangements was 0.49 (standard error (SE) 0.22) and the cumulative incidence of relapse was 0.46 (SE 0.12). The most unfavorable outcome was observed in patients with IKZF1plus profile. Of note, the persistence of minimal residual disease at the end of remission induction did not have a statistically significant impact on the prognosis of patients with ALL and CRLF2 rearrangements. Conclusions. In our cohort of pediatric patients with B-lineage ALL the incidence of CRLF2 rearrangements was 6.1%. These patients showed significant genetic heterogeneity and unfavorable outcome.