PF357 A NOVEL REFINED PROGNOSTIC MODEL FOR CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS COMBINING IGH TRANSLOCATIONS AND NEXT-GENERATION SEQUENCING
Authors: C. Pérez-Carretero, M. Hernández-Sánchez, T. González-Martínez, M. Quijada-Álamo, M. Martín-Izquierdo, J.M. Hernández-Sánchez, S. Santos-Minguez, M.J. Vidal-Manceñido, A. García-Coca, C. Aguilar-Franco, M. Vargas-Pabon, S. Alonso-Álvarez, M. Sierra-Pacho, A. Rubio-Martínez, J. Dávila-Valls, J.R. Díaz-Valdéz, J.A. Queizán-Hernández, J.A. Hernández-Rivas, R. Benito-Sánchez, A.E. Rodríguez-Vicente, J.M. Hernández-Rivas
Journal: HemaSphere (2019)

Background: Chromosome 14q32 translocations involving the immunoglobulin heavy chain gene (IGH) are uncommon in chronic lymphocytic leukemia (CLL) patients. The outcome of CLL patients with IGH translocations (IGHR) is controversial. Moreover next-generation sequencing (NGS) has expanded our knowledge of the genomic alterations and their clinical impact in CLL, the mutational background of IGHR-CLLs is still unknown. Aims: To analyze the mutational landscape of IGHR-CLLs by NGS to assess their genetic signature and the clinical implications. Methods: The study included 870 CLL patients well-characterized at clinical level. Median follow up was 60 months (0–340). A targeted-capture NGS strategy was used to analyze the mutational status of 54 CLL-related and recurrent mutated genes (NextSeqSeq, Illumina). 97% of regions were sufficiently covered (>100X) and the mean depth was 600X. The translocated partner in IGHR-CLLs was assessed by RNA sequencing (TakaraBio). NGS was performed in 231 samples: 117 with 13q-, 27 11q-, 26 +12, 43 with IGHR and 18 with normal FISH (NF). Results: 1. IGHR-CLLs showed an intermediate-poor prognosis, with median time to first treatment (TFT) shorter than low-risk patients (13q-/NF) (19 vs 124 months; p < 0.0001), longer than high-risk patients (11q-/17p-) (19 m vs 5 m; p = 0.03) and similar to +12 (19 m vs 28 m; p = 0.37). A total of 101 mutations located in 35 genes were identified in IGHR-CLLs.79% of patients (34/43) harbored at least one mutation. The most frequently mutated genes were NOTCH1 (28%), SF3B1, IGLL5 and POT1 (14% each), TP53, FBXW7 and MGA (9.3% each), BCL2, BRAF and EGR2 (7% each). Of note, the presence of mutations in NOTCH1, FBXW7, MGA, BCL2, BRAF and EGR2 were associated with IGHR-CLLs (p = 0.032, p = 0.012, p = 0.020, p = 0.021, p = 0.046 and p = 0.046). 2. Patients with t(14;18) (IGH/BCL2): a) had a lower mutation rate than non-t(14;18) cases within IGHR-CLLs (0.5 m vs 2 m, p = 0.049); and b) were enriched in BCL2 and IGLL5 mutations (25%). Interestingly, the presence of these mutations was associated with a better outcome (median TFT >120 m vs 10 m p = 0.038), that could be related with the longer TFT observed in t(14;18) patients (56 m vs 4 m, p = 0.05). 3. BRAF mutations were significantly associated with shorter TFT in IGHR-CLLs (2 m vs 21 m, p = 0.044). Interestingly, the presence of mutations in this gene, together with NOTCH1, TP53, SF3B1 or BIRC3 mutations (previously associated with bad prognosis) was independently related to shorter TFT (HR 0.265, CI95% 0.08–0.9, p = 0.018). 4. Low-risk CLL patients (13q-/NF) and intermediate risk patients (IGHR/+12) in our series, were better stratified into two different subgroups each according to the presence of the 5-mutated genes (median TFT>120 m vs 24 m; p < 0.0001, 52 m vs 2 m; p < 0.0001) (Figure1). Therefore, this model allowed to reclassify 26% (35/135) of low-risk patients into an intermediate-risk subgroup, and 50% (35/70) of intermediate-risk patients into a high-risk subgroup in our series.Summary/Conclusion: 1. IGHR-CLLs had an intermediate-negative outcome and a distinct mutational profile. 2. IGH/BCL2 translocation had lower mutation frequency, with mutations in IGLL5 and BCL2, associated to longer TFT. 3.NOTCH1, TP53, SF3B1, BIRC3 and BRAF mutations had a negative clinical impact in IGHR-CLLs. 4. Integrative cytogenetic and mutational model including IGHR and BRAF mutations allowed to better define the prognosis of CLL patients.