39. Chronic lymphocytic leukemia with gain of 2p responds favorably to ibrutinib despite frequent co-occurrence with additional adverse cytogenetic markers

      Gain or amplification of the 2p14-16 region occurs in approximately 3-10% of chronic lymphocytic leukemia (CLL). The minimally gained region contains several genes of interest; including the NFKB subunit REL, nuclear transporter XPO1, and proto-oncogene BCL11A. Previous reports suggest that 2p gain is associated with poor overall survival, drug resistance, and increased risk of Richter's transformation. In recent years, the treatment paradigm for CLL has evolved. Tyrosine kinase inhibitors, such as ibrutinib, have become a standard therapy and previous studies have not addressed the role of 2p gain as a prognostic marker in this setting. Here we examined 2p gain in primarily previously treated patients enrolled across four ibrutinib clinical trials with extensive correlative studies and follow-up data available. FISH was performed on patient samples collected prior to starting therapy. Two hundred nuclei were enumerated for each patient using FISH probes targeting REL (2p) and DIRC (2q). 2p gain was observed in 44 (14.9%) of 296 patients. Presence of 2p gain was significantly associated with other adverse cytogenetics, including BCL6 (p=0.009) as well as MYC abnormalities (p= 0.004) by FISH, and complex karyotype (≥ 3 unrelated chromosome abnormalities, p=0.03). With a median follow-up of 60 months, cumulative incidence of CLL progression and Richter's transformation was similar in patients with gain of 2p compared to those without (p=0.10 and p=0.66, respectively). In comparison with no 2p gain, patients with gain of 2p had no significant difference in progression-free survival (p=0.94) and overall survival (p=0.81). While 2p gain has previously been associated with poor survival and risk for Richter's transformation, we found no significant association with these outcomes in an ibrutinib-treated cohort. Gain of 2p frequently co-occurred with other adverse cytogenetic abnormalities, which may contribute to the previously described negative outcomes associated with 2p gain.
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