Rearrangement of 14q32 in the Absence of t(14;18) Is Associated with Short Time to First Treatment in Chronic Lymphocytic Leukemia
Authors: Davids Matthew S. , Vartanov Alexander R. , Werner Lillian , Neuberg Donna , Cin Paola Dal , Brown Jennifer R 
Published: October 2019

Abstract
Abstract 1438
The hierarchical cytogenetic classification for chronic lymphocytic leukemia (CLL) provides a valuable prognostic framework validated in several studies; however, the relationship between these cytogenetic abnormalities and IGHV and ZAP-70 has not been as well studied. Less is also known about the prognostic significance of different 14q32 rearrangements and combined cytogenetic abnormalities. We retrospectively examined cytogenetic abnormalities in 576 CLL patients seen at the Dana-Farber Cancer Institute between 2005 and the present. Interphase FISH analysis was performed using commercial probe sets (Abbott Molecular, Des Plaines, IL, USA) including P53/ATM, 12cen/13q14.1, and CCND1-IGH to exclude mantle cell lymphoma and identify chromosome 14q32 rearrangements, which were further evaluated with a t(14;18) probe. t(14;18) was evaluated separately from other 14q32 rearrangements. Fisher's exact test was used to assess the association of ZAP-70 and IGHV mutation status with cytogenetics. Median time to first treatment (TTFT) was summarized using Kaplan Meier estimates. In univariate analysis, the log rank test was used to assess associations of TTFT and cytogenetics, and in multivariable analysis, a Cox regression model was used. P-values were not adjusted for multiplicity of testing. The median age at diagnosis was 55 (range 25–86). At time of analysis, 43% (n=247) of patients had been treated, and 78% (n=452) of patients were still alive. Of 432 patients tested, 57.4% (n=248) had mutated IGHV, and of 420 patients tested, 42% (n=243) were ZAP-70 positive. Cytogenetic abnormalities of the 576 patients are summarized in table 1. Patients with 2 abnormalities were classified as the poorer risk abnormality by the Dohner hierarchy. The del(13q) group was significantly associated with negative ZAP-70 status (p = 0.003), whereas del(11q) was associated with positive ZAP-70 (p=0.02). A significant association was observed between unmutated IGHV and del(17p), del(11q), and trisomy 12 (p < 0.001 for each), and with complex cytogenetics (p = 0.03), whereas del(13q) had a significant association with mutated IGHV (p < 0.0001). In univariate analysis, a shorter median TTFT was associated with del(17p) vs. other (44 vs. 77 months, p = 0.0006), del(11q) vs. other (22 vs. 77 months, p < 0.0001), and 14q32 rearrangement vs. other (44 vs. 76 months, p=0.001), whereas a longer TTFT was observed for del(13q) vs. other (131 vs. 51 months, p < 0.0001). Of note, TTFT was not associated with trisomy 12 (p=0.20), trisomy 12 + del(13q) (p=0.61), IgH t(14;18) (p=0.57), normal cytogenetics (p=0.27), or complex cytogenetics (p=0.15). TTFT was similar between patients with mono-allelic, bi-allelic, or mixed del(13q) (131, 103, or 153 months, respectively, p = 0.97). In multivariable analysis, adjusting for ZAP-70 and IGHV, shorter TTFT was independently associated with 14q32 rearrangement (HR 2.51, 95% CI (1.41, 4.45), p=0.002) and del(17p) (HR 1.53, 95% CI (1.0, 2.33), p = 0.047). Del(13q) remained independently associated with longer TTFT (HR 1.97, 95% CI (1.40, 2.77), p < 0.0001). Overall, we show that high risk abnormalities such as del(17p) and del(11q) are associated with unmutated IGHV status and shorter TTFT, and that low risk del(13q) is associated with mutated IGHV, negative ZAP-70 status, and longer TTFT. Also, TTFT is similar between mono- and biallelic del(13q). Interestingly, trisomy 12 was highly associated with unmutated IGHV, but not shorter TTFT, suggesting that trisomy 12 may somehow mitigate the risk of unmutated IGHV. In contrast, 14q32 rearrangement was not associated with either IGHV or ZAP-70, but did predict a short TTFT of 44 months. This suggests that 14q32 rearrangement may hasten the need for treatment, regardless of IGHV or ZAP-70 status. Notably, 14q32 rearrangement due to t(14;18) did not confer increased risk of requiring early therapy. Ongoing analysis will assess overall survival for these cytogenetic abnormalities.Table 1.Cytogenetic abnormalities in 576 CLL patientsCytogenetic Abnormalityn%TTFT (months)del(13q)–total27548131· del(13q x 1)–mono-allelic18667.6% of del(13q)131· del(13q x 0)–bi-allelic238.4% of del(13q)103· del(13q)–mixed5118.5% of del(13q)153Normal701268Trisomy 12631154Trisomy 12 + del(13q)19353Del(17p)47844Del(11q)4172214q32 rearrangement25444IgH t(14;18)19395Complex (3 or more abnormalities)17358

Disclosures:
No relevant conflicts of interest to declare.