The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL
Authors: Haferlach Claudia , Zenger Melanie , Grossmann Vera , Dicker Frank , Jeromin Sabine , Kohlmann Alexander , Schnittger Susanne , Kern Wolfgang , Haferlach Torsten 
Published: October 2019

Abstract
Abstract 3892

Background:
13q deletions (del(13q)) are the most frequent abnormalities in CLL and, if present as a sole abnormality, associated with favorable outcome. Since the size of the deletion varies considerably, class I (del(13q) not including the RB1 locus) and class II (del(13q) including the RB1 locus) deletions were defined. Previous data suggested that class II deletions were associated with genomic complexity and an unfavorable clinical course. However, confirmation in a large patient cohort was lacking.

Aim:
Cytogenetic and molecular genetic characterization of patients with class I and class II deletions and evaluation of the impact on outcome.

Patients and Methods:
263 cases with newly diagnosed CLL and del(13q) were analyzed by FISH using probes for RB1, D13S25, D13S319 (13q14), ATM (11q22), TP53 (17p13), SEC63 (6q21) and 12 cen. Data from chromosome banding analyses (CBA) (n=263), IGHV mutation status (n=230) and TP53 mutation status (n=206) were also available.

Results:
145/263 patients (55.1%) showed a class I and 118 cases (44.9%) a class II deletion. In 79/263 patients (30%) a homozygous del(13q) was observed. No significant difference in frequency of homozygous deletions was observed between cases with class I vs class II deletions (48/145 (33.1%) vs 31/118 (26.3%)).

Abnormalities in addition to del(13q):
Based on FISH data 66 cases (25.1%) showed abnormalities in addition to del(13q) (del(6q): 5, del(11q): 28, +12: 27, del(17p): 11). The frequency of additional abnormalities did not differ between patients with class I vs class II deletions (25.5% vs 24.6%). Considering also CBA 101 patients (38.4%) showed additional abnormalities. A complex karyotype defined as 3 or more abnormalities in addition to del(13q) was observed in 34 cases (12.9%) and was more frequent in cases with class II deletion (17.8% vs 9.0%, p=0.042). The mean number of abnormalities per case was significantly higher in patients with class II deletions (1.25 vs 0.7, p=0.002). Patients with homozygous del(13q) less frequently showed additional chromosome abnormalities compared to patients with heterozygous del(13q) (22.8% vs 45.1%, p=0.001).
IGHV mutation status: In the total cohort, 156/230 patients (67.8%) showed a mutated and 74 (32.2%) an unmutated IGHV status. No difference with respect to the IGHV mutation status was observed between class I vs class II cases. However, an unmutated IGHV status was more frequent in cases with additional abnormalities detected by FISH or CBA compared to those without (52.6% vs 25.4%, p<0.0001 and 48.3% vs 22.4%, p<0.0001). A mutated IGHV status was more frequent in patients with homozygous as compared to heterozygous del(13q) (81.2% vs 62.1%, p=0.005).
TP53 mutation status: TP53 mutations were observed in 15/206 cases (7.3%). The TP53 mutation frequency did not differ between class I vs class II patients (6.9% vs 7.8%). However, TP53 mutations were more frequent in cases with additional abnormalities detected by FISH or CBA as compared to those without (18.8% vs 3.8%, p=0.002 and 13.2% vs 3.8%, p=0.023), in cases with complex karyotype (19.2% vs 5.6%, p=0.027), and in cases with TP53 deletions detected by FISH as compared to those without (70.0% vs 4.1%, p<0.0001).

Overall survival and time to treatment:
OS at 3 yrs in the total cohort was 94% (median time of follow-up of 3.0 yrs). Only Binet stage B/C was significantly associated with shorter OS (p=0.014; relative risk (RR): 6.56). A trend for shorter OS was observed for additional TP53 mutations and/or deletions, while no difference in OS was observed between class I vs class II and homozygous vs heterozygous deletions. The following parameters were associated with longer TTT: no additional abnormalities present in CBA or FISH (p=0.009; RR: 0.55; p=0.010; RR: 0.54), and a mutated IGHV status (p<0.0001; RR: 0.381). A complex karyotype (p=0.040; RR: 1.80) and ATM deletions (p=0.013; RR: 2.04) were associated with shorter TTT.

Conclusions:
1. Neither the size nor homozygosity of del(13q) showed impact on OS or TTT. However, a mutated IGHV status and the absence of additional abnormalities were associated with longer TTT. Patients with an additional del(11q) or a complex karyotype showed shorter TTT. 2. A complex karyotype was significantly associated with class II deletions. 3. CLL with del(13q) can be further subdivided by the RB1 deletion status, additional chromosome abnormalities based on CBA and IGHV mutation status.

Disclosures:
Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.