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Impact of translocations in mutated IGHV CLL at diagnosis
117 (79.1%) had non-complex karyotypes. Of the 144 patients with mutated IGHV, 20 (13.9%) had a transloca- tion, 124 (86.1%) did not have a translocation, 12 (8.3%) had complex karyotypes, and 132 (91.7%) had non-com- plex karyotypes.
Outcome
The median follow-up for censored patients was 30 months (range, 0.03-102 months). The median TFT for the entire cohort was 47 months (95% confidence interval [95% CI]: 39-61 months). Higher karyotype complexity was significantly associated with TFT (hazard ratio [HR]=1.16, 95% CI: 1.11-1.22; P<0.001), as was complex karyotype defined using ≥3 aberrations (HR=2.92, 95% CI: 1.98-4.31; P<0.001) and ≥5 aberrations (HR=2.93, 95% CI: 1.79-4.79; P<0.001). Since there was no difference in the ability to discriminate TFT when defining complexity as ≥3 or ≥5 aberrations (Online Supplementary Table S1, Online Supplementary Figure S1), all further analyses used the definition of ≥3 abnormalities.
In univariable models, the following variables were sig- nificant for a shorter TFT: presence of a translocation (HR=2.64, 95% CI: 1.87-3.71; P<0.001), Rai stage 3-4 (HR=3.73, 95% CI: 2.32-5.99; P<0.001), karyotype com- plexity (HR=2.92, 95% CI: 1.98-4.31, P<0.001), unmutat- ed IGHV (HR=3.48, 95% CI: 2.38-5.08; P<0.001), three copies of MYC (HR=2.53, 95% CI: 1.36-4.71; P=0.003), del(17p) (HR=2.10, 95% CI: 1.31-3.37; P=0.002), del(11q) (HR=2.92, 95% CI: 1.98-4.31; P<0.001), b2-microglobulin >3.5 mg/L (HR=2.33, 95% CI: 1.11-4.88; P=0.025), and log-transformed WBC count (HR=1.72, 95% CI: 1.35- 2.20; P<0.001) (Table 1).
In the multivariable regression model, there was signifi-
cant effect modification of IGHV status on the relation- ship between translocations and TFT (P=0.002) (Table 4). In IGHV-mutated patients, those with a translocation had over 3.5 times the risk of starting treatment relative to those without a translocation (HR=3.53, 95% CI: 1.76- 7.06; P<0.001); however, in IGHV-unmutated patients, a translocation did not significantly increase the risk of start- ing treatment (HR=1.00, 95% CI: 0.61-1.64; P=0.99) (Figure 1). This effect modification appears consistent across groups defined by complex karyotype (Online Supplementary Figure S2). We did not detect a significant interaction between IGHV and karyotype complexity (Figure 2A), nor between translocations and complexity (Figure 2B). Examination of both the presence of a translo- cation and karyotype complexity in the analysis of TFT showed that among the 85 patients with a translocation, karyotype complexity added prognostic information (HR=2.31, 95% CI: 1.25-4.26; P=0.007). Independently of IGHV status and translocations, Rai stage 3-4 (HR=1.78, 95% CI: 1.06-2.98; P=0.029), log-transformed WBC count (HR=1.44, 95% CI: 1.13-1.85; P=0.004) and karyotype complexity (HR=1.78, 95% CI: 1.08-2.93; P=0.025) remained statistically significant in the multivariable model (Table 4). Notably, once these variables were accounted for in the model, del(17p) did not add signifi- cant information (P=0.51). Using a higher frequency of del(17p) with a 20% cut off, del(17p) still was not signifi- cant in the multivariable analysis (P=0.51). Similarly, del(11q) was no longer significant in the multivariable model.
Among 139 patients who started CLL treatment, 54 received chemoimmunotherapy. With a median follow-up of 43.9 (range, 3.4-94.0) months from the start of CLL
Table 2. Association between karyotype complexity (≥3 aberrations) and translocations. Unbalanced translocations are more frequent in patients with complex karyotypes, but balanced translocations are more frequent in those with non-complex karyotypes.
Translocation No Translocation Total Total Balanced Unbalanced
Complexkaryotype 46 5 41 7 53
Non-complex karyotype 39 24 15 237 276
Total 85 29 56 244 329
Table 3. Associations of IGHV with karyotype complexity (≥3 aberrations) and translocations. Translocations and complex karyotypes occur more frequently in unmutated IGVH chronic lymphocytic leukemia.
Mutated IGHV
Unmutated IGHV
Total
132 144
117 148
249 292
P-value 0.002
0.025 0.004 0.029
Translocation No Translocation
20 124
51 97
71 221
Complex karyotype
12
31
43
Non-complex karyotype Total
mIGHV, mutated IGHV; unmIGHV. unmutated IGHV
Table 4. Multivariable model of factors significantly associated with time to first treatment.
Characteristics
IGHV mutated: translocation present vs. absent
HR
3.53 1.00 1.78 1.44 1.78
95% CI
1.76-7.06 0.61-1.64 1.08-2.93 1.13-1.85 1.06-2.98
IGHV unmutated: translocation present vs. absent
Karyotype complexity, ≥3 abnormalities: present vs. absent
WBC (log-transformed)
Rai stage: 3-4 vs. 0-2
HR: hazard ratio; 95% CI: 95% confidence interval; WBC: white blood cell count.
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