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S. Jaramillo et al.
ed and unmutated state, which, however, does not seem to explain the unfavorable clinical prognosis.29,32,33
It has been reported that subset #2 has a higher progres- sion rate to disease requiring treatment and also a shorter OS.15,33,34 In our analysis, in both early and advanced stage CLL, m-subset #2 showed higher presence of del(11q) and unfavorable prognosis compared to other IGHV-mutated CLL cases. This difference was also observed in a multi- variate analysis, where m-subset #2 patients had a worse outcome compared to m-IGHV with regards to TTFT in early stage CLL, and TTNT in advanced stage CLL
patients. Our data showed for the first time in clinical studies that subset #2 is an independent prognostic factor for earlier TTFT in early stage CLL. There was a signifi- cant difference in TTFT between mutated subsets #2 and m-IGHV in both the univariate and multivariate analysis. This finding was also based on multiple validation analy- ses that corroborated our results. Therefore, it is safe to say that the conclusion is valid despite the small sample. No significant differences were observed between m-sub- set #2, m-IGHV3-21 and m-IGHV in early or advanced stage CLL in terms of PFS or OS. This implies that patients
AB
C
P<0.001
P=0.161 P=0.011
Figure 3. Outcomes of early stage chronic lymphocytic leukemia (CLL) cases according to subset #2 classification and IGHV mutation. (A) Median time-to-first-treatment (TTFT) for u-subset #2: 26.8 months, m- subset #2: 65.0 months, u-HV3-21: 45.7 months, m-HV3-21: not reached, u-IGHV: 51.4 months, m-IGHV: not reached. (B) Median pro- gression-free survival (PFS) from diagnosis for u-subset #2: 11.2 months, m-subset #2: 35.7 months, u-HV3-21: 29.8 months, m-HV3- 21: not reached, u-IGHV: 28.1 months, m-IGHV: 92.6 months. (C) Median overall survival (OS) from diagnosis for u-subset #2: not reached, m-subset #2: not reached, u-HV3-21: not reached, m-HV3-21: not reached, u-IGHV: not reached, m-IGHV: not reached; Cum: cumula- tive.
P=0.221
Table 3. Time-to-first-treatment (TTFT) Cox regression in early stage chronic lymphocytic leukemia (CLL) subsets # 1, 2 and 8.
Cox regression TTFT
U-CLL
M-CLL and subset #4
Yes
Yes
≥ 50
Univariable comparison
vs. Subset #1,2,8 vs. Subset #1,2,8
vs. no
vs. no vs.< 50
vs. > 12 months
Hazard ratio
Subset and IGHV analysis group 0.812
0.195 2.332 1.765
95% confidence interval Lower Upper
0.504 1.308 0.119 0.318
1.287 4.224 1.182 2.635 2.251 4.541 1.632 2.907
P
0.392 < 0.001
0.005
0.005 < 0.001 < 0.001
Deletion in 17p
Deletion in 11q
Leukocyte count (x 109/L) 3.197
2.178
≤ 12 months
TTFT: time to first treatment; U: unmutated; M: mutated; IGHV: immunoglobulin heavy variable; HR: hazard ratio.
Lymphocyte doubling time
2604
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