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Chronic lymphocytic leukemia with trisomy 12
Table 1. Clinical and laboratory characteristics at diagnosis of patients with +12 chronic lymphocytic leukemia.
Characteristic
Age (range), years
Male sex
Binet stage A
Binet stage B
Binet stage C
Median white blood cell count, x109/L Absolute lymphocyte count, >30*109/L Splenomegaly
Hepatomegaly
González-Gascón y Marín (n=289)82
68 (22-88)
61.6% 71.1% 23.6% 5.4%
19 (4.5-294.2) 16.8%
15.5%
5.7%
28.9%a
53.8%
37.4%
55.8%
3.9%
6.1%
17.0%
Strati (n=250)25
60 (32-87)
58.8% 71% 13% 16%
18 (2-681) 26.0% 16.0% 6.0% 18.1%b 55.1% 55.0% 45.1%
0%
0%
17.6%
Del Giudice (n=104)91
65 (56-72)
54 (52%)
36% Binet B to C 36% Binet B to C
58.0%
8.0% 5.0% 18.0%
Falisi (n=44)33
62.8 (45-86)
32 (73%)
70.6%
4.5% 2.3% 9.1%
High β microglobulin 2
Unmutated IGHV CD38 positivity ZAP-70 positivity +12 and del11q +12 and del17p +12 and del13q
aHigh β2 microglobulin level defined as above normal range. bHigh β2 microglobulin level defined as ≥4 mg/L.
mon in the del11q subgroup and second most common in the +12 subgroup, which had poor outcomes with the second shortest TTFT. ATF5 may be a key gene responsi- ble for inducing cell proliferation in CLL patients, and it may explain the mechanisms of disease progression due to cytogenetic abnormalities in these patients.97
TTFT and OS in patients with +12 CLL
Few reports detail the clinical outcomes of CLL cases with +12. Characteristics of the patients in these main series are summarized in Table 1.25,33,82,91 Here, we review data from the two largest series of patients with +12 CLL published so far. Outcomes from these studies are sum- marized in Table 2.
A multicenter analysis by González-Gascón y Marín et al. included 2561 patients diagnosed with CLL from 25 Spanish institutions, of whom 289 (11.3%) patients showed +12 at diagnosis; the analysis excluded patients with monoclonal B-cell lymphocytosis, patients who acquired +12 as clonal evolution, and patients with inad- equate follow up.82 +12 patients had a median TTFT of 42 months (95%CI: 34-49 months) and a median OS of 129 months (95%CI: 100-158 months). The findings in this series are similar to those of previous studies that includ- ed a lower frequency of +12 cases, approximately 15- 20%, with a median TTFT of 32 months and a median OS of 111 months.18 These patients were a median 68 years old, were predominantly male, and had a high fre- quency of low lymphocyte counts (83%), low β2 microglobulin levels (71%), early Binet stage (71%), low levels of CD38 (63%), and an absence of significant organomegaly.
González-Gascón y Marín et al.82 correlated the propor- tion of +12 CLL cells with prognosis and identified 60% as the cut-off value associated with survival. One hun- dred and seventy-four patients (60.2%) carried +12 in less than 60% of cells, whereas 115 patients (39.8%) carried
+12 in 60% or more of cells. The patients with +12 in 60% or more of cells had more marked leukocytosis (P=0.001), higher lymphocyte counts (P=0.006), higher levels of serum lactate dehydrogenase (P=0.03), more pronounced splenomegaly (P=0.001), and more advanced Binet stage (P=0.04). In the cohort of 289 +12 patients, 175 (60.6%) required treatment initiation. The patients with +12 in less than 60% of cells had a lower rate of treatment initiation and longer TTFT (51.2% with a median TTFT of 49 months) than did patients with +12 in 60% or more of cells (75.7% with a median TTFT of 30 months; P<0.001) in both univariate and multivariate analyses. At the time of analysis, 69 patients (23.9%) had died, and there was a significant difference in frequency of deaths (P=0.009) between patients with less than 60% +12 cells (16.7% with a median OS of 159 months) and patients with 60% or more +12 cells (29.6% with a medi- an OS of 96 months). On multivariate analysis, only Binet stage (P=0.04), del11q in addition to +12 (P=0.01), and high β2 microglobulin levels (P=0.03) were significantly associated with shorter OS. TTFT and OS were shorter in +12 and del11q patients compared with those with +12 as a unique aberration (23 months vs. 44 months, P=0.02 for TTFT; 44 months vs. 159 months, P=0.02 for OS), but no difference could be found in TTFT or OS when +12 was accompanied by del17p or del13q.
Strati et al. analyzed a single-center experience of 250 untreated CLL patients with +12 followed for nine years and compared their outcomes with those of 516 treat- ment-naïve CLL patients who lacked common recurrent abnormalities on FISH analysis (negative for del11q, del13q, del17p, and +12), evaluated at the same institu- tion during the same period.25 On multivariate analysis, factors significantly associated with +12 were a platelet count of less than 100x109/L [odds ratio (OR) 2.4; P=0.03], positivity for CD38 (OR 2.4; P=0.001), and a Matutes score of less than 4 (OR 2.4; P<0.001). At a median follow
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