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A gain of function mutation in the enhancer of zeste homolog 2 (EZH2) has been associated with the development of both follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell-like type. EZH2 is the catalytic center of the polycomb repressive complex 2 (PRC2) that is responsible for gene silencing via histone methylation.1 You can read more about this topic, here.
Inhibition of EZH2 has demonstrated promising clinical activity in patients with FL, contributing to the plethora of novel targeted agents in FL. However, there remains little information regarding the role of EZH2 expression in mantle cell lymphoma (MCL), and so Diana Martinez-Baquero and colleagues sought to evaluate the prevalence of EZH2 mutations in a MCL population.1
Of the 166 patients with MCL who were identified, 29 (17%) were women; the median age of the cohort was 61 years (39‒88). Table 1 lists the baseline characteristics for the total cohort.
Table 1. Baseline characteristics*
Characteristic |
Total cohort |
---|---|
Age, years, n (%) |
|
<60 |
75 (45) |
≥60 |
91 (55) |
Site, n (%) |
|
Lymph node |
125 (75) |
Spleen |
5 (3) |
Tonsils |
14 (8) |
Extranodal sites |
22 (13) |
Stage, n (%) |
|
I/II |
13 (8) |
III/IV |
146 (92) |
MIPI score, n (%) |
|
Low |
59 (45) |
Intermediate |
42 (32) |
High |
29 (22) |
Pathology, n (%) |
|
Classic |
99 (60) |
Aggressive |
67 (40) |
Pattern, n (%) |
|
Mantle zone |
2 (1) |
Diffuse |
88 (53) |
Nodular |
76 (46) |
Treatment regimen, n |
|
hyperCVAD ± rituximab |
106 |
CHOP ± rituximab |
31 |
Bendamustine + rituximab |
5 |
Observation |
14 |
Not available |
10 |
CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; MIPI, mantle cell lymphoma-international prognostic index. |
Treatment response was available for 142 of the 166 patients:
EZH2 expression (≥40%) was seen in 57 (38%) of the 150 patients in whom it was assessed; when compared with EZH2-negative patients, those with EZH2-positive MCL had more aggressive histology, high Ki-67 proliferation rate, and p53 overexpression (all p <0.001; Table 2). No significant associations were observed between EZH2 expression and other patient/disease characteristics.
Table 2. Clinicopathologic features associated with EZH2 expression in patients with MCL*
Characteristic |
EZH2+ |
EZH2− |
p value |
---|---|---|---|
Female gender, n |
10 |
15 |
0.8214 |
Age, years, median (range) |
61 (42‒87) |
60 (39‒88) |
0.347 |
<60, n |
28 |
47 |
0.8664 |
≥60, n |
29 |
46 |
|
Site, n |
0.6317 |
||
Lymph node |
44 |
69 |
|
Spleen |
3 |
2 |
|
Tonsils |
4 |
8 |
|
Extranodal sites |
6 |
14 |
|
Stage, n (%) |
0.7675 |
||
I/II |
5 (9) |
7 (8) |
|
III/IV |
50 (91) |
82 (92) |
|
MIPI, n (%) |
0.2839 |
||
Low |
18 (42) |
38 (50) |
|
Intermediate |
13 (30) |
26 (34) |
|
High |
12 (28) |
12 (16) |
|
Pathology, n (%) |
<0.0001 |
||
Classic |
20 (35) |
66 (71) |
|
Aggressive |
37 (65) |
27 (29) |
|
Pattern, n (%) |
0.2826 |
||
Mantle zone |
0 (0) |
2 (2) |
|
Diffuse |
33 (58) |
44 (47) |
|
Nodular |
24 (42) |
47 (51) |
|
Biomarkers, n (%) |
|||
SOX11+ |
48/49 (98) |
64/67 (96) |
0.4774 |
Ki-67 high |
41/57 (72) |
17/91 (19) |
<0.0001 |
P53 overexpression |
15/35 (43) |
1/48 (2) |
<0.0001 |
CD5+ |
57/57 (100) |
86/91 (95) |
0.1568 |
CD10+ |
2/38 (5) |
0/71 (0) |
0.1194 |
MHC-I loss |
1/40 (3) |
0/56 (0) |
0.1734 |
MHC-II loss+ |
3/36 (8) |
4/50 (8) |
>0.9999 |
MIPI, mantle cell lymphoma-international prognostic index. |
When compared with other components of the PRC2 complex—embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12), specifically—there was a weak correlation with EZH2 expression. No correlation was found between EZH2 expression and expression of trimethylated histone 3 at lysine 27 (H3K27me3), another component of PRC2, nor between EZH2 expression and loss of MHC-I or MHC-II (Table 2).
Survival data was available for 148 patients, with a median follow up of 5.3 years. Inferior overall survival (OS) was seen in patients with EZH2 expression compared to those without EZH2 expression (median OS, 3.9 years and 9.4 years, respectively; p <0.001), though there was no significant difference in relapse-free survival (RFS) between these groups (median RFS, 3.8 years and 2.7 years, respectively; p = 0.7430).
On the subgroup analysis by treatment regimen:
On the subgroup analysis by histology:
EZH2 expression, high (≥30%) Ki-67 proliferation rate, p53 overexpression (≥50%), and aggressive histologic variants showed increased hazard ratios for OS in univariate analysis. However, in multivariate analysis, only Ki-67 proliferation rate demonstrated a marginal p value (p = 0.063); EZH2 expression, p53 expression, and aggressive histology failed to remain as independent predictors of OS.
In this analysis, EZH2 expression in MCL was associated with a high Ki-67 proliferation rate, more aggressive histology, p52 overexpression, and poorer OS; in the case of aggressive MCL variants, this association was significant. However, EZH2 expression was not an independent risk factor of poorer OS in multivariate analysis. Despite this, the authors note that EZH2 may be useful for the identification of patients with high-risk MCL, especially in the setting of high proliferation rate, and this can identify patients who may benefit from treatment with EZH2 inhibitors.
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