Background
Methods
Patients
Immunohistochemistry and classification of germinal center B-cell (GCB) and non-GCB phenotype DLBCL
Statistical analysis
Results
Clinical features of rituximab-treated DLBCL
Variables | Total n (%) | GCB*n (%) | Non-GCB*n (%) |
---|---|---|---|
Age, years | |||
Mean (range) | 57.7 (14–79) | 60.5 (23–79) | 56.2 (14–78) |
<60 | 50 (49%) | 13 (35%) | 35 (56%) |
≥60 | 53 (51%) | 24 (65%) | 27 (44%) |
Sex | |||
Male | 61 (59%) | 23 (62%) | 36 (58%) |
Female | 42 (41%) | 14 (38%) | 26 (42%) |
Primary site | |||
Nodal | 37 (36%) | 14 (38%) | 21 (34%) |
Extranodal | 66 (64%) | 23 (62%) | 41 (66%) |
Ann Arbor stage | |||
I, II | 47 (46%) | 19 (51%) | 27 (44%) |
III, IV | 56 (54%) | 18 (49%) | 35 (56%) |
IPI group†
| |||
Low (0–2) | 60 (63%) | 24 (65%) | 33 (60%) |
High (3–5) | 36 (37%) | 13 (35%) | 22 (40%) |
B symptoms†
| |||
Absent | 74 (76%) | 31 (84%) | 43 (72%) |
Present | 24 (24%) | 6 (16%) | 17 (28%) |
ECOG PS†
| |||
0, 1 | 86 (84%) | 34 (92%) | 49 (80%) |
≥2 | 16 (16%) | 3 (8%) | 12 (20%) |
LDH† | |||
Normal | 43 (45%) | 14 (39%) | 26 (46%) |
Elevated | 53 (55%) | 22 (61%) | 30 (54%) |
BM involvement†
| |||
Absent | 85 (86%) | 34 (92%) | 48 (83%) |
Present | 14 (14%) | 3 (8%) | 10 (17%) |
Number of extranodal sites | |||
0, 1 | 75 (73%) | 26 (70%) | 46 (74%) |
≥2 | 28 (27%) | 11 (30%) | 16 (26%) |
EBER†
| |||
Negative | 95 (94%) | 37 (100%) | 55 (90%) |
Positive | 6 (6%) | 0 (0%) | 6 (10%) |
Treatment | |||
Rituximab + CHOP | 97 (94%) | 37 (100%) | 57 (92%) |
Rituximab + others | 6 (6%) | 0 (%) | 5 (8%) |
Expression patterns of S1PR1 and pSTAT3 in DLBCLs
variables | S1PR1 | pSTAT3 | ||||||
---|---|---|---|---|---|---|---|---|
Negative | Positive | Total | P*
| Negative | Positive | Total | P*
| |
Age, years | ||||||||
Mean (range) | ||||||||
<60 | 30 (48%) | 20 (49%) | 50 (49%) | 0.969 | 21 (50%) | 29 (48%) | 50 (49%) | 0.806 |
≥60 | 32 (52%) | 21 (51%) | 53 (51%) | 21 (50%) | 32 (52%) | 53 (51%) | ||
Sex | ||||||||
Male | 34 (55%) | 29 (67%) | 61 (59%) | 0.265 | 28 (67%) | 33 (54%) | 61 (59%) | 0.202 |
Female | 28 (45%) | 14 (33%) | 42 (41%) | 14 (33%) | 28 (46%) | 42 (41%) | ||
Primary nodal disease | ||||||||
Nodal | 27 (44%) | 10 (24%) | 37 (36%) | 0.047†
| 21 (50%) | 16 (26%) | 37 (36%) | 0.013†
|
Extranodal | 35 (56%) | 31 (76%) | 66 (64%) | 21 (50%) | 45 (74%) | 66 (64%) | ||
Primary UAT disease | ||||||||
Non-UAT | 55 (89%) | 28 (68%) | 83 (81%) | 0.010†
| 39 (93%) | 44 (72%) | 83 (81%) | 0.009†
|
UAT | 7 (11%) | 13 (32%) | 20 (19%) | 3 (7%) | 17 (28%) | 20 (19%) | ||
Ann Arbor stage | ||||||||
I, II | 26 (42%) | 21 (51%) | 47 (46%) | 0.354 | 18 (43%) | 29 (48%) | 47 (46%) | 0.639 |
III, IV | 36 (58%) | 20 (49%) | 56 (54%) | 24 (57%) | 32 (52%) | 56 (54%) | ||
IPI group‡
| ||||||||
Low (0–2) | 36 (61%) | 24 (65%) | 60 (63%) | 0.705 | 23 (59%) | 37 (65%) | 60 (63%) | 0.555 |
High (3–5) | 23 (39%) | 13 (35%) | 36 (37%) | 16 (41%) | 20 (35%) | 36 (37%) | ||
B symptoms‡
| ||||||||
Absent | 46 (76%) | 31 (78%) | 77 (76%) | 0.809 | 36 (86%) | 41 (69%) | 77 (76%) | 0.059 |
Present | 15 (24%) | 9 (22%) | 24 (24%) | 6 (14%) | 18 (31%) | 24 (24%) | ||
ECOG PS‡
| ||||||||
0, 1 | 54 (87%) | 32 (80%) | 86 (84%) | 0.336 | 36 (86%) | 50 (83%) | 86 (84%) | 0.745 |
≥2 | 8 (13%) | 8 (20%) | 16 (16%) | 6 (14%) | 10 (17%) | 16 (16%) | ||
LDH‡
| ||||||||
Normal | 25 (43%) | 18 (47%) | 43 (45%) | 0.681 | 16 (42%) | 27 (47%) | 43 (45%) | 0.668 |
Elevated | 33 (57%) | 20 (53%) | 53 (55%) | 22 (58%) | 31 (53%) | 53 (55%) | ||
BM involvement‡
| ||||||||
Absent | 56 (90%) | 29 (78%) | 85 (86%) | 0.099 | 38 (95%) | 47 (80%) | 85 (86%) | 0.032†
|
Present | 6 (10%) | 8 (22%) | 14 (14%) | 2 (5%) | 12 (20%) | 14 (14%) | ||
Number of extranodal sites | ||||||||
0, 1 | 45 (73%) | 30 (73%) | 75 (73%) | 0.947 | 30 (71%) | 45 (74%) | 75 (73%) | 0.793 |
≥2 | 17 (27%) | 11 (27%) | 28 (27%) | 12 (29%) | 16 (26%) | 28 (27%) | ||
EBER‡
| ||||||||
Negative | 58 (94%) | 37 (95%) | 95 (94%) | 0.784 | 39 (93%) | 56 (95%) | 95 (94%) | 0.666 |
Positive | 4 (6%) | 2 (5%) | 6 (6%) | 3 (7%) | 3 (5%) | 6 (6%) | ||
Hans classification‡
| ||||||||
GCB | 24 (40%) | 13 (33%) | 37 (37%) | 0.503 | 21 (53%) | 16 (27%) | 37 (37%) | 0.010†
|
Non-GCB | 36 (60%) | 26 (67%) | 62 (63%) | 19 (47%) | 43 (73%) | 62 (63%) | ||
pSTAT3 nuclear expression | ||||||||
Negative | 28 (45%) | 14 (34%) | 42 (41%) | 0.265 | - | - | - | - |
Positive | 34 (55%) | 27 (66%) | 61 (59%) | - | - | - | ||
Total | 62 (100%) | 41 (100%) | 103 (100%) | 42 (100%) | 61 (100%) | 103 (100%) |
Relationships between S1PR1/pSTAT3 expression and clinicopathologic variables
Univariate survival analysis with conventional clinicopathologic variables and S1PR1/pSTAT3
Clinicopathologic variables | P values in each group*by univariate analysis | ||||||||
---|---|---|---|---|---|---|---|---|---|
Rituximab –treated DLBCL (total cohort) (N =103) | Primary site | Stage | IPI† | Hans classification† | |||||
Nodal subgroup (n = 37) | Extranodal (n = 66) | Low stage (n = 47) | High stage (n = 56) | Low (0–2) (n = 60 ) | High (3–5) (n = 36 ) | GCB (n = 37) | Non-GCB (n = 62) | ||
Age >60 | 0.019 | 0.027 | NS (0.239) | NS (0.050) | NS (0.223) | NS (0.141) | NS (0.391) | NS (0.052) | 0.036 |
Stage (III, IV) | 0.016 | 0.034 | NS (0.145) | NA | NA | NS (0.147) | NS (0.110) | NS (0.652) | NS (0.008) |
High IPI (3–5) | 0.009 | 0.039 | NS (0.087) | <0.001 | 0.339 | NA | NA | NS (0.104) | 0.047 |
B symptoms | 0.014 | NS (0.576) | 0.002 | NS (0.481) | 0.038 | NS (0.836) | NS (0.052) | NS (0.569) | 0012 |
High LDH | 0.016 | NS (0.078) | NS (0.063) | NS (0.083) | NS (0.376) | NS (0.585) | NS (0.157) | NS (0.955) | 0.002 |
BM involvement | NS (0.663) | NS (0.790) | NS (0.323) | NS | NS (0.711) | NS (0.418) | NS (0.362) | NS (0.326) | NS (0.478) |
No. of extranodal sites | NS (0.959) | NS (0.175) | NS (0.556) | NS | NS (0.116) | NS (0.787) | 0.026 | NS (0.701) | NS (0.662) |
ECOG PS | NS (0.115) | NS (0.528) | NS (0.147) | NS (0.264) | NS (0.540) | NS (0.531) | NS (0.679) | 0.006 | NS (0.756) |
Hans classification | NS (0.764) | NS (0.118) | NS (0.429) | NS (0.336) | NS (0.404) | NS (0.789) | NS (0.709) | NA | NA |
S1PR1 | 0.018 | 0.041 | NS (0.127) | NS (0.880) | 0.002 | NS (0.347) | 0.014 | NS (0.092) | NS (0.238) |
pSTAT3 | NS (0.713) | NS (0.536) | NS (0.996) | 0.022 | NS (0.267) | NS (0.067) | NS (0.248) | NS (0.143) | NS (0.256) |
S1PR1/pSTAT3 risk category | 0.010 | NS (0.079) | NS (0.254) | NS (0.059) | 0.006 | NS (0.055) | 0.034 | NS (0.136) | NS (0.498) |
Survival analysis with risk stratification model using S1PR1/pSTAT3
Multivariate survival analysis with conventional clinicopathologic variables, S1PR1 and S1PR1/pSTAT3 risk category
Multivariate analysis with IPI, B symptoms, and S1PR1 | ||||
---|---|---|---|---|
Clinicopathologic variables | Category | Univariate analysis | Multivariate analysis | |
P*
| P*
| HR [95% CI] | ||
IPI | 3-5 vs. 0-2 | 0.009 | 0.019 | 2.7 [1.2-6.2] |
B symptoms | present vs. absent | 0.014 | 0.180 | 1.7 [0.8-3.9] |
S1PR1 | positive vs. negative | 0.018 | 0.005 | 3.0 [1.4-6.5] |
Multivariate analysis with IPI, B symptoms, and S1PR1/pSTAT3 risk category
| ||||
Clinicopathologic variables
|
Category
|
Univariate analysis
|
Multivariate analysis
| |
P
*
|
P
*
|
HR [95% CI]
| ||
IPI | 3-5 vs. 0-2 | 0.009 | 0.021 | 2.7 [1.2-6.2] |
B symptoms | present vs. absent | 0.014 | 0.208 | 1.6 [0.7-3.9] |
S1PR1/pSTAT3 risk category | 0.010 | 0.019 | ||
high risk (S1PR1+) vs. intermediate risk (S1PR1-/pSTAT3+) | 0.024 | 2.7 [1.1-6.2] | ||
high risk (S1PR1+) vs. low risk (S1PR1-/pSTAT3-) | 0.021 | 3.8 [1.2-11.6] |