Patient characteristics
In total, 76 patients with available data were included in this study. All patients were histologically diagnosed with PTCL and received chemotherapy as induction therapy. Of these, 25 (32.9%) patients were classified into the high CAR group, while 51 (67.1%) patients were classified into the low CAR group. Baseline characteristics of both groups are presented in Table 1. The most common diagnosis was PTCL-NOS (n=31, 40.8%), followed by AITL (n=24, 31.6%), ALK-negative ALCL (n=12, 15.8%), and ALK-positive ALCL (n=9, 11.8%). The high CAR group showed a significantly higher proportion of patients with advanced stage, poor performance status, elevated LDH, and extranodal involvement (>1), which are all components of the IPI. The percentage of patients with B-symptoms at diagnosis was also significantly higher in the high CAR group than in the low CAR group (72.0% vs. 29.4%, p<0.001). More than two-thirds of the high CAR group initially had bone marrow involvement, while only approximately 20% of the low CAR group presented with it. The distributions of IPI, PIT, and T cell scores revealed significant differences between the two groups, as all factors predicted favorable outcomes for the low CAR group. Importantly, the regimens of induction therapy and the number of patients for whom autologous HSCT was performed were not significantly different between the groups.
Table 1
Baseline characteristics of patients with peripheral T cell lymphoma.
Variable
|
|
Total (n=76)
|
Low CAR (n=51)
|
|
High CAR (n=25)
|
p-value
|
Diagnosis
|
PTCL-NOS
|
31 (40.8%)
|
24 (47.1%)
|
|
7 (28.0%)
|
0.236
|
|
AITL
|
24 (31.6%)
|
14 (27.5%)
|
|
10 (40.0%)
|
|
|
ALCL, ALK-
|
12 (15.8%)
|
6 (11.8%)
|
|
6 (24.0%)
|
|
|
ALCL, ALK+
|
9 (11.8%)
|
7 (13.7%)
|
|
2 (8.0%)
|
|
Sex
|
Male
|
52 (68.4%)
|
33 (64.7%)
|
|
19 (76.0%)
|
0.433
|
|
Female
|
24 (31.6%)
|
18 (35.3%)
|
|
6 (24.0%)
|
|
Age
|
>60
|
34 (44.7%)
|
24 (47.1%)
|
|
10 (40.0%)
|
0.628
|
|
≤60
|
42 (55.3%)
|
27 (52.9%)
|
|
15 (60.0%)
|
|
Stage
|
1–2
|
26 (34.2%)
|
23 (45.1%)
|
|
3 (12.0%)
|
0.005
|
|
3–4
|
50 (65.8%)
|
28 (54.9%)
|
|
22 (88.0%)
|
|
ECOG PS
|
0, 1
|
61 (80.3%)
|
47 (92.2%)
|
|
14 (56.0%)
|
<0.001
|
|
>1
|
15 (19.7%)
|
4 (7.8%)
|
|
11 (44.0%)
|
|
B-Symptom
|
Present
|
33 (43.4%)
|
15 (29.4%)
|
|
18 (72.0%)
|
<0.001
|
|
None
|
43 (56.6%)
|
36 (70.6%)
|
|
7 (28.0%)
|
|
LDH
|
Normal
|
35 (46.1%)
|
31 (60.8%)
|
|
4 (16.0%)
|
<0.001
|
|
Elevated
|
41 (53.9%)
|
20 (39.2%)
|
|
21 (84.0%)
|
|
EN
|
≤1
|
49 (64.5%)
|
37 (72.5%)
|
|
12 (48.0%)
|
0.044
|
|
>1
|
27 (35.5%)
|
14 (27.5%)
|
|
13 (52.0%)
|
|
BM involvement
|
Not involved
|
49 (64.5%)
|
41 (80.4%)
|
|
8 (32.0%)
|
<0.001
|
|
Involved
|
27 (35.5%)
|
10 (19.6%)
|
|
17 (68.0%)
|
|
IPI
|
0
|
10 (13.2%)
|
9 (17.6%)
|
|
1 (4.0%)
|
<0.001
|
|
1
|
14 (18.4%)
|
14 (27.5%)
|
|
0 (0.0%)
|
|
|
2
|
17 (22.4%)
|
13 (25.5%)
|
|
4 (16.0%)
|
|
|
3
|
20 (26.3%)
|
10 (19.6%)
|
|
10 (40.0%)
|
|
|
4
|
8 (10.5%)
|
2 (3.9%)
|
|
6 (24.0%)
|
|
|
5
|
7 (9.2%)
|
3 (5.9%)
|
|
4 (16.0%)
|
|
PIT
|
0
|
14 (18.4%)
|
12 (23.5%)
|
|
2 (8.0%)
|
<0.001
|
|
1
|
27 (35.5%)
|
25 (49.0%)
|
|
2 (8.0%)
|
|
|
2
|
14 (18.4%)
|
7 (13.7%)
|
|
7 (28.0%)
|
|
|
3
|
14 (18.4%)
|
6 (11.8%)
|
|
8 (32.0%)
|
|
|
4
|
7 (9.2%)
|
1 (2.0%)
|
|
6 (24.0%)
|
|
T cell score
|
0
|
19 (25.0%)
|
19 (37.3%)
|
|
0 (0.0%)
|
<0.001
|
|
1
|
30 (39.5%)
|
22 (43.1%)
|
|
8 (32.0%)
|
|
|
2
|
13 (17.1%)
|
6 (11.8%)
|
|
7 (28.0%)
|
|
|
3
|
13 (17.1%)
|
4 (7.8%)
|
|
9 (36.0%)
|
|
|
4
|
1 (1.3%)
|
0 (0.0%)
|
|
1 (4.0%)
|
|
Induction
|
CHO(E)P
|
46 (60.5%)
|
33 (64.7%)
|
|
13 (52.0%)
|
0.513
|
|
ICED
|
19 (25.0%)
|
11 (21.6%)
|
|
8 (32.0%)
|
|
|
IMEP
|
9 (11.8%)
|
5 (9.8%)
|
|
4 (16.0%)
|
|
|
ESHAOx
|
2 (2.6%)
|
2 (3.9%)
|
|
0 (0.0%)
|
|
Response
|
CR
|
47 (61.8%)
|
39 (76.5%)
|
|
8 (32.0%)
|
<0.001
|
|
PR
|
7 (9.2%)
|
3 (5.9%)
|
|
4 (16.0%)
|
|
|
SD
|
2 (2.6%)
|
2 (3.9%)
|
|
0 (0.0%)
|
|
|
PD
|
17 (22.4%)
|
6 (11.8%)
|
|
11 (44.0%)
|
|
|
Not evaluated
|
3 (3.9%)
|
1 (2.0%)
|
|
2 (8.0%)
|
|
Autologous HSCT
|
Not performed
|
54 (71.1%)
|
34 (66.7%)
|
|
20 (80.0%)
|
0.288
|
|
Performed
|
22 (28.9%)
|
17 (33.3%)
|
|
5 (20.0%)
|
|
Data are presented as number (frequency). CAR, C-reactive protein-to-albumin ratio; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; EN, extranodal involvement; BM, bone marrow; IPI, International Prognostic Index; PIT, prognostic index for PTCL-unspecified; CHO(E)P, cyclophosphamide, doxorubicin, vincristine, and prednisone (plus etoposide); ICED, ifosfamide, carboplatin, etoposide, dexamethasone; IMEP, ifosfamide, methotrexate, etoposide, prednisone; ESHAOx, etoposide, methylprednisolone, high-dose cytarabine, oxaliplatin; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; HSCT, hematopoietic stem cell transplantation |
Response and survival outcomes according to the biomarkers
The responses after induction chemotherapy are presented in Table 1, which shows that the high CAR group had a significantly lower rate of CR than the low CAR group (32.0% vs. 76.5%, p<0.001). With a median follow-up of 57.5 months, the high CAR group had significantly lower 5-year PFS (6.6% vs. 43.8%, p<0.0001) and OS (20.2% vs. 62.2%, p<0.0001) rates (Fig. 1). When we classified patients into low and high IPI groups (0–2 vs. 3–5), the high IPI group showed significantly poorer 5-year PFS (11.3% vs. 52.2%, p<0.0001) and OS (21.1% vs. 73.4%, p<0.0001) rates (Fig. 2). We also dichotomized patients with PIT (0–2 vs. 3–4) and T cell score (0–1 vs. 2–4), and the results were statistically significant for both PFS and OS (Figs. 3 and 4). We applied the same method to designate the appropriate cutoff values for the other biomarkers, including beta-2 microglobulin (3.73), NLR (2.479), AGR (1.338), PLR (74.9), and ferritin (602.5). All results showed statistically significant differences in survival outcomes, except for AGR for PFS (Supplementary Figs. 1–5). During the follow-up period, 32 deaths occurred. Of these, 19 deaths were related to disease progression, and eight deaths were due to infectious conditions. One patient died of hemophagocytic lymphohistiocytosis, which occurred immediately after disease progression. Other causes of death included acute myocardial infarction, aspiration, cerebral infarction, and hepatic failure.
Univariable and multivariable analyses of survival outcomes according to CAR
The results of the univariate analysis for PFS and OS demonstrated that most components of the IPI and PIT were significantly associated with survival outcomes. High CAR was also significantly related to both PFS (HR: 5.12, 95% CI 2.74–9.59, p<0.001) and OS (HR: 3.85, 95% CI 2.13–6.97, p<0.001) (Table 2). After adjustment for components of the IPI, PIT, and T cell score, high CAR remained a significant factor for both PFS (HR: 2.83, 95% CI 1.34–5.95, p=0.006) and OS (HR 3.02, 95% CI 1.23–7.43, p=0.016) (Table 3).
Table 2
Univariable analyses of progression-free survival and overall survival in patients with peripheral T-cell lymphoma
|
|
Progression-free Survival
|
Overall Survival
|
|
HR
|
(95% CI)
|
p-value
|
HR
|
(95% CI)
|
p-value
|
Age >60 years
|
|
1.79
|
(0.98–3.27)
|
0.057
|
2.82
|
(1.48–5.36)
|
0.002
|
Stage (III, IV)
|
|
3.91
|
(1.87–8.17)
|
<0.001
|
3.74
|
(1.80–7.79)
|
<0.001
|
LDH >UNL
|
|
2.29
|
(1.26–4.16)
|
0.007
|
2.98
|
(1.62–5.48)
|
<0.001
|
ECOG PS >1
|
|
2.99
|
(1.54–5.82)
|
0.001
|
2.80
|
(1.44–5.44)
|
0.002
|
EN >1
|
|
2.52
|
(1.41–4.50)
|
0.002
|
2.95
|
(1.62–5.39)
|
<0.001
|
B-Symptom (+)
|
|
2.12
|
(1.19–3.80)
|
0.011
|
2.29
|
(1.28–4.09)
|
0.005
|
BM involvement (+)
|
|
4.88
|
(2.65–9.00)
|
<0.001
|
4.27
|
(2.32–7.87)
|
<0.001
|
ANC>6500
|
|
1.98
|
(1.04–3.77)
|
0.037
|
1.29
|
(0.67–2.46)
|
0.438
|
CAR>0.794
|
|
5.12
|
(2.74–9.59)
|
<0.001
|
3.85
|
(2.13–6.97)
|
<0.001
|
HR, hazard ratio; CI, confidence interval; LDH, lactate dehydrogenase; UNL, upper normal limit; ECOG PS, Eastern Cooperative Oncology Group performance status; EN, extranodal involvement; BM, bone marrow; ANC, absolute neutrophil count; CAR, C-reactive protein-to-albumin ratio |
Table 3
Multivariable analyses of progression-free survival and overall survival in patients with peripheral T-cell lymphoma
|
|
Progression-free Survival
|
Overall Survival
|
|
HR
|
(95% CI)
|
p-value
|
HR
|
(95% CI)
|
p-value
|
Age >60 years
|
|
1.86
|
(0.87–3.98)
|
0.112
|
3.88
|
(1.22–12.33)
|
0.022
|
Stage (III, IV)
|
|
1.58
|
(0.65–3.85)
|
0.318
|
3.34
|
(0.88–12.59)
|
0.075
|
LDH >UNL
|
|
0.96
|
(0.43–2.14)
|
0.919
|
2.57
|
(0.92–7.16)
|
0.072
|
ECOG PS >1
|
|
1.26
|
(0.60–2.62)
|
0.540
|
1.51
|
(0.65–3.52)
|
0.339
|
EN >1
|
|
1.43
|
(0.72–2.85)
|
0.309
|
1.31
|
(0.57–3.00)
|
0.524
|
B-Symptom (+)
|
|
1.14
|
(0.54–2.40)
|
0.726
|
0.84
|
(0.32–2.17)
|
0.716
|
BM involvement (+)
|
|
2.62
|
(1.14–6.01)
|
0.023
|
1.02
|
(0.37–2.80)
|
0.969
|
ANC>6500
|
|
1.93
|
(0.84–4.44)
|
0.122
|
1.37
|
(0.39–4.83)
|
0.622
|
CAR>0.794
|
|
2.83
|
(1.34–5.95)
|
0.006
|
3.02
|
(1.23–7.43)
|
0.016
|
HR, hazard ratio; CI, confidence interval; LDH, lactate dehydrogenase; UNL, upper normal limit; ECOG PS, Eastern Cooperative Oncology Group performance status; EN, extranodal involvement; BM, bone marrow; ANC, absolute neutrophil count; CAR, C-reactive protein-to-albumin ratio |
To compare the statistical significance of CAR directly to IPI, PIT, and T cell scores, we performed multivariable Cox analyses separately. After adjusting for the IPI, high CAR was significantly associated with inferior PFS (HR: 3.79, 95% CI 1.94–7.39, p<0.001) and OS (HR: 2.85, 95% CI 1.32–6.16, p=0.008), with a high IPI (HR: 3.23, 95% CI 1.68–6.22, p<0.001 for PFS; HR: 4.97, 95% CI 2.05–12.00, p<0.001 for OS) (Table 4). After adjusting for the PIT, both high CAR and PIT presented with significant PFS (HR: 4.20, 95% CI 2.14–8.23, p<0.001 for high CAR; HR: 3.42, 95% CI 1.79–6.56, p<0.001 for PIT≥2) and OS (HR: 3.14, 95% CI 1.41–6.99, p=0.005 for high CAR; HR: 3.54, 95% CI 1.60–7.82, p=0.002 for PIT≥2). In regard to T cell score, high CAR remained a significant factor for both PFS (HR: 4.01, 95% CI 2.04–7.86, p<0.001) and OS (HR: 2.97, 95% CI 1.33–6.64, p=0.008). After adjusting for IPI, PIT, and T cell score, high CAR was significantly associated with PFS (HR: 3.69, 95% CI 1.87–7.26, p<0.001) and OS (HR: 2.33, 95% CI 1.07–5.09, p=0.034).
Table 4
Multivariable analyses of progression-free survival and overall survival according to IPI, PIT, T cell score, and CAR
|
|
Progression-free Survival
|
Overall Survival
|
|
HR
|
(95% CI)
|
p-value
|
HR
|
(95% CI)
|
p-value
|
IPI≥3
|
|
3.23
|
(1.68–6.22)
|
<0.001
|
4.97
|
(2.05–12.00)
|
<0.001
|
CAR>0.794
|
|
3.79
|
(1.94–7.39)
|
<0.001
|
2.85
|
(1.32–6.16)
|
0.008
|
PIT≥3
|
|
3.42
|
(1.79–6.56)
|
<0.001
|
3.54
|
(1.60–7.82)
|
0.002
|
CAR>0.794
|
|
4.20
|
(2.14–8.23)
|
<0.001
|
3.14
|
(1.41–6.99)
|
0.005
|
T cell score≥2
|
|
1.85
|
(0.98–3.49)
|
0.059
|
3.19
|
(1.43–7.11)
|
0.005
|
CAR>0.794
|
|
4.01
|
(2.04–7.86)
|
<0.001
|
2.97
|
(1.33–6.64)
|
0.008
|
IPI≥3
|
|
2.18
|
(0.98–4.87)
|
0.056
|
3.27
|
(1.15–9.31)
|
0.027
|
PIT≥3
|
|
1.92
|
(0.86–4.29)
|
0.111
|
1.39
|
(0.57–3.39)
|
0.473
|
T cell score≥2
|
|
1.23
|
(0.64–2.36)
|
0.530
|
1.90
|
(0.82–4.38)
|
0.134
|
CAR>0.794
|
|
3.69
|
(1.87–7.26)
|
<0.001
|
2.33
|
(1.07–5.09)
|
0.034
|
IPI, International Prognostic Index; PIT, prognostic index for PTCL-unspecified; CAR, c-reactive protein-to-albumin ratio; HR, hazard ratio; CI, confidence interval |