Patient characteristics
The median patient age was 64 years (range, 21–88 years), and 148 patients (55.8%) were male. A total of 47 patients (17.7%) experienced B symptoms. 152 patients (57.4%) presented with Ann Arbor stages III-IV, and 124 patients (46.7%) presented with high–intermediate- or high-risk IPI. Forty-six patients (17.4%) showed germinal center B (GCB) cell type, and in 92 (34.7%) cases, the cell of origin could not be identified. Fifty-one patients (19.2%) showed bulky disease. All the patients were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone combined with rituximab. Other patient characteristics are summarized in Table 1.
Table 1
Patient demographics and characteristics according to the EASIX score
Factor | Total (n = 265) | Low EASIX (n = 172) | High EASIX (n = 93) | P |
Sex | | | | 0.428 |
Male | 148 (55.8) | 93 (54.1) | 55 (59.1) | |
Female | 117 (44.2) | 79 (45.9) | 38 (40.9) | |
Age, years | | | | < 0.001 |
≤60 | 102 (38.5) | 83 (48.3) | 24 (25.8) | |
> 60 | 163 (61.5) | 89 (51.7) | 69 (74.2) | |
ECOG PS | | | | < 0.001 |
0–1 | 189 (71.3) | 140 (81.4) | 49 (52.7) | |
2–3 | 76 (28.7) | 32 (18.6) | 44 (47.3) | |
Symptom stage | | | | < 0.001 |
A | 218 (82.3) | 153 (89.0) | 65 (69.9) | |
B | 47 (17.7) | 19 (11.1) | 28 (30.1) | |
Ann Arbor Stage | | | | < 0.001 |
I-II | 113 (42.6) | 90 (52.3) | 23 (24.7) | |
III-IV | 152 (57.4) | 82 (47.7) | 70 (75.3) | |
International Prognostic Index | | | | < 0.001 |
Low | 86 (32.5) | 78 (45.4) | 8 (8.6) | |
Low-intermediate | 55 (20.8) | 42 (24.4) | 13 (14.0) | |
High-intermediate | 56 (21.1) | 26 (15.1) | 30 (32.3) | |
High | 68 (25.6) | 26 (15.1) | 42 (45.2) | |
Bone marrow involvement | | | | < 0.001 |
Yes | 231 (87.2) | 13 (7.6) | 21 (22.6) | |
No | 34 (12.8) | 159 (92.4) | 72 (77.4) | |
Number of extranodal sites of involvement | | | | < 0.001 |
< 2 | 182 (68.7) | 132 (76.7) | 50 (53.8) | |
≥ 2 | 83 (31.3) | 40 (23.3) | 43 (46.2) | |
Bulky disease | | | | 0.769 |
Yes | 214 (80.8) | 34 (19.8) | 17 (18.3) | |
No | 51 (19.2) | 138 (80.2) | 76 (81.7) | |
Lactate dehydrogenase | | | | < 0.001 |
Elevated | 108 (40.8) | 72 (41.9) | 85 (91.4) | |
Normal | 157 (59.2) | 100 (58.1) | 8 (8.6) | |
Cell of origin | | | | 0.113 |
GCB | 46 (17.4) | 26 (15.1) | 20 (21.5) | |
Non-GCB | 127 (47.9) | 79 (45.9) | 48 (51.6) | |
Not available | 92 (34.7) | 67 (39.0) | 25 (26.9) | |
Data are presented as the number of patients (%). |
EASIX, endothelial activation and stress index; ECOG PS, Eastern Cooperative Oncology Group performance status; GCB, germinal center |
Treatment Response
The CR, partial response (PR), no response or stable disease (NR/SD), and progressive disease (PD) rates were 80.8%, 14.0%, 0%, 1.7%, and 3.5% in the low EASIX group and 61.3%, 22.6%, 3.2%, 0%, and 12.9% in the high-EASIX group, respectively (p < 0.001). In a subgroup analysis of patients who did not early discontinue treatment, except for the progression of lymphoma, the CR rates were 88.7% and 79.1% in the low- and high-EASIX groups, respectively (p = 0.060).
Survival Outcome
At a median follow-up period of 57 months, 118 patients (44.5%) showed disease relapse and 107 patients (40.4%) had died. The 5-year PFS and OS rates were 55.1% and 57.9%, respectively. On the basis of the cutoff EASIX score of 1.33 (Fig. 1), 93 and 172 patients were categorized as having high and low EASIX, respectively. The 5-year PFS (67.9% vs. 31.6%) and 5-year OS (70.6% vs. 34.3%) rates differed significantly between the low- and high-EASIX groups (p < 0.001, Fig. 2).
Factors Affecting Overall Survival And Progression-free Survival
The symptom stage (B vs. A), IPI (high–intermediate to high vs. low-to-low-intermediate), bone marrow involvement (yes vs. no), and EASIX score (high vs. low) were significantly associated with OS and PFS in a univariate analysis. In multivariate analysis, IPI (high–intermediate to high vs. low to low-intermediate) and EASIX score (high vs. low) were significant prognostic factors (Table 2). There was no multicollinearity among the factors because the VIF value was less than 1.5. The OS results favored the low EASIX group in most subgroups based on disease characteristics at baseline (Fig. 3).
Table 2
Univariate and multivariate Cox regression analyses for PFS and OS
| Progression-free survival |
| Univariate | Multivariate |
| HR (95% CI) | P | HR (95% CI) | P |
Sex (men vs. women) | 1.245 (0.861–1.801) | 0.244 | | |
Symptom stage (B vs. A) | 2.270 (1.517–3.398) | < 0.001 | 1.471 (0.970–2.232) | 0.070 |
IPI (HI to high vs. low to LI) | 5.002 (3.309–7.562) | < 0.001 | 3.741 (2.385–5.870) | < 0.001 |
BM involvement (yes vs. no) | 2.664 (1.704–4.162) | < 0.001 | 1.412 (0.886–2.248) | 0.147 |
Bulky disease (yes vs. no) | 0.777 (0.470–1.284) | 0.325 | | |
EASIX (high vs. low) | 2.879 (1.998–4.148) | < 0.001 | 1.606 (1.077–2.395) | 0.020 |
| Overall survival |
| Univariate | Multivariate |
| HR (95% CI) | P | HR (95% CI) | P |
Sex (men vs. women) | 1.297 (0.878–1.916) | 0.191 | | |
Symptom stage (B vs. A) | 2.208 (1.447–3.371) | < 0.001 | 1.463 (0.946–2.262) | 0.087 |
IPI (HI to high vs. low to LI) | 5.104 (3.300-7.894) | < 0.001 | 3.895 (2.431–6.240) | < 0.001 |
BM involvement (yes vs. no) | 2.484 (1.547–3.988) | < 0.001 | 1.350 (0.825–2.210) | 0.232 |
Bulky disease (yes vs. no) | 0.762 (0.448–1.298) | 0.317 | | |
EASIX (high vs. low) | 2.898 (1.975–4.253) | < 0.001 | 1.621 (1.066–2.464) | 0.024 |
HR, hazard ratio; CI, confidence interval; IPI, International Prognostic Index; BM, bone marrow; EASIX, endothelial activation and stress index |
Toxicity
Table 3 lists the incidences of the toxicities according to the NCI-CTC toxicity criteria. Hematologic toxicity grade ≥ 3 was reported in 210 patients (79.2%) at least once in the course of chemotherapy. Non-hematologic toxicity grade ≥ 3 was reported in 101 patients (38.1%). The low- and high-EASIX groups showed significant differences in terms of the incidence of hematologic toxicity grade ≥ 3, non-hematologic toxicity grade ≥ 3, dose reduction, and early treatment discontinuation. Treatment-related mortality did not exhibit a significant difference between the groups.
Table 3
Treatment-related toxicities
| Total (n = 265) | Low EASIX (n = 172) | High EASIX (n = 93) | P |
Hematologic toxicity, grade ≥ 3 | | | | |
Anemia | 53 (20) | 21 (12.2) | 32 (34.4) | < 0.001 |
Thrombocytopenia | 75 (28.3) | 25 (14.5) | 50 (53.8) | < 0.001 |
Neutropenia | 206 (77.7) | 124 (72.1) | 82 (88.2) | 0.003 |
Febrile neutropenia | 76 (28.7) | 32 (18.6) | 44 (47.3) | <0.001 |
Non-hematologic toxicity, grade ≥ 3 | 101 (38.1) | 55 (32.0) | 46 (49.5) | 0.005 |
Treatment-related mortality | 22 (8.3) | 11 (6.4) | 11 (11.8) | 0.126 |
Dose reduction | 125 (47.2) | 69 (40.1) | 56 (60.2) | 0.002 |
Early treatment discontinuation | 47 (17.7) | 21 (12.2) | 26 (28.0) | 0.001 |
Data are presented as the number of patients (%). |
EASIX, endothelial activation and stress index; RDI, relative dose intensity |