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. 2020 Sep 17;35(6):1671–1682. doi: 10.1038/s41375-020-01042-y

Progression-free survival at 24 months and subsequent survival of patients with extranodal NK/T-cell lymphoma: a China Lymphoma Collaborative Group (CLCG) study

Yong Yang 1,#, Ying Wang 2,#, Xin Liu 1,#, Xia He 3, Li-Ling Zhang 4, Gang Wu 4, Bao-Lin Qu 5, Li-Ting Qian 6, Xiao-Rong Hou 7, Fu-Quan Zhang 7, Xue-Ying Qiao 8, Hua Wang 9, Gao-Feng Li 10, Yuan Zhu 11, Jian-Zhong Cao 12, Jun-Xin Wu 13, Tao Wu 14, Su-Yu Zhu 15, Mei Shi 16, Li-Ming Xu 17, Hang Su 18, Yu-Qin Song 19, Jun Zhu 19, Yu-Jing Zhang 20, Hui-Qiang Huang 20, Chen Hu 21, Shu-Nan Qi 1,✉, Ye-Xiong Li 1,✉
PMCID: PMC8179849  PMID: 32943751

Abstract

Limited evidence supports the use of early endpoints to evaluate the success of initial treatment of extranodal NK/T-cell lymphoma (ENKTCL) in the modern era. We aim to analyze progression-free survival at 24 months (PFS24) and subsequent overall survival (OS) in a large-scale multicenter cohort of patients. 1790 patients were included from the China Lymphoma Collaborative Group (CLCG) database. Subsequent OS was defined from the time of PFS24 or progression within 24 months to death. OS was compared with age- and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Patients who did not achieve PFS24 had a median OS of 5.3 months after progression, with 5-year OS rate of 19.2% and the SMR of 71.4 (95% CI, 62.9–81.1). In contrast, 74% patients achieved PFS24, and the SMR after achieving PFS24 was 1.77 (95% CI, 1.34–2.34). The observed OS rate after PFS24 versus expected OS rate at 5 years was 92.2% versus 94.3%. Similarly, superior outcomes following PFS24 were observed in early-stage patients (5-year OS rate, 92.9%). Patients achieving PFS24 had excellent outcome, whereas patients exhibiting earlier progression had a poor survival. These marked differences suggest that PFS24 may be used for study design and risk stratification in ENKTCL.

Subject terms: T-cell lymphoma, Risk factors

Introduction

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) is an aggressive and heterogeneous disease with an unusual geographical distribution. Although rare globally, it is more prevalent in East Asia and South America [1–4]. Clinically, the majority of patients with ENKTCL present with early-stage disease and are male adults. Extensive primary tumor invasion (PTI) is usually present, involving the upper aerodigestive tract (UADT) site, and extranodal failure is common [5–7]. Over the past decade, substantial treatment advances have been made with the introduction of novel prognostic models and risk stratifications [8–10], upfront radiotherapy [11–14], and non-anthracycline (ANT)-based chemotherapy [15–21]. The treatment outcome has improved, with 5-year overall survival (OS) rates of 60–90% reported for localized diseases, but only 10–40% for disseminated diseases [10, 13, 22–25]. A large proportion of patients suffers disease progression or relapse after employment of the current standard treatment. Thus, there is an urgent requirement for the identification of early efficacy endpoints or novel therapeutic agents from prospective trials in patients with ENKTCL.

Previous studies have demonstrated that event-free survival (EFS) at 24 months (EFS24) and progression-free survival (PFS) at 24 months (PFS24) are important milestones to stratify patients with diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL); survival beyond these time points is similar or equivalent to that of the general population [26–29]. Normalization to the survival of a country-matched general population was recently proposed as an alternative to the use of “time to event” analysis for lymphoma. However, clinical characteristics and treatment strategies differ notably between lymphoma subtypes. The clinical significance of PFS24 in ENKTCL remains unknown, and the impact of achieving PFS24 on subsequent OS remains unaddressed. In the present study, we aimed to examine the timing of events, post-treatment milestones and subsequent OS in patients with ENKTCL, with reference to the general background population.

Patients and methods

Eligibility criteria and study population

Patients diagnosed with ENKTCL between 2008 and 2016 were retrospectively reviewed using information from the China Lymphoma Collaborative Group (CLCG) database [5, 9, 13, 21]. The eligibility criteria in this study included patients who had received non-ANT-based chemotherapy and/or radiotherapy. Patients who had received ANT-based or unknown regimen chemotherapy were excluded. A total of 1790 patients formed the study population. The institutional review boards ethically approved this project and waived the requirement for informed consent because of the de-identification of patient data.

Risk stratification and treatment

Patients were staged using the Ann Arbor staging system and stratified using the ENKTCL-specific models: the nomogram-revised risk index [8, 9], the prognostic index of natural killer lymphoma [10] and the Korea prognostic index [30]. Patients with early-stage disease received combined modality treatment (n = 1091, 69.8%), radiotherapy alone (n = 283, 18.1%) or chemotherapy alone (n = 189, 12.1%). Patients with advanced-stage disease received primary chemotherapy with (n = 89, 39.2%) or without (n = 138, 60.8%) consolidation radiotherapy. The most commonly used non-ANT-based chemotherapies were asparaginase- or platinum-containing (n = 1367, 90.7%). Extended involved-site radiation therapy (E-ISRT) was administered, with a median dose of 50 Gy.

Statistical methods

Progression-free survival (PFS) was defined as the time from the date of treatment to the first of either disease progression, relapse or death from any cause. Subsequent OS was defined as the time from achieving PFS24 (24 months after treatment) or time from progression in patients who did not achieve PFS24 (progression within 24 months of treatment) to death from any cause. The estimated hazard rates provide the trajectory of progression and death overtime and were smoothed by the Epanechnikov kernel. PFS24 was defined as being alive and progression-free 24 months after initial therapy. PFS was also evaluated at other landmark time points (12 and 36 months) for sensitivity analysis. OS was compared with the age- and sex-matched general Chinese population via standardized mortality ratios (SMRs), and expected survival was predicted using a conditional approach via the ‘survexp’ function in R (package survival). Survival curves we analyzed using Kaplan–Meier method. A two-sided P value of < 0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using SPSS (version 22.0; IBM Inc.) and R (version 3.6.2; http://www.r-project.org/).

Results

Patient characteristics and survival

The baseline clinical characteristics of the included patients are listed in Table 1. The median age was 44 years old (interquartile range, 32–55 years) and the male:female ratio was 2.4:1. Most patients had good performance status and primary UADT site. Elevated lactate dehydrogenase was noted in 27.6% of patients, and the majority exhibited early-stage disease (87.3%).

Table 1.

Clinical characteristics and treatment outcomes of patients with extranodal nasal-type NK/T-cell lymphoma.

Patients 5-year OS rate post-treatment SMR
Characteristics No. (%) % (95% CI) P (95% CI) Pa
Sex 0.181
 Male 1261 (70.4) 71.7 (68.9–74.6) 5.6 (5.1–6.3) <0.001
 Female 529 (29.6) 74.5 (70.4–78.7) 1.3 (1.1–1.5) <0.001
Age (years) 0.013
 ≤60 1527 (85.3) 73.5 (71.1–76.0) 14.7 (13.2–16.3) <0.001
 >60 263 (14.7) 66.4 (59.9–73.6) 1.9 (1.5–2.3) <0.001
Primary site <0.001
 UADT 716 (40.0) 73.9 (71.6–76.3) 6.3 (5.7–7.0) <0.001
 Extra-UADT 1074 (60.0) 45.4 (34.0–60.8) 14.3 (10.6–19.3) <0.001
Regional lymph nodes <0.001
 Yes 1674 (93.5) 64.7 (60.9–68.8) 13.3 (11.6–15.2) <0.001
 No 116 (6.5) 77.4 (74.6–80.3) 4.5 (3.9––5.1) <0.001
Distant lymph nodes <0.001
 Yes 1671 (93.4) 46.3 (35.7–60.2) 17.8 (13.2–24.2) <0.001
 No 119 (5.6) 73.8 (71.5–76.2) 6.2 (5.7–6.9) <0.001
Primary tumor invasion <0.001
 Yes 1004 (56.1) 67.9 (64.8–71.2) 9.7 (8.6–10.8) <0.001
 No 786 (43.9) 78.4 (75.1–81.8) 4.1 (3.5–4.8) <0.001
B symptoms 0.006
 Yes 687 (38.4) 68.9 (65.2–72.9) 9.9 (8.6–11.5) <0.001
 No 1103 (61.6) 74.8 (71.9–77.8) 5.3 (4.6–6.0) <0.001
Elevated LDH <0.001
 Yes 100 (5.6) 60.1 (55.3–65.3) 1.2 (1.1–1.4) <0.001
 No 1690 (94.4) 77.1 (74.5–79.7) 5.1 (4.5–5.8) <0.001
ECOG score <0.001
 0–1 1563 (87.3) 74.7 (72.4–77.1) 6.2 (5.6–6.8) <0.001
 ≥2 227 (12.7) 39.1 (30.2–50.7) 12.9 (10.1–16.5) <0.001
Ann Arbor stage <0.001
 I-II 1296 (72.4) 75.9 (73.5–78.3) 5.5 (5.0–6.1) <0.001
 III-IV 494 (27.6) 44.4 (36.7–53.7) 24.4 (19.9–29.8) <0.001
KPI <0.001
 Group 1 550 (30.7) 81.8 (78.3–85.5) 3.1 (2.5–3.8) <0.001
 Group 2 636 (35.5) 75.0 (71.2–79.0) 6.2 (5.2–7.3) <0.001
 Group 3 373 (20.9) 67.4 (62.4–72.9) 10.6 (8.7–12.8) <0.001
 Group 4 231 (12.9) 49.6 (42.6–57.9) 27.9 (22.9–34.1) <0.001
PINK <0.001
 Low risk 1269 (70.9) 78.1 (75.6–80.6) 11.4 (10.1–12.9) <0.001
 Intermediate risk 363 (20.3) 61.7 (55.9–68.1) 3.1 (2.6–3.7) <0.001
 High risk 158 (8.8) 45.5 (36.6–56.6) 12.8 (10.0–16.3) <0.001
NRI <0.001
 Low risk 390 (21.8) 86.4 (82.6–90.3) 5.6 (4.2–7.4) <0.001
 Intermediate-low risk 517 (28.9) 78.3 (74.3–82.5) 3.9 (3.2–4.8) <0.001
 Intermediate-high risk 469 (26.2) 69.8 (65.3–74.8) 7.0 (5.9–8.4) <0.001
 High risk 263 (14.7) 59.4 (52.9–66.6) 11.0 (8.9–13.6) <0.001
 Very high risk 151 (8.4) 43.2 (24.8–53.7) 12.2 (9.7–15.3) <0.001
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OS overall survival, SMR standardized mortality ratio, CI confidence interval, UADT upper aerodigestive tract, LDH lactate dehydrogenase, ECOG Eastern Cooperative Oncology Group, KPI Korean Prognostic Index, PINK Prognostic Index of Natural Killer Lymphoma, NRI nomogram-revised risk index.

aCompared with the age- and sex-matched general Chinese population.

With a median follow-up time of 46 months for surviving patients, 598 patients (33.4%) exhibited disease progression and 430 patients (24.0%) passed away. The 5-year OS and PFS rates for all patients were 72.5% and 62.2%, respectively.

Annual hazard rate over time

After initial treatment, 82% of progression and 80% of mortalities occurred within 24 months. Consistently, smoothed hazard plots illustrated maximal annual death and progression hazards of 15.4% and 27.1%, respectively during the first year. These hazard rates decreased to 6.1% and 7.6%, respectively, at 2 years (Fig. 1a). From 3 years the annual hazards for progression and death were <5%. Thus, PFS at 24 months (PFS24) is a logistical cutoff time point for further evaluation.

Fig. 1. Estimated annual hazards and overall survival (OS) based on 24-month progression-free survival (PFS24) in the whole cohort.

Fig. 1

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a Smoothed hazard plots of death and progression over time. b Subsequent OS of patients who achieved PFS24 after initial treatment vs. expected OS based on age-, sex-, and country-matched general population data. c Subsequent OS of patients who did not achieve PFS24 after initial treatment vs. expected OS based on age-, sex-, and country-matched general population data.

PFS24 and subsequent OS

Kaplan–Meier analysis estimated that the 2-year PFS rate of the total cohort (1790 patients) was 70.5% (95% CI, 68.3–72.7%) and the SMR from initial treatment was 6.7 (95% CI, 6.1–7.3). The 5-year OS and SMR among subgroups were shown in Table 1.

A total of 1362 patients were sufficiently followed-up for PFS24 assessment. Of these patients, 1014 (74.4%) were progression-free at 24 months (PFS24 was achieved). The 5-year OS rate after achieving PFS24 was 92.2% (95% CI, 89.6–94.9%; Fig. 1b). The expected 5-year OS rate was 94.3% in the age and sex-matched general Chinese population. The SMR after achieving PFS24 was 1.8 (95% CI, 1.3–2.3; P < 0.001). In contrast, the median OS after progression within the first 24 months was only 5.3 months (95% CI, 4.0–6.7). The 5-year OS rate after progression was 19.2% (Fig. 1c) and SMR was 71.4 (95% CI, 62.9–81.0; P < 0.001).

Subgroup analysis of PFS24 and subsequent OS

In early-stage disease, 950/1239 (76.7%) patients achieved PFS24 and 289/1239 (23.3%) patients did not. The 5-year OS rate after achieving PFS24 was 92.9% (95% CI, 90.2% to 95.6%), almost equivalent to that of the age and sex-matched general population (94.3%, Fig. 2a). The SMR after achieving PFS24 was 1.5 (95% CI, 1.1–2.0; P = 0.009). In contrast, the median OS after progression within the first 24 months was only 5.0 months (95% CI, 3.7–6.3). The 5-year OS rate after progression was 20.1% (Fig. 2b) and SMR was 67.3 (95% CI, 58.5- 77.2; P < 0.001).

Fig. 2. Overall survival (OS) based on 24-month progression-free survival (PFS24) of patients with early-stage and advanced-stage.

Fig. 2

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a Subsequent OS of patients who achieved PFS24 after initial treatment vs. expected OS based on age-, sex- and country-matched general population data. b Subsequent OS of early-stage patients who did not achieve PFS24 vs. expected OS based on age-, sex-, and country-matched general population data. c Subsequent OS of advanced-stage patients who achieved PFS24 vs. expected OS based on age-, sex-, and country-matched general population data. d Subsequent OS of advanced-stage patients who did not achieve PFS24 vs. expected OS based on age-, sex-, and country-matched general population data.

In advanced-stage disease, 123 patients were sufficiently followed-up for PFS24 assessment. PFS24 was achieved for 52.0% patients. The 3-year OS rate after achieving PFS24 was 83.1% (95% CI, 73.4–94.2%), which is lower than that of the age and sex-matched population (97.5%; Fig. 2c). The SMR after achieving PFS24 was 9.6 (95% CI, 5.0–18.4; P < 0.001). In contrast, the median OS after progression within the first 24 months was only 6.9 months (95% CI, 4.9–9.1 months), with a 3-year OS rate of 13.7% (Fig. 2d) and SMR of 103.6 (95% CI, 76.0–141.3; P < 0.001).

Subsequently, outcomes were examined with regard to other clinical factors and risk groups. Despite a significant difference in OS of patients between treatment subgroups (Table 1), the OS rate of patients after achieving PFS24 were favorable compared with the background population (Table 2). There was little difference in subsequent outcomes after progression regardless of clinical characteristics or risk-stratified grouping (Table 2). PFS24 status was informative for subsequent OS in all patient subgroups and could be used as a prognostic indicator.

Table 2.

Subsequent outcomes based on achieving or failing PFS24 in subgroups.

Outcomes from time of achieving PFS24 Outcomes from time of failing PFS24
No. of 5-year OS SMR No. of 3-year OS SMR
Subgroups patients % (95%CI) P (95% CI) Pa patients % (95%CI) P (95% CI) Pa
Sex 0.564 0.229
  Male 708 91.2 (87.7–94.9) 1.5 (1.1–2.1) 0.015 242 22.2 (17.0–29.1) 66.9 (57.6–77.8) <0.001
  Female 306 94.6 (91.7–97.6) 3.8 (2.2–6.5) <0.001 106 29.0 (20.9–40.2) 85.3 (67.5–107.9) <0.001
Age (years) 0.050 0.856
  ≤60 883 93.3 (90.7–96.0) 3.7 (2.7–5.0) <0.001 305 23.9 (19.1–30.0) 158.2 (138.2–180.9) <0.001
  >60 131 84.8 (75.1–95.9) 0.6 (0.3–1.1) 0.119 43 28.6 (17.4–47.0) 13.9 (9.6–20.1) <0.001
Primary site <0.001 0.126
  UADT 982 92.7 (90.1–95.4) 1.6 (1.2–2.1) 0.002 315 24.4 (19.7–30.3) 74.4 (65.2–84.9) <0.001
  Extra-UADT 32 76.2 (60.2–96.5) 9.2 (4.1–20.5) <0.001 33 21.6 (9.4–49.6) 48.9 (31.2–76.7) <0.001
Regional lymph nodes 0.030 0.210
  Yes 338 92.0 (88.4–95.7) 3.7 (2.4–5.6) <0.001 159 20.4 (14.5–28.9) 106.4 (88.5–127.8) <0.001
  No 676 92.7 (89.5–96.0) 1.3 (0.9–1.8) 0.222 189 27.6 (21.3–35.7) 55.1 (46.2–65.6) <0.001
Distant lymph nodes 0.005 0.944
  Yes 31 85.8 (73.8–99.7) 6.6 (2.5–17.6) <0.001 30 11.6 (3.4–40.0) 106.2 (69.9–161.3) <0.001
  No 983 92.5 (89.8–95.2) 1.7 (1.2–2.2) <0.001 318 25.4 (20.6–31.3) 69.1 (60.6–79.0) <0.001
Primary tumor invasion 0.908 0.006
  Yes 524 93.6 (90.9–96.3) 1.9 (1.3–2.9) <0.001 220 21.0 (15.7–28.0) 116.0 (99.3–135.5) <0.001
  No 490 91.0 (86.8–95.5) 1.6 (1.1–2.4) 0.015 128 30.2 (22.4–40.6) 40.7 (32.7–50.6) <0.001
B symptoms 0.472 0.659
  Yes 380 90.8 (85.9–96.0) 2.6 (1.7–3.9) <0.001 146 24.2 (17.5–33.5) 100.2 (82.2–122.2) <0.001
  No 634 93.1 (90.2–96.0) 1.5 (1.0–2.1) 0.045 202 24.3 (18.5–32.0) 59.6 (50.6–70.3) <0.001
Elevated LDH 0.053 0.061
  Yes 229 92.2 (88.5–96.1) 3.0 (1.8–4.8) <0.001 113 16.5 (9.9–27.4) 88.0 (71.1–108.8) <0.001
  No 785 92.3 (89.2–95.5) 1.5 (1.1–2.1) 0.020 235 27.7 (22.1–34.8) 64.7 (55.3–75.8) <0.001
ECOG score <0.001 <0.001
  0–1 979 93.3 (91.0–95.6) 1.7 (1.2–2.3) <0.001 323 26.2 (21.3–32.1) 66.9 (58.6–76.4) <0.001
  ≥2 35 56.2 (24.9–100) 3.0 (1.3–6.6) 0.008 25 0 216.9 (142.8–329.4) <0.001
Ann Arbor stage <0.001 0.753
  I–II 950 92.9 (90.2–95.6) 1.5 (1.1–2.1) 0.009 289 25.8 (20.9–32.0) 67.3 (58.5–77.2) <0.001
  III–IV 64 83.1 (73.4–94.2)b 9.6 (5.0–18.4) <0.001 59 13.7 (5.9–31.8) 103.6 (76.0–141.3) <0.001
KPI 0.006 0.492
  Group 1 367 94.1 (90.5–97.9) 1.9 (0.5–1.5) 0.644 83 27.3 (18.9–39.5) 48.0 (37.1–62.1) <0.001
  Group 2 375 90.1 (84.7–95.8) 2.2 (1.4–3.4) <0.001 124 29.4 (21.6–40.1) 60.6 (48.7–75.5) <0.001
  Group 3 192 95.8 (92.8–98.9) 2.0 (1.0–3.9) 0.056 81 17.4 (11.1–35.4) 131.7 (102.1–170.0) <0.001
  Group 4 80 86.5 (78.5–95.3) 9.3 (4.9–17.9) <0.001 60 17.0 (8.8–32.7) 111.9 (83.0–150.8) <0.001
PINK <0.001 0.928
  Low risk 798 94.5 (91.9–97.2) 2.6 (1.8–3.9) <0.001 234 26.0 (20.5–32.9) 145.8 (125.1–170.0) <0.001
  Intermediate risk 172 83.9 (75.6–93.0) 1.0 (0.7–1.7) 0.839 69 22.8 (13.7–37.9) 27.5 (20.7–36.6) <0.001
  High risk 44 85.4 (75.2–96.9) 5.0 (2.2–11.1) <0.001 45 14.3 (5.7 –36.3) 56.2 (39.3–80.4) <0.001
NRI 0.001 0.186
  Low risk 285 94.5 (90.6–98.7) 2.3 (1.2–4.4) 0.012 48 32.5 (21.2–49.8) 99.2 (70.5–139.6) <0.001
  Intermediate-low risk 314 92.8 (87.8–98.2) 1.0 (0.5–1.8) 0.978 101 27.2 (19.1–38.9) 47.7 (37.4–60.94) <0.001
  Intermediate-high risk 260 90.8 (85.9–96.0) 2.0 (1.3–3.2) 0.003 95 29.2 (20.8–41.1) 77.2 (60.4–98.6) <0.001
  High risk 110 92.5 (87.2–98.1) 2.4 (1.2–5.1) 0.019 69 13.9 (6.4–29.9) 116.6 (88.4–153.9) <0.001
  Very high risk 45 85.1 (74.8–96.8) 2.9 (1.3–6.5) 0.008 35 13.4 (5.1–35.6)c 68.6 (47.4–99.4) <0.001
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PFS24 progression-free survival at 24 months; SMR standardized mortality ratio; OS overall survival; UADT upper aerodigestive tract; LDH lactate dehydrogenase; ECOG Eastern Cooperative Oncology Group.

aCompared with the age- and sex-matched general Chinese population.

b3-year OS rate from PFS24.

c2-year OS rate from progression.

Sensitivity analysis of PFS24 vs. other time points

For sensitivity analysis, we examined outcomes according to other landmark time points of PFS, including 12 (PFS12), 24 (PFS24) and 36 (PFS36) months. Although the subsequent 5-year OS rate continued to increase from PFS12 (86.5%) to PFS24 (92.2%), there was little benefit in examining beyond PFS36 (93.0%) and no significant difference between the PFS-based OS and expected OS (Table 3). Furthermore, there was little difference in the 5-year OS rate after progression regardless of the time point chosen (17.1% at 12 months vs. 20.3% at 36 months). Similar results were obtained when considering early-stage and advanced-stage diseases.

Table 3.

SMR and OS after achieving or failure of PFS at selected time points.

3 years from time point 5 years from time point
No. of SMR No. of Actual 3-y OSa Expected No. of Actual 5-y OSa Expected
PFS time point Patients (95% CI) Pb Patients % (95% CI) 3-year OS (%) Patients % (95% CI) 5-year OS (%)
All stages (I–IV)
  12 months 1274 3.1 (2.6–3.7) <0.001 594 88.8 (86.9–90.8) 96.9 195 86.5 (84.1–88.9) 94.4
  24 months 1014 1.8 (1.3–2.3) <0.001 380 94.8 (93.2–96.4) 96.9 100 92.2 (89.6–94.9) 94.3
  36 months 793 1.0 (0.6–1.6) 0.953 188 97.0 (95.2–98.8) 97.0 32 93.0 (88.7 –97.5) 94.7
Stage I–II
  12 months 1169 2.7 (2.3–3.3) <0.001 573 90.2 (88.3–92.1) 96.9 190 87.8 (85.4–90.2) 94.4
  24 months 950 1.5 (1.1–2.0) 0.009 366 95.5 (94.0–97.1) 96.9 100 92.9 (90.2–95.6) 94.3
  36 months 752 1.0 (0.6–1.6) 0.929 183 97.0 (95.2–98.8) 97.0 32 93.0 (88.7–97.6) 94.6
Stage III–IV
  12 months 105 11.4 (7.5–17.4) <0.001 21 69.7 (59.4–81.7) 97.3 5 69.7 (59.4–81.7) 95.4
  24 months 64 9.6 (5.0–18.4) <0.001 14 83.1 (73.4–94.2) 97.5 – – –
  36 months 41 2.5 (0.4–18.0) 0.352 5 96.4 (89.8–100) 97.7 – – –
All stage (I–IV)
  12 months 246 65.8 (56.8–76.2) <0.001 27 22.9 (17.9–29.5) 96.4 8 17.1 (11.6–25.2) 94.8
  24 months 348 71.4 (62.9–81.1) <0.001 40 24.3 (19.8–30.0) 97.1 14 19.2 (14.3–25.9) 95.8
  36 months 388 55.0 (48.7–62.0) <0.001 41 25.4 (20.9–30.8) 96.4 14 20.3 (15.3–26.8) 93.2
Stage I–II
  12 months 201 62.7 (53.3–73.7) <0.001 25 23.9 (18.4–31.1) 96.3 7 17.4 (11.5–26.4) 94.6
  24 months 289 67.3 (58.5–77.2) <0.001 37 25.8 (20.9–32.0) 97.0 13 20.1 (14.7–27.4) 95.6
  36 months 325 50.4 (44.2–57.6) <0.001 38 26.9 (22.1–32.9) 96.3 13 21.2 (15.9–28.4) 92.8
Stage III–IV
  12 months 45 85.9 (60.4–122.2) <0.001 2 14.5 (5.6–37.4) 97.4 – – –
  24 months 59 103.6 (76.0–141.3) <0.001 3 13.7 (5.9–31.8) 97.9 – – –
  36 months 63 103.4 (76.4–140.0) <0.001 3 13.8 (6.0–31.9) 97.9 – – –
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SMR standardized mortality ratio, OS overall survival, PFS progression-free survival.

aActual 3- or 5-year OS was defined as subsequent OS of patients who achieved or failed to achieve PFS at 12, 24 or 36 months after initial treatment based on patients with ENKTCL vs. expected 3- or 5-year OS based on age-, sex- and country-matched general population data.

bCompared with the age- and sex-matched general Chinese population.

Discussion

This is the first study to evaluate PFS-based endpoints among patients with ENKTCL, primarily treated with non-ANT-based chemotherapy and frontline radiotherapy. Using a large multicenter cohort of patient data collected from the CLCG database, we verified that PFS24 acts as a prognostic indicator of subsequent survival under current treatment strategies. Patients who were progression-free within 24 months after initial treatment resulted in favorable long-term outcomes, with OS times not distinguishable from that of age-, sex- and country-matched populations. Conversely, patients who experienced disease progression within 24 months had poor prognoses. This finding suggests PFS24 as a dichotomous variable, providing a clear benchmark for evaluating the success of initial treatment and for designing clinical trials for ENKTCL.

The introduction of asparaginase- or platinum-based chemotherapy regimens and early implementation of high-dose E-ISRT for localized disease have been the most important advances in the treatment of ENKTCL [11–21, 31]. Although phase I/II trials or retrospective studies have reported improved survival with the use of non-ANT-based chemotherapy, the optimal chemotherapy regimens remain to be identified by prospective trials. Early efficacy endpoints such as PFS and EFS are required to reduce the duration of evaluation of treatment regimens, to deliver optimal treatment strategies to the clinic sooner, and so that ineffective regimens can be abandoned without prolonged evaluation [32]. However, due to the rarity of ENKTCL and the heterogeneity of treatments used, limited patient numbers make formal surrogate endpoint analysis difficult. Normalization to the survival of a matched general population is important in rare diseases such as PTCL and ENKTCL [29]. In the present study, PFS24 is identified as a dichotomous variable that may allow individualized prognosis prediction for patients with ENKTCL, as well as inform patient counseling, clinical decision making and prospective clinical trial design.

In previous studies, we have demonstrated that improved locoregional control is associated with prolonged PFS and OS in early-stage ENKTCL [33], and that the survival probability increased and the hazards of failure decreased in a risk-dependent manner [34]. In the present study, we demonstrate that the estimated risk of disease progression and mortality was initially high, but decreased dramatically within the first 24 months after current standard treatment for ENKTCL (Fig. 1a). Given that the vast majority of ENKTCL-related events occur within the first 24 months, patients achieving PFS24 are highly likely to have a near-normal life expectancy, with actual and expected 5-year OS rates of 92.2% and 94.3%. Sensitivity analysis, examining time points at 12, 24, and 36 months, indicated that there was little OS improvement at PFS36, whereas the PFS12 endpoint did not dichotomize the two groups as effectively as PFS24, regardless of stage. In consistence with the observations of the current study, other studies have reported PFS24 to be an important endpoint for DLBCL and PTCL, associated with subsequent long-term outcomes [28, 29]. Regarding ENKTCL patients who failed to achieve PFS24, the median OS after progression was only 5.3 months, indicating that few patients who suffer early progression can be successfully treated. As observed by other studies [35, 36], ENKTCL patients who suffer disease progression after initial treatment had extremely poor prognoses, regardless of stage or risk group. In a recent study of 179 patients with ENKTCL who suffered disease relapse or progression after initial non-ANT-based chemotherapy, the median OS was only 6.4 months [35]. Similarly, for patients who failed to achieve PFS24 or EFS24, the subsequent median OS was 7.2 months after ANT-based immunochemotherapy for DLBCL and 4.9 months after ANT-based chemotherapy for PTCL [28, 29]. These findings indicate that PFS24 could be safely incorporated into routine clinical practice without detrimental effects on long-term disease control or survival outcomes in aggressive lymphomas under current standard treatments. PFS24 should be further validated in the context of randomized controlled trials as a potential early efficacy endpoint for patients with ENKTCL. Furthermore, there is an urgent requirement to identify patients at high risk of early progression who would benefit from innovative treatment strategies. Following the achievement of PFS24, research for ENKTCL survivors should focus on less-intensive surveillance, long-term treatment toxicity, quality of life, and other outcomes [34, 37, 38].

Previous studies, mainly using the randomized controlled trial (RCT) or real-world data, have demonstrated that the surrogate endpoints of EFS and PFS are strongly related to OS at both trial- and individual-level in different lymphoma subtypes [26–29, 32, 39–41]. Consistent with the present finding, the subsequent survival of patients with DLBCL or PTCL who achieved EFS24 or PFS24 is almost equal to that of the age-, sex-, and country-matched general population [26–29, 32]. Furthermore, we have confirmed the association of PFS24 with OS in trial- and treatment arm-level in RCTs on DLBCL patients treated with immunochemotherapy; its association has been externally validated using the literature-based data from high-quality phase II and retrospective studies [40]. Similarly, in patients with follicular lymphoma and marginal zone lymphomas [39, 41], early progression of disease within 24 months after initial treatment stratified subsequent OS and identifies a high-risk population. Consistent with the present study, these findings highlight the important role of PFS or EFS as early efficacy endpoint in designing prospective trials. The further work is needed to determine the prognostic factors for PFS24 in patients with ENKTCL.

The limitations of this study are as follows: first, the impact of salvage treatment on survival outcome after progression was not assessed, as it is beyond the scope of this study. Originally, our dataset was designed to collect only baseline characteristics, initial treatments, and events during follow-up. Second, these findings were mostly based on patients with early-stage disease, primarily treated with non-ANT-based regimens and radiotherapy. Extrapolation of these results when considering patients who underwent other treatments would be speculative. Third, despite the wide enrollment of ENKTCL patients primarily treated with non-ANT-based chemotherapy and upfront radiotherapy from a real-world CLCG database, more work is required to externally validate the correlation between PFS24 and OS using independent data from other large database, particularly from nonendemic areas. Furthermore, the retrospective design of this study does not allow for assessment of EFS as endpoint. The evaluation of EFS24 vs. PFS24 may be explored in a future study using CLCG data. The patients included in this study represent a young population with few comorbidities; longer follow-up and comparison to other collaboration data will give more insight into the importance of these endpoints.

In conclusion, assessment of PFS24 stratifies subsequent outcomes in patients with ENKTCL. Patients who achieve PFS24 have favorable subsequent survival regardless of stage and risk group. However, patients who suffer early progression have extremely poor prognoses. These results support the use of PFS24 as an efficacy endpoint, and should be considered in future studies evaluating novel therapies and biomarkers for risk stratification.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81670185), Chinese Academy of Medical Science (CAMS), Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1-001), and the National Key Projects of Research and Development of China (2016YFC0904600). The funding sources had no influence on the design, performance, or reporting of this study.

Author contributions

Conception and design: Y-XL, S-NQ, YY, XL. Financial support: Y-XL, YW. Administrative support: Y-XL, YW. Provision of study material or patients: YY, XL, YW, XH, L-LZ, GW, B-LQ, L-TQ, X-RH, X-YQ, HW, G-FLi, YZ, J-ZC, J-XW, TW, S-YZ, MS, L-MX, HS, Y-QS, Y-JZ, S-NQ, and Y-XL. Collection and assembly of data: YY, XL. Data analysis and interpretation: YY, XL, YW, S-NQ, CH, Y-XL. Manuscript writing: all authors. Final approval of manuscript: all authors. Accountable for all aspects of the work: all authors.

Compliance with ethical standards

Conflict of interest

CH has received grants from National Cancer Institute and personal fees from Merck & Co., outside the submitted work. All other authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Yang Y, Wang Y, Liu X

Change history

8/2/2021

A Correction to this paper has been published: 10.1038/s41375-021-01371-6

Contributor Information

Shu-Nan Qi, Email: medata@163.com.

Ye-Xiong Li, Email: yexiong12@163.com.

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