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Association of improved overall survival with decreased distant metastasis following asparaginase-based chemotherapy and radiotherapy for intermediate- and high-risk early-stage extranodal nasal-type NK/T-cell lymphoma: a CLCG study

Background This study evaluated the survival benefit of asparaginase (ASP)-based versus non-ASP-based chemotherapy combined with radiotherapy in a real-world cohort of patients with early-stage extranodal nasal-type natural killer/T-cell lymphoma (ENKTCL). Patients and methods We identified 376 patients who received combined radiotherapy with either ASP-based (ASP, platinum, and gemcitabine; n = 286) or non-ASP-based (platinum and gemcitabine; n = 90) regimens. The patients were stratified into low-, intermediate-, and high-risk groups using the early stage-adjusted nomogram-revised risk index. Overall survival (OS) and distant metastasis (DM)-free survival (DMFS) between the chemotherapy regimens were compared using inverse probability of treatment weighting (IPTW) and multivariable analyses. Results ASP-based (versus non-ASP-based) regimens significantly improved 5-year OS (84.5% versus 73.2%, P = 0.021) and DMFS (84.4% versus 74.5%, P = 0.014) for intermediate- and high-risk patients, but not for low-risk patients in the setting of radiotherapy. Moreover, ASP-based regimens decreased DM, with a 5-year cumulative DM rate of 14.9% for ASP-based regimens compared with 25.1% (P = 0.014) for non-ASP-based regimens. The survival benefit of ASP-based chemotherapy and radiotherapy remained consistent after adjusting the confounding variables using IPTW and multivariate analyses; additional sensitivity analyses confirmed these results. Conclusions The findings provided support for ASP-based chemotherapy and radiotherapy as a first-line treatment strategy for intermediate- and high-risk early-stage ENKTCL.

Acknowledging discrepancies in treatment between countries and limited high-quality clinical trial data, we designed a study to investigate the role of ASP-based chemotherapy and radiotherapy in early-stage ENKTCL using patient data from the China Lymphoma Collaborative Group (CLCG) database.

Patient eligibility and study population
Data on patients with newly diagnosed ENKTCL between 2000 and 2016 from the CLCG database were retrospectively reviewed. The institutional review board of our institution approved the study and waived the requirement for informed consent, as patients were deidentified in the database. The eligible criteria included stage I-II patients who received combined radiotherapy and non-anthracycline-based chemotherapy. Patients who received either radiotherapy alone or chemotherapy alone were excluded. Because both ASP-and PLA/GEM-based regimens are most commonly used for early-stage ENKTCL in China, 8 PLA/GEM-based regimens with (ASP-based) or without ASP (non-ASP-based) were selected in this study to reduce the heterogeneity of chemotherapy regimens (Supplementary Table S1

Risk stratification and treatment
The patients were staged with the Ann Arbor system and stratified according to the nomogram-revised risk index (NRI). 41,42 The early-stage-adjusted NRI (ES-NRI) includes five risk factors as follows: age >60 years, stage II, elevated lactate dehydrogenase, poor performance status [Eastern Cooperative Oncology Group (ECOG) score 2], and primary tumor invasion. Early-stage patients in the study were stratified into the low-(0), intermediate- (1)(2), and high-(3) risk groups.
All patients received CMT. Bone marrow function, normal liver and kidney function, underlying cardiovascular diseases, and contraindications to chemotherapy drugs were evaluated according to each institutional guideline before treatment. Chemotherapy was administrated with ASPbased (ASP/PLA/GEM; n ¼ 286) or non-ASP-based (PLA/ GEM; n ¼ 90) regimens (Supplementary Table S1, available  at

Endpoints
Primary endpoints included OS and distant metastasis (DM) free survival (DMFS). OS was defined as the period from the date of initial treatment to the date of any death. Progression-free survival (PFS) was defined as the period from the date of initial treatment to the date of locoregional and/or distant disease failure. DMFS was defined as the period from the date of initial treatment to the date of extranodal and/or distant lymphatic dissemination, and locoregional recurrence (LRR)-free survival (LRRFS) was defined as the period from the date of initial treatment to the date of disease failure in the primary site and/or regional lymph node.

Statistical analyses
The differences in clinical characteristics between ASPbased and non-ASP-based regimens were adjusted by inverse probability of treatment weighting (IPTW) method. 44 IPTW aims to simulate a cohort in which treatments are randomly assigned to patients. The probability of being in the two groups (ASP-based and non-ASP-based regimens) was estimated from a logistic regression model that incorporated prognostic factors associated with the receipt of ASP-based regimen. Standardized mean difference was used to assess the balance of covariate distribution between treatment groups before and after weighting.
The categorical data and response rates between groups were compared with the chi-square test. Survival data before or after weighting were analyzed with the Kaplane Meier method and compared with the log-rank test. Weighted Cox proportional hazards model was applied to calculate the IPTW-adjusted hazard ratio (HR). 45 Additional sensitivity analyses without assumptions were conducted to assess the potential influence of unmeasured confounders on OS. The cumulative incidences of DM and LRR were investigated via competing risk analysis using the Gray's test. Statistical analyses were performed using SPSS 26.0 (IBM, New York, NY) and the simPH, survival, cmprsk, and RISCA packages in R, version 4.0.2 (http://www.rproject.org/).

Baseline characteristics and outcomes
The baseline clinical features for the entire cohort are summarized in Table 1. The majority of patients (89.6%) were 60 years old (median age 43 years; range 13-78 years). The male-to-female ratio was 2.42:1. Most patients showed good performance status (ECOG score 0-1, 97.3%) and upper aerodigestive tract site (96.5%). Elevated lactate dehydrogenase, primary tumor invasion, and stage II disease were present in 27.1%, 65.4%, and 44.1% of patients, respectively. According to the ES-NRI, the majority of patients (84.3%) were classified into intermediate-and highrisk groups, whereas 15.7% of patients were classified into the low-risk group.
With a median follow-up of 50 months, the 5-year OS and PFS were 83.4% and 68.7% for all patients, respectively. The ES-NRI is a powerful predictor for survival and showed an excellent 5-year OS of 93% for the low-risk group and worse outcomes (81.5%) for intermediate-and high-risk groups.

Decreased DM and improved DMFS with ASP-based chemotherapy
We further investigated the effect of ASP-based chemotherapy on DM and DMFS. Among the entire cohort, 54 (14.4%) of the 376 patients developed DM after CMT. The crude DM rate was significantly higher in non-ASP-based regimens (21/90, 23.3%) compared with ASP-based regimens (33/286, 11.5%; P ¼ 0.005). ASP-based regimens showed a significantly lower 5-year cumulative DM rate (13.1% versus 23.9%; P ¼ 0.008; Figure 2A) than non-ASPbased regimens. Similarly, in intermediate-and high-risk patients, the 5-year cumulative DM rate was 14.9% for ASP-based regimens compared with 25.1% for non-ASPbased regimens (P ¼ 0.014; Figure 2B). These results indicated that ASP-based chemotherapy and radiotherapy significantly decreased distant and extranodal failure in intermediate-and high-risk early-stage ENKTCL.

Effect of ASP-based chemotherapy on LRRFS
We evaluated the effect of ASP-based chemotherapy on LRR and LRRFS. As many as 44 of the 286 patients (15.4%) in ASP-based regimens and 15 of the 90 patients (16.7%) in non-ASP-based regimens developed LRR. ASP-based and non-ASP-based regimens resulted in a comparable 5-year cumulative LRR rate for the entire cohort (19.0% versus 18.4%, P ¼ 0.628; Figure 3A), as well as for intermediateand high-risk patients (19.1% versus 19.0%, P ¼ 0.673; Figure 3B).

Sensitivity analysis
A sensitivity analysis without assumptions showed that the results remained consistent under the influence of unmeasured confounders (Supplementary Figure S3,

DISCUSSION
In this CLCG multicenter study, we explored the benefit of ASP-based chemotherapy for the first-line CMT of early-stage ENKTCL. In the context of radiotherapy, adding ASP into PLA/GEM-based chemotherapy significantly improved OS in intermediate-and high-risk early-stage patients. Improved OS after ASP-based chemotherapy  e  g  a  t  s  -y  l  r  a  e  k  s  i  r  -h  g  i  h  d  n  a  -e  t  a  i  d  e  m  r  e  t  n  I  e  g  a  t  s  -y  l  r   was associated with decreased DM and increased DMFS, but not with LRRFS. The survival benefit of ASP-based chemotherapy remained constant after adjustment of the confounding variables by IPTW and multivariate analyses. These results provided additional evidence for the clinical use of ASP-based CMT for early-stage ENKTCL.
Risk-adapted therapy with introduction of nonanthracycline-based regimens and early implementation of radiotherapy have been the most important advances for the first-line treatment of early-stage ENKTCL. [5][6][7][8][9][10][11] Despite the absence of high-level evidence, ASP-based regimens have been widely accepted as the standard of care in advanced-stage disease. [9][10][11][12][13][14][15][16][17][18] Given favorable outcomes with upfront radiotherapy for early-stage ENKTCL, adding chemotherapy to radiotherapy conferred survival benefit for intermediate-and high-risk patients but not for low-risk patients. 22,23 A variety of ASP-based or PLA-based regimens have been used as the appropriate CMT approach. [24][25][26][27][28][29][30][31][32][33][34][35][36][37] There are no comparative data describing the benefit of ASP-based regimens over non-ASP-based regimens for early-stage ENKTCL. The goal of this CLCG study was to identify active agents and optimal combinations to improve survival in early-stage ENKTCL. We confirmed that some portion of intermediate-and high-risk early-stage patients could benefit from the addition of ASP to PLA/GEM-based CMT. In this study, the 5-year OS rate of 286 early-stage patients that received ASP-based CMT was~85%, higher than previous large multi-institutional reports from Japan (72%), 11 China (73.3%), 8 Asian joint (72-74%), 46 and the International T-cell Project registry data (median, 59 months), 47 probably because of the use of heterogeneous non-anthracycline-based regimens in the latter studies. We could not differentiate the efficacy of ASP-based versus non-ASP-based regimens in a small cohort of low-risk earlystage patients with favorable prognoses. These findings suggest that ASP may be a fundamental agent of nonanthracycline-based regimens in the first-line CMT for patients with intermediate-and high-risk early-stage ENKTCL. However, different types of treatment selection bias may have existed in these patients. Patients with favorable prognostic factors tended to receive non-ASP-based chemotherapy, while patients who are younger or in good performance status were more likely to receive ASP-based chemotherapy.
In the present CLCG study of early-stage patients treated with radiotherapy, ASP-based chemotherapy significantly decreased DM and improved DMFS and OS. Multivariate analyses revealed that ASP-based chemotherapy was an independent prognostic factor for DMFS and OS. In addition, ASP-based chemotherapy showed limited effect on locoregional control and LRRFS in the CMT setting. The high DMFS rate with ASP-based chemotherapy could translate into a significant improvement in OS. In our previous CLCG studies, 19,48 improved locoregional control using optimal radiotherapy was associated with prolonged PFS and OS in early-stage patients, 19 and the survival probability increased and failure hazard decreased in a risk-dependent manner. 48 Moreover, in a subgroup analysis of 240 early-stage patients who achieved CR after ASP-based chemotherapy, additional radiotherapy significantly decreased LRR and improved survivals. 21 The 5-year OS, disease-free survival, and locoregional control rates were 84.9%, 76.2%, and 84.9% for CMT compared with 58.9% (P ¼ 0.006), 43.6% (P ¼ 0.001), and 62.1% (P ¼ 0.026) for chemotherapy alone. Based on competing risk analysis, the 5-year cumulative rates of LRR and systemic recurrence were 14.2% and 10.1% for CMT compared with 30.6% (P ¼ 0.044) and 18.4% (P ¼ 0.225) for ASP-based chemotherapy alone. These data suggest that in contrast to radiotherapy, ASP-based chemotherapy improves OS by acting on distant micrometastatic disease more than via locoregional effects. Early-stage ENKTCL is not only a localized disease, but also a systemic disease. The use of upfront locoregional radiotherapy and systematic ASP-based chemotherapy provide the ideal spatial combination for first-line therapy in intermediate-and high-risk early-stage ENKTCL patients.
The sequencing strategy for chemotherapy and radiotherapy in early-stage ENKTCL varies across countries and between collaborative study groups. 11,23,46,47 In a recent CLCG study of 1360 NRI-stratified early-stage patients, the sequence and optimal cycles of non-anthracycline-based chemotherapy have been especially addressed in the setting of radiotherapy. 23 For intermediate-and high-risk patients treated with sequential chemoradiotherapy, radiotherapy-first CMT showed similar 5-year OS (77.7% versus 72.4%; P ¼ 0.290) and PFS (67.1% versus 63.1%; P ¼ 0.592) to chemotherapy-first CMT. 23 Moreover, for patients who achieved CR after induction chemotherapy, initiation of radiotherapy within or beyond three cycles of nonanthracycline-based chemotherapy resulted in comparable 5-year OS (78.2% versus 81.7%; P ¼ 0.915) and PFS (68.2% versus 69.9%; P ¼ 0.519). However, for patients who did not achieve CR, early radiotherapy within three cycles of chemotherapy yielded better PFS compared with delayed radiotherapy beyond three cycles of chemotherapy (63.4% versus 47.6%; P ¼ 0.019). 23 In another study of 244 earlystage patients, 46 concurrent (early radiotherapy) versus sequential non-anthracycline-based chemotherapy and radiotherapy (delayed radiotherapy) yielded equivalent OS (P ¼ 0.582) but better PFS (P ¼ 0.035). These findings suggest that sequential combination of forefront radiotherapy and short-course ASP-based chemotherapy may constitute a reasonable treatment option for selected earlystage patients.
The strengths of this study included the heterogeneous early-stage population, use of current-era chemotherapy regimens, and unique effect of ASP-based regimens on DMFS. First, because of the heterogeneous population in the cohort of early-stage patients, we examined the variability of outcomes with risk-adapted first-line CMT and improved the generalizability of our study. Second, the most commonly used chemotherapy for early-stage ENKTCL was ASP-based or PLA-based regimens in China. 8,23 Although the comparison of different ASP-based regimens has not been extensively investigated, the emerging results suggested that incorporation of ASP into PLA-based regimens is effective and safe for early-stage ENKTCL. 16,[25][26][27][28][29]34 Third, this study was the first to demonstrate clear associations of decreased DM and improved DMFS with OS benefit in earlystage ENKTCL patients; this unique finding is critical to understand that the therapeutic efficacy of ASP-based chemotherapy may mostly rely on DMFS. The analysis of DMFS as an endpoint, which is not commonly reported in lymphomas, was not confounded by locoregional factors related to radiotherapy. DMFS may provide an additional clinically relevant endpoint to evaluate the effect of novel systemic therapy in ENKTCL patients.
Our retrospective study had several limitations. First, ASP-based and non-ASP-based chemotherapy regimens were not randomly assigned. We attempted to reduce the selection bias using IPTW and multivariable analyses; however, there remains a chance that the underlying confounders may have influenced the treatment outcomes. Before generalizing the hypothetical survival benefit of additional ASP proposed in this retrospective study, it needs further evidence from prospective studies controlling confounding factors. Second, the toxicity profiles were not available in this retrospective, observational study. The toxicities of the chemotherapy regimens affected clinical decision making and could be considered in different risk groups of early-stage patients. However, the toxicity profiles of two categories of regimens in early-stage ENKTCL have been reported in other studies. 25,27,38,40,49,50 The addition of ASP into PLA and GEM would inevitably result in increased toxicities. Previous studies showed that non-ASPbased (PLA/GEM) CMT in early-stage ENKTCL resulted in less grade 3/4 toxicities (18%-30% versus 12.5%-65.8%) than ASP-based (ASP/PLA/GEM) CMT. 25,27,38,40,49,50 The thrombosis, hypersensitivity, and pancreatitis induced by ASP in early-stage ENKTCL were rare, but should be taken into consideration. However, both ASP-based (ASP/PLA/ GEM) regimens and non-ASP-based (PLA/GEM) regimens were well tolerated in early-stage ENKTCL, when combined with radiotherapy. 25,27,38,40,49,50 In addition, our study focused on the efficacy comparison of ASP/PLA/GEM versus PLA/GEM regimens and did not include other ASP-based regimens with inclusion of MTX and/or etoposide because of a small number of patients. 8 Thus, our results may not be applicable to patients receiving ASP/MTX-based regimens. However, given the severe toxicities 9,10,14 and low risk of central nervous system involvement, 51 the role of incorporation of MTX into ASP-based regimens remains uncertain for the first-line CMT of early-stage ENKTCL. Using PFS at 24 months as an efficacy endpoint, 52 further work is needed to optimize systemic therapies or novel regimens with inclusion of ASP and radiotherapy in intermediate-and high-risk early-stage patients.
In summary, ASP-based chemotherapy was associated with improved OS and DMFS. With the limited data available, patients with intermediate-and high-risk early-stage ENKTCL could be offered subsequent ASP-based chemotherapy and radiotherapy. This approach needs to be validated in a prospective trial. The funding sources had no influence on the design, performance, or reporting of the study.