Efficacy of a short sandwich protocol, methotrexate, gemcitabine, L-asparaginase and dexamethasone chemotherapy combined with radiotherapy, in localised newly diagnosed NK/T-cell lymphoma: A French retrospective study.

Extranodal NK/T-cell lymphoma, nasal type is a rare and aggressive form of lymphoma, historically associated with poor prognosis. We report here the results of a retrospective multi-centre study evaluating the efficacy of MGAD (methotrexate, gemcitabine, L-asparaginase and dexamethasone) regimen (two cycles) combined with 'sandwich' radiotherapy in 35 patients with localised newly diagnosed extranodal NK/T-cell lymphoma. Thirty-two patients (91%) reached complete remission. With a long median follow-up of 59.6 months, progression-free and overall survival at 2 and 5 years were 71%, 80% and 53%, 73%, respectively. Around one third of the patients experienced relapse within a median time of 14.5 months. Side-effects were manageable with grades 3-4 cytopenias, mucositis and infection in 50%, 24% and 21% of the cases, respectively. Monitoring of asparaginase activity was performed in 13 patients and showed inactivation of the drug in seven (54%) patients. Our results indicate that a short therapy by sandwich MGAD chemoradiotherapy is a tolerable and effective treatment option in localised newly diagnosed extranodal NK/T-cell lymphoma patients.

A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma.

Current prognostic scoring systems based on clinicopathologic variables are inadequate in predicting the survival and treatment response of extranodal natural killer/T-cell lymphoma (ENKTL) patients undergoing nonanthracyline-based treatment. We aimed to construct a classifier based on single-nucleotide polymorphisms (SNPs) for improving predictive accuracy and guiding clinical decision making. Data from 722 patients with ENKTL from international centers were analyzed. A 7-SNP-based classifier was constructed using LASSO Cox regression in the training cohort (n = 336) and further validated in the internal testing cohort (n = 144) and in 2 external validation cohorts (n = 142 and n = 100). The 7-SNP-based classifier showed good prognostic predictive efficacy in the training cohort and the 3 validation cohorts. Patients with high- and low-risk scores calculated by the classifier exhibited significantly different progression-free survival (PFS) and overall survival (OS) (all P < .001). The 7-SNP-based classifier was further proved to be an independent prognostic factor by multivariate analysis, and its predictive accuracy was significantly better than clinicopathological risk variables. Application of the 7-SNP-based classifier was not affected by sample types. Notably, chemotherapy combined with radiotherapy significantly improved PFS and OS vs radiotherapy alone in high-risk Ann Arbor stage I patients, whereas there was no statistical difference between the 2 therapeutic modalities among low-risk patients. A nomogram was constructed comprising the classifier and clinicopathological variables; it showed remarkably better predictive accuracy than either variable alone. The 7-SNP-based classifier is a complement to existing risk-stratification systems in ENKTL, which could have significant implications for clinical decision making for patients with ENKTL.

"Sandwich" protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.

GELAD chemotherapy with sandwiched radiotherapy for patients with newly diagnosed stage IE/IIE natural killer/T-cell lymphoma: a prospective multicentre study.

Early-stage natural killer/T-cell lymphoma (NK/TCL) patients usually receive a combination of chemotherapy and radiotherapy, but the optimal treatment approach has not yet been established. This study aimed to investigate the efficacy and safety profile of a novel chemotherapy regimen and sandwiched radiotherapy in early-stage NK/TCL. Patients with newly diagnosed stage IE/IIE disease were eligible. Patients were initially treated with two courses of the GELAD regimen (gemcitabine 1·0 g/m2 day 1, etoposide 60 mg/m2 days 1-3, pegaspargase 2000 units/m2 day 4, and dexamethasone 40 mg days 1-4), followed by intensity-modulated radiotherapy (IMRT; 50-56 Gy in 25-28 fractions) and two additional courses of GELAD chemotherapy. A total of 52 patients were enrolled. The overall response rate and complete response rate per Lugano 2014 criteria were 94·2% and 92·3% respectively. With a median follow-up of 32 months, the estimated four-year overall survival rate and progression-free survival rate were 94·2% [95% confidence interval (CI), 83·2% to 93·1%] and 90·4% (95% CI, 78·4% to 95·9%) respectively. The most common adverse events were related to pegaspargase. Haematological toxicities were mild, with grade 3/4 neutropenia in 15·4% of patients. Our study provides a new approach with high activity and improved safety for the treatment of early-stage NK/TCL patients. This study was registered at www.clinicaltrials.gov as NCT02733458.

First-line LVDP (L-asparaginase, etoposide, dexamethasone, and cisplatin) regimen combined with radiotherapy is effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type.

Chemotherapy combined with radiotherapy could reduce the risk of recurrence in early-stage extranodal NK/T lymphoma (ENKTL). However, the optimal combined chemotherapy regimen is still unknown. Our previous study reported that LVDP (L-asparaginase, etoposide, dexamethasone, and cisplatin) combined with radiotherapy was a potentially effective and safe treatment regimen for early-stage ENKTL. This study further validated the efficacy and safety of LVDP chemotherapy combined with radiation for early-stage ENKTL with more patients and longer follow-up. We retrospectively studied 112 patients with early-stage ENKTL from September 2010 to September 2019. All patients received the LVDP regimen, and 101 of them received radiotherapy. The patients' characteristics, treatment responses, survival outcomes, prognostic factors, and toxicities were analyzed. The median follow-up was 60 months (range, 4 to 117). All patients received median 4 cycles of the LVDP chemotherapy. At the end of therapy, the objective response rate and complete response rate were 88.3% and 77.6%, respectively. The 3- and 5-year OS were 79.6% and 73.2%, and the 3- and 5-year PFS were 75.4% and 71.6%, respectively. Among them, the LVDP regimen combined with radiotherapy yielded more favorable treatment outcomes (the 3-year OS and PFS were 83.1% and 80.8%). The most common severe hematologic toxicity was leukopenia (25% grade 3/4), and the most common severe non-hematologic toxicity was increased transaminase (4.5% grade 3/4). No pancreatitis or treatment-related death occurred. The LVDP regimen combined with radiotherapy had a good therapeutic response and long-term survival with tolerable toxicity for patients with early-stage ENKTL.

Comparison analysis of first-line asparaginase- versus non-asparaginase-based regimens for early-stage extranodal NK/T-cell lymphoma.

The present study investigated the efficacy and toxicity profile of first-line asparaginase (ASP)-based versus non-ASP-based regimens in treating early-stage extranodal NK/T-cell lymphoma (ENKTCL) in non-anthracycline therapy era. This multi-center, real-world retrospective study consisted 305 newly diagnosed localized ENKTCL patients who were treated with sequential chemoradiation between 2010 and 2020 in China: 190 cases received ASP-based regimens and 115 cases received non-ASP-based regimens. Propensity score matching and multivariable analyses were used to compare survivals and toxicities between the two treatment groups. Non-ASP-based regimens achieved comparable survivals compared with ASP-based regimens in the entire cohort. The 5-year overall survival (OS), progression-free survival (PFS) rates were 84.7% and 73.5% for non-ASP-based regimens, and 87.7% (P=0.464) and 74.6% (P=0.702) for ASP-based regimens. The non-inferior survivals of non-ASP-based regimens were consistent after adjustment using PSM and multivariable analyses. However, survival benefits of ASP varied in different treatment modalities. Among patients receiving sequential chemotherapy and radiation (CT+RT±CT), ASP-based regimens achieved higher complete remission rate (54.3 vs. 34.5%, P=0.047) and more favorable survivals compared with non-ASP-based regimens (5-year OS, 87.0 vs. 69.0%, P=0.028). However, for patients receiving sequential radiation and chemotherapy (RT+CT), non-ASP-based regimens achieved comparable favorable survivals as ASP-based regimens. Besides, liver injury, malnutrition, and coagulative dysfunction were significantly more commonly documented in ASP-based regimens. These findings suggested that ASP was an effective agent in treating ENKTCL, especially among those receiving induction CT and RT. For patients who received upfront RT, non-ASP-based regimens might be a comparably effective and more tolerable treatment option.

[Pretreatment evaluation of 18F-FDG PET-CT in extranodal NK/T-cell lymphoma].

Objective: To investigate the clinical value of pretreatment 18F-fluorodeoxy glucose positron emission tomography/computed tomography (18F-FDG PET-CT) in extranodal NK/T-cell lymphoma. Methods: Eighty-one patients with pathologically confirmed extranodal NK/T-cell lymphoma and pretreatment with PET-CT scan in Cancer Hospital, Chinese Academy of Medical Sciences from August 2006 to December 2017 were enrolled in the study. The clinical, follow-up and imaging data were analyzed retrospectively. The relationship between maximum standard uptake value (SUVmax) and prognosis were evaluated by Mann-Whitney U test and Spearman rank correlation analysis. Results: Among the 81 patients, 98.8% (80/81) were upper aerodigestive tract (UAT) involved. Lesions at extra-UAT sites were detected in 7 cases, involving parotid gland (n=1), breast (n=1), spleen (n=1), pancreas (n=1), skin and subcutaneous soft tissue (n=1), muscle (n=1), lung (n=2) and bone (n=3). Lymph node involvement were demonstrated in 33 cases. All of the lesions had increased uptake of PET, the median SUVmax was 8.6. PET-CT changed staging in 15 cases, and 12 cases were adjusted treatment methods. 21 cases were changed radiotherapy target because of PET-CT. The 1-, 2-year progression-free survival (PFS) rates were 88.7% and 80.3% while 1-, 2-year overall survival (OS) rates were 97.2% and 94.4% respectively. The median SUVmax of patients with local lymph nodes involvement was significantly higher than those without local lymph nodes involvement (P=0.007). The SUVmax was positively associated with Ann Arbor stage (r=0.366, P=0.001), lactate dehydrogenase (r=0.308, P=0.005) and Ki-67 level (r=0.270, P=0.017). The SUVmax was inversely associated with lymphocyte count (r=-0.324, P=0.003) and hemoglobin content (r=-0.225, P=0.043). Conclusions: Extranodal NK/T-cell lymphoma predominantly occurs in extra-nodal organs, mainly in the upper respiratory and gastrointestinal tracts, with marked FDG-addiction. Compared with conventional imaging, 18F-FDG PET-CT is sensitive and comprehensive in detecting extra-nodal NK/T-cell lymphoma involvement, assisting in accurate clinical staging and treatment planning. Pretreatment SUVmax is potential for prognosis evaluation since it is correlated with prognostic factors.

Radiotherapy vs sequential pegaspargase, gemcitabine, cisplatin and dexamethasone and radiotherapy in newly diagnosed early natural killer/T-cell lymphoma: A randomized, controlled, open-label, multicenter study.

To compare the efficacy and safety of radiotherapy (RT) and chemotherapy of pegaspargase, gemcitabine, cisplatin and dexamethasone (DDGP) combined with RT in newly diagnosed stage I-II natural killer/T-cell lymphoma (NKTL), we designed a randomized, controlled, open-label, multicenter clinical trial. Data from 65 stage I-II NKTL patients whose diagnoses were confirmed using immunohistochemistry were enrolled from January 2011 to December 2013 in the First Affiliated Hospital of Zhengzhou University. Patients were randomly divided into the RT group (n = 35) and the DDGP combined with RT group (n = 30). There was a difference between the Eastern Cooperative Oncology Group (ECOG) score in the two arms (P = .013). The complete response rate (CRR) and objective response rate (ORR) of DDGP combined with RT group were superior to those in the RT group (CRR: 73.3% vs 48.6%; ORR: 83.3% vs 60.0%, respectively). The 5-year progression-free survival (PFS) rate and overall survival (OS) rate in the DDGP combined with RT group were higher than those in the RT group (82.9% vs 56.5% for PFS, P = .023; 85.7% vs 60.4% for OS, P = .040), and treatment methods and lactate dehydrogenase were independent risk factors. Myelosuppression (P < .001), gastrointestinal reactions (P < .001), abnormal liver function (P = .007), coagulation abnormalities (P < .001) and baldness (P < .001) were more likely to occur in the DDGP combined with RT group. In conclusion, DDGP combined with radiotherapy obviously obtained great efficacy and prolonged the survival time of patients, also the side effects were mild for stage I-II NKTL. This trial was registered at https://register.clinicaltrials.gov as #NCT01501136.

The optimal timing of radiotherapy in the combination treatment of limited-stage extranodal natural killer/T-cell lymphoma, nasal type: an updated meta-analysis.

This study was designed to explore the relative efficacy and toxicity of upfront radiotherapy (RT) and late RT in combination treatments for patients with limited-stage extranodal natural killer/T-cell lymphoma nasal type (LS-ENKTL). We searched for clinical trials in the PubMed database that compared upfront RT with late RT in the combined treatment of patients with LS-ENKTL. We systematically evaluated the differences in survival, treatment response, and treatment-related adverse events (AEs) between these two groups. Ten retrospective studies with a total of 1752 patients were included. Upfront RT significantly prolonged the overall survival (OS) and progression-free survival (PFS) of patients compared to late RT in combination with chemotherapy (CT) (HR = 0.72, 95% CI 0.59-0.88, P = 0.001 for OS; HR = 0.57, 95% CI 0.41-0.79, P = 0.0007 for PFS). The complete remission (CR) rate in the upfront RT group was superior to that in the late RT group (HR = 1.61, 95% CI 1.09-2.37, P = 0.02). Patients experienced similar local recurrence-free survival (LRFS), objective response rates (ORR), and toxicity between these two arms (P > 0.05 for all) in the analysis of each subgroup. The survival benefit of upfront RT was not correlated with the RT dose, concurrent chemoradiotherapy (CCRT) (or not), or the CT regimen (P > 0.05 for all). Without compromises in terms of toxicity, RT dose, and treatment modality, upfront RT can significantly benefit OS, PFS, and CR compared to late RT in combination treatment. These findings verified that the upfront RT regimen is more suitable for patients with LS-ENKTL.

Elevated expression of HMGB1 is prognostic of poor survival in patients with relapsed/refractory T/NK-CL.

Despite the clinical value of HMGB1 in non-Hodgkin lymphoma (NHL), the impact of HMGB1 protein expression on survival of patients with mature T-cell and NK-cell lymphoma (T/NK-CL) is unknown. Here, we evaluated correlations of HMGB1 expression in tumor tissues with pathophysiological characteristics of disease and determined the prognostic value of HMGB1 expression in relapsed/refractory T/NK-CL. HMGB1 expression was detected by immunohistochemistry (IHC) in 66 cases of relapsed/refractory T/NK-CL, and specimens were classified as high or low HMGB1 expression. Univariate and multivariate Cox regression analyses identified prognostic factors associated with progression-free survival (PFS) and overall survival (OS). High HMGB1 expression was significantly correlated with increased Ki67 levels and progressive lymphoma subtypes. Univariate Cox regression analysis showed that high HMGB1 expression was associated with unfavorable PFS (P = 0.006) and poorer OS (P < 0.001). Prognostic factors identified by univariate analysis were prognostic index for peripheral T-cell lymphoma non-specified (PIT) score ≥ 2, bone marrow involvement, Ki67 ≥ 70%, and high HMGB1 expression. Multivariate Cox regression analysis revealed that high HMGB1 expression was an independent prognostic factor for poorer PFS [hazard ratio (HR) 3.593; 95% confidence interval (CI) 1.171-11.027; P = 0.025] and OS [HR 7.663; 95% CI 2.367-24.803; P = 0.001]. A proposal prognostic model combining HMGB1 and Ki67 expression showed improved prognostic capacity and may help guide treatment planning. High HMGB1 expression may be a promising prognostic predictor and a potential therapeutic target for relapsed/refractory T/NK-CL. Furthermore, to apply HMGB1 as one of the best bio-maker, an external independent control cohort is needed.

Dynamic evaluation of the prognostic value of 18F-FDG PET/CT in extranodal NK/T-cell lymphoma, nasal type.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.

Sequential P-GEMOX and radiotherapy for early-stage extranodal natural killer/T-cell lymphoma: A multicenter study.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease. Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with early-stage ENKTL. However, the optimal CMT has not been fully clarified. This study reports the efficacy and toxicity of sequential P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) and radiotherapy in a large Chinese cohort comprising of 202 patients diagnosed with early-stage ENKTL from six medical centers. The observed best overall response rate was 96.0% and 168 (83.2%) patients achieved complete remission. With a median follow-up of 44.1 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 74.6% and 85.2%, respectively. Multivariate analysis suggested that extensive primary tumor (PFS, hazard ratio [HR] 3.660, 95% CI 1.820-7.359, p < 0.001; OS, HR 3.825, 95% CI 1.442-10.148, p = 0.007) and Eastern Cooperative Oncology Group performance status ≥ 2 (PFS, 3.042, 95% CI 1.468-6.306, p = 0.003; OS, HR 3.983, 95% CI 1.678-9.457, p = 0.02) were independent prognostic factors for survival outcomes. Among the established prognostic models for ENKTL, the nomogram-revised risk index model had optimal prognostic risk stratification ability (PFS, p < 0.001; OS, p < 0.001) and relatively balanced population distribution. The adverse events of this CMT were well-tolerated and manageable. In conclusion, sequential P-GEMOX and radiotherapy showed favorable efficacy with acceptable toxicity, and could be an effective treatment option for early-stage ENKTL patients.

[Outcome of radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type].

Objective: To evaluate the prognosis and determine the failure patterns after radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type (ENKTCL). Methods: A total of 557 patients from 2000-2015 with low-risk early-stage ENKTCL who received radiotherapy (RT) with or without chemotherapy (CT) from China Lymphoma Collaborative Group were retrospectively reviewed. Among them, 427 patients received combined modality therapy, whereas 130 patients received RT alone. Survivals were calculated by Kaplan-Meier method and compared with Log-rank test. Overall survival (OS) was compared with age and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Cox stepwise regression model was used for multivariate analysis. Results: The 5-year OS and progression-free survival (PFS) were 87.2% and 77.2%. The SMR was 3.59 (P<0.001) at 1 year after treatment, whereas it was 1.50 at 4 years after treatment, without significant difference between ENKTCL group and country-matched general population (P=0.146). Compared with RT alone, CMT did not result in significantly superior 5-year OS (87.0% vs 87.4%, P=0.961) or PFS (76.1% vs 80.7%, P=0.129). Local failure (11.5%, 64/557) and distant failure (10.8%, 60/557) were the main failure modes, while regional failure was rare (2.9%, 16/557). The 5-year locoregional control rate (LRC) was 87.2% for the whole group, with 89.5% for ≥50 Gy versus 73.7% for <50 Gy (P<0.001). Radiotherapy dose was an independent factor affecting LRC(P<0.05). Conclusions: Radiotherapy achieves a favorable prognosis in patients with low-risk early-stage ENKTCL. The incidence of either locoregional or distant failure is low. Radiation dose still is an important prognostic factor for LRC.

Pegaspargase Combined with Concurrent Radiotherapy for Early-Stage Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Two-Center Phase II Study.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is expected to improve local and systemic disease control and has been established as a standard therapy for several types of solid tumors. Considering the benefits of frontline radiation and pegaspargase in localized extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL), we conducted a phase II study on pegaspargase-based CCRT to explore an effective treatment. MATERIALS AND METHODS: In this study, 30 patients with newly diagnosed nasal ENKTL in stages IE to IIE received CCRT (radiation 50 Gy and two cycles of pegaspargase 2,500 unit/m2 every 3 weeks). Four courses of pegaspargase were performed after CCRT. RESULTS: The patients completed CCRT and four cycles of pegaspargase. The complete remission (CR) rate was 90%, with a 95% confidential interval (CI) of 73.5%-97.9% after CCRT. The CR rate was 100% (95% CI, 88.4%-100%) at the end of the treatment. The 2-year overall survival and progression-free survival rates were 90.9% (95% CI, 78.4%-100%) and 92.8% (95% CI, 83.2%-100%), respectively. The major adverse events were in grades 1-2. CONCLUSION: Preliminary data indicate that pegaspargase combined with concurrent radiotherapy for newly diagnosed patients with nasal ENKTL was efficacious and well tolerated. Registered at www.chictr.org. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OIC-15007662. IMPLICATIONS FOR PRACTICE: This clinical trial, evaluating the efficacy and toxicity of concurrent chemoradiotherapy by using single-drug pegaspargase for patients with extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) in stage IE to IIE, showed pegaspargase combined with concurrent radiotherapy was efficacious and well tolerated. Pegaspargase has a long half-life and is easy to administer via intramuscular injection. Consequently, pegaspargase combined with concurrent radiotherapy for patients with ENKTL can be completed in the outpatient clinic.

The correlation of clinicopathological features and prognosis in extranodal natural killer/T cell lymphoma: a report of 42 cases in the early stage.

This study aimed to explore the clinicopathological features and prognostic correlation of extranodal natural killer (NK)/T cell lymphoma (ENKTCL) in the early stage, screen out the prognostic markers of ENKTCL, and to establish the molecular model of ENKTCL prognosis. A retrospective study was conducted in 88 patients from May 1999 to Dec 2013 in Chinese Academy of Medical Sciences Cancer Hospital, who were diagnosed with ENKTCL according to WHO lymphoid hematopoietic tumor classification (published in 2008). The clinical data and paraffin-embedded tissue blocks were collected. The expressions of CD56, MLH1, PDGFRA, VEGF, PD-L1, PD-1, CyclinD1, p53, and Ki-67 were detected by high-throughput tissue microarray and immunohistochemistry (IHC) staining. The relationship between nine protein expressions and the clinicopathological features and prognosis of patients with ENKTCL were analyzed. The survival time of the 42 patients with complete clinical and follow-up data was 0~153 months. The average survival time was 60.1 months. The survival rates of 1 year, 2 years, and 3 year were 85.7%, 78.6%, and 71.4%, respectively. Single factor survival analysis showed that the increase of serum lactate dehydrogenase (LDH ≥ 240UI/L) before treatment was associated with poor prognosis, and there was a significant difference in survival rate (P = 0.006). Different therapy methods were related with prognosis (P = 0.011); in specifically, radiotherapy alone had the best treatment effect, followed by concurrent chemoradiotherapy, and the worst was chemotherapy alone. But, multivariate statistics indicated that the LDH level and the treatment approach were not independent prognostic factors of ENKTCL. There was no statistical difference between epidemiological factors such as gender, age, and other clinicopathological factors including tumor location, B symptoms, ß2-microglobulin levels before treatment, and prognosis. Survival analysis of single factor showed that the positive expression of PDGFRA and PD-L1 was, respectively, related to the poor prognosis of patients with ENKTCL (P = 0.040, 0.007). The patients with Ki-67 overexpression (≥ 50%) had a worse prognosis than those with lower expression (< 50%), and the difference of survival rate between the two groups has statistical significance (P = 0.038). The expression of CD56, MLH1, VEGF, PD-1, CyclinD1, and p53 has no effect on survival rate (P > 0.05). Multivariate survival analysis showed that the expression levels of PDGFRA, PD-L1, and Ki-67 were independent factors in the prognosis of patients with ENKTCL. And the positive expressions of these three proteins were risk factors for prognosis of patients with ENKTCL (PDGFRA: P = 0.045, HR = 8.265, 95% CI: 1.050-65.054; PD-L1: P = 0.005, HR = 9.369, 95% CI: 1.950-45.003; Ki-67: P = 0.023, HR = 3.545, 95% CI: 1.187-10.585). The elevation of serum lactate dehydrogenase (LDH ≥ 240UI/L) before treatment and the treatment approach were associated with poor prognosis, which could be used as adjunct indexes to the prognosis. However, they were not independent factors for the prognosis of patients with ENKTCL. The expressions of PDGFRA, PD-L1, and Ki-67 were independent factors in the prognosis of patients with ENKTCL and these three proteins were risk factors of prognosis. The above markers combined with clinical factors may establish the prognosis model of ENKTCL.

[Long-term effect of risk-adaptive therapy for early stage extranodal NK/T cell lymphoma].

Objective: This study aimed to evaluate the role of extended involved-field intensity modulated radiation therapy (IMRT) for patients with early stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) in a single center, and to explore the long-term effect of risk-adaptive therapy. Methods: Among 238 patients with early stage NKTCL, there were 191 in high-risk group [any risk factor of age > 60, elevated serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) score≥2, primary tumor invasion, or Ann Arbor stage Ⅱ] and 47 in low-risk group (no risk factor). A total of 204 patients received radiotherapy combined with chemotherapy, 15 received radiotherapy alone and 19 received chemotherapy alone. One-hundred and eighty-six patients had radiotherapy at a dose ≥50 Gy and 159 patients received chemotherapy with asparaginase-based regimen. Results: The 5-year overall survival (OS) rate and progression- free survival (PFS)rate of all patients were 66.2% and 57.5%. Five-year OS and PFS rates in low-risk group were 91.8% and 88.0%, while 59.3% and 49.3% in high-risk group. The survival of patients in low-risk group were better than those in high-risk group (both P<0.001). The five-year OS rate in combined therapy group, radiotherapy group and chemotherapy group were 71.7%, 52.3% and 20.7%, respectively (P<0.001). The five-year PFS rate were 63.5%, 23.3% and 24.1%, respectively (P<0.001). Among 219 patients receiving radiotherapy, the 5-year OS and PFS rate of patients with primary site radiotherapy dose ≥ 50 Gy were 72.6% and 66.1%, higher than those of patients with a dose <50 Gy (57.3% and 30.9%, respectively; P=0.031, P<0.001). In the high-risk group, the 5-year OS and PFS rate of the patients who received radiotherapy combined with more than 4 cycles of chemotherapy were 66.5% and 62.6%, higher than those of patients received less than 4 cycles of chemotherapy (56.7% and 46.4%, P=0.045 and 0.020, respectively). Cox multivariate analysis showed that ECOG score (HR=2.208, P=0.001), primary site (HR=4.887, P<0.001), primary tumor invasion (HR=3.265, P=0.001) and radiation dose (HR=1.895, P=0.011) were independent factors of OS in early NKTCL patients. Conclusion: Extended-involved field IMRT with radiation dose more than 50 Gy was the main treatment for patients with early stage NKTCL. Radiotherapy combined with adequate cycle chemotherapy significantly improved prognosis of high-risk patients.

Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma.

Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT + RT; RT + CT) and concurrent modalities (CCRT; CCRT + CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P = 0.027), prognostic index for NK/T-cell lymphoma (PINK) (P = 0.026) and types of initial treatment (P = 0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P = 0.021) and PINK-EBV DNA (PINK-E) (P = 0.002) significantly impacted on PFS; whereas ECOG performance score (P = 0.008) and stage (P < 0.001) significantly impacted on OS. For comparing CCRT ± CT and sequential CT + RT, CCRT ± CT patients (n = 190) were similar to sequential CT + RT patients (n = 54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT ± CT patients had CR rate, PFS and OS comparable with sequential CT + RT patients on multivariate and Cox regression analyses. Conclusions: In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT + RT gave similar outcome.

PEG-L-CHOP treatment is safe and effective in adult extranodal NK/T-cell lymphoma with a low rate of clinical hypersensitivity.

BACKGROUND: The combination of chemotherapy and L-asparaginase (L-ASP) treatment significantly increased survival rate in an adult patient with extranodal natural killer (NK)/T-cell lymphoma (NKTCL). However, hypersensitivity reactions of L-ASP in some patients limited its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and longer circulating half-life than unconjugated L-ASP, and has been reported to be effective and well-tolerated in children with acute lymphoblastic leukemia. Cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisolone (CHOP) is the most common chemotherapy for non-Hodgkin lymphoma. In this report, we sought to study the efficacy and safety of PEG-L- CHOP in NKTCL in adult Chinese patients. METHODS: Our study is a prospective, multi-center, open-label clinical trial. Patients with newly diagnosed adult NKTCL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included six cycles of PEG-L-CHOP regimen. Radiotherapy was scheduled after 2-4 cycles of PEG-L-CHOP regimen, depending on the stage and primary anatomic site. RESULTS: We enrolled a total of 33 eligible patients. All 33 patients completed 170 cycles of chemotherapy combined with radical radiotherapy. The overall response rate was 96.9% (32/33) with 75.8% (25/33) achieving complete responses and 21.2% (7/33) achieving partial responses. The overall survival (OS) at 1, 2, 3-year were 100, 90.61 and 80.54%, respectively. The major adverse effects were bone marrow suppression, reduction of fibrinogen level, liver dysfunction, and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. CONCLUSIONS: PEG-L-CHOP chemotherapy in combination radiotherapy is safe and durably effective treatment for adult extranodal NK/T-cell lymphoma with fewer allergic reactions. This study was approved by the Peking University Beijing Cancer Hospital Ethics Review Committee (reference number: 2011101104). The clinical trial registration number ChiCTR1800016940 was registered on July 07, 2018 at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ). The clinical trial was registered retrospectively.

Nasal NK/T-cell lymphoma: RT, CT, or both.

In this issue of Blood, Yang et al have proposed that for early-stage nasal type natural killer (NK)/T-cell lymphoma, combined radiotherapy (RT), and chemotherapy (CT) improve survival, but CT can be safely omitted in certain low-risk patients treated with RT.

Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study.

The optimal combination and sequence of radiotherapy (RT) and chemotherapy (CT) for extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) are not well-defined. The aim of this study was to create a risk-adapted therapeutic strategy for early-stage NKTCL. A total of 1273 early-stage patients from 10 institutions were reviewed. Patients received CT alone (n = 170), RT alone (n = 253), RT followed by CT (n = 209), or CT followed by RT (n = 641). A comprehensive comparative study was performed using multivariable and propensity score-matched analyses. Early-stage NKTCL was classified as low risk or high risk based on 5 independent prognostic factors (stage, age, performance status, lactate dehydrogenase, primary tumor invasion). RT alone and RT with or without CT were more effective than CT alone (5-year overall survival [OS], 69.6% and 67.7% vs 33.9%, P < .001). For low-risk patients, RT alone achieved a favorable OS (88.8%); incorporation of induction or consolidation CT did not provide additional benefit (86.9% and 86.3%). For high-risk patients, RT followed by CT resulted in superior OS (72.2%) compared with induction CT and RT (58.3%, P = .004) or RT alone (59.6%, P = .017). After adjustment, similar significant differences in OS were still observed between treatment groups. New CT regimens provided limited benefit in early-stage NKTCL. Risk-adapted therapy involving RT alone for low-risk patients and RT consolidated by CT for high-risk patients is a viable, effective strategy for early-stage NKTCL.