Combination of gemcitabine, pegaspargase, etoposide, and dexamethasone (GPED) in treatment of advanced extranodal NK/T-cell lymphoma.

Abstract

To the Editor: Extranodal natural killer/T-cell lymphoma (ENKTCL) is a highly aggressive lymphoma (NHL), closely associated with Epstein–Barr virus (EBV) infection. By using the combination of radiotherapy (RT) and asparaginase-based chemotherapy, more than 70% of patients with early stage ENKTCL have been cured.[1] However, great challenges exist among patients at newly diagnosed advanced stage or relapsed/refractory ENKTCL. Hemophagocytic lymphohistiocytosis (HLH) is a fatal syndrome characterized by persistent fever, cytopenia, hepatosplenomegaly, and multi-organ dysfunction a previous study demonstrated that patients with concurrent HLH and ENKTCL had a 6-month overall survival (OS) rate of merely 34.4%.[2] Thus, new regimens are urgently needed to improve the prognosis of patients with advanced disease, especially those with concurrent HLH. In this study, we reported a new combination chemotherapy regimen of gemcitabine, pegaspargase, etoposide, and dexamethasone (GPED), and GPED was shown to be effective and well tolerable, which is worthy of validation in future prospective clinical trials. From January 2020 to June 2022, a total of 32 patients diagnosed as ENKTCL received at least one cycle of GPED regimen in Beijing Tongren Hospital. As shown in Figure 1A, 20 patients with Ann Arbor stage IV ENKTCL were enrolled into the final analysis, all of whom received at least two cycles of GPED and could be evaluated for responses. The concurrent diagnosis of HLH was based on the HLH-2004 diagnosis and treatment guidelines.[3] All patients were meant to be treated with GPED regimen for a total of 6–8 cycles. Gemcitabine was given at 1 g/m2 intravenously on days 1 and 8; pegaspargase was given at 2500 IU/m2 (no more than 3750 IU) intramuscularly on day 1; etoposide was given at 100 mg/m2 intravenously on days 1–3; and dexamethasone was given at 20 mg/day from day 1–4. The GPED regimen was repeated every 21 days. Local consolidative RT at a dose of 50 Gy could be given to patients with primary lesion located in upper aerodigestive tract if extranasal lesions got complete remission (CR). Tumor responses to GPED were evaluated by magnetic resonance imaging (MRI) or positron emission tomography-computed tomography (PET-CT) scan after each two cycles of treatments. The best response during the treatment with GPED was reported. Progression free survival (PFS) was calculated from the date of diagnosis to the date of disease progression, death of any reason, or last follow-up, whichever came first. OS was calculated from the date of diagnosis to the date of death, or last follow-up, whichever came first. The chi-squared test was used to calculate statistical group comparisons of categorical variables. Survival analysis was performed using the Kaplan–Meier method. This study was approved by the Ethics Committee of Beijing Tongren Hospital with the approval certificate No. TREC2022-KY103. Because all private information of patients were de-identified and anonymous, informed consent from patients was waived.Figure 1: Efficacy of GPED regimen in the treatment of advanced ENKTCL. (A) Study profile. (B) Best responses to GPED regimen in all 20 patients with advanced-stage ENKTCL. (C) Best responses to GPED regimen in the 11 patients of ENKTCL with concurrent HLH. (D) Survival curves. CR: Complete remission; ENKTCL: Extranodal NK/T-cell lymphoma; GPED: Gemcitabine, pegaspargase, etoposide, and dexamethasone; HLH: Hemophagocytic lymphohistiocytosis; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; PR: Partial remission; SD: Stable disease.As shown in Supplementary Table 1 [https://links.lww.com/CM9/B412], all 20 patients had stage IV disease. The median age of this cohort was 50 (20–71) years, and 60% (12/20) of patients had poor performance status (Eastern Cooperative Oncology Group-Performance Status [ECOG-PS] score of ≥2). All but one patient had systemic symptoms, mainly persistent fever. Of note, 11 patients (55%) were confirmed to have concurrent HLH. According to nomogram-revised risk index (NRI), all patients were classified as high or very high risk group (NRI ≥3). All 20 patients received a median of four cycles (ranging from two to eight) of GPED, with a total of 80 cycles. As shown in Figure 1B, the best CR rate was 40% (8/20) and the best partial remission rate (PR) was 45% (9/20), rendering an overall response rate (ORR) of 85% (17/20). For those 11 patients with concurrent HLH, general condition of eight patients was recovered after the first cycle of GPED, and the disease progressed in two patients, and the remaining one patient had obvious shrinkage of tumor without improvement of the concurrent HLH. The best lymphoma-based CR rate and ORR were 36% (4/11) and 73% (8/11), respectively, among patients with HLH [Figure 1C]. Eight patients received RT consolidation, and the best ORR was 88% (7/8), and CR rate was 75% (6/8). No statistically significant differences in outcomes were found between patients with or without RT. Until July 1, 2022, all patients were followed up for a median of 14.5 (2.1–28.4) months. Nine patients had disease progression at a median of 6.0 (3.0–21.6) months, and five of them died. As shown in Figure 1D, the median PFS was 21.6 months, with 1- and 2-year PFS rates being 51.0% and 25.0%, respectively. The median OS was not reached yet, with 1- and 2-year OS rates being 72.0% and 54.0%, respectively. For patients with concurrent HLH, the 6-month and 1-year OS rate were 90.0% and 57.0%, respectively. Of note, most patients without HLH could be successfully salvaged with novel agents, such as programmed cell death protein 1 (PD-1) blockade and chidamide. Patients with concurrent HLH had a fulminant behavior after failure to GPED, and all the five patients that died in this study were those with HLH. As shown in Supplementary Table 2, https://links.lww.com/CM9/B412, leukopenia was the most common hematologic adverse event (AE), with 65% (13/20) of patients suffering from grades 3 and 4 leukopenia. Concerning non-hematologic AEs, fibrinogen was decreased in 75% (15/20) of patients, and 25% (5/20) of them had grade 3 decrease that needed repeated infusions of human fibrinogen. 55% (11/20) of patients had albumin reduction, which could be improved by repeated infusion of human albumin. 40% (8/20) of patients had grades 1 to 2 increase of alanine transaminase. No patients died of AEs in this study, and GPED regimen was well tolerated in whole. No standard chemotherapy regimens have been defined yet for patients with ENKTCL. In this study, we reported the efficacy and safety of GPED regimen in newly diagnosed or relapsed/refractory advanced-stage ENKTCL. GPED was well tolerated and provided impressive ORR in advanced-stage patients with or without concurrent HLH. Asparaginase or pegaspargase has long been used as the backbone of treatment for ENKTCL. The therapy of pegaspargase, gemcitabine, and oxaliplantin (P-GEMOX) is widely used in China for its efficacy and acceptable safety profiles. P-GEMOX could achieve an ORR of 80.0% and a CR rate of 51.4% in patients at stages III and IV, relapsed or refractory ENKTCL, and the 1- and 2-year PFS rates were 45.0% and 38.6%, respectively.[4] Recently, the final results of a randomized clinical trial comparing the therapy of cisplatin, dexamethasone, gemcitabine and pegaspargase (DDGP) vs. the therapy of steroid, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE) in newly diagnosed advanced ENKTCL were reported, which demonstrated that DDGP had an overwhelming superiority over SMILE regarding both efficacy and safety. DDGP could attain an ORR of 90.0% and 3-year PFS rate of 56.6%. However, the data reported in this trial by Wang et al[5] should be interpreted with caution. The staging system used to define advanced diseases in this trial was not based on the well-recognized Ann Arbor system, and the stage III disease in their trial indicates localized disease with regional lymph node involvement. Lymphoma-associated HLH is a highly fatal disease, with the mortality of about 90%. Our previous study has found that patients who responded to the ENKTCL treatment also achieved responses concerning their HLH, and etoposide plus dexamethasone-based chemotherapy regimens were associated with better outcomes in ENKTCL-associated HLH.[2] Thus, we recommend prompt treatment targeting ENKTCL rather than HLH in patients with ENKTCL-associated HLH. However, considering etoposide and dexamethasone are critical elements in treating HLH in the HLH-2004 guidelines,[3] and our previous experiences,[2] we integrated etoposide and dexamethasone into commonly used P-GEMOX regimen. Due to toxicities brought by oxaliplatin and its modest activity toward ENKTCL, we removed it from our final GPED regimen. The best ORR of 85.0% attained by GPED was comparable with DDPG or SMILE.[5,6] The 1-year OS rate of 72.0% achieved by GPED seems better than SMILE (55.0%).[6] Moreover, our study demonstrated impressive efficacy in patients with concurrent HLH, the ORR of whom (72.8%), and the 6-month and 1-year OS rate (90.0% and 57.0%, respectively) seems better than our historic data (6-month OS rate: 34.4%). Thus, our study provided an attractive regimen for patients with ENKTCL-associated HLH and is worthy of further validation. Several studies have tried upfront autologous stem cell transplantation (ASCT) or PD-1 blockade in the first-line setting, hoping to improve the dismal outcomes in patients with advanced disease. A 4-year OS rate of 92.0% and a 4-year PFS rate of 80.0% has been reported in a prospective trial evaluating the role of front-line ASCT in patients with stage IV disease who got CR after induction therapy.[7] Addition of PD-1 inhibitors to P-GEMOX was found to be highly effective in advanced ENKTCL, with 66.7% of patients having durable CR,[8] which needs to be validated in a larger cohort study. However, considering that anti-PD-1 antibody has shown impressive monotherapy activity toward relapsed/refractory ENKTCL and EBV-associated HLH,[9] it is rational to consider integration of PD-1 blockade with GPED regimen in future clinical trials, especially for those with ENKTCL-associated HLH. Several limitations presented in our study. First, due to the retrospective nature of our study, several biases may exist. For example, we tend to treat patients with more high risk factors (NRI score of ≥3) or HLH with GPED. Second, we did not perform next-generation sequencing to define molecular subtypes in this study, which may be helpful in guiding precision medicine in ENKTCL. Finally, the sample size is too small to draw a robust conclusion. In conclusion, GPED regimen was effective in advanced ENKTCL, especially those with concurrent HLH, and well tolerated. Our findings need to be validated in well-designed prospective, randomized clinical trials. Funding This work was supported by National Natural Science Foundation of China (No. 82170181), Beijing Hospitals Authority Youth Programme (No. QML20200201), Beijing Natural Science Foundation (No. 7222027), and CSH Young Scholars and 3SBioPharmaceutical joint research project (No. KYC2201001). Conflicts of interest None.