L‑asparaginase‑based regimen as a first‑line treatment for newly diagnosed nasal type extranodal natural killer cell/T‑cell lymphoma
- Authors:
- Published online on: April 11, 2016 https://doi.org/10.3892/etm.2016.3249
- Pages: 2437-2445
Abstract
Introduction
Extranodal natural killer (NK) cell/T-cell lymphoma (ENKTL) is a type of non-Hodgkin's lymphoma that presents significantly different distributions patterns according to population and geography, and is relatively common in Asia and South America (1,2). The incidence of patients with lymphoma is as high as 11% in China (3). NK/T-cell lymphomas usually occur in middle-aged patients, and their features are characterized by localized disease in approximately two-thirds of patients, along with frequent adjacent tissue invasion, a high frequency of ‘B’ symptoms, despite apparently limited disease, and rare bone marrow involvement (4–6). In addition, ENKTL is highly invasive, resistant to conventional chemotherapy, highly malignant, associated with short survival time and rapid clinical progression, and has a relatively poor prognosis (7–9).
ENKTL is thought to arise from NK cells or occasionally from a subset of γδd or αβ cytotoxic T-cells, and is strongly associated with Epstein-Barr virus infection (10,11). The ENKTL phenotype is characterized by the expression of cytoplasmic CD3ε in the absence of surface CD3, T-cell receptor expression, or T-cell receptor gene rearrangement, as well as an activated cytotoxic profile with expression of perforin, granzyme B, TIA-1, and frequent CD56 expression (12,13).
As ENKTL is rare, and prospective group studies are limited, no standard treatment regimen is currently available. Early NK/T-cell lymphoma is sensitive to radiotherapy if confined to the nasal cavity; however, recurrence at the primary site or distant sites occurred in 50% of patients who received radiotherapy, with a five-year survival rate of 29.8–66% (14–17). Since the multidrug resistance (MDR) gene is highly expressed in ENKTL tumor cells, the tumors are insensitive to conventional chemotherapy regimens (such as CHOP) that are applied to other pathological types of non-Hodgkin's lymphoma (18). Asparaginase is not regulated by the MDR gene, and numerous studies have demonstrated that the application of asparaginase to relapsed or refractory ENKTL induced promising responses and high survival rates (19–22). Few clinical studies on asparaginase-based regimens as first-line treatments for newly diagnosed ENKTL are available (22,23), and, to the best of our knowledge, no previous studies have compared the short-term efficacy and long-term survival impacts of asparaginase and CHOP treatment regimens in patients with ENKTL. Therefore, the present study investigated the effects of asparaginase in patients with previously untreated ENKTL. The clinical characteristics of 181 patients with newly-diagnosed pathologically ENKTL were retrospectively analyzed. The patients were divided into CHOP treatment regimen and asparaginase-based chemotherapy groups according to the administered treatment regimen. Short-term efficacy, long-term survival, and safety were compared in the two groups and the results are reported herein.
Materials and methods
Clinical data
A total of 181 patients with newly diagnosed ENKTL received either CHOP treatment or L-asparaginase-based chemotherapy along with radiotherapy between October 2003 and June 2013 at the Henan Tumor Hospital, First Affiliated Hospital of Henan University of Science and Technology (Luoyang, China), the Xinzheng City People's Hospital (Xinzheng, China), and the Jiaozuo City Second People's Hospital (Jiaozuo, China). Of these patients, 69 were included in the CHOP treatment group and 112 were included in the L-asparaginase treatment group. All patients were diagnosed via imaging studies and pathological analyses. Differences in the main clinical characteristics between the two groups of patients were not statistically significant (P>0.05), as shown in Table I.
Prognostic factors
The International Prognostic Index (IPI)clinical tool was used to predict the prognosis of patients (24). IPI factors include: Age, >60 years; serum lactate dehydrogenase (LDH) level above normal; performance status, 2–4; stage of disease, III or IV; and extranodal involvement, >1 site (24). In addition, the gender, B-symptoms (including unexplained fever, >10% weight loss or sweating), Eastern Cooperative Oncology Group performance status and primary anatomic sites of lymphomatous involvement for all patients were evaluated for their potential prognostic importance. The serum LDH and β2-microglobulin levels were analyzed using an automated biochemical analyzer (Modular P800; Hitachi, Ltd., Tokyo, Japan), and the expression of Ki67 in ENKTL tumor samples were assessed by immunohistochemistry. Briefly, the tumor samples were cut into sections using a microtome (Leica RM2235; Leica Microsystems GmbH, Wetzlar, Germany), followed by incubation with mouse anti-Ki67 monoclonal antibody (1:200; cat. no. M7240; Dako, Glostrup, Denmark), and then ready-to-use EnVision reagent (cat. no. K5007; Dako). Subsequently, positive cells (yellow/tan color) were counted in 10 fields of view under a microscope (Olympus IX81; Olympus Corporation, Tokyo, Japan). Phosphate-buffered saline was used as a negative control.
Treatment
The CHOP treatment regimen included 750 mg/m2 (d1) cyclophosphamide (Baxter Oncology GmbH, Halle, Germany), 50 mg/m2 (d1) adriamycin (Pfizer, New York, USA), 1.4 mg/m2 (d1) vincristine (Zhejiang Hisun Pharmaceutical, Co., Ltd., Taizhou, China) and 40 mg/m2 (d1–5) prednisone (Zhejiang Xianju Pharmaceutical Co., Ltd., Taizhou, China), which was administered to 69 patients. L-asparaginase (Guangzhou Baiyun Shan Ming Xing Pharmaceutical, Co., Ltd., Guangzhou, China) treatment was given to 112 patients. The patients who received L-asparaginase treatment were subdivided into the following treatment groups: CHOP-L (65 patients), VLP (22 patients), COP-L (10 patients), or L-asparaginase alone (15 patients). The patients in the CHOP-L group received the entire CHOP treatment regimen, whereas the patients in the VLP group received the vincristine and prednisone only, and the patients in the COP-L group received the cyclophosphamide, vincristine and prednisone only. All patients received 6,000 U/m2 (d1–7) L-asparaginase and the other drugs at the reference doses described for the CHOP treatment. The patients who responded positively to an L-asparaginase skin test (25 patients), which was indicated by the presence of erythemas or wheals, were treated with 2,500 U/m2 pegaspargase (Jiang Su Heng Rui Medicine, Co., Ltd., Lianyungang, China). During chemotherapy, the heart, liver and kidneys were protected by intravenous injection with 5 mg tropisetron hydrochloride (Jiang Su Heng Rui Medicine, Co., Ltd.) 30 min prior to chemotherapy, hydration (250–300 ml/m2 H2O) and 1.25% sodium bicarbonate (Tianjin Pharmaceuticals Group Co., Ltd., Tianjin, China) intravenous injection. Following chemotherapy, patients with leukocytopenia (white blood cells count, <4.0×109/l) were treated with granulocyte colony-stimulating factor (Harbin Pharmaceutical Group Bioengineering, Co., Ltd., Harbin, China) to elevate their white blood cell counts, patients with anaemia were injected with red blood cells, and patients with low platelets were transfused with platelets (both Henan Red Cross Blood Centre, Zhengzhou, China). All patients underwent involved-field radiation therapy (TrueBeam™ Radiotherapy System; Varian Medical Systems, Inc., Palo Alto, CA, USA) following two cycles of chemotherapy. Three-dimensional radiotherapy counting was performed with a 6–8 MV photon ray at a median dose of 52 Gy (range, 40–60 Gy) and was administered in fractionated doses of 2 Gy five times/week. The radiotherapy target covered the edge of the lesion and the infiltration. Subsequent chemotherapy continued until completion following radiotherapy. All patients provided signed written-informed consent prior to treatment.
Evaluation of short-term efficacy and adverse reactions
All patients underwent at least six cycles of chemotherapy combined with radiotherapy. Following two cycles of chemotherapy and the entire treatment regimen, the efficacies of the treatments in all patients were evaluated by a physical examination, B-ultrasound and computed tomography (CT; GE LightSpeed Pro 32; GE Healthcare Life Sciences, Chalfont, UK) or positron emission/CT (GE Discovery STE 16; GE Healthcare Life Sciences). Clinical efficacy was assessed according to World Health Organization (WHO) criteria (25), which classify responses as complete remission (CR), partial remission (PR), stable disease and progressive disease. The overall response rate (ORR) was calculated as CR + PR. Based on the WHO evaluation criteria for adverse reactions, the adverse reactions were divided into 0-IV degrees of severity. Toxicity assessments were conducted at the end of each chemotherapy cycle.
Evaluation of survival
Overall survival (OS) was defined as the time between the date of diagnosis and the date on which the patient succumbed to the disease or the end of the follow-up period. Progression-free survival (PFS) was defined as the time between the date of diagnosis and the date of tumor progression/relapse, the date on which the patient succumbed to the disease, or the end of the follow-up period. For patients who were lost to follow-up, survival ended at the time of the last follow-up.
Statistical analysis
Statistical analysis was conducted with SPSS 18.0 software (SSPS, Inc., Chicago, IL, USA). Categorical variables were compared between the groups using a χ2 test, and continuous variables were compared between groups using a t-test for independent samples. Kaplan-Meier survival analysis was applied to calculate the patient survival rates. The survival rates were compared between groups using a log-rank test. Variables with P<0.05 were included in the Cox proportional hazards regression model for multivariate analysis. P<0.05 was considered to indicate a statistically significant result.
Results
Short-term efficacy and long-term survival
Treatment efficacies were evaluated in the 181 patients, and the overall efficacies in the two treatment groups are shown in Table II. The 69 patients in the CHOP treatment group included 10 cases of CR and 22 cases of PR for an ORR of 46.4% following two cycles of chemotherapy; 29 cases of CR and 21 cases of PR for an ORR of 72.46% was shown at the end of the treatment. The χ2 test results (Table III) demonstrated that among the various clinical factors, patient age, clinical stage, and IPI score significantly affected the ORR (P<0.001) at the end of the treatment period. The 112 patients in the asparaginase group included 38 cases of CR and 38 cases of PR for an ORR of 67.9% following two cycles of chemotherapy, and 72 cases of CR and 29 cases of PR for an ORR of 90.18% at the end of the treatment period. Among the various clinical factors, clinical staging, IPI score, ECOG score, primary lesion site, and leukocytopenia affected the ORR (P<0.05).
 | Table III.Clinical characteristics and response rates following CHOP and L-asparaginase-based treatment regimens followed by radiation. |
The patients were followed-up until 31 October 2013, with a median follow-up time of 29 months (range, 6–96 months). A total of 10 cases were lost to follow-up. In the CHOP treatment group, the median OS duration was 34 months, the median PFS duration was 21 months, the one, two, and five-year OS rates were 82.6, 61.9 and 28.4%, respectively, and the one, two, and five-year PFS rates were 63.8, 44.0 and 21.0%, respectively (Table IV, Fig. 1A and B). Univariate analysis demonstrated that patient age, clinical staging, IPI score, ECOG score, primary lesion site, LDH levels, leukocytopenia, Ki67 levels and early treatment response significantly affected patient OS and PFS (P<0.05). Other factors such as gender, B symptoms, and β2-microglobulin had no impact on the OS and PFS (P>0.05; Table V). Multivariate analysis demonstrated that early treatment response was an independent predictor of OS (P<0.001), whereas primary lesion site, early treatment response, and age were independent predictors of PFS (P=0.010, P<0.001, and P=0.017, respectively; Table VI). In the asparaginase treatment group, the median OS duration was 77 months, the median PFS duration was 56 months, the one, two, and five-year OS rates were 96.0, 88.3 and 65.1%, respectively, and the one, two, and five-year PFS rates were 94.2, 79.8 and 50%, respectively. Univariate analysis demonstrated that patient age, clinical stage, IPI score, ECOG score, primary lesion site, LDH level, leukocytopenia, Ki67 level, and early treatment response affected patient OS and PFS (P<0.05); other factors such as gender, B symptoms, and β2-microglobulin had no impact on OS and PFS (P>0.05). Multivariate analysis demonstrated that early treatment, clinical staging, LDH levels, and Ki67 levels were independent predictors of OS and PFS (P<0.001, P=0.001, 0.035 and 0.001, and P=0.011, 0.002, 0.002 and 0.02, respectively).
| Table VI.Cox proportional hazard regression analysis for the CHOP and L-asparaginase treatment groups. |
Adverse reactions
The adverse reactions observed in the patients in the two groups are shown in Table VII. The primary adverse reactions to chemotherapy included bone marrow suppression, gastrointestinal reactions, infections, and liver dysfunction, the majority of which were rapidly relieved following symptomatic treatment. In the asparaginase treatment group, 68 cases (60.7%) showed a statistically significant reduction in fibrinogen levels, as compared with the CHOP treatment group (P<0.001). Associated bleeding and thrombotic events occurred in two cases; these were of low severity and improved following active treatment. During L-asparaginase treatment, a rash occurred in 29 patients and improved following symptomatic treatment; 25 of these patients were treated with pegaspargase subsequent to receiving positive results (detection of erythemas or wheals) from an L-asparaginase skin test. No treatment interruptions or treatment-associated mortality occurred in either group.
Discussion
ENKTL is a type of non-Hodgkin's lymphoma that accounts for 11% of lymphoma cases in China (3). Given the rapid course of clinical progression and relatively poor prognosis of ENKTL, the optimal treatment strategy for this disease remains unclear. Previously, either CHOP chemotherapy alone or radiotherapy alone was not able to achieve satisfactory results. Efficacy of the CHOP chemotherapy regimen for ENKTL is poor (26–29). Several studies have reported that radiotherapy is an important treatment method that is beneficial to local lesion control (15,28,30,31). However, the rates of recurrence and distant metastasis were high, and the five-year survival rate was low in the early-stage patients who received radiotherapy alone (28,32). As chemoradiotherapy strategies have progressed, chemotherapeutic regimens based on CHOP-class anthracycline compounds have been reported (29). However, the efficacy remained low even following an increase in cyclophosphamide dose or the combination with other drugs such as semustine. In addition, these treatment regimens did not significantly improve patient survival in the early stages of ENKTL (30).
The insensitivity of ENKTL to conventional CHOP-class chemotherapy may be associated with tumor cell overexpression of P-glycoprotein, which is encoded by the MDR1 (33). Doxorubicin and vincristine, components of the CHOP-class treatment, may be actively pumped out by P-glycoprotein, thereby reducing the therapeutic effect. L-asparaginase hydrolyses asparaginase in the serum thereby reducing the levels of amino acids required in certain tumor cells that do not produce asparagine synthetase, resulting in the inhibition of DNA, RNA, and protein synthesis, which acts as an anti-tumor agent (18,34). In vitro studies have demonstrated that asparaginase is able to reduce the activity of normal NK cells and induce apoptosis in NK tumor cells, whereas the conventional chemotherapy drugs used to treat lymphoma do not have this property (35,36). Yong et al (37) reported the use of an L-asparaginase-based treatment as the primary therapy for 11 patients with refractory midline peripheral T-cell lymphoma, and reported an efficacy of 63.6% and a two-year survival rate of 45.5%. Subsequently, this L-asparaginase treatment was applied in 45 patients with relapsed or refractory ENKTCL and led to a CR rate of 56%, an ORR of 82%, and a five-year survival rate of 67% (19). A recent study on CHOP-L treatment combined with radiotherapy for newly diagnosed ENKTL demonstrated that, among 38 newly diagnosed patients with ENKTL who received CHOP-L chemotherapy and sequential radiotherapy, the CR rate was 81.6%, the ORR rate was 84.2%, and the two-year OS rate was 80.1% (23). The results of the present study demonstrated that, compared with the CHOP treatment group, the ENKTL patient group that received an L-asparaginase-based treatment combined with radiotherapy had significantly improved remission rate and improved long-term survival. Among the 112 patients in the L-asparaginase treatment group, the overall efficacy following two cycles of chemotherapy was 67.9%, the overall efficacy at the end of the treatment was 90.18%, the median OS duration was 77 months, the median PFS duration was 56 months, the one, two, and five-year OS rates were 96.0, 88.3 and 65.1%, respectively, and the one, two, and five-year PFS rates were 94.2, 79.8 and 50.0%, respectively.
The incidence of allergic reactions in patients who were treated with L-asparaginase has been reported to be 30% (38). Studies have reported that pegaspargase therapy had a similar efficacy to L-asparaginase as a treatment in children with acute lymphoblastic leukaemia (39,40). In the present study, allergic reactions occurred in 29 patients in the asparaginase treatment group (25.9%) during the application of L-asparaginase, and 25 of these patients (22.3%) switched to treatment with pegaspargase following a positive L-asparaginase skin test results. The statistical results indicated that switching to pegaspargase did not affect the CR rate, OS, or PFS. A study on treatment with pegaspargase in newly diagnosed ENKTL patients is currently on-going in China. Pegaspargase may be another treatment option for ENKTL patients.
Prognostic factors that have been reported to be closely associated with ENKTL include patient age, B symptoms, ECOG score, regional lymph node invasion, clinical staging, CR rate, leukocytopenia, IPI score and Ki67 expression levels (41–43). In the present study, a univariate analysis of the 112 patients in the asparaginase regimen group demonstrated that patient age, clinical staging, IPI score, ECOG score, primary lesion site, LDH, leukocytopenia, Ki67 levels, and early treatment response affected patient OS and PFS (P<0.05). Other factors such as gender, B symptoms, and β2-microglobulin had no impact on OS and PFS (P>0.05). Multivariate analysis demonstrated that early treatment response (P<0.001), clinical staging (P<0.001), and LDH level (P=0.006) were independent predictors of OS, whereas Ki67 expression levels (P=0.011), early treatment response (P=0.001), clinical staging (P=0.002), and LDH level (P=0.001) were independent predictors of PFS.
In the present study the primary adverse reactions to treatment experienced by the patients in the two groups included bone marrow suppression, gastrointestinal reactions, infections, and liver dysfunction, most of which were rapidly relieved following symptomatic treatment. The incidence of hypofibrinogenemia was significantly higher in the asparaginase treatment group compared with the CHOP treatment group, although associated bleeding and thrombotic events occurred in only two cases and at a low severity, and no treatment-associated mortality was recorded.
In conclusion, L-asparaginase-based chemotherapy combined with radiotherapy is effective as a first-line treatment for ENKTL. The patients who received this type of treatment showed significantly increased improvements compared with those treated with the CHOP regimen combined with radiotherapy, with regard to short-term efficacy and long-term survival, as well as safety performance.
Acknowledgements
The present study was supported by grants from the National Natural Science Foundation of China (grant no. 81170520), the Henan Department of Health/Provincial Departmental collaboration project (grant no. 2011010014), and the National Natural Science Foundation of Henan Province (grant nos. 81170520 and 81000921).
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