Abstract
Purpose: Optimal treatment strategies for advanced natural killer/T (NK/T)-cell lymphoma have not been fully defined. We compared the safety and efficacy of DDGP and SMILE regimens for advanced NK/T-cell lymphoma in a randomized controlled, multicenter, and open-label clinical trial.
Experimental Design: Patients were newly diagnosed in stages III–IV and had performance scores in 0 to 2. Six cycles of DDGP (dexamethasone, cisplatin, gemcitabline, and pegaspargase) or SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy were randomly assigned to them. The primary end point was progression-free survival (PFS). Secondary end points included response rate and overall survival (OS). The trial is ongoing and is registered with ClinicalTrials.gov (No. NCT01501149).
Results: Of 42 patients enrolled, 21 were treated with DDGP therapy, and 21 patients were treated with SMILE therapy. The 1-year PFS and 2-year OS rates were better in the DDGP group than that in the SMILE group (86% vs. 38% for 1-year PFS, P = 0.006; 74% vs. 45% for 2-year OS, P = 0.027). Complete remission (CR) rate and overall response rate (ORR) of the DDGP group were higher than that in the SMILE group (71% vs. 29%, P = 0.005 for CR rate; 95% vs. 67%, P = 0.018 for ORR). The SMILE group showed more serious leucopenia (P = 0.030) and severe allergic reaction (P = 0.015) than the DDGP group. In addition, two cases in the SMILE group underwent grade 4 mucosal reaction.
Conclusions: DDGP chemotherapy resulted in significant improvement in PFS, OS, and better tolerability compared with SMILE chemotherapy for newly diagnosed advanced NK/T-cell lymphoma patients. Clin Cancer Res; 22(21); 5223–8. ©2016 AACR.
Translational Relevance
Natural killer/T (NK/T)-cell lymphoma is a distinct lymphoid neoplasm with aggressive course and poor outcomes. Optimal treatment strategies for advanced NK/T-cell lymphoma have not been fully defined. We carried out a randomized, open-label, multicenter clinical trial enrolled patients with newly diagnosed in stage III–IV NK/T-cell lymphoma to compare the safety and efficacy of DDGP and SMILE. In this study, DDGP chemotherapy resulted in significant improvement in progression-free survival and overall survival, higher complete remission rate and overall response rate, and better tolerability compared with SMILE chemotherapy for newly diagnosed patients with advanced NK/T-cell lymphoma.
Introduction
Extranodal natural killer/T-cell lymphoma (ENKL) is a rare, distinctive clinicopathologic disease entity with aggressive clinical feature and strong association with Epstein-Barr virus infection. It is much more frequent in Asian and Latin American countries than in Western countries (1). NK cells express high concentrations of the multidrug-resistant P-glycoprotein (P-gp), so that anthracycline-containing regimens, such as CHOP and CHOP-like regiments usually provide poor clinical outcomes (2–4). Recently, an L-asparaginase (L-Asp)–based regimen, including dexamethasone, methotrexate, ifosfamide, L-Asp and etoposide (SMILE), has been devised to tackle these problems. It brought higher response rate, prolonged overall survival (OS) and progression-free survival (PFS) than anthracycline-containing regimens. But at the same time, severe hematologic toxicity leaded serious chemotherapy-related infection or even death. Up to 92% of patients were at risk of undergoing a grade 4 neutropenia. Allergic reactions also happened in half of the patients (5, 6). In addition, the short plasma half-life of L-Asp causes frequent dosing that adds the patients' suffering. Physicians were looking for new chemotherapeutic regimens with high efficacy and low toxicity for ENKL. The Lymphoma Center of the First Affiliated Hospital of Zhengzhou University formulated a novel pegaspargase (PEG-Asp)–based chemotherapy regimen: dexamethasone, cisplatin, gemcitabline, pegaspargase (DDGP), and performed related research.
In our previously prospective and retrospective studies, Li and colleagues (7) showed that patients with newly diagnosed stages II–IV ENKL who were initially treated with a DDGP regimen had a complete remission (CR) rate of 83.3% and partial remission (PR) rate of 16.7%. Zhou and colleagues (8) conducted a study and showed that 17 relapsed/refractory ENKL patients treated with DDGP regimen had an overall response rate (ORR) of 88.2%. Currently, there are no articles comparing the efficacy, toxicity, and survival analysis of DDGP versus SMILE regimens in patients with newly diagnosed advanced stage NK/T-cell lymphoma. On the basis of our previous studies, we designed this randomized controlled trial.
Materials and Methods
Study design and patient eligibility
This randomized controlled, open-label, multicenter study compared the efficacy and safety of DDGP regimen with SMILE in patients with newly diagnosed ENKL in III–IV stages. The trial was registered on the Clinicaltrials. gov website in 2011 (Reg. No. NCT01501149). Patients were selected in the study from March 2011 to June 2014, whose date of diagnosis was no later than September 2013. Diagnosis of ENKL based on clinical features, histopathologic morphology, immunohistology (CD2+, CD3ε+, CD43+, CD56+ CD20−, TIA-1+, perforin+, granzyme B), and Epstein-Barr virus (EBV) by in situ hybridization. All biopsies were independently reviewed and confirmed by more than two pathologists in accordance with WHO 2008 morphologic, immunophenotypic, and genetic criteria.
The inclusion criteria were: (i) 14 to 70 years of age and had satisfactory performance scores (0–2). (ii) Granulocytes ≥1.5 × 109 cells/L, platelets ≥100 × 109/L, hemoglobin ≥90 g/L, AST and ALT levels ≤2× the upper limit of normal, total bilirubin ≤1.5 × the upper limit of normal, serum creatinine ≤1.5 × the upper limit of normal and serum albumin ≥30 g/L. (iii) Primary tumor sites were extra nodal sites. (iv) Never accept chemotherapy or radiotherapy. Patients were excluded if they had CNS involvement or a prior malignancy.
The pretreatment staging procedures included physical examination, tests for complete blood cell count, β2-microglobulin, lactate dehydrogenase (LDH), liver and kidney functions, blood coagulation function, urinalysis, electrocardiography, and computed tomography scans of the head, neck, thorax, and abdomen. Bone marrow aspiration and biopsy were also carried out to determine whether the bone marrow was involved or not.
Six cycles of DDGP or SMILE chemotherapy were randomly assigned to the patients based on a computer-generated randomization schedule. The specific details of the DDGP and SMILE regimens are shown in Table 1.
The DDGP and SMILE regimens
The study was carried out with Good Clinical Practice Guidelines and the Helsinki Declaration. This work was approved by the Local Ethics Committee of Zhengzhou University and the Scientific Council of Faculty of Medicine. All patients were fully informed about the nature and possible toxicities of the treatment protocol and submitted written informed consent.
Staging and response evaluation
Clinical stage based on the modified Ann Arbor new staging system for NK/T-cell lymphoma. Stage I: lesions confined within nasal cavity or nasopharynx without local invasiveness (paranasal sinuses or bony or skin invasion); stage II: localized disease with local invasiveness; stage III was defined localized disease with regional lymph node involvement (cervical lymph nodes); and stage IV: disseminated disease (lymph nodes on both sides of diaphragm, multiple extranodal site; ref. 9).International Prognostic Index (IPI) scores were used to determine the classification of risks (10). Performance status was evaluated on the basis of the Eastern Cooperative Oncology Group scale (11). Treatment responses, including CR, PR, stable disease (SD), and progressive disease (PD), evaluated according to response criteria of Cheson and colleagues (12). Evaluation was conducted every two cycles.
Assessment of adverse effects
Adverse reactions were monitored by biochemistry and hematological tests, urinalysis, electrocardiogram, and routine physical examination. They were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 and assessed from the first cycle of the regimen until 1 month after terminal treatment (13).
Statistical analysis
The primary endpoint was PFS, which was defined as the interval from date of randomization to the date of disease progression or date of death, whichever occurred first, irrespective of the use of subsequent antineoplastic therapy. Patients who were progression-free and alive were censored at the time of their last disease assessment, and patients who were alive with no post-baseline disease assessment were censored at randomization. Secondary endpoints included ORR (CR and PR), OS, and safety.
We compared the clinical and laboratory data, response rate, and adverse effects between DDGP and SMILE groups by χ2 test and Mann–Whitney U test. OS and PFS were estimated with the Kaplan–Meier method. Survival rates were compared by the long-rank test. Prognostic risk factors were estimated with univariate analysis. Statistical significance was determined at a level of P < 0.05. SPSS version 17.0 was used for the statistical analysis.
Result
Baseline characteristics of patients
Forty-two patients were enrolled from March 2011 to June 2014. Their baseline characteristics are listed in Table 2. The median age was 42 years (range, 14–64 years) and the male: female ratio was 1.625:1. Ninety percent of the patients were diagnosed as upper aerodigestive tract ENKL. Thirty-eight percent of the cases had newly diagnosed stage IV disease. Systemic B symptoms were present in 20 patients (48%), and the elevation of LDH level was observed in 19 patients (45%). Between the DDGP (21 cases) and SMILE (21 cases) groups, there were no obvious differences in the baseline characteristics of patients.
Baseline patient characteristics
Treatment
The mean cycles of chemotherapy for patients receiving DDGP was 5.57 cycles (range, two to six cycles), whereas for those receiving SMILE, it was 3.9 cycles (range, 1–6 cycles). In the DDGP arm, 17 patients received six cycles, and two cases received four cycles. One case received five cycles, and one case received two cycles. In the SMILE arm, nine patients received six cycles, and three cases received four cycles. Two cases received three cycles. Four patients completed less than one cycle because of the severe methotrexate-related mucositis and myelosuppression-related septic shock, and three of them died within 15 days. Three cases in the SMILE group received two cycles because of tumor progression and upper gastrointestinal hemorrhage, and one of them died within 12 days.
Response
The ORR in the DDGP group was obviously better than the SMILE group (95% vs. 67%, P = 0.018), with CR and PR rates of 71% and 24% for DDGP whereas 29% and 38% for SMILE (Table 3).
Response rates of DDGP and SMILE regimens
OS and PFS
At a median follow-up of 14 months (range, 1–39 months) for overall patients, four patients died of disease progression. One patient died of cerebral hemorrhage, and one patient died of gastrointestinal hemorrhage. Two patients died of septic shock, and one patient died of infection combined with hemorrhage. Two patients died of the methotrexate–related mucosa reaction, and three patients died of unknown reasons.
The DDGP arm had a significantly better OS and PFS than SMILE arm: 90% versus 57% for 1-year OS, 74% versus 45% for 2-year OS and 86% versus 38% for 1-year PFS, respectively (Fig. 1).
A, overall survival is shown for all patients, showing that the DDGP group has a better OS than the SMILE group (P = 0.027). B, progression-free disease is shown for all patients, showing that the DDGP group has a better PFS than the SMILE group (P = 0.006).
The univariate analysis of OS (Table 4) showed that only site of involvement at diagnosis was predictor of OS in the 42 patients.
Univariate analysis of OS in the 42 patients
Adverse events
Adverse events were assessed in all patients (Table 5). Adverse events included hematologic and non-hematologic adverse reactions. Compared with the DDGP arm, the SMILE arm had more instances of grade 3/4 leukopenia (P = 0.030) and grades 3/4 allergy (P = 0.015). Moreover, three cases underwent grade 3 diarrhea, and two cases underwent grade 4 mucositis, which led the patients to death in the SMILE arm. At the same time, two patients had a grade 4 heart failure, and one patient had a grade 3 arrhythmia in the SMILE group. However, there were more instances of grade 3/4 anemia (P = 0.039) in the DDGP arm than the SMILE arm.
Adverse effects between DDGP and SMILE groups
Discussion
ENKL was labeled with high invasiveness, easy to develop drug resistance, low curative effect, dismal prognosis, and short survival time. Though physicians conducted many clinical trials, there was no optimal treatment modality before (14). Kim and colleagues (4) found a low CR rate and 2-year OS rate for 59 ENKL patients receiving anthracycline-based chemotherapy as an initial treatment. Lee and colleagues (15) showed that 26 patients with early-stage ENKL receiving ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) chemotherapy as first-line treatment had a CR rate of 13% and median OS of 2.7 months, which was also unsatisfactory. Bortezomib, which was considered to induce the apoptosis in NK cell lymphoma, plus cyclophosphamide, doxorubicin, vincristine, and prednisolone, was undertaken by patients with NK/T-cell lymphoma, and only 33.3% of the patients achieved CR (16).
The mechanisms of ENKL resistance to conventional chemotherapy were not fully understood, but it related to the frequent expression of P-gp by lymphoma cells, which was the product of the multidrug resistance gene (2). L-Asp was not affected by multidrug resistance of ENKL and had an original antitumoral mechanism. L-Asp hydrolyzes serum asparagines and deprives some cells of the required amino acid to yield anticancer effects in lymphoma cells lacking L-asparagine synthetase (17). Studies demonstrated that L-Asp could reduce the activity of normal NK cells in vitro and induced the apoptosis of tumoral NK cells (18, 19).
In recent years, the L-Asp–based chemotherapy (SMILE) was considered as an optimal treatment for patients with ENKL. In a retrospective study developed among patients with stage IV, relapsed or refractory ENKL, 20 patients receiving SMILE had significant higher CR and ORR and longer OS and PFS than patients receiving the CHOP regimen (20). But Yamaguchi and colleagues (6) found that in the 38 stage IV, relapsed/refractory ENKL patients treated with SMILE, grade 3/4 neutropenia occurred in all patients and that transferred into serious infections in 61% of the patients. Kwong and colleagues (5) showed SMILE regimen brought a good therapeutic effect in 43 newly diagnosed and 44 relapsed/refractory ENKL patients, but 73% of them had a grade 3/4 neutropenia. In addition, 50% of the patients underwent the allergy. The acute allergic reactions were induced by L-Asp and characterized by circulating antibodies and rapid clearance of the enzyme from the blood (21).
To ensure the efficacy and avoid the severe toxicity in treating with ENKL, a novel regimen was formulated by our center. PEG-Asp was a modified type of native E coli asparaginase, in which the enzyme was covalently linked to polyethylene glycol. The binding preserved the enzymatic activity of the drug and decreased the immunogenicity of the protein, which reduced the risk of hypersensitivity reactions (22). Another advantage of PEG-Asp was its prolonged half-life of elimination compared with the L-Asp. The elimination half-life of PEG-Asp was approximately 6 days, five times longer than L-Asp, which was important in improving the pharmacokinetic profile of the drug and alleviating the suffering of patients (21, 23, 24).
Currently, the safety and effectiveness of PEG-Asp against ENKL had been confirmed by some reports (7, 8, 25). Li and colleagues (7) reported that patients with newly diagnosed stages II–IV ENKL who were initially treated with a DDGP regimen had a CR rate of 83.3% and PR rate of 16.7%. The objective ORR was 100%. Zhou and colleagues (8) conducted a retrospective study and showed that 17 relapsed/refractory ENKL patients treated with the DDGP regimen had an ORR of 88.2% with 52.9% of the patients achieving CR and 35.3% of them achieving PR. Wen and colleagues found that for patients treated with PEG-Asp combination with CHOP (n = 5), EPOCH (n = 7), or GEMOX (n = 7), 25% of them achieved CR, and 35% of them achieved PR. No allergic reactions were detected, and no treatment-related death was reported (26).
Gemcitabine is a novel nucleoside analogue that inhibits DNA synthesis. Gemcitabine-containing therapy has shown promising results in patients with ENKL. Ahn and colleagues (27) showed that 20 patients with refractory or relapsed ENKL were given gemcitabine-containing regimen. The ORR was 40% with a CR rate of 20%. Four complete responders had a disease-free status for more than 7 months. A retrospective study showed that for the 93 patients newly diagnosed with stage IE to IIE ENKL, patients in GELOX (Gemcitabine, Oxaliplatin, and L-Asp) group had a higher CR rate and ORR than those in the EPOCH group (70.0% vs. 41.5%, P = 0.007 for CR rate; 87.5% vs. 67.9%, P = 0.047 for ORR). The GELOX regimen resulted in significantly superior 5-year PFS (79.0% vs. 46.5%, P = 0.005) and OS (78.9% vs. 50.4%, P = 0.003) rates. And the toxicity of both regimens was acceptable (28).
But until now, there have not been any prospective clinical trials to compare DDGP and SMILE regimens in the side effects and efficacy. Thus, we designed this randomized controlled trial and found that the DDGP group showed prolonged PFS and OS than the SMILE group. The ORR and CR rate in the DDGP group was also higher than that in the SMILE group.
Moreover, the SMILE group had a higher incidence of leucopenia, allergic reaction, nephrotoxicity, diarrhea, cardiotoxicity, and mucositis. The major side effects of DDGP regimen were myelosuppression and coagulation abnormalities. Though there was no drug-related death, we need careful handle the DDGP-associated anemia and thrombocytopenia.
In conclusion, our study demonstrated that the DDGP regimen can result in a higher CR rate, a longer survival time, and a lower toxicity than the SMILE regimen. This regimen offers a much safer and much more effective regimen for patients with ENKL stage III/IV.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: X. Li, W. Li, M. Zhang
Development of methodology: X. Li, X. Fu, F. Nan, M. Zhang
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): X. Li, Y. Cui, Z. Sun, L. Zhang, L. Li, X. Wang, J. Wu, X. Fu, W. Ma, X. Zhang, Y. Chang, F. Nan, W. Li, L. Su, J. Wang, H. Xue, M. Zhang
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Y. Cui
Writing, review, and/or revision of the manuscript: X. Li, Y. Cui, W. Li
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): X. Li, Z. Sun, L. Zhang, L. Li, X. Wang, J. Wu, X. Fu, W. Ma, X. Zhang, Y. Chang, F. Nan, W. Li, L. Su, J. Wang, H. Xue, M. Zhang
Study supervision: X. Li, Y. Cui, Z. Sun, L. Zhang, L. Li, X. Wang, J. Wu, X. Fu, W. Ma, X. Zhang, Y. Chang, F. Nan, W. Li, L. Su, J. Wang, H. Xue, M. Zhang
Grant Support
This work was supported by the National Natural Science Foundation of China (no. 81172118), Medical science and technology plan project of Henan province, China (contract/grant number: 201302001), and by the assistance of the Lymphoma Diagnosis and Treatment Center of Henan Province, Shanxi Cancer Hospital, Nanjing General Hospital of Nanjing Military Command, and The Affiliated Hospital of Qingdao University.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Received January 19, 2016.
- Revision received March 8, 2016.
- Accepted March 30, 2016.
- ©2016 American Association for Cancer Research.
Reference
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