Chemotherapy of GEP Regimen(Gemcitabine,etoposide and Pegaspargase) for the Patients with Newly Diagnosed Extranodal Natural Killer/T Cell Lymphoma: a Phase II Clinical Trial

Introduction: Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive form of non-Hodgkin's lymphoma,which is relatively more common in Asia and Latin America.Radiation therapy(RT) is widely administered for patients with localized nasal disease. However, local and systemic failures are observed frequently in patients who receive RT alone.Therefore, chemotherapy is needed in combination with RT to reduce the risk of recurrence. The patients with newly diagnosed stage III/IV ENKTL were rare and their prognosis was poorer.Chemotherapy was the major therapeutic tool for them.However,the optimal chemotherapy regimen for this disease has not been fully defined. Therefore, the purpose of this study is to prospectively evaluate efficacy and safety of GEP Regimen ( Gemcitabine, Etopie and Pegaspargase ) in patients with newly diagnosed ENKTL(ClinicalTrials.gov number, NCT02705508).

Methods: Enrolment began in March 2016 for a Phase II single-center clinical trial.Treatment GEP dosages were as follows: days 1 and 8,30min intravenous infusion of 1000mg/m² gemcitabine;day1-3,4h intravenous infusion of 100mg/m² etoposide;day1,deep intramuscular injection of 2500unit/m² PEG-ASP at three different sites.The regimen was repeated every 3 weeks.Stage IE/IIE patients underwent four cycles induction chemotherapy, followed by involved-field radiotherapy after got complete remission,partial regression or stable disease.Three-dimensional conformal radiotherapy was done by linear accelerator at 2.0 grays (Gy) per daily fraction with 5-6 weeks. The involved-field radiation (IFRT) dose was 50-56Gy.Stage IIIE/IVE patients were given for six cycles unless there was disease progression or unacceptable side effects, or withdrawal of patient consent.

Results: Until August 2, 2017, we have completed the enrolment of 20 patients with newly-diagnosed untreated ENKTL.The main clinical characteristics of the 20 patients are presented in Table 1.The median age was 50 years andranged from 20 to 70 years. The majority of patients initially presented withlocalized disease (stagesI and II; n = 17, 85%).All patients(n=20)have begun treatment and are evaluable for response. Of the 20 patients, complete remission (CR) rates is 100% to chemotherapy alone.Fifteen patients with localized disease(stage IE/IIE) achieved a CR after two cycles of GEP regimen. CR was achieved after 2 courses of chemotherapy in two stage IIIE/IVE patients and after 4 courses in one patient.Toxicities are recorded as the number of patients experiencing a certain adverse event.The most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=12), nausea (n=10),oral mucositis (n=4).Fourteen(n=15) patients were confirmed to have decreased fibrinogen. Most of these were grade 1/2 and no bleeding or other adverse events were observed.Grade 3 non-heme AEs included fatigue (n=3), oral nausea (n=2), mucositis (n=1).There was no grade 4 non-heme toxicities during chemotherapy.Grade 1-2 hematological (heme) AEs included neutropenia (n=9), anemia (n=12) and thrombocytopenia(n=3). Common grade 3-4 haematological AEs was neutropenia (n=11), anemia (n=4) and thrombocytopenia(n=10).No patients interrupted treatment for severe adverse events and no treatment-related deaths occurred.

Conclusions: Preliminary data indicate that the GEP regimen chemotherapy in newly diagnosedENKTL patients was efficacious and well-tolerated, while the long-term outcome is required to be followed up.

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