| Background and PurposeExtranodal NK/T cell lymphoma,nasal type(ENKTCL)is a subtype of highly aggressive non-Hodgkin’s lymphoma(NHL).80%of which involves the upper aerodigestive tract(such as nasal cavity,nasopharynx,paranasal sinuses,and palate),while 20%of which occurs in extra-nasal tissues(such as skin,mucous membrane,lungs,gastrointestinal tract,reproductive system etc.).The incidence is higher in Asia and South America than Europe.The 5-year survival rate is only 17%in patients with advanced stage(stage Ⅲ and Ⅳ).Asparaginase-based chemotherapy is recommended for newly ’treated and advanced stage of ENKTCL according to National Comprehensive Cancer Network(NCCN)guidelines,however,there are still more than 20%of patients who do not respond to the recommended chemotherapy regimens.For the relapsed/refractory patients,asparaginase-based chemotherapy is still recommended or participate in clinical trials;As there is still no uniform recommendations,clinical trials are recommended for the asparaginase-resistant or multiple relapsed/refractory ENKTCL(failed after 2 lines treatment).Thus,the study of the treatment of relapsed/refractory ENKTCL has an important clinical significance.Chidamide is an original histone deacetylase inhibitor in China,which has promising effects in peripheral T-cell lymphoma(PTCL),however,the study of therapeutic effect of chidamide in ENKTCL is still rare.Etoposide(topoisomerase II inhibitor)is an important chemotherapeutic drug in the treatment of ENKTCL,while,the study of oral etoposide combined with chidamide in the treatment of ENKTCL is still rare.In order to explore the efficacy,prognosis and adverse reactions of chidamide combined with oral etoposide in the treatment of relapsed/refractory ENKTCL,our center has launched a combination of chidamine and etoposide capsules in the treatment of relapsed/refractory NK/T cell lymphomas,a single-arm,prospective clinical study.This trial is now undergoing mid-term evaluation.This study has been registered with Clinical trials.gov,number NCT04490590.Materials and Methods1.22 patients diagnosed with relapsed/refractory ENKTCL(failed after 2 lines treatment)that were admitted in the Lymphoma Ward of the Oncology Department in the First Affiliated Hospital of Zhengzhou University from June 2016 to February 2020 were including in this study,according to the inclusion criteria and exclusion criteria of clinical trials.2.The clinical data of the enrolled patients,including sex,age,Epstein-Barr virus(EBV)-DNA replication rate,previous baseline treatment,clinical stage,lactate dehydrogenase(LDH)levels,eastern cooperative oncology group(ECOG)score,prognostic index of natural killer lymphoma(PINK)score,B2-MG,LDH,B symptoms,presence or absence of bone marrow invasion,and treatment baseline were collected.The expressions of CD30,CD20,CD43,CD56,Granzyme-B,TIA-1 and Ki-67 in the lesion tissue were detected by HE staining and immunohistochemical techniques.3.The enrolled patients were given oral chidamide 30mg PO(30 min after breakfast,twice a week)and etoposide capsules(50 mg QD PO,d1-d14),21 days as a cycle,treatment until progression disease,patients voluntarily withdraw,toxic effects intolerable reaction or death.4.The short-term and long-term efficacy and adverse reactions of patients with relapsed/refractory ENKTCL were analyzed.The clinical characteristics and pathological factors which could be affected the prognosis of ENKTCL were analyzed.Statistical methodEXCEL 2016 application software was used to organize the data,SPSS statistical software version 22.0 was utilized to perform the data analysis.Count data were analyzed as rate.The 95%confidence interval(CI)was calculated for ORR and DCR.Survival curves were analyzed by Kaplan-Meier method.Log-rank method was used to compare the survival rate,the test significance was α=0.05.Results1.General clinical data:The median age of 22 patients was 34.5 years(range 18-65 years),and the male to female ratio was 1.4:1;there were 6 patients with stageⅠ-Ⅱ and 16 patients with stage Ⅲ-Ⅳ.There were 5 patients with elevated EB virus replication rate;7 patients had an PINK score of 0-1,15 patients had an PINK score of 2-4;6 patients with B-symptom positive,5 patients had high B2-MG,and 10 patients had increased LDH;all patients were used two or more chemotherapy regimens,of which 8 cases were after radiotherapy,and 3 cases were after autologous hematopoietic stem cell transplantation.1 of the 22 patients was unable to obtain detailed pathological information due to pathological consultation.The remaining patients expressed CD3,TIA-1,Granzyme B particles,EBER,and a total of 4 patients tested CD8(2 specimens were positive,2 specimens were negative).17 cases(81.0%)were positive for CD56;5 cases(25.0%)were positive for CD20;10 cases(71.4%)were positive for CD30;10 patients(47.6%)expressed Ki-67 over 50%,and 11 patients(52.4%)were less than 50%;and 4 specimens were tested for CD5,of which were positive There were 2 cases and 2 cases were negative.2.Short-term curative effect:Among 22 patients,2 patients achieved CR,9 patients obtained PR,4 patients obtained SD and 7 patients PD appeared,ORR was 50.0%(95%CI 27.3%-72.7%),and DCR was 68.2%(95%CI 47.0%-89.3%).3.Long-term efficacy:By June 1,2020,22 patients could be evaluated for long-term efficacy,the follow-up time was 1-50 months,and the median follow-up time was 25.6 months.Among them,6 patients were dead(5 patients were dead from disease progression,1 was dead from unknown cause);4 cases were recurrent(recurrent time was 19.9 months,25.6 months,21.6 months,3.8 months respectively),3 cases changed the treatment plan,1 case temporarily stopped treatment due to tuberculosis.The median PFS was 20.9 months(95%CI 18.3-23.5 months),and the 1-year,2-year,and 3-year PFS rates were 63.6%,39.8%,and 31.8%,respectively;the median OS has not been reached.The 1-year,2-year and 3-year OS rates were 72.4%,72.4%,and 63.4%,respectively.4.Subgroup analysis:high EBV-DNA replication rate,high LDH,ECOG≥2 points were adverse factors affecting the long-term prognosis,while gender,age,clinical stage,B symptoms,β2-MG,recurrent after HSCT and radiotherapy,the expression of Ki-67,CD56,CD20,CD30,were no statistical difference(p>0.05).However,for the patients with higher Ki-67 expression(≥50%)the disease progression-free survival rate had a tendency to increase.5.Adverse reactions:22 patients were assessable for adverse reactions,they are divided into hematological adverse reactions and non-hematological adverse reactions.Hematological adverse reactions mainly were Grade 1-2,including 8 cases had leukopenia(36.4%),8 cases had anemia(36.4%),7 cases had thrombocytopenia(31.8%);3 patients(13.6%)had Grade 3-4 leukopenia.All the hematological adverse effects could be recovered after symptomatic treatment.Non-hematological adverse reactions were Grade 1-2.The adverse reactions of the digestive system are mostly anorexia(36.4%),nausea and vomiting(18.2%),abdominal pain and diarrhea(13.6%),constipation(9.1%),and elevated transaminase(9.1%),increased bilirubin(4.5%),decreased fibrinogen(13.6%),fatigue in the mental system(22.7%),and increased thyroid-stimulating hormone(TSH)in the endocrine system(9.1%).Patients with diarrhea could be recovered,and the other adverse reactions did not affect the patient’s normal quality of life,and no chemotherapy-related deaths or secondary tumors was observed.Conclusion1.Chidamide combined with oral etoposide in the treatment of relapsed/refractory ENKTCL is convenient and effective,and the adverse reactions are tolerable.It is worthwhile further clinical trials to verify its effectiveness.2.High EBV-DNA replication rate,high LDH,ECOG≥2 points may be adverse factors affecting the long-term prognosis of ENKTCL patients. |
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