Clinical Efficacy And Safety Analysis Of Apatinib In The Treatment Of Relapsed And Refractory Diffuse Large B-cell Lymphoma

BackgroundAs the most common type of non-Hodgkin's lymphoma,diffuse large B-cell lymphoma is highly heterogeneous and aggressive.Without appropriate treatment options,patients survive for no longer than one year.The traditional standard first-line regimen for diffuse large B-cell lymphoma is CHOP(cyclophosphamide+doxorubicin+vincristine+prednisone).In the postrituximab era,the addition of rituximab to traditional CHOP regimen has greatly increased the response rate of first-line treatment of diffuse large B lymphoma to more than 70%.Despite a high response rate,approximately 30-40%of patients tend to relapse after first remission and eventually develop a refractory disease.In order to achieve a long term disease-free survival for patients who relapse after first-line treatment,a large dose of salvage chemotherapy is often given,followed by autologous stem cell transplantation.However,more than 60%of patients are not eligible for autologous stem cell transplantation,which poses a great treatment challenge.At present,there is no standardized treatment for patients with relapsed and refractory diffuse large B-cell lymphoma.In this context,to explore effective new salvage treatment options for these patients presents an unmet and urgent medical need.Apatinib,a new generation of oral multi-target small molecule tyrosine kinase inhibitors,is independently developed by the People's Republic of China with complete intellectual property rights.It selectively binds to vascular endothelial growth factor receptor-2 and further inhibits its downstream Ras/Raf/MEK/ERK pathway,thereby inhibiting tumor angiogenesis,promoting tumor cell apoptosis,and reducing tumor metastasis through blood flow.Apatinib was approved by the National Drug Administration(NMPA)in 2014 for patients with advanced gastric adenocarcinoma who have failed second-line treatments.In addition,in non-small cell lung cancer,breast cancer,ovarian cancer and other solid tumors,apatinib has also achieved considerable curative effects,making it a new research hotspot in the field of anti-angiogenesis.Like solid tumors,lymphomas are closely related to neovascularization in terms of tumor growth,progression,and metastasis.Vascular endothelial growth factor levels and tumor microvessel density are significantly related to the inferior prognosis of patients.In vitro and in vivo studies have shown that apatinib can significantly inhibit the proliferation of tumor cells,inhibit tumor growth,and prolong the survival events of xenograft models in non-Hodgkin's lymphoma.An exploratory study of apatinib in relapsed/refractory non-Hodgkin's lymphoma previously conducted in our center showed that apatinib has effect in relapsed/refractory non-Hodgkin's lymphoma,but that study included only a small group of patients and did not discuss the efficacy and safety of apatinib in specific pathological types of disease.This study explored for the first time the clinical efficacy of apatinib monotherapy or combination with second/third line chemotherapy in relapse/refractory diffuse large B-cell lymphoma,analyzed its safety and possible factors affecting prognosis,discussed the possibility of using apatinib as a new salvage treatment option for relapsed and refractory diffuse large B-cell lymphoma,also provides valuable references for the development of further clinical researches.Materials and MethodsA total of 43 patients with relapsed and refractory diffuse large B-cell lymphoma admitted to the Oncology Department of the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2019 were retrospectively collected.Patients were divided into 2 groups considering their different treatment.Apatinib group(21 patients)took apatinib 500 mg/day as the initial dose and 3 weeks as one treatment cycle,patients continued to take the drug until disease progression or intolerable adverse events.Treatment interval due to adverse reactions per cycle does not exceed 7 days.Apatinib+chemotherapy group(22 patients)had the same dose and cycle of apatinib,with combination of DHAP,ICE,or GDP regimen(?DHAP:cisplatin 20mg/m2 intravenous infusion d1-4,cytarabine 2g/m2 intravenous infusion q12h d2,dexamethasone 20mg intravenous infusion dl-5;ICE:ifosfamide 2g intravenous infusion d1-3,400-500mg carboplatin intravenous infusion d1,dexamethasone 20mg intravenous infusion d1-5;?GDP:gemcitabine 1g/m2 intravenous infusion d1,d8,cisplatin 75mg/m2 intravenous infusion in 3-4 days,dexamethasone 20mg intravenous infusion d1-5.Efficacy was evaluate every 2 months within the first 6 months and every 3 months after 6 months.Adverse events were recorded in detail during the whole treatment process,including their occurrence time,duration,grade degree,intervention measures,recovery status,etc.The overall response rate and disease control rate are used as the evaluation indicators of short-term efficacy,and the long-term efficacy evaluation indicators were progression-free survival and overall survival.SPSS Statistics software and GraphPad Prism software were used for statistical analysis.Survival of patients was estimated using Kaplan-Meier method,and independent influence factors for survival was analyzed by Cox regression model.?=0.05 is considered as the threshold for statically significant.Results1.By the cut-off time of follow-up,7 patients in the apatinib group achieved response,including 1 CR and 6 PR,accounting for 4.8%and 28.5%,respectively.In the apatinib+chemotherapy group,14 patients achieved response,with 18.2%CR and 45.5%PR.ORR of apatinib group and the apatinib+chemotherapy group were 33.3%and 63.6%respectively,the difference was statistically significant(P=0.047),while the DCR was 57.1%and 73.7%respectively,and the difference was not statistically significant(P=0.159).The median PFS of the apatinib plus chemotherapy group and the apatinib group were 10.0 months(95%CI 6.2-13.8)and 7.2 months(95%CI 4.9-9.5)respectively,and the difference of which is not statistically significant(P=0.135).The OS of the apatinib group was 8.2 months(95%CI 4.7-11.7),while the median OS of the apatinib plus chemotherapy group was not reached,difference of which is not statistically significant(P=0.259).The median follow-up time was 12.8 months(95%CI 8.4-17.2),and the median time of taking apatinib was 8.1 months(95%CI 4.2-12.0).2.Most adverse events noted of apatinib in the treatment of relapsed and refractory diffuse large B-cell lymphoma were of grade 1-2,adverse events higher than grade 3 are rare,no fatal serious adverse events,and no death related to adverse events were observed.The most common adverse reactions recorded in the apatinib group were hypertension(56.4%),proteinuria(38.1%),hand-foot syndrome(33.4%),leukopenia(33.4%),and fatigue(33.4%).In the apatinib plus chemotherapy group,adverse reactions such as hypertension(56.4%),fatigue(40.8%),proteinuria(44.6%),and hand-foot syndrome(31.8%)were also frequent.In addition,the rate of common chemotherapy related adverse reactions such as leukopenia and nausea were significantly higher,accounting for 63.6%and 72.5%respectively.The most common grade 3-4 non-hematological adverse reactions were hypertension,which accounted for 9.1%in the apatinib plus chemotherapy group and 13.5%in the apatinib group.Two or more adverse events are often observed in the same patient.Adverse events associated with apatinib were usually alleviated by short-term treatment interval and appropriate symptomatic supportive treatment.3.During the process of apatinib treatment,some patients had experienced treatment interval and dose adjustments due to adverse events and other reasons.The first treatment interval or dose adjustments were mostly recorded in the first cycle of therapy,and the median days from first medication to first dose interval was 18 days(IQR,13-22).Of all 40 patients,11(25.6%)patients remained on the original dose,while 14(32.6%)patients had one dose reduction from 500 mg daily to 500 mg and 250 mg on alternate days,and 18(41.8%)had their dose reduced to 250 mg daily.31 patients experienced a short treatment interval during the treatment period,accounting for 72.1%of the total number of patients.Most of these patients could continue to take apatinib at the original dose after treatment interval.4.In this study,ECOG score,Ann Arbor stage,and whether combined chemotherapy were significantly associated with PFS and OS.ECOG score of 0-1,Ann Arbor stage of ?-?,and apatinib plus chemotherapy had prolonged PFS and OS.In addition to the above factors,the presence of hand-foot syndrome and fatigue is also related to prolonged PFS.Conclusion1.The short-term clinical efficacy of apatinib combined with chemotherapy for relapsed and refractory diffuse large B-cell lymphoma is superior to that of apatinib monotherapy,and the adverse reactions are tolerable.2.Patients with apatinib-related hand-foot syndrome and fatigue tend to obtain longer PFS.