Clinical Study On Reactive Cutaneous Capillary Endothelial Proliferation Induced By Camrelizumab

Objective（s）:Camrelizumab（Cam）is a human immunoglobulin G4（Ig G4）monoclonal antibody（Hu MAb）that targets programmed cell death protein-1（PD-1）binds to the programmed cell death protein ligand 1（PD-L1）,and blocks the PD-1/PD-L1 pathway mediation,induced immunosuppressive response,inhibiting tumor growth.At present,it is mainly used for the treatment of various solid malignant tumors such as classical Hodgkin’s lymphoma,hepatocellular carcinoma,non-small cell lung cancer,esophageal cancer,and nasopharyngeal carcinoma.Reactive cutaneous capillary endothelial proliferation（RCCEP）is the most common and unique skin immune-related adverse event observed in camrelizumab-treated patients.In this study,we observed the morbidity,location,onset time,severity,and regression of RCCEP in 112 patients with malignant tumors who were treated by camrelizumab.To provide scientific basis for the clinical prevention and treatment of RCCEP induced by the using the PD-1 inhibitor camrelizumab.Methods:A retrospective analysis of 112 patients with solid tumors who received Carrelizumab treatment in the First Affiliated Hospital of Kunming Medical University from January 2021 to July 2022.The age,gender,primary tumor type,mode of medication,first onset time,severity classification,treatment experience and regression of patients with RCCEP were observed and recorded.According to different mode of medication,the sampled population were divided into Cam single-drug immunotherapy group（control group）,Cam combined with chemotherapy drug therapy group（observation group A）,and Cam combined with anti-angiogenic drug therapy group（observation group B）.The RCCEP classification based on the CSCO Guidelines for the Management of Toxicities Related to Immune Checkpoint Inhibitors 2019^[34].The differences in the morbidity,first onset time,and severity of RCCEP among the groups were observed.The datas of this study were processed and analyzed by SPSS 26.0 software.The factors affecting the incidence and severity of RCCEP were statistically analyzed by chi-square test,Fisher’s exact probability method,Mann-Whitney U test,and rank sum test.P<0.05 was considered statistically significant.Results:1.Patient information:A total of 112 patients with advanced malignant tumors treated with camrelizumab alone or in combination were collected,including 85 males（75.22%）and 27 females（23.89%）.The median age was 58 years old（range 17-85years old）,mainly concentrated in the age group of 51-70 years old,with 70 cases（62.50%）.2.Incidence of RCCEP:The median of follow-up time was 12.5 months（range:0.6-23.5 months）,RCCEP were identified in 53.54%（60/112）of the patients who were treated by Camrelizumab.3.Factors affecting the incidence of RCCEP:（1）Gender:85 male patients,46 of which（54.12%）developed RCCEP;27female patients,14 of which（51.85%）developed RCCEP.There was no gender difference in the incidence of RCCEP after using Cam（p>0.05）.（2）Age:The patients were divided into two groups:the group under 58 years old and the group over 58 years old.Among them,61 patients were under 58 years old,34 cases（55.74%）had RCCEP;51 patients were over 58 years old,26 cases（50.98%）had RCCEP.There was no significant difference in the incidence of RCCEP after the use of Cam monoclonal antibody in patients of different age groups（p>0.05）.（3）Method of medication:Among the 112 patients included in this study,4（100%）patients in the control group developed RCCEP;In experimental group A（70cases）,38 cases（58.6%）developed RCCEP.Of 38 patients included in experimental group B,15（39.5%）had RCCEP.Experimental Group B included 24 patients treated with two antiangiogenic drugs,bevacizumab and anrotinib:Cam combined with the antiangiogenic drug bevacizumab;16 patients（63.6%）developed RCCEP.In 16patients treated with Cam combined with antiangiogenic agent anrotinib,1 patient（6.3%）developed RCCEP.There was statistical significance in the incidence of RCCEP between Cam combined with bevacizumab group and Cam combined with anrotinib group（p<0.05）.The incidence of ARCCEP in Cam combined with bevacizumab group was not statistically significant between the control group and the experimental group（p>0.05）,while the incidence of RCCEP in Cam combined with anrotinib group was significantly lower than that in control group and experimental group A,with statistical significance（p<0.05）.4.first onset time of RCCEP:In this study,Cam monoclonal antibody was administered intravenously with 200mg every three weeks until intolerable toxicity or disease progression appeared.That is,every 3 weeks（21 days）is a treatment cycle.The time from the start of Cam treatment to the appearance of RCCEP was recorded as the first episode of RCCEP.Among the 60 patients who developed RCCEP after Cam use,the median time to onset was 15 days（range:10–28 days）.42（70.00%）patients experienced RCCEP for the first time in the first treatment cycle,11（18.33%）experienced RCCEP in the second treatment cycle,and 7 patients（11.67%）experienced RCCEP in the third treatment cycle and later RCCEP appeared for the first time.5.The relationship between the way of medication and the first onset time of RCCEP:the median time of first RCCEP in the control group was 15 days（range:11.25～26.25 days）and the experimental group A:the median time was 15 days（range:11.5～24.25 days）and the experimental group A:Group B:Median time 17.5（range7-120 days）no significant difference（p>0.05）.6.Severity:In this study,almost all RCCEPs after using Cam were grade 1 and grade 2（98.33%）,and there was 1 case of grade 3（1.67%）,and no grade 4 or grade 5reactions were observed.There were no reports of visceral hemorrhage or death due to RCCEP.No patient interrupted or discontinued treatment due to RCCEP.7.The relationship between the way of medication and the severity of RCCEP:the incidence of grade 2 and above RCCEP in experimental group B was higher than that in experimental group A,and the difference was statistically significant（p<0.05）.There was no statistically significant difference in the incidence of PCCEP between the control group and the experimental group A and experimental group B（p>0.05）8.Regression of RCCEP:As of January 2023,54 of the 60 patients who developed RCCEP after using Cam monoclonal antibody have all subsided（6 patients are still being treated with Camrelizumab,and the skin lesions have not completely subsided）.4 patients underwent local surgical resection,1 patient with multiple facial lesions received 3 laser treatments,and 1 patient was treated with oral Chinese medicine after drug withdrawal,and the skin lesions completely disappeared after 1-2months.The remaining patients received no special treatment.Among them,16patients had complete skin lesions 2-4 weeks after stopping the use of camrelizumab;32 patients had complete skin lesions 4-8 weeks after stopping the drug;4 patients stopped the drug for 8-12 weeks The lesions resolved completely.In 2 patients,the skin lesions completely disappeared more than 12 weeks after drug withdrawal.Conclusion（s）:1.The incidence of RCCEP was not related to gender or age.2.Most patients developed RCCEP about 15 days after first use of Cam.There was no significant difference in the first occurrence time of RCCEP in the carrilizumab monotherapy group,the carrilizumab combined chemotherapy group and the carrilizumab combined anti-angiogenesis drug group.For the cases with RCCEP,the initial onset time is close,which may be related to the individual constitution of the patient,and the influence of drugs is slightly.3.The severity of RCCEP lesions was mainly concentrated in Grade 1,Grade 2and Grade 3（mild and moderate）,and no grade 4 and grade 5 cases（severe）were observed.The probability of grade 2 or above RCCEPs in the carrilizumab combined with antiangiogenic drugs was greater than that in the carrilizumab combined with chemotherapy drugs.Overall,most of the RCCEP lesions were mild and moderate,and no severe cases were observed.4.The incidence of RCCEP was high in Cam monotherapy,and there was no difference between the incidence of RCCEP and Cam monotherapy combined with chemotherapeutic drugs and Cam combined with anti-angiogenic drug bevacizumab.The incidence of RCCEP was significantly reduced when Cam was used in combination with the antiangiogenic drug anrotinib.It is suggested that the mechanism of RCCEP after the use of Cam may be related to the overactivation of VEGFR.Therefore,the combination of Cam with anti-angiogenic drugs targeting VEGFR may reduce the incidence of RCCEP.5.Most patients can completely resolve within 3 months after withdrawal.After using Cam 2 weeks,It would be pay more attention to whether RCCEP occured.RCCEP might be self-limited,and it could resolve within 3 months after drug withdrawal in mild cases.In severe cases,appropriate medical intervention should be taken to improve the quality of life.