Sirolimus In Combination With Calcineurin Inhibitors For Hormone Resistant/dependentcGVHD

Background:Allogeneic hematopoietic stem cell transplantation(Allo-HSCT)is one of the key methods to cure hematologic malignancies.Post-transplant complications,such as graft-versus-host disease(GVHD)are major limiting factors for the success of transplantation.Chronic Graft Versus Host Disease(cGVHD)generally refers to the rejection reaction in the late stage of allogeneic hematopoietic stem cell transplantation.According to statistics,the incidence of cGVHD is as high as 50%～70%.Due to the complex mechanism of cGVHD,the symptoms of patients with rejection often persist,and the clinical manifestations are not the same.Oral cavity,skin mucosa,digestive tract,liver,lung,joints,fascia and other organs and tissues are often affected,and patients often show rejection symptoms of varying severity,which not only seriously affects the quality of life of patients,but even leads to death of patients.At present,the first-line treatment of cGVHD is generally recognized as glucocorticoids(with or without calcineurin inhibitors),but the effective rate of first-line treatment is only50%,50% of patients have poor response to first-line treatment,and long-term use of high dose of hormones often brings serious side effects and complications to patients,including an increased risk of infection,high blood pressure and osteoporosis.In addition,for some patients with glucocorticoid dependence and refractory relapse,the effectiveness of traditional immunosuppressant therapy of cGVHD is challenged due to its hormone dependence or ineffectiveness.It is necessary to combine other immunosuppressant therapies,including mycophenolate mofetil and interferon,etc,but the efficacy is often not ideal.Patients with cGVHD who have failed first-line treatment often have poor outcomes.Second-line treatment of cGVHD needs to be initiated,but the existing second-line treatment regimens have low effective rates,and long-term use can lead to obvious toxic and side effects such as infection,gastrointestinal reactions,and recurrence.The therapeutic effect is still controversial,and new clinical treatment methods are urgently needed.Sirolimus is a novel immunosuppressant with good efficacy and low nephrotoxicity,which has attracted attention due to its low nephrotoxicity.Meanwhile,sirolimus has an anti-fibrosis effect,which makes it have a good effect on cGVHD in the skin.In addition,sirolimus has been found to have a synergistic effect with calcineurin inhibitors.Therefore,in this study,sirolimus combined with calcineurin inhibitors was used to form a new regimen for the treatment of steroid-resistant/dependent patients with cGVHD,and its efficacy and safety were observed.Objective:To observe the efficacy and safety of sirolimus combined with calcineurin inhibitor(CNI)in the treatment of extensive cGVHD with glucocorticoid resistance/dependence,and to evaluate the efficacy and safety of this regimen.To explore the effective regimen for glucocorticoid resistance/dependence of cGVHD.Methods:This single-arm,single-center clinical trial included 27 patients with extensive type of cGVHD who developed glucocorticoid resistance/dependence after Allo-HSCT treatment in the hematology department,Xinqiao Hospital,from November 2015 to January 2019.They were given sirolimus in combination with cyclosporine or tacrolimus.Reference in 2014,the national institutes of health(NIH)about cGVHD curative effect evaluation standard for the patient degree of rejection rate.The NIH scores of each organ of cGVHD patients were observed at 6 months and 1 year after treatment and compared with the baseline before treatment.What`s more,we also absorved the overall response rate(ORR=CR+PR),the progression-free survival of the enrolled patients(PFS)for 6 months and 1 year after treatment,the overall survival(OS)of all the enrolled patients,at recorded adverse reactions the same time.To evaluate the efficacy and safety of sirolimus combined with CNI in the treatment of extensive cGVHD with glucocorticoid resistance or dependence.Results:A total of 27 patients were enrolled,and 27 patients could be analyzed in the end.There were 17 male patients and 10 female patients.In these imported patients,the median follow-up time counts 24.1(12.0-50.1)months.Including 13 AML patients,4 ALL patients,4CML patients,3 MDS patients,1 lymphoma patients,1 AA patient and 1 PNH patient.When the drug has been used for half a year,we observed complete remission(CR)in 3 patients,partial response(PR)in 12 patients,stable disease(SD)in 6cases and progressed disease(PD)in 6 cases.The overall response rate(ORR)was 55.6%,the 6-month Progression Free Survival(PFS-6)was 88.9%,and the 6-month overall survival(OS-6)was 100%.And when were followed up for 1 year,we observed CR in 5 cases,PR in 11 cases,9 cases of SD and PD in 2 cases,ORR was 59.3%,PFS-12 counted 62.9%,OS-12 counted 100%.The treatment regimen was more effective in cGVHD patients with male donors than in cGVHD patients with female donors.And The treatment regimen has a good effect on patients with rejection symptoms of oral cavity,skin,liver and other organs.Adverse reactions were rare,grade 1-2,and no new cytomegalovirus or Epstein-Barr virus infection occurred.None of the included patients had serious toxic and side effects.Conclusions:In terms of effectiveness and safety of glucocorticoid-resistant or dependent extensive cGVHD treatment,sirolimus combined with CNI has certain advantages in long-term effect control,high safety during medication,and is suitable for long-term treatment of patients with cGVHD,with certain clinical application prospects.