The Clinical Research Of Using Ruxolitinib To Prevent AGVHD After Alternative Donor Hematopoietic Stem Cell Transplantation

Background and ObjectiveGraft-versus-host disease(GVHD)is caused by the recognition of alloantigens of host antigens by donor lymphocytes and is the major cause of non-relapse mortality(NRM)in patients receiving allogeneic hematopoietic stem cell transplantation(allo-HSCT).Although there are hormones and other therapies for GVHD,the immunosuppressive effects of these therapies can cause secondary infection and other complications,which bring huge life burden and life threat to patients.So it is important to give preventive measures in advance to reduce the incidence of GVHD.Although the application of the classic duplex program has made great progress in HSCT,some studies have shown that this program can inhibit graft anti-leukemia effect(GVL)while reducing acute graft-versus-host disease(aGVHD),increasing the risk of disease recurrence,and there is still>40%patients developing aGVHD of grade ? to ?.According to Johnston's study,the incidence of aGVHD is 30%-50%in patients receiving HSCT from all HLA allied relative donors,and the incidence of aGVHD is 50%-70%in patients receiving HSCT from unrelated donors.Ruxolitinib is a selective Janus kinase(JAK)1/2 inhibitor,which inhibits the expression of proinflammatory cytokines IL6,IL12,TNF-?,Th1 and Th17 by inhibiting the JAK1/2 pathway and thereby inhibiting T cell signal transmission,playing an anti-GVHD effect.Experiments in animal models have shown that ruxolitinib can down-regulate GVHD-related inflammation while sustaining T-cell allogeneic responses after transplantation,thereby not only generating anti-GVHD activity,but also retaining the GVL effect.At present,there have been many clinical studies at home and abroad,which have confirmed that ruxolitinib is active in hormone-refractory GVHD,has small side effects,is safer,and may not affect the GVL effect.Some experts speculate that ruxolitinib also has the potential to prevent GVHD.However,most domestic and foreign literatures use ruxolitinib to treat hormone-refractory GVHD,and there are few studies using ruxolitinib to prevent the occurrence of GVHD.We know very little about using ruxolitinib to prevent GVHD,including the effectiveness in preventing GVHD,the appropriate dosage,the patients' tolerance,and the rate of disease relapse of patients.The purpose of this study was to evaluate the clinical effect of using ruxolitinib to prevent aGVHD after alternative donors(unrelated donors and half-matched donors)HSCT early in the period after transplantation,so as to explore whether ruxolitinib can be used as a new drug to prevent aGVHD after allo-HSCT.MethodsWe retrospectively analyzed 67 patients with hematological diseases who received allo-HCST from irrelevant donors and half-matched donors at The Affiliated Cancer Hospital of Zhengzhou University from October 1,2017 to October 1,2019.We divided 67 patients into 41 patients of the combination group using ruxolitinib combined with " cyclosporine A(CsA)(or tacrolimus)+mycophenolate mofetil(MMF)+short course of Methotrexate(MTX)" program and 26 patients of the standard group only using "CsA(or tacrolimus)+MMF+short course of MTX" program.We collected patients' data including the clinical data before transplantation,the incidence of aGVHD after transplantation,the recurrence rate of primary disease,the incidence of bacterial and fungal infections,the incidence of cytomegaloviremia,the incidence of EB virusemia,and bleeding bladder Differences in the incidence of inflammation,and analyzed the differences in data between the two groups of patients.Kaplan-Meier curves were used to analyze the overall survival time(OS)and the disease-free survival time(DFS)in both groups of patients.ResultsThe total incidence of aGVHD in the combination group was 36.6%(15/41),of which 3 patients had grade I aGVHD,6 patients had grade ? aGVHD,and 6 patients had grade ?-? aGVHD.Organ involvement of aGVHD included Single organ involvement and multiple organ involvement.Single organ involvement included 3 patients of skin,4 patients of gastrointestinal tract,4 patients of liver.Multiple organ involvement included 4 patients,including 2 patients of liver and gastrointestinal tract,1 patients of skin and liver,1 patients of skin and stomach Intestine.One patient died of severe aGVHD and hepatic encephalopathy in the liver,one patient died of severe aGVHD in the gastrointestinal tract,one patient died of severe pulmonary infection and severe liver aGVHD,and the remaining patients were better controlled.The incidence of aGVHD in the standard group was 61.5%(16/26),of which 4 patients had grade I aGVHD,8 patients had grade ? aGVHD,and 4 patients had grade ?-? aGVHD.Single organ involvement included 4 patients of skin,2 patients of gastrointestinal tract,3 patients of liver.Multiple organ involvement included 7 patients,including 1 patients of liver and gastrointestinal tract,4 patients of skin and liver,and 1 patients of skin and stomach Intestine,1 patients of skin liver and gastrointestinal tract.One patient died of severe liver and gastrointestinal aGVHD+septic shock+severe pulmonary infection+acute cardiac insufficiency,and the remaining patients were better controlled.There was a significant difference in the total incidence of aGVHD between the combination group and the standard group(P=0.046).The incidences of lung infection,intestinal infection,and bacteremia in the combination group were 58.5%,17.1%,and 12.2%,respectively,while those in the standard group were 57.7%,30.8%,and 15.4%,respectively.There was no significant difference between the two groups(P>0.05).The incidences of cytomegaloviremia,EB viremia,and hemorrhagic cystitis in the combination group were 75.6%,7.3%,and 43.9%,respectively,and the standard group were 65.4%,3.8%,and 26.9%,respectively.There was no significant difference between the two groups(P>0.05).By the time of follow-up,38(56.7%)of all 67 patients had survived.The median time of OS in the combination group was 185 days(49-777 days),the rate of OS was 56.1%(23/41),the median time of DFS was 141 days(46-777 days),and the rate of DFS was 48.8%(20/41).In the standard group,the median time of OS was 143.5 days(13 to 690 days),the rate of OS was 57.7%(15/26),the median time of DFS was 143.5 days(13 to 673 days),and the rate of DFS was 53.8%(14/26).There was no significant difference between the two groups(P>0.05).A total of 8 patients(11.9%)had relapsed of the primary disease,including 7 patients in the combination group(17.1%)and 1 patient in the standard group(3.8%).There was no significant difference between the two groups(P=0.138).A total of 25 patients(37.3%)died due to factors other than relapse.The rate of NRM in the combination group was 34.1%(14/41)and in the standard group was 42.3%(11/26).There was no significant difference between the two groups(P=0.501).Conclusions1.Ruxolitinib has anti-GVHD activity,which can reduce the incidence of aGVHD in patients receiving allo-HSCT from alternative donors(unrelated donors and half-matched donors).2.Ruxolitinib may not increase the risk of relapse of the primary disease while playing an anti-GVHD effect.3.Ruxolitinib may not increase the risk of infection in patients,but the severe infection is still the main cause of NRM,and more active measures should be used to prevent infection during and after transplantation.