Cytoprotection By Amifostine During Allo-hematopoietic Stem Cell Transplantation

[Objective]To observe the cytoprotection effect,safety and related toxicity when recombinant amifostine during myeloablative conditioning therapy of allo-hematopoietic stem cell transplantation.[Design]The patients of experimental group and control group who were eligible for this research were all diagnosed of hematologic malignancies,and they all had related or unrelated HLA phenotypically matched donor,had conditions to complete allo-hematopoietic stem cell transplantation.Patients of the experimental group were given amifostine at a daily dose of 400mg/ m~2 intravenous drip on each day of conditioning before chematherapy and radiotherapy,each infusion was given 15 minutes.The control group weren't given amifostine before chematherapy and radiotherapy.This research belongs to clinical research.[Setting]This research was completed in 307 hospital,which attached to Academy of Military Medical Sciences.From the beginning of conditioning to the recovery of hemogram,the research was progressed in Aseptic ward;after the recovery of hemagram,the patients switched to general ward or leaved hospital.[Object and Method]The patients of experimental group and control group were all diagnosed of hematologic malignancies,and they all had related or unrelated HLA phenotypically matched donor,had conditions to complete allo-hemapoietic stem cell transplantation.Select patients who are going to complete allo-hematopoietic stem cell transplantation during July 2008 to April 2009 as experimental group,patients who had completed allo-hematopoietic stem cell but not received amifostine during March 2006 to June 2008 as historical control group according to balance and control principles.Amifostine 400 mg/m~2 had been intravenously given to the 21 patients of experimental group 30 minutes before chematherapy and radiotherapy,the persistence time was 15 minutes,while nothing had been given to the 20 patients of control group.The drug was given as a single daily dose because total body irradiation(TBI) or chemotherapy was delivered to the patient only once a day.The specific informations of the two groups are discripted as follows:of the experimental group,there are 16 males,5 females,the median age is 33(range 17-52 years old),including 6 patients with ALL,8 with AML,1 with CML,1 with MDS,1 with Chronic Neutrophilic Leukemia;of the control group,there are 13 males,7 females,the median age is 33.5(range 18-56 years old),including 5 patients with ALL,12 with AML,2 with CML,1 with MDS;the morbid state of the two groups before allo-hematopoietic stem cell transplantation:there are 16 patients who reached complete remission,2 reached partial remission,2 were non-remission in the experimental group,while the control group have 15 patients who reached complete remission,5 were non-remission,there were no patient who reached partial remission in the control group.Compare the sex characteristic of the two groups,the P value is 0.505,P value of the age characteristic of the two groups is 0.960,0.532 of the diagnose characteristic.Compare the morbid state of the two groups,the P value is 0.577,the P value of the donor resource is 0.920,the P value of the graft-versus-host-disease is 0.580,all of the P value of the disease characteristics are greater than 0.05,the two groups don't have statistical significance on disease characteristics.Patients in the experimental group were given amifostine 400 mg/m~2/d which soluted in 0.9%physiological saline 30 minutes before chematherapy and radiotherapy,the persistence time was 15 minutes,from the first day to the last day of the conditionging.Because amifostine can induce severe nausea and vomiting,antiemetics were administered prior to amfostine,the patients were given 5-HT3 receptor antagonist(granisetron hydrochloride 3mg or ramosetron 0.3mg)intravenous drip and dexamethasone 5mg intravenous injection to prevent nausea and vomiting.If hypotention happenned,the patients who experienced it were immediately given fluid 500-1000ml intravenous drip for fluid replacement therapy,monitered blood perssure simultaneously untill the blood pressure recovered to normal.The historical control group didn't received amifostine during the conditioning.[Main Outcome Measures]Because during the process of intravenous drip of amifostine,some patients may experience transient hypotension,or hypocalcemia,hypomagnesium,the blood pressure should be monitored every 5 minutes,from 5 minutes before amifostine was given to 5 minutes after drug withdrawal.Monitored serum calcium and serum magensium during conditioning;from the beginning of conditionning,monitored hepagram every day,hepatic and renal function were examined at least three times a week.Observe the incidance rate of venous occlusive disease(for example,fluid retention,hepatomegaly accompanied by pain,elevated biulirubin),haemorrhagic cystitis(for example,gross hematuria or cystitis symptome),oral mucositis(for example,pain,ulcer,condition of food take) and acute GVHD(for example,hyperemia rash,skin denudation,diarrhea with abdominal pain,jaundice).If oral mucositis or aGVHD happened,evaluate the grade according to WHO or Blucksberg standard.After 3 months of allo-hematopoietic stem cell transplantation,examine the Bone Marrow Examination and chimerism,recording the survival rate.[Result]The result of effect:NEUT recoveries after allo-HSCT at d14.63±2.22 in the experimental group,as well as d15.55±1.64 in the control group(P=0.148>0.05);PLT recoveries after allo-HSCT at d17.11±8.43 in the experimental group,as well as d21.55±8.40 in the control group(P=0.108>0.05);the mean tank of the units of RBC transfusion before hematologic recovery is 17.53 in the experimental group,as well as 22.35 in the control group(P=0.179>0.05);the mean tank of the units of PUT transfusion before hematologic recovery is 15.37 in the experimental group,as well as 24.40 in the control group(P=0.013<0.05).The result of safety:P value of the two groups on hepatic function is 0.972,P value of the two groups on renal function is 0.142.Comparition of the two groups on aGVHD,the incidence rate:P=0.019<0.05,on the grade of aGVHD:P=0.026<0.05.The incidence rate of venous occlusive disease is 4.8%in the experimental group,compare with 5.0%in the control group(P >0.05);the incidence rate of haemorrhagic cystitis is 9.5%in the experimental group,compare with 20.0%in the control group(P >0.05);the incidence rate of oral mucositis is 14.3%in the experimental group,compare with 15.0%in the control group(P >0.05);P value of the two groups on the grade of oral mucositis is 0.983(P>0.05).The relapse rate of 3 months is 5.3%in the experimental group,while 0.0%in the control group(P=0.487>0.05).The survival rate of 3 months is 84.2%in the experimental group,while 100.0%in the control group(P=0.106>0.05).[Conclusion]The use of cytoprotection amifostine 400mg/m~2 intravenous drip given during allo-hematopoietic stem cell transplantation 30 minutes before conditioning cannot effect the neutrophil and platelet recovery,also cannot decrease the units of RBC transfusion,but can decrease the units of PLT transfusion.However,the drug doesn't protect the hepatic function,renal fuction,in the complications of allo-HSCT,amifostine dosen't decrease the incidence rate on oral mucositis,VOD and HC,comparing the grades of oral mucositis,there is no statistical significance.Amifostine can decrease the incidence rate and relieves severity of aGVHD after allo-HSCT.In the prognosis aspect,amifostine probably does not increse the relapse rate,as well as the survival rate at three months after allo-HSCT,indicating that amifostine 400mg/m probably doesn't protect malignant cells,has no impression to curative effect.