Patient Related Risk Factors For Non-relapse Mortality(NRM) In Allogenic Hematopoietic Stem Cell Transplantation(Allo Hsct):A Multicenter Retrospective Cohort Study

Introduction;Non relapse mortality(NRM)is a hematopoietic stem cell transplantation(HSCT)outcome,referring to deaths from other causes apart from disease relapse following HSCT.Patients with advanced hematological malignancies and other non-malignant conditions get remission for their underlying conditions following allo HSCT.However,this therapy is potentially a high risk therapy for these patients in that,long term survival after HSCT remain limited by significant transplantation related a mortality and relapse.Methods;This was a retrospective cohort study,involving four hospitals(transplant centers)purposely selected,and included a convenient sample of 173 patients with both hematological and non-hematological malignancies,aged 12 to 70 years at the time of transplantation who underwent allo HSCT between January 2016 and December 2019.The study pooled the previously studied factors for NRM and termed them as "standard factors for NRM",then,recategorized them as patient related factors and/or treatment related factors,with;(i)Primary objective of determining the patient factors for NRM from the standard factors.(ii)Secondary objective included determining to what extent were patient factors associated with NRM compared with treatment factors.Patients who underwent second transplant within 1 year and patients who were undergoing their second or third transplant were excluded from this study.Data were collected from data registry of the hospital information system(HIS)of the four selected transplant centers.Patients were retrospectively followed for one year after being discharged from transplant centers through their clinic visiting records from both discharging transplant centers and other health centers linked to the discharging transplant centers.All statistical analyses were performed using Statistical Package for Social Sciences(SPSS)version 26.Cox proportional hazards analysis was employed to identify risk factors.Multivariable risk factors were identified using stepwise analysis.Results were reported as hazard ratios(HRs)and 95%CIs.Post-transplant complications were analysed as competing risk endpoints.Patient transplant outcomes surviving 1 year post transplantation were calculated from the date of transplantation(NRM,relapse and overall survival,OS).NRM was estimated using the cumulative incidence method.Survival curves were estimated using the Kaplan-Meier approach for OS in 1 year post transplant survivals.Results;76.9%of patients were<40 year old at transplant,52.6%among them had high risk diseases,in which 34.7%had AML and 14.5%had ALL.23.6%of patients who had leukemia,MDS and other diseases(except SAA)received MeCCNU/Bu/Cy/Ara C and 8.2%of those who had SAA received Flu/Cy.85%were infused PBSCs and 65.3%received a combination of MTX/CsA/MMF as GvHD prophylaxis.Following transplant,all HSCT recipients were followed up to 365 days to monitor their transplant outcomes(neutrophils engraftment duration,immune reconstitution duration,liver function(total bilirubin,AST,ALT and LDH),kidney function(sCr),viral activation(EBV and CMV)and clinical blood picture(Hb,Plt and Neu).90.2%achieved their primary neutrophils engraftment with a median duration of 12 days,and 84.4%achieved immune reconstitution with a median duration of 45 days.79 had elevated AST,37 had elevated ALT,34 had elevated total bilirubin,13 had elevated LDH and 3 had decreased LDH.Moreover,134 were anemic,109 were thrombocytopenic,12 had high ANC values and 46 had low ANC values.At 1 year post allo HSCT 13.8%(n=24)had died,85%(n=147)were alive without relapse and 1.2%(n=2)were alive with relapsed disease.70.8%of deaths were observed among HSCT recipients aged>40 years or more.However,leukemic patients were observed to have low NRM incidence rates(20.8%,AML and 29.2%,ALL)compared with 50%for other diseases.MeCCNU/Bu/Cy/Ara C conditioning accounted for 33.3%deaths for patients who had leukemia,MDS and other conditions except SAA,whereas,Flu/Cy and Cy alone accounted for 16.7%and 12.5%respectively for patients who had SAA.79.2%deaths were observed among HSCT recipients infused HSCs from MSD,and 54.2%deaths were observed among recipients infused HSCs from male donors.The use of a combination of MTX/CsA/MMF+ATG as a GvHD prophylaxis accounted for 75%deaths.Neutrophils engraftment duration≥12 days and immune reconstitution duration≥45 days accounted for 75%and 36.8%deaths respectively.Furthermore,53.8%of the HSCT recipients who were neutropenic as a result of marrow suppression following MAC died,and 100%of those who were both anemic and thrombocytopenic died as well.In univariate Cox regression,AML(HR,0.28;95%CI;0.089-0.88;p=0.03),and neutrophils engraftment duration≥12 days post HSCT(HR,3.09;95%CI;0.997-9.59;p=0.05)were associated with NRM incidence rates.Moreover,elevation of both sCr(HR,10.2;95%CI;2.5541.2;p=0.001)and total bilirubin(HR,3.17;95%CI;1.11-9.03;p=0.03)were associated with NRM incidence rates.However,organ failure(HR,256;95%CI;0.18-2610;p<0.001)was found to be the main cause of NRM.In multivariate Cox regression,HSCT recipients age of 21-41 years(HR,2.9;95%CI;1.36.5;p<0.05)and that of 41-62 years(HR,4.9;95%CI;1.2-20;p<0.05)were associated with NRM incidence rates.Organ failure was found to be main cause for NRM(HR,300;95%CI;312900;p<0.05).Among 173 allo HSCT recipients,13.8%(n=24)had died,85%(n=147)were alive without relapse and 1.2%(n=2)were alive with relapsed disease at 1 year.Variables independently associated with the increased incidence of NRM included patient age.Of note,organ failure was found to be the main cause of NRM.Conclusion;The study found that HSCT recipient age was the only patient risk factor for NRM in allo HSCT,and organ failure being the main cause of NRM.Treatment factors were directly associated with NRM regardless of patient factors.Despite of conditioning regimen used,Allo HSCT recipients experienced marrow suppression leading to prolonged cytopenia and other marrow suppression related complications post HSCT.Yet,long neutrophils engraftment duration was found to be associated with NRM incidence rates as the results of transplantation treatment procedures.These results describes how the standard factors were related to NRM,how treatment could be adjusted for the given risk factors,and which interventions prior or post allo HSCT can be implemented for better outcomes.The results also shade some light on patient related risk factors for NRM in allo HSCT.More comprehensive studies are needed to replicate this study.