Medium-dose VP-16 Intensified Conditioning Regimen Is Effective In Allogeneic Hematopoietic Stem Cell Transplantation For Acute Lymphoblastic Leukemia

Objective:ALL(acute lymphoblastic leukemia)is the second common acute leukemia in adults.Despite a high rate of response to induction chemotherapy,followed by consolidation and long-term maintenance chemotherapy,owing to high incidence of recurrence,only 30-40%of adult patients with ALL will achieve long-term remission.Thus allogeneic hematopoietic stem cell transplantation(allo-HSCT),which could decrease incidence of relapse and increase survival,has become an effective therapeutic option for ALL.Pretreatment is the initial and important part of allo-HSCT in ALL.It is closely related to the relapse and transplantation complications.Various conditioning regimens have been adopted in HSCT since its emergence in the clinical field.Standard-intensity conditioning as myeloablative regimens(MAC)TBI/Cy,Bu/Cy and so on are the most popular in China.Intensified conditioning,generally added with a drug,such as Ara-C,VP-16,Melphalan,Fludarabine,or Tespamin to standard conditioning regimens for patients with relapse/refractory malignant diseases,may reduce the high leukemia cell burden and improve outco,mes.VP-16 is one of the most active anticancer drugs for the treatment of hematological diseases.VP-16 has been used in conditioning regimens for ALL and has achieved promising curative effect,especially combined with TBI/Cy regimen.The effect of Bu/Cy added with medium-dose VP-16 as conditioning regimens in ALL was not certain.Retrospectively analyze the outcome of additional medium-dose etoposide(VP-16 30mg/kg)in allo-HSCT precondition for acute lymphoblastic leukemia.We not only added VP-16 to Cy/TBI(n=12)but also mostly Bu/Cy(n=41)to research the effect of medium-dose VP-containing regimens for HSCT in ALL.Methods:From 2010.10.1 to 2018.7.1,fifty-three ALL patients received first allo-HSCT in Shandong provincial hospital affiliated to Shandong University.Twenty patients conditioning with medium-dose VP-16(VP-16 group)and thirty-three patients conditioning without medium-dose VP-16(control group)were enrolled.The basic conditions of the primary disease,treatment-related toxicity,leukemia-free survival(LFS),overall survival(OS),graft-versus-nost disease(GVHD)and relapse-free survival(GRFS),non-relapse mortality(NRM),relapse rate(RR),GVHD and so on were compared between the two groups.Results:The median patient age in the VP-16 group were 25.5 years old(range:13-54),while that in control group were 31 years old(range:12-54),P = 0.707.Acute T cell lymphoblastic leukemia(T-ALL)accounted for 25%in VP-16 group and 21%in control group,p=0.749.The VP-16 group contained five(25%)Ph-chromosome positive cases and control group contained thirteen(39%)Ph-chromosome positive cases,P = 0.283.In general,most patients(84.9%)achieved complete remission(CR)when they received allo-HSCT.The VP-16 group contained fifteen CR cases and five refractory and/or relapse(R/R)cases,while control group contained thirty-two CR cases and only one refractory case.When undergoing allogeneic hematopoietic stem cell transplantation,six(30%)patients in VP-16 group were MRD(minimal residual disease)positive,seven(21%)patients in control group were MRD positive,P =0.471.Except remission status at HSCT,two groups did not differ with respect to other characteristics.The most common RRTs were gut and mucosa toxicities,mucosa toxicities mainly manifested in oral mucosa.The VP-16-combined conditioning regimens enhanced the intensity of pretreatment,and the incidence of mucosa toxicities were higher than that of control group(?-?:50%vs.36%,?-?:25%vs.9%,P = 0.072)with no significant difference.The combination of VP-16 exerted similar gut toxicity compared with control(grade ?-?:25%vs.39%,grade?-?:5%vs.3%,p=0.543).The VP-16 group included more R/R(refractory and/or relapse)patients but was associated with higher 5-year-LFS(70.7%vs.52.1%,p=0.464)and 5-year-OS(68%vs.49.5%,p=0.825),although there was no statistical difference.Moreover,the additional of VP-16 lead to reduced incidence of sever aGVHD(?-?)(10%vs.21%,p=0.499)and cGVHD(5%vs 18.2%,p=0.144),resulting in improved GRFS(63.6%vs.44.3%p=0.268).RR was similar between the two group(29.3%vs.32.4%,p=0.915).Meanwhile,the addition of VP-16 enhanced the intensity of conditioning regimen,its NRM was relatively lower than control group(0%vs.20.2%,P=0.371).Multivariate analysis showed that no significant effect of the VP-16 added conditioning regimens was observed on any of the end-points.Among other risk factors,gender and MRD status at allo-HSCT were significantly associated with LFS(p=0.044,0.002;HR:0.278,4.729)and GRFS(p=0.01,0.000;HR:0.23,6.319)in multivariate study.MRD status at HSCT was an independent risk factor for cumulative incidence of RR(p=0.001,HR:6.147).HLA mismatch and disease status at allo-HSCT were significantly associated with aGVHD(p=0.009,HR;0.237;p=0.001,HR:2.331).Conclusion:The intensified conditioning regimen with medium-dose VP-16 did not increase RRT and NRM,leading to lower incidence of sever(?-?)aGVHD and cGVHD,with tendency to increase OS and LFS,and might become an effective pre-treatment scheme in allo-HSCT for ALL.