Research On Efficacy And Safety Of Autologous Hematopoietic Stem Cell Transplantation And PEG-ASP-based Chemotherapy In Lymphoma

Lymphoma is a category of heterogeneous lymphoproliferative malignant tumors.Since the pathological subtypes are complex,standard treatment has not been established for some subtypes.Autologous hematopoietic stem cell transplantation(AHSCT)is an important therapy for lymphoma patients which can help recovery and reconstitute hematopoietic function in bone marrow after high dose treatment.Polyethylene glycol conjugated asparaginase(pegASP)is one of the effective drugs for leukemia and lymphoma patients.However,safety and efficacy data on pegASP in adult lymphoma patients are limited.This study is aimed to analyze the efficacy and safety of AHSCT and pegASP-based chemotherapy regimens in lymphoma patients.The main contents are divided into two parts.Part 1.Research on efficacy and prognosis of AHSCT in lymphomaChapter 1.Association of conditioning regimens and infused CD34+ dose with hematopoietic recovery and prognosis of lymphoma patients after AHSCTObjective:This study is aimed to investigate the correlation of different conditioning regimens and infused CD34+ cells dose with hematopoietic recovery and prognosis after AHSCT in lymphoma patients.Methods:The study retrospectively analyzed data from 161 lymphoma patients who underwent AHSCT from September 1996 to September 2013 in a single institution.Results:Patients were divided into CBV group,BEAM group and BEAC group according to conditioning regimens.In 129 non-Hodgkin's lymphoma patients,no differences were observed in the time to WBC recovery(WBC>1.0×109/L)and PLT recovery(PLT>50×109/L)after transplantation,while CBV group needed less PLT transfusion(median 2 units,range 0?6 units)(p=0.007)and BEAM group had more frequent grade 2 or higher mucositis,diarrhea and fever.At a median follow-up of 42.5 months(range 0.7?216.1),the 3-year OS rate for the CBV,BEAM and BEAC groups was 64.6%,74.8%and 80.8%,respectively(p=0.584)with 3-year PFS rate of 46.7%,64.8%and 65.4%(p=0.403).In 55 relapsed/refractory NHL patients,the 3-year OS rate for the CBV,BEAM and BEAC groups was 62.5%?65.0%and 95.8%,respectively(p=0.054)with 3-year PFS rate of 16.7%?54.5%and 69.8%,respectively(p=0.025).In 32 Hodgkin's lymphoma patients,no statistic differences were found in aspects of time to hematopoietic recovery,transfusion needs,side effects and outcomes.When patients were divided into CD34low-4 group(infused CD34+ cells<4×106/kg)and CD34high-4 group(infused CD34+ cells>4×106/kg),the time to WBC recovery was 10 days(range 9-14days)and 10 days(range 7-14 days)(p=0.003)and the time to PLT recovery was 13 days(range 6?38 days)and 12 days(range 7-29 days)(p=0.006),respectively.The 3-year OS rate was 81.5%and 79.0%(p=0.658)with 3-year PFS rate was 61.4%and 66.0%(p=0.557),respectively in CD34low-4 group and CD34high4 group?Conclusion:There was no differences between CBV,BEAM and BEAC conditioning regimens in time to hematopoietic recovery and long-time survival for HL and initially treated NHL patients.For relapsed/refractory NHL patients,BEAC regimen results in superior outcome while CBV regimen showed inferior one.Low infused CD34+ dose(CD34+ cells<4×106/kg)was associated with longer hematopoietic recovery time and more transfusion needs,but not with prognosis.Chapter 2.Prognostic value of hemoglobin and lymphocyte/monocyte ratio in mature T/NK cell lymphoma treated with AHSCTObjective:This study was designed to explore the correlation of pre-transplant hemoglobin(Hb)and lymphocyte/monocyte ratio(LMR)in peripheral blood with prognosis of mature T/NK cell lymphoma after AHSCT.Methods:The study retrospectively analyzed data from 59 mature T/NK cell lymphoma patients who underwent AHSCT from December 1995 to October 2015 in a single institution.Results:The median follow-up was 43.9 months(range 0.8-218.6).In 38 initially treated and 21 relapsed/refractory patients,the 3-year PFS was 69.4%and 39.4%(p=0.020)and the 3-year OS was 80.1%and 48.7%(p=0.045),respectively.In initially treated ALCL,PTCL-NOS and ENKTL subgroups,the 2-year PFS was 85.7%,71.1%and 50.0%(p=0.750),respectively.The 2-year OS was 92.3%,77.0%and 50.0%(p=0.154),respectively.Patients with pre-transplant Hb<120 g/L displayed inferior 3-year PFS(49.3%vs.78.7%,p=0.028)and 3-year OS(60.0%vs.88.7%,p=0.030)compared with those without anemia.LMR<1.98 is an independent risk factor of PFS(HR 3.465,95%Cl:1.026-11.703,p=0.045)and OS(HR 6.423,95%Cl:2.466-16.728,p<0.001)on multivariate analysis.We divided patients into 3 groups based on the two risk factors(Hb<120 g/L and LMR<1.98).The 3-year OS was 100.0%,68.9%and 38.9%(p=0.001),respectively,in low-risk group(without risk factor),intermediate-risk group(with 1 risk factor)and high-risk group(with 2 risk factors).Conclusion:Pre-transplant Hb and LMR in peripheral blood are associated with long-term survival in mature T/NK cell lymphoma after AHSCT.LMR<1.98 is an independent risk factor.Those two factors(Hb<120 g/L and LMR<1.98)could be included to establish a prognostic model for T/NK cell lymphoma patients who received AHSCT,which would provide new idea for further large-sample studies in the future.Chapter 3.AHSCT in lymphoblastic lymphoma:efficacy and prognosisObjective:This study aimed to investigate the value of hematopoietic stem cell transplantation(HSCT)in lymphoblastic lymphoma(LBL).It also compared the efficacy of Hyper-CVAD regimen with or without AHSCT in LBL.Methods:This study retrospectively analyzed data from 41 LBL patients who underwent HSCT from December 1989 to December 2009 and 26 patients who were initially treated with Hyper-CVAD regimen from November 2004 to November 2010 in a single institution.Results:The median follow-up was 97.1 months(range 24.6-173.1).For 36 previously untreated patients,the 5-year overall survival(OS)rate and progression-free survival(PFS)rate was 64%and 47%,respectively.And for 5 relapsed/refractory patients,the 5-year OS rate and PFS rate were both 20%.Bone marrow(BM)infiltration and patients receiving less than 4 cycles of chemotherapy prior to HSCT were identified as significantly independent prognostic factors for PFS.In 26 patients who initially treated with Hyper-CVAD regimen,complete remission(CR)rate was 61.5%.The median follow-up was 29.5 months(range 3.0-108.0).Patients without BM infiltration(n=22)were divided into Hyper-CVAD group and Hyper-CVAD combined with AHSCT group.The 2-year OS rate was 60.0%and 80.8%(p=0.438),respectively.The 2-year PFS rate was 43.6%and 62.3%(p=0.209),respectively.Conclusion:HSCT is an effective treatment choice for chemotherapy-sensitive LBL patients.Hyper-CVAD could be considered as an effective first-line chemotherapy regimen for LBL.For LBL patients without BM infiltration,Hyper-CVAD regimen combined with AHSCT showed a trend toward superior outcome.Part 2.Research on pegASP-based chemotherapy and related gene polymorphism in lymphoma Objective:This study was aimed to evaluate the efficacy and safety of pegASP-based chemotherapy in lymphoma.It was also designed to explore the correlation of side effects with known single nucleotide polymorphism(SNP)(rs3757676)in promoter region of asparagine synthetase(ASNS)gene.Methods:The study collected blood cell samples and clinical data of T/NK cell lymphoma patients from January 2011 to June 2016 in a single institution including 105 blood cell samples for gene detection,82 patients' data who received chemotherapy for clinical analysis,and 77 patients' data whose results of gene detection and information of pegASP-associated toxicities were both available for correlation study.Results:Eighty-two T/NK cell lymphoma patients received pegASP-based chemotherapy and achieved a CR rate of 56.1%and an ORR rate of 84.1%.At a median follow-up of 12.3 months(range 0.6-50.6),3-year PFS rate and OS rate were 54.5%and 66.9%in 21 LBL patients and were 49.6%and 72.3%in 56 ENKTL patients.IPI score?3(p=0.017),ECOG PS score ?2(p=0.002)and application of pegASP<2 times(p=0.023)were independently risk factors for OS.Neutropenia(89.0%),anemia(81.7%),nausea(80.5%),hypoproteinemia(79.3%)and ALT/AST elevation(63.4%)were the most common side effects.In patients with BMI<18.5 the morbidities of neutropenia(100.0%vs.55.7%,p=0.037),transaminase elevation(100.0%vs.60.0%,p=0.044)and INR elevation(42.9%vs.8.6%,p=0.031)were higher than those in other patients.The morbidity of neutropenia in patients of C/C wild genotype on rs3757676 locus of ASNS gene was 73.7%,which was higher than that in patients of C/T mutant genotype(92.7%,p=0.095)and T/T mutant genotype(100.0%,p=0.047).The morbidity of hypertriglyceridemia in patients of C/C genotype was 10.5%,which was higher than that in patients of C/T genotype(36.6%,p=0.037)and T/T mutant genotype(58.8%,p=0.002).Conclusion:For T-LBL and mature T/NK cell lymphoma patients,pegASP-based chemotherapy regimens have good efficacy and tolerability.Nausea,hypoproteinemia and transaminase elevation are the most common non-hematological toxicities.SNP(rs3757676)in promoter region of ASNS gene is associated with neutropenia and hypertriglyceridemia after pegASP-base chemotherapy.