Clinical And Biological Study On Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Objectives1.To investigate the clinical and biological characteristics,and factors affecting the prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia(Ph~+ALL).2.To investigate the efficacy of first-line administration of second-generation tyrosine kinase inhibitors(TKI)and first-generation TKI(imatinib)in patients with Ph~+ALL treated by allogeneic hematopoietic stem cell transplantation(allo-HSCT).3.To investigate the efficacy of administration of generic dasatinib and imatinib in newly diagnosed patients with Ph~+ALL treated by hematopoietic stem cell transplantation(HSCT).4.To explore the curative effect of CD19-targeted chimeric antigen receptor T(CAR-T)cell therapy on refractory/relapsed Ph~+ALL with T315 I mutation.Methods1.A database review was undertaken of the newly diagnostic characteristics of 108 Ph~+ALL patients treated by hematopoietic stem cell transplantation in our center from June 2011 to June 2017.Effects of major molecular response(MMR;BCR-ABL/ABL reduce 3log)on recurrence and prognosis were evaluated.2.Retrospective analysis of clinical features,and prognosis of 76 newly diagnosed Ph~+ALL patients from June 2011 to December 2015 treated by allo-HSCT combined with first-line administration of second-generation or first-generation TKI were performed with the efficacy compared.3.Retrospective analysis of clinical features and prognosis of 63 newly diagnosed Ph~+ALL patients from Jan 2014 to June 2017 treated by HSCT combined with first-line administration of generic dasatinib or imatinib were performed with the efficacy compared.4.We report on 7 relapsed Ph~+ALL patients with T315 I mutation.These patients were treated pre or post allogeneic hematopoietic stem cell transplantation(allo-HSCT)with T cells expressing chimeric antigen receptor specific to the CD19 antigen with or without ponatinib.Results1.The clinical and biological characteristics of Ph~+ALL included: The clinical and biological features of 108 patients with Ph~+ALL were 62 males and 46 females,with a median age of 31(14-61)years,a median white blood cell count of 46(1-650)× 109/L,a median hemoglobin The level of 97.5(40-174)g / L,the median platelet count 36(2-349)× 109/L.Cytogenetic analysis showed that there were 15 cases(13.9%)of normal karyotypes,33 cases(30.6%)of t(9;22)cases and 36 cases(33.3%)with additional chromosomal abnormalities.The median time from initial diagnosis to transplant were 4(2-14)months.There were 29 cases(26.9%)with HLA-matched sibling donors,55 cases(50.9%)with haploid donors,20 cases(18.5%)with unrelated donors and 4 cases(3.7%)with autograft.BU/CY Conditioning regimen was administered in 102 cases(94.4%),and TBI/CY program in 6 cases(5.6%).Pre-transplant efficacy analysis: Among 108 patients,CR were obtained in 102 cases(94.4%)4 weeks after induction therapy;BCR-ABL copies were detected in 101 cases 4 weeks after induction therapy,and the MMR rate at 4 weeks was 44.6%(45/101).Pre-transplant recurrence were detected in 12 patients(11.1%)and ABL kinase mutation detected in 10(9.3%)patients before transplantation.T315 I mutation were detected in 8 cases,4 cases of E255 K mutation and 1 case of V229 A,I314N and Q252 H,respectively.The MMR rate before transplantation was 63.9%(69 cases).Relapse and Survival: median following time of all patients were 23.5(4-70)months.The 2-year OS and EFS rates were 72.5% and 60.1%,respectively.The 2-year OS rates were 77.7% and 33.3%,respectively(P = 0.014).The 2-year OS rates in patients without ABL mutations and those with ABL kinase mutations before transplantation were 76.4% and 30.0%,respectively(P = 0.011).The 2-year OS and EFS rates of patients with MMR or without MMR recipients before transplantation were 78.8% and 62.2%(P= 0.037),69.9% and 42.3%(P= 0.001),respectively.The remaining clinical and biological characteristics such as age,gender,WBC count,HB,PLT count,additional chromosomal abnormalities,transplantation type,conditioning regimens,time from initial diagnosis to transplantation were not the prognostic factors of OS or EFS.2.Of 76 Ph~+ALL patients,first-generation TKI was administered in 57 cases,second-generation TKI in 19 cases,with 10 cases of nilotinib and 9 cases of dasatinib in the latter group.No significant differences were found in age,WBC counts,extra chromosomal abnormalities,time form diagnosis to transplantation,transplantation type,conditioning regimen or TKI initiation time between the two groups.Complete remission(CR)rates at the fourth week of induction therapy in first-generation TKI group and second-generation TKI group was 93.0% and 94.7%(p=0.851)respectively.Major molecular response(MMR;BCR-ABL/ABL reduce 3log)rates meanwhile were 46.0% and 40.0%(p=0.593).Relapse rates before transplantation were 14.0% and 10.5%(p=0.695).MMR rates before transplantation were 54.4% and 68.2%(p=0.283).There was no significant differences in CR rates,relapse rates or MMR rates before transplantation between the two groups.However,the MMR rates pre-transplantation in the second-generation TKI group seemed higher.EFS time was significantly prolonged in patients with MMR obtained pre-transplantation(p=0.040).The 2-year overall survival(OS)rates of first-generation and second-generation TKI group were 62.0% and 94.7%(p=0.016),2-year event-free survival(EFS)rates were 46.3% and 84.2%(p=0.018)respectively,statistically significant differences of both OS and EFS reached.3.Of 63 Ph~+ALL patients,generic dasatinib was administered in 31 cases,imatinib in 32 cases.Complete remission(CR)rates at the fourth week of induction therapy in generic dasatinib group and imatinib group was 96.8% and 93.8%(p=1.000),respectively.Major molecular response(MMR;BCR-ABL/ABL reduce 3log)rates meanwhile were 41.9% and 43.8%(p=0.884).Relapse rates before transplantation were 6.5% and 12.5%(p=0.672).MMR rates before HSCT were 83.9% and 68.8%(p=0.159).The 20-monthes overall survival(OS)rates of generic dasatinib group and imatinib group were 95.5% and 76.5%(p=0.320),20-monthes event-free survival(EFS)rates were 93.5% and 61.4%(p=0.015),respectively.Statistically significant differences of EFS was reached.Univariate analysis showed that MMR before transplantation could improve OS(p=0.047).Multiple factors analysis showed that generic dasatinib(p=0.035)and MMR before transplantation(p=0.041)could improve EFS.4.6/7 cases were in a morphologic complete remission within 1 month after the first infusion of anti-CD19 CAR-T cells.Minimal residual disease(MRD)by means of multiparametric flow cytometry revealed a rapid decline in 6 patients,positive in 1 patients.BCR/ABL fusion transcripts of bone marrow cells were negative in 4/5 cases,with 2 patients not performed.3 patients maintained sustained remission without evidence of MRD by real-time quantitative polymerase chain reaction(QPCR)until the final follow-up,of which,2 received anti-CD19 CAR-T cells and ponatinib at the same time.Of the 7 cases reported,4 exhibited grade 1 cytokine release syndrome(CRS),1 patient died of CRS.Second infusion of anti-CD19 CAR-T cells when relapsed again after allo-HSCT following first infusion for case7 was invalid.Conclusions1.TKI combined with chemotherapy followed by hematopoietic stem cell transplantation significantly improved the prognosis of patients with Ph~+ALL.And better long-term survival were reached in these patients with MMR obtained before transplantation.2.There was significant difference in the efficacy of second-generation TKI and first-generation TKI for Ph~+ALL patients treated by allo-HSCT.First-line administration of second-generation TKI improved the outcome of Ph~+ALL patients.3.First-line administration of generic dasatinib could improve EFS time for Ph~+ALL patients treated by HSCT in compered with imatinib,and may be a better option for newly diagnosed Ph~+ALL patients.4.Our study confirmed the efficacy of anti-CD19 CAR-T therapy in the treatment of Ph~+ALL with T315 I mutation pre or post allo-HSCT.They also suggest that concurrent use of anti-CD19 CAR-T therapy with ponatinib may be a more valuable choice for T315 I mutation positive Ph~+ALL patients.As CRS was the most commonly even fatal observed toxicity,a systemic prophylaxis and intervention solution against CRS was urgent to be concluded.