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Objective:To investigate the clinical characteristics and efficacy of children with acute lymphoblastic leukemia (ALL) and TP53 mutation, and to explore the relationship between TP53 mutation and the prognosis of children with ALL.Methods:The clinical data of 141 children with newly diagnosed ALL from November 2016 to December 2019 in Fujian Medical University Union Hospital were collected, and the whole-exome gene assay was performed in bone marrow samples of the children by using next-generation sequencing technology. The clinical characteristics of children with TP53 mutation were retrospectively analyzed, and the Kaplan-Meier method was used to compare the overall survival (OS) and event-free survival (EFS) of children with or without TP53 mutation.Results:Among the 141 children with newly diagnosed ALL, TP53 mutations were detected in 5 children (3.5%), all of which were B-precursor acute lymphoblastic leukemia (B-ALL). No TP53 mutation was detected in T-cell acute lymphoblastic leukemia (T-ALL) children, and TP53 mutation accounted for 4.0% (5/126) of B-ALL children. The types of TP53 mutation were all single nucleotide variants. Five ALL children with TP53 mutation were male, with a median age of 60 months (16- 156 months). At the time of onset, all children had anemia and elevated lactate dehydrogenase, and 4 children had subcutaneous hemorrhage and hyperuricemia. The immunophenotypes of all children were precursor B-cell type, and 4 children had myeloid antigen expression. Among 4 ALL children with TP53 mutation who received standard treatment, 2 cases relapsed, and the recurrence time was 8.9 months and 12.1 months, respectively. The expected 15-month EFS rate and OS rate of ALL children with TP53 mutation were lower than those of ALL children without TP53 mutation (37.5% vs. 97.7%, χ2 = 29.90, P < 0.001; 37.5% vs.98.3%, χ2 = 24.90, P < 0.001). Conclusions:ALL children with TP53 mutation are more commonly found in male and B-cell type, with high early recurrence rate and poor efficacy. TP53 mutation may become a necessary supplement for prognostic assessment.
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Objective:To explore the characteristics of BCR-ABL1 kinase domain mutations in imatinib-resistant chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) patients from Northeast China and their impact on prognosis. Methods:The clinical data of 252 CML patients and 49 Ph + ALL patients who were admitted to the First Hospital of Jilin University from January 2013 to October 2018 were retrospectively analyzed. The samples of bone marrow or peripheral blood were collected from patients when imatinib treatment was not effective. Nested polymerase chain reaction (PCR) was used to amplify the BCR-ABL1 kinase domain, and Sequencing Analysis v5.4 software was used to analyze the mutation of BCR-ABL1 kinase domain. Patients were followed up for 6-48 months, and the survival analysis was performed. Results:Among 252 CML patients, the mutations in ABL1 kinase domain were found in 57 patients (22.6%), including 25 patients in the chronic phase, 21 patients in the accelerated phase and 11 patients in the blast crisis; 50 patients had 20 types of single point mutation, and the most common mutation types were E255K (16.0%, 8/50), T315I (14.0%, 7/50), M244V (8.0%, 4/50) and G250E (8.0%, 4/50), which were all concentrated in the P-loop and C-helix domains; 7 patients had double mutations; patients with multiple mutations had the worst prognosis, with a median overall survival (OS) time of 3.2 months. Among 49 Ph + ALL patients, 17 cases (34.7%) were positive for mutations in the BCR-ABL1 kinase domain, 14 patients had 12 types of single point mutation, and 3 patients had multiple mutations; the median OS time of patients with multiple mutations, mutations located in the P-loop and C-helix domains and mutations located in the other domains was 2.0, 8.0 and 18.0 months, and the difference in OS among the three groups was statistically significant ( P < 0.01). Conclusions:Among the imatinib-resistant CML and Ph + ALL patients from Northeast China, point mutations in the P-loop and C-helix domains are most commonly found. Multiple mutations, mutations in the P-loop and C-helix domains are related to the poor prognosis of the patients.
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Objective: This study analyzed the correlation between genetic mutation and prognostic significance in childhood acute lymphoblastic leukemia (ALL) . Methods: Targeted exome by next-generation sequencing (NGS) technology was used to carry out molecular profiling of untreated 141 children with ALL in Fujian Medical University Union Hospital from November 2016 to December 2019. Correlation of genetic features and clinical features and outcomes was analyzed. Results: Among the 141 pediatric patients with ALL, 160 somatic mutations were detected in 83 patients (58.9% ) , including 37 grade Ⅰ mutations and 123 grade Ⅱ mutations. Single nucleotide variation was the most common type of mutation. KRAS was the most common mutant gene (12.5% ) , followed by NOTCH1 (11.9% ) , and NRAS (10.6% ) . RAS pathway (KRAS, FLT3, PTPN11) , PAX5 and TP53 mutations were only detected, and NRAS mutations was mainly found in B-ALL while FBXW7 and PTEN mutations were only found, and NOTCH1 mutation was mainly detected in T-ALL. The average number of mutations detected in each child with T-ALL was significantly higher than in children with B-ALL (4.16±1.33 vs 2.04±0.92, P=0.004) . The children were divided into mutation and non-mutation groups according to the presence or absence of genetic variation. There were no statistically significant differences in sex, age, newly diagnosed white blood cell count, minimal or measurable residual disease monitoring results, expected 3-year event-free survival (EFS) and overall survival (OS) between the two groups (P>0.05) . On the other hand, the proportion of T-ALL and fusion gene negative children in the mutant group was significantly higher than the non-mutation group (P=0.021 and 0.000, respectively) . Among the patients without fusion gene, the EFS of children with grade I mutation was significantly lower than children without grade I mutation (85.5% vs 100.0% , P=0.039) . Among children with B-ALL, the EFS of those with TP53 mutation was significantly lower than those without TP53 mutation (37.5% vs 91.2% , P<0.001) . Conclusion: Genetic variation is more common in childhood ALL and has a certain correlation with clinical phenotype and prognosis. Therefore, targeted exome by NGS can be used as an important supplement to the traditional morphology, immunology, cytogenetics, and molecular biology classification.
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Child , Humans , High-Throughput Nucleotide Sequencing , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Prognosis , TechnologyABSTRACT
Objective@#To compare the difference of efficacy between traditional Hyper-CVAD/MA regimen and the adolescents inspired chemotherapy regimen, CH ALL-01, in treatment of adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) .@*Methods@#In this study we retrospectively analyzed 158 Ph+ ALL patients receiving Hyper-CVAD/MA regimen (n=63) or CHALL-01 regimen (n=95) in our center and Changzheng hospital from January 2007 to December 2017, excluding patients with chronic myeloid leukemia in blast crisis. Tyrosine kinase inhibitor (TKI) was administered during induction and consolidation chemotherapy. Patients who underwent hematopoietic stem cell transplantation received TKI as maintenance therapy.@*Results@#Of them, 91.1% (144/158) patients achieved complete remission (CR) after 1-2 courses of induction. CR rate was 90.5% (57/63) for patients in Hyper-CVAD/MA group and 91.6% (87/95) for patients in CHALL-01 group. There was no difference in CR rates between the two groups (χ2=0.057, P=0.811) . The last follow-up was June 2018. A cohort of 134 CR patients could be used for further analysis, among them, 53 patients received Hyper-CVAD/MA regimen and other 81 patients received CHALL-01 regimen. The molecular remission rates were significantly higher in CHALL-01 group (complete molecular response: 44.4%vs 22.6%; major molecular response: 9.9% vs 18.9%) (χ2=7.216, P=0.027) . For the patients in Hyper-CVAD/MA group, the 4-year overall survival (OS) was 44.81% (95%CI: 30.80%-57.86%) and the 4-year disease free survival (DFS) was 37.95% (95%CI: 24.87%-50.93%) . For patients received CHALL-01 regimen, the 4-year OS was 55.63% (95%CI: 39.07%-69.36%) (P=0.037) and 4 year DFS was 49.06% (95%CI: 34.24%-62.29%) (P=0.015) , while there was no significant difference in 4 year cumulative incidence of relapse (CIR) (P=0.328) or cumulative incidence of nonrelapse mortality (CI-NRM) (P=0.138) . The rate of pulmonary infection was lower in patients received CHALL-01 regimen compared with patients received Hyper-CVAD regimen (43.4% vs 67.9%, χ2=7.908, P=0.005) .@*Conclusions@#Outcome with CHALL-01 regimen appeared better than that with the Hyper-CVAD/MA regimen in Ph+ ALL, which has lower incidence of pulmonary infection, higher molecular remission rate and better OS and DFS.
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Objective@#To explore the clinical efficacy and prognostic factors of first-generation and second-generation tyrosine kinase inhibitors (TKI) based regimen in the treatment of patients with BCR-ABL positive acute lymphoblastic leukemia (ALL) .@*Methods@#Retrospectively analyze the clinical characteristics and prognostic factors of 89 patients with BCR-ABL positive ALL from April 2012 to June 2018 in our hospital, the clinical efficacy of first-generation and second-generation TKI was compared.@*Results@#60 patients were classified into the first-generation TKI (imatinib) group, and 29 patients were in the second-generation TKI (dasatinib) group. There were no significant differences in gender, age, WBC, hemoglobin concentration, PLT, chromosomal karyotype, the types of fusion genes, allogeneic hematopoietic stem cell transplantation (allo-HSCT) and TKI initiation time between the two groups. The first-generation and second-generation TKI groups, for which the complete remission (CR) rate at the fourth week of induction therapy was 83.3% and 89.7% (P=0.637) , respectively, and the complete molecular remission (CMR) was 48.3%and 58.6% (P=0.363) , respectively, the difference was not statistically significant. The 2-year overall survival (OS) rate of first-generation and second-generation TKI group was 34.9% and 64.0% (χ2=4.743, P=0.029) , the 2-year relapse free survival (RFS) rate was 17.2% and 55.0% (χ2=8.801, P=0.003) , respectively. Multivariate analysis showed that complete molecular remission (HR=0.281, 95%CI 0.151-0.523, P<0.001) was independent favorable prognostic factor for overall survival (OS) , complete molecular remission (HR=0.209, 95%CI 0.112-0.390, P<0.001) and second-generation TKI (HR=0.318, 95%CI 0.158-0.641, P=0.001) were independent favorable prognostic factors for RFS.@*Conclusion@#For TKI-based regimen of BCR-ABL positive ALL, second-generation TKI is superior to first-generation TKI in OS and RFS time.
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Acute leukemia is a kind of malignant proliferative disease originating from hematopoietic stem cells, which is characterized with molecular and clinical heterogeneity. Chemotherapy and hematopoietic stem cell transplantation are the major treatments for acute leukemia. In recent years, the development of targeted therapy has significantly improved the prognosis of acute leukemia patients. This article reviews the part of the work of Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences on the research of pathogenesis, diagnosis and treatment of acute leukemia.
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Acute leukemia is a kind of malignant proliferative disease originating from hematopoietic stem cells, which is characterized with molecular and clinical heterogeneity. Chemotherapy and hematopoietic stem cell transplantation are the major treatments for acute leukemia. In recent years, the development of targeted therapy has significantly improved the prognosis of acute leukemia patients. This article reviews the part of the work of Institute of Hematology&Blood Diseases Hospital, Chinese Academy of Medical Sciences on the research of pathogenesis, diagnosis and treatment of acute leukemia.
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Objective To investigate the efficacy of blood purification for acute lymphoblastic leukemia pediatric patients with high-dose methotrexate (MTX)-induced hypermethotrexemia and acute kidney injury (AKI). Methods The clinical data of 50 acute lymphoblastic leukemia pediatric patients with hypermethotrexemia (the 45th hour MTX blood concentration ＞20 μmol/L) and AKI who were admitted to Beijing Children's Hospital Capital Medical University from May 2010 to August 2018 were collected. After the treatment of blood purification, the declining rate of MTX concentration, the incidence of drug-related side effects and the clinical transition were analyzed retrospectively. Results The median MTX blood concentration at the 45th hour after high-dose MTX chemotherapy was 31.5 μmol/L (20.0-80.3 μmol/L). After blood purification treatment, 48 patients (96%) survived, 1 patient (2%) died, and 1 patient (2%) gave up treatment. It costed 10.0 days (7.0-15.0 days) to decline the MTX concentration to the normal level by using blood purification. The median time of purification was 32.5 hours (2.0-168.0 hours), and the days of dialysis were 3.0 days (1.0-9.0 days). The AKI occurred in approximately 96% (48/50) of patients, which was the main side effect. The time of declining the high MTX concentration to the normal was positively correlated with the increase times of serum creatinine (r ＝ 0.371, P＝ 0.009) and urea nitrogen (r ＝ 0.486, P＝ 0.001), and the value of the alanine aminotransferase (r ＝0.364, P＝0.010) and gamma glutamyl transpeptidase (r ＝ 0.344, P＝ 0.010), and the days of dialysis (r ＝ 0.532, P < 0.01), but there was no relationship with the 45th hour MTX blood concentration (r＝0.110, P＝0.248). The reduction of MTX blood concentration from the 45th hour to the 69th hour after high-dose MTX chemotherapy was negatively correlated with the increase times of urea nitrogen (r ＝ -0.336, P＝ 0.009) and serum creatinine (r ＝ -0.260, P＝ 0.035). Conclusion When the MTX blood concentration of patients with hypermethotrexemia and AKI couldn't be declined to the normal level by using high-dose leucovorin, hydration and alkalization, and without the effective detoxification drug (carboxypeptidase G2), they should be offered blood purification, especially continuous renal replacement therapy as soon as possible, which can reduce the blood concentration of MTX quickly and decrease the incidence of side effects effectively.
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Objective To explore the role of E2A﹣HLF fusion gene in the prognosis evaluation of B﹣cell acute lymphoblastic leukemia (B﹣ALL), and to improve the accuracy of stratified treatment. Methods The clinical characteristics, treatment effect and survival time of two B﹣ALL patients with E2A﹣HLF fusion gene who were admitted to the Second Hospital of Shanxi Medical University were retrospectively analyzed, and the related literature was reviewed. Results The first patient was an 8 years old girl, developed with fever, abdominal pain, and slightly increased white blood cells (WBC), and also accompanied by hypercalcemia. Another patient was a 27 years old man, developed with jaw pain and anemia, WBC was normal. Precursor B﹣ALL (pre﹣B﹣ALL) was identified by flow cytometry (FCM) in the two cases. E2A﹣HLF fusion gene was screened out at first diagnosis for the girl, but found after relapse for the man. Both patients early received intensive treatment with high﹣dose methotrexate after the first complete remission, but relapsed after 3 and 6 months respectively. The girl did not receive allogeneic hematopoietic stem cell transplantation (allo﹣HSCT) after relapse and died of severe infection. The man received allo﹣HSCT complete remission, and maintained complete remission within 5 months after HSCT, E2A﹣HLF fusion gene was also negative, but eventually died of multiple transplantation﹣related complications. Conclusions E2A﹣HLF fusion gene occurs mostly in the pre﹣B﹣ALL patients with hypercalcemia, and it shows extremely poor prognosis with a high multidrug resistance rate and high early recurrence rate. The allo﹣HSCT can increase the leukemia﹣free survival rate, and the relapse and overall survival may be improved when these patients received allo﹣HSCT in the first complete remission.
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Objective To investigate the association between miR146a(rs2910164)G>C polymorphism and susceptibility to acute lymphoblastic leukemia(ALL)in children.Methods Two hundred blood specimens were ob-tained from children with ALL as patient group and 100 blood specimens were obtained from healthy children as healthy control group,who were all from Baoding First Central Hospital between March 2010 and October 2016.There were no significant differences in sex and age between patient group and healthy control group(χ2=0.430,P=0.512;χ2=2.839,P=0.092).The distribution of gene frequency of patient group and healthy control group conformed to Hardy-Weinberg equilibrium.miR146a(rs2910164)G>C polymorphism was identified by adopting restriction fragment length polymorphism(RFLP).The relation of genotype and ALL was demonstrated by odds ratio(OR)and 95% credibility interval(CI). Results Gene frequency of miR146a(rs2910164)GG,GC and CC genotypes in patient group and healthy control group was 16.0%,44.5%,39.5% and 29.0%,41.0%,30.0%,respectively.The GC/CC genotypes were significantly higher in patient group than those in healthy control group(GG genotype as reference,GC genotype:OR=1.967,95%CI:1.054-3.672,P=0.037;CC genotype:OR=2.386,95%CI:1.239-4.595,P =0.012). Conclusion miR146a(rs2910164)G>C polymorphism is significantly associated with susceptibility to ALL in chil-dren.
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Objective To explore the differences in clinical and laboratory parameters between elderly and non-elderly patients with acute lymphoblastic leukemia (ALL).Poor prognostic factors in elderly patients were explored to guide the individualized treatment.Methods Two hundred and seventy-nine ALL patients were divided into two groups:elderly group with their age more than 60 years (60-79 years) and nonelderly group with their age less than 60 years (14-59 years).The differences in clinical and laboratory parameters,abnormal molecular genetics on related genes,including IKZF1,PAX5,NOTCH1,PHF6,SH2B3,LEF1,and JAK1,as well as the correlations with treatment response and clinical outcome were compared between the two groups.Results Males accounted for a smaller part in elderly group [42.9 ％ (21/49) vs.61.7 ％ (142/230),P =0.015].The percentage of B cell lineage ALL (B-ALL),Philadelphia chromosome positive (Ph+) and CD33 positive rate were higher in elderly group compared with those in non-elderly group [87.8 ％ (43/49) vs.70.4 ％ (162/230),P=0.009;47.8 ％ (22/49) vs.27.4 ％ (58/230),P=0.007;56.8 ％ (21/49) vs.39.0 ％ (64/230),P =0.049,respectively].While both lymphodenopathy and total complete remission (CR) rate gained the upper hand in non-elderly group [38.9 ％ (81/230) vs.20.0 ％ (9/49),P=0.016;91.3 ％ (178/195) vs.68.3 ％ (28/41),P＜ 0.001,respectively].Moreover,elderly group had lower 3-month,6-month,12-month and 24-month overall survival (OS) rates (64.6 ％ vs.84.4 ％,P=0.001;50.0 ％ vs.73.8 ％,P=0.001;29.2 ％ vs.52.4 ％,P=0.003;6.2 ％ vs.26.2 ％,P=0.003,respectively) than those of non-elderly group.No significant differences in mutation rates of PAX5,NOTCH1,PHF6,SH2B3,LEF1 and JAK1 were found (all P ＞ 0.05).Conclusions Compared with non-elderly ALL patients,elderly ones harbor their intrinsic characteristics which might give rise to inferior outcomes.As a consequence,more attention should be poured into treating this particular group of ALL patients to improve their prognosis.
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Objective To study the relationship between the cytogenetic and the prognosis in children with acute lymphoblastic leukemia (ALL).Methods RT-PCR was used to detect the common fusion gene,chromosome number and structure in 103 children with ALL.The effects of chromosome and fusion gene changes on treatment response and survival time were analyzed.Resuts Among 103 children with ALL,52 cases had normal gene number and no fusion gene,and 51 cases had fusion gene,including 22 cases with TEL-AML1 positive,10 cases with bcr-abl positive,11 cases with E2A-PBX1 positive,2 cases with MLL-AF4 positive,3 cases with HOX11 positive,1 case with SIL-TAL1,1 case with dupMLL and 1 case with TLS-ERG.The average survival time of bcr-abl group was shorter than that of non-fusion gene group,TEL-AML1 group and E2A/PBX1 group respectively,and there were significant differences [(16.5±3.8) months vs (34.6±1.7) months,(31.6±1.4) months,(34.5±3.3) months,all P ＜ 0.05],but there was no significant difference between bcr-abl group and other fusion gene group [(12.8±1.5) months,P ＞0.05].The average survival time of non-fusion gene group had no significant differences compared with TEL-AML1 group and E2A-PBX1 group(both P ＞ 0.05),but had significant differences with other fusion gene group (P ＜ 0.05).There were 18 patients with abnormal chromosome number and structure,including 4 cases with diploid,14 cases with super diploid.The patients with diploid had shorter survival time [(19.8±4.8) months vs (37.5 ±2.2) months,x2 =7.375,P =0.007] and were easier to relapse than ones with super diploid.The average survival time of patients with different white blood cell count and lactate dehydrogenase levels had significant differences (both P ＜ 0.05).Conclusion Detection of cytogenetics and chromosome fusion genes can be used to determine the prognosis and outcome of children with ALL,which has important guiding significance for the realization of individualized treatment.
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Whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the optimal treatment for adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph - ALL) after the first complete remission (CR1) or not is still a controversial issue. Many studies have recently reported that adolescents and young adults with Ph- ALL may benefit from pediatric chemotherapy. Conventional baseline risk factors cannot satisfactorily predict prognosis, conversely, the early minimal residual disease (MRD) is the best stratification tool to offer different treatments for patients with different MRD status. Novel therapies, such as CAR-T cells and blinatumomab, have shown promising results in relapsed/refractory patients. Through comprehensive application of pediatric chemotherapy protocols, MRD driven strategy and novel therapies, it is hopeful to change the paradigm of how to treat adults with Ph - ALL in the future, and to bring improved outcomes and decreased adverse events.
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Recent studies showed that copy number variations in certain genes are closely correlated to progression and prognosis of pediatric acute lymphoblastic leukemia. Relevant reports in the 57th American Society of Hematology(ASH) annual meeting in 2015 will be reviewed together with research progress in recent years.
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Objective To explore the feasibility of low-dose chemotherapy (LDCT) combined with tyrosine kinase inhibitor (TKI) (LDCT+TKI regimen) as the first-line induction regimen for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL).Methods The efficacies and adverse effects of various induction regimens in 61 newly diagnosed patients with Ph+ ALL were retrospectively analyzed.Results The complete remission (CR) rate of the first induction therapy was 73.8 ％ (45/61) for all 61 cases,and that of the second induction therapy was 86.7 ％ (13/15) for non-remission (NR) patients after the first induction.The total CR rate for two-course induction was 95.1％ (58/61).Treatment related mortality happened in one case (1.6 ％) after the first induction therapy.The response rates between conventional-dose chemotherapy (CDCT)±TKI group and LDCT±TKI group were not statistically different [without TKI,65.5 ％ (19/29) vs 60.0 ％(3/5),P =0.812;with TKI,90.5 ％ (19/21) vs 100.0 ％ (6/6),P =0.432].The response rate of LDCT+TKI group was not statistically different from that of CDCT alone group (P =0.089).The introduction of TKI to LDCT and CDCT could improve the response rate (CDCT+TKI group,P =0.041;LDCT+TKI group,P =0.087).The total response rate of the induction therapy with TKI was significantly higher than that without TKI [92.6 ％ (25/27) vs 64.7 ％ (22/34),P =0.01].The response rate of the TKI-based second induction therapy for non-CR cases after the first induction therapy without TKI was significantly higher than that after the first induction therapy with TKI [100.0 ％ (8/8) vs 33.3 ％ (1/3),P =0.011].There were no significant differences in the efficacies of the first induction therapy between various genetic subgroups (all P ＞ 0.05),and the introduction of TKI to the treatment of various genetic subgroups could improve the efficacies to a certain extent without statistical significance (all P ＞ 0.05).The incidences of treatment related infections and bleeding due to the first induction therapy in all patients were 50.8 ％ (31/61) and 4.9 ％ (3/61),respectively.Compared with LDCT±TKI group,the overall incidences of treatment related infections and bleeding in CDCT±TKI group were higher,but there were no statistical significances [infection,56.0 ％ (28/50) vs 27.3 ％ (3/11),P =0.084;bleeding,6.0 ％ (5/30) vs 0 (0/1 1),P =0.405].The incidence of treatment related infections in LDCT+TKI group was significantly lower than that in CDCT+TKI group [0 (0/6) vs 71.4 ％ (15/21),P =0.002] or that in CDCT alone group [0 (0/6) vs 44.8 ％ (13/29),P =0.039].The incidence of bleeding in LDCT+TKI group was not statistically different from that in CDCT+TKI group or that in CDCT alone group (all P ＞ 0.05).Conclusion LDCT+TKI regimen as the first-line induction regimen in Ph+-ALL is deserved to be investigated further.
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Objective To observe the clinical response and safety of second-generation tyrosine kinase inhibitor dasatinib in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). Methods The clinical data of 10 adult Ph + ALL patients treated with dasatinib were analyzed with review of literatures. Results All the 10 Ph+ ALL patients treated with dasatinib achieved remission in 7 weeks, including 9 cases of complete remission [7 cases achieved complete molecular remission (CRm) in 13 weeks]. The median overall survival time (OS) was 13.8 months (5-33), and the median disease-free survival (DFS) time was 10.8 months (4-25). There were 3 cases of pleural effusion, 4 cases of Ⅳ degree of bone marrow suppression and 6 cases of extremely low blood platelet, which could be that was improved via by symptomatic treatment and, with no case of the death occurred during the treatment of dasatinib, the safety was high. Conclusion Dasatinib can deepen molecular biological reaction and prolonged the survival time of patients in the treatment of adult Ph+ ALL, with high remission rate and safety, and which can be considered as first-line treatment.
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Objective To improve the cognition of sever liver injury of treating Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) with salvage chemotherapy of dasatinib combined with high-dose methotrexate (HD-MTX) and L-asparaginase (L-Asp).Methods Severe drug-induced liver injury caused by dasatinib with HD-MTX and L-Asp in one patient with Ph+ ALL was reported.Results Severe drug-induced liver injury happened on the seventh day after treatment,TBIL 221.7 μmol/L,DBIL 156.1 μmol/L,IBIL 65.6 μmol/L,ALT 111 U/L,AST 131 U/L,ALP 354 U/L,GGT 256 U/L,TBA 199.2 μmol/L.Through proper treatment,the patient recovered quite good,and the patient achieved complete remission after this chemotherapy.Conclusion Salvage chemotherapy which contains dasatinib,MTX and L-Asp can be effectively used in Ph+ ALL,but they are all of the hepatotoxicity,so drug-induced Liver injury may happen while they are used together.
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Objective To analyze the outcomes and the prognostic factors of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for acute lymphoblastic leukemia (ALL).Method From Feb.2002 to Feb.2014,a total of 95 patients with ALL were treated with alloPBSCT in our hospital.Of these,73 cases obtained the first CR (CR1),11 cases obtained late CR,7 patients were in relapse and 3 patients suffered from primarily refractory disease (PRD) before transplant.The median age was 26 (4-57) years.Conditioning regimens including total body irradiation (TBI)/ etoposide/semustine/cyclophosphamide or busulfan/semustine/cyclophosphamide were used.Matched sibling transplantation was performed on 68 patients,and matched unrelated donor transplantation was performed on 27 patients.Combination of CsA,MTX and low-dose,short-course mycophenolate mofetil was used for graft-versus-host disease (GVHD) prophylaxis.The average fellow-up was 57 months.Result Hematopoietic reconstitution was achieved in all 95 patients.Five-year estimate of overall survival (OS) was 54.3％,disease free survival (DFS) was 51.2％,relapse rate (RR) was 30.2％ and transplant-related mortality (TRM) was 24.0％.The 5 year OS and DFS were significantly longer in patients with CR1 than in late CR and relapse/PRD patients before allo-PBSCT (P＜0.001).There was no significant difference in OS between the two different conditioning regimens.Multivariate analyses revealed that Ⅱ-Ⅳ aGVHD and cGVHD were correlated with higher TRM,CR1 before allo-PBSCT and TBI were associated with a lower RR,and non Ⅱ-Ⅳ aGVHD and CR1 before allo-PBSCT were favorable factors which were associated with OS and DFS.In the patients with DFS≥1 year after allo-PBSCT,DFS and OS were shorter in patients with cGVHD (P =0.008).Conclusion Allo-PBSCT in adult ALL patients should be performed in CR1.Severe acute and chronic GVHD are not associated with improved survival.
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Objective To explore the relationship between T-cell acute lymphoblastic leukemia and the Notch signaling pathway.Methods Human T-cell acute lymphoblastic leukemia SupT1 cells were infected with the lentiviral vector made up specific Notch1-shRNA gene and nonspecific Notch1-shRNA gene.The inhibitive rate of SupT1 cells was detected by CCK-8.The rates of early apoptotic cells (Annexin V+/ 7-AAD-) and late apoptotic cells (Annexin V+/7-AAD+) were analyzed by flow cytometry and the expression levels of Notch1 receptor gene and downstream target genes were assessed by quantitative reverse transcription and polymerase chain reaction (QT-PCR).Results The cell inhibition rates of Notch1 interference group,control group and empty vector group at 96 h were 0.902±0.013,0,and 0.486±0.084,respectively,and it was increased obviously in Notch1 interference group (both P ＜ 0.05).The cell early apoptosis rates of the three groups were (15.27±0.31) ％,(5.57±0.25) ％,(5.80±0.20) ％,respectively.The cell early apoptosis rate of Notch1 interference group was increased obviously compared with the control group and empty vector group (both P ＜ 0.05).While the cell late apoptosis rates had no significant difference among the three groups (P ＞ 0.05).The mRNA expression levels of Notch1 receptor gene and its target genes (Hesl,c-myc,NF-κB) at 48 h,72 h and 96 h were higher than those in the control group and empty vector group (all P ＜ 0.05).Conclusions The specificity of Notch1-shRNA can effectively decrease the Notch1 mRNA expression,and reduce the expression level of downstream target genes.Notch1 cut can inhibit the proliferation of SupT1 cells,and promote the early apoptosis.
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Objective To investigate the detection methods of atypical bcr-abl rearrangement with b3a3 fusion transcript,and to describe the characteristics of this fusion gene.Methods Karyotype analysis,FISH and RT-PCR were applied to detect the break point of bcr-abl fusion gene in a patient who was diagnosed as acute lymphoblastic leukemia.Results The karyotype of the patient was expressed as 45,XY,-7,t(9;22)(q34;q1 1).The translocation event in chromosome 9 and 22 could be successfully detected by FISH,and a rare bcr-abl rearrangement with b3a3 fusion transcript was detected by RT-PCR with specific primers.Conclusions The rare e14a3 (b3a3) fusion of bcr-abl gene is present in this patient.Clinical laboratories using commercial kits that do not cover such rare fusions are likely to generate false result,thereby declaring combination of various methods to detect fusion genes is necessary.More studies are needed to explore the function and significance of rare bcr-abl fusion genes.