A longitudinal study of the peripheral and central auditory pathways in individuals with acute lymphoid leukemia

Abstract Objective To characterize the peripheral and central auditory pathways in individuals with Acute Lymphoid Leukemia (ALL) and compare assessment results before and during chemotherapy. Method The study included 17 subjects with ALL, divided into two age groups: 3 to 6 (11 individuals) and 7 to 16 years old (6 individuals). Each subject was evaluated twice (before and 3 to 6 months after chemotherapy treatment) with the following procedures: medical history survey, otoscopy, Pure-Tone Threshold (PTA) and speech audiometry, acoustic immittance measures, Brainstem Auditory Evoked Potentials (BAEP) and Long-Latency Auditory Evoked Potentials (LLAEP). Results PTA was normal. Tympanometry was abnormal in the second assessment in 2 individuals aged 3 to 6 years. One subject in each age group had absent ipsilateral acoustic reflexes. In high-frequency audiometry, 1 individual had abnormal results. BAEP was abnormal in 5 (first assessment) and 7 individuals (second assessment) aged 3 to 6 years and 2 (first assessment) and 1 individual (second assessment) aged 7 to 16 years. As for LLAEP, P1 latency was increased in 5 (first assessment) and 7 individuals (second assessment) aged 3 to 6 years. Conclusion No hearing loss was identified in the behavioral audiological assessment. BAEP was more affected in the 3-to-6-year-old group, with greater impairment in the lower brainstem in the first and second assessments. In LLAEP, P1 was the most impaired component in children aged 3 to 6 years, and P2 and N2 were so for those 7 to 16 years old, especially in the second assessment.

Status and significance of BCR-ABL1 kinase domain mutations in imatinib-resistant chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia patients from Northeast China / 白血病·淋巴瘤

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.

Mutational spectrum and its prognostic significance in childhood acute lymphoblastic leukemia based on next-generation sequencing technology / 中华血液学杂志

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.

Clinical characteristics and prognosis analysis of children with acute lymphoblastic leukemia and TP53 mutation / 白血病·淋巴瘤

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.

Comparison of clinical efficacy between first-generation and second-generation tyrosine kinase inhibitors based regimen in the treatment of patients with BCR-ABL positive acute lymphoblastic leukemia / 中华血液学杂志

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% (χ(2)=4.743, P=0.029) , the 2-year relapse free survival (RFS) rate was 17.2% and 55.0% (χ(2)=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.

Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old / 中华血液学杂志

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 (χ(2)=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%) (χ(2)=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%, χ(2)=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.

Progress of the diagnosis and treatment of acute leukemia in China: work review of Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences / 白血病·淋巴瘤

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.

Progress of the diagnosis and treatment of acute leukemia in China: work review of Institute of Hematology&Blood Diseases Hospital, Chinese Academy of Medical Sciences / 白血病·淋巴瘤

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.

Comparison of clinical efficacy between first-generation and second-generation tyrosine kinase inhibitors based regimen in the treatment of patients with BCR-ABL positive acute lymphoblastic leukemia / 中华血液学杂志

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.

Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old / 中华血液学杂志

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.

Application of blood purification in acute lymphoblastic leukemia pediatric patients with hypermethotrexemia accompanied with acute kidney injury / 白血病·淋巴瘤

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.

B﹣cell acute lymphoblastic leukemia with E2A﹣HLF fusion gene: report of two cases and review of literature / 白血病·淋巴瘤

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.

Clinical significance of minimal residual disease in patients with Ph-negative precursor B-acute lymphoblastic leukemia / 中华血液学杂志

Objective: To explore the predictive value of minimal residual disease (MRD) level in Ph-negative precursor B-acute lymphoblastic leukemia (ALL) patients. Methods: De novo 193 Ph-negative B-ALL patients from Sep 2010 to Nov 2017 were involved in the study. The patients' MRD evaluation which can be performed by multiparametric flow cytometry (MFC) after 1 month, 3-month, 6-month treatment. Relapse free survival (RFS) and overall survival (OS) were compared in patients with different MRD level. Results: The median follow-up was 22 months. All patients was evaluated at 497 MRD level. Patients who reach the good MRD level at 1 month (<0.1% or ≥0.1%), 3-month (negative or positive), 6-month (negative or positive) had a significantly higher probability of estimated RFS (74.5% vs 29.9%; 75.6% vs 29.7%; 74.6% vs 11.6%) and of estimated OS (67.5% vs 30.3%; 71.6% vs 27.8%; 74.0% vs 15.7%). Patients who reach the MRD negative at all 3 times had a significantly higher probability of estimated RFS (80.5% vs 30.5%) and better estimated OS (77.1% vs 29.4%) compared to patients with at least MRD failure in one time (P<0.001). Multivariable analysis showed MRD level at 3-month was an independent prognostic factor for DFS and OS. Conclusion: MRD is an important prognosis factor for Ph-negative B- ALL patients.

Multicenter clinical trial of acute lymphoblastic leukemia in elder children and adolescents / 中华血液学杂志

Objective: To analyze the clinical characteristics and long-term outcomes with multicenter study for acute lymphoblastic leukemia (ALL) in children over 10 years old and adolescents. Method: Newly diagnosed ALL patients aged from 10 to 18 years old in three hospitals were included in the study from May 1(st) 2005 to April 30(th) 2015. They were received ALL-2005/2009 protocol following up to December 31(st) 2016. The clinical characteristics, outcomes and the prognostic analysis were evaluated between the two protocols. Results: Totally, 237 patients were involved in the study, 76 cases for ALL-2005 and 161 cases for ALL-2009 protocol. Complete remission (CR) after induction therapy was 94.5%. 64 (28.6%) patients relapsed with a median time of 14.5 months and 70 (29.5%) patients passed away during the following time. In long-term follow-up, the 5-year event-free survival (EFS) and 5-year overall survival (OS) of ALL patients were (63.1±3.3)% and (68.4±3.2)%. The 7-year EFS and OS were (61.0±3.5)% and (67.6±3.3)%.The 5-year EFS of intermediate risk group in ALL-2005 and ALL-2009 protocol were (73.6±6.1)% and (71.7±4.3)% with no difference (χ(2)=0.064, P=0.801). The 5-year EFS of high risk group in two protocols were (27.6±9.6)% and (33.9±9.3)%, showing no significant difference (χ(2)=0.296, P=0.586). Five years relapsed rate of two protocols were (33.8±5.7)% and (32.6±4.1)% with no difference (χ(2)=0.055, P=0.815). The mortalities were 36.8% and 29.8% separately (χ(2)=2.869, P=0.090). Univariate analysis indicated that age, male, risk, BCR/ABL translocation/t(9;22) and resistant to induction were risk prognostic factors in long-term survival (χ(2)=4.764, 4.796, 46.410, 9.560, 25.450; P=0.029, 0.029, <0.001, 0.049, <0.001). Cox multivariate analysis showed male, risk and resistant to induction were independent risk prognostic factors (RR=1.790, 2.727, 2.719; P=0.021, 0.000, 0.012). Conclusion: Protocol ALL-2009 enhanced the chemotherapy intensity in intermediate risk group with no benefit of survival. BCR-ABL fusion or t(9;22) translocation was still the risk factor of prognosis. TKI inhibitor used in these patients could improve survival. EFS rate was increased a little and death rate was decreased in ALL-2009 protocol with no significant lower relapsed rate comparing with ALL-2005 protocol.

Clinical significance of minimal residual disease in patients with Ph-negative precursor B-acute lymphoblastic leukemia / 中华血液学杂志

Objective@#To explore the predictive value of minimal residual disease (MRD) level in Ph-negative precursor B-acute lymphoblastic leukemia (ALL) patients.@*Methods@#De novo 193 Ph-negative B-ALL patients from Sep 2010 to Nov 2017 were involved in the study. The patients' MRD evaluation which can be performed by multiparametric flow cytometry (MFC) after 1 month, 3-month, 6-month treatment. Relapse free survival (RFS) and overall survival (OS) were compared in patients with different MRD level.@*Results@#The median follow-up was 22 months. All patients was evaluated at 497 MRD level. Patients who reach the good MRD level at 1 month (<0.1% or ≥0.1%), 3-month (negative or positive), 6-month (negative or positive) had a significantly higher probability of estimated RFS (74.5% vs 29.9%; 75.6% vs 29.7%; 74.6% vs 11.6%) and of estimated OS (67.5% vs 30.3%; 71.6% vs 27.8%; 74.0% vs 15.7%). Patients who reach the MRD negative at all 3 times had a significantly higher probability of estimated RFS (80.5% vs 30.5%) and better estimated OS (77.1% vs 29.4%) compared to patients with at least MRD failure in one time (P<0.001). Multivariable analysis showed MRD level at 3-month was an independent prognostic factor for DFS and OS.@*Conclusion@#MRD is an important prognosis factor for Ph-negative B- ALL patients.

Multicenter clinical trial of acute lymphoblastic leukemia in elder children and adolescents / 中华血液学杂志

Objective@#To analyze the clinical characteristics and long-term outcomes with multicenter study for acute lymphoblastic leukemia (ALL) in children over 10 years old and adolescents.@*Method@#Newly diagnosed ALL patients aged from 10 to 18 years old in three hospitals were included in the study from May 1st 2005 to April 30th 2015. They were received ALL-2005/2009 protocol following up to December 31st 2016. The clinical characteristics, outcomes and the prognostic analysis were evaluated between the two protocols.@*Results@#Totally, 237 patients were involved in the study, 76 cases for ALL-2005 and 161 cases for ALL-2009 protocol. Complete remission (CR) after induction therapy was 94.5%. 64 (28.6%) patients relapsed with a median time of 14.5 months and 70 (29.5%) patients passed away during the following time. In long-term follow-up, the 5-year event-free survival (EFS) and 5-year overall survival (OS) of ALL patients were (63.1±3.3)% and (68.4±3.2)%. The 7-year EFS and OS were (61.0±3.5)% and (67.6±3.3)%.The 5-year EFS of intermediate risk group in ALL-2005 and ALL-2009 protocol were (73.6±6.1)% and (71.7±4.3)% with no difference (χ2=0.064, P=0.801). The 5-year EFS of high risk group in two protocols were (27.6±9.6)% and (33.9±9.3)%, showing no significant difference (χ2=0.296, P=0.586). Five years relapsed rate of two protocols were (33.8±5.7)% and (32.6±4.1)% with no difference (χ2=0.055, P=0.815). The mortalities were 36.8% and 29.8% separately (χ2=2.869, P=0.090). Univariate analysis indicated that age, male, risk, BCR/ABL translocation/t(9;22) and resistant to induction were risk prognostic factors in long-term survival (χ2=4.764, 4.796, 46.410, 9.560, 25.450; P=0.029, 0.029, <0.001, 0.049, <0.001). Cox multivariate analysis showed male, risk and resistant to induction were independent risk prognostic factors (RR=1.790, 2.727, 2.719; P=0.021, 0.000, 0.012).@*Conclusion@#Protocol ALL-2009 enhanced the chemotherapy intensity in intermediate risk group with no benefit of survival. BCR-ABL fusion or t(9;22) translocation was still the risk factor of prognosis. TKI inhibitor used in these patients could improve survival. EFS rate was increased a little and death rate was decreased in ALL-2009 protocol with no significant lower relapsed rate comparing with ALL-2005 protocol.

Association between miR146a(rs2910164)G>C polymorphism and susceptibility to acute lymphoblastic leuke-mia in children / 中华实用儿科临床杂志

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.

AVALIAÇÃO DOS EFEITOS ÓSSEOS TARDIOS E COMPOSIÇÃO CORPORAL DE CRIANÇAS E ADOLESCENTES TRATADOS DE LEUCEMIA LINFOIDE AGUDA SEGUNDO PROTOCOLOS BRASILEIROS / ASSESSMENT OF THE LATE EFFECTS ON BONES AND ON BODY COMPOSITION OF CHILDREN AND ADOLESCENTS TREATED FOR ACUTE LYMPHOCYTIC LEUKEMIA ACCORDING TO BRAZILIAN PROTOCOLS

RESUMO Objetivo: Avaliar o impacto da terapia sobre a densidade mineral óssea (DMO) e composição corporal em sobreviventes da leucemia linfoide aguda (LLA), tratados de acordo com os protocolos brasileiros do Grupo Cooperativo Brasileiro de Tratamento de Leucemia Linfoide Aguda na Infância (GBTLI), LLA-93 e LLA-99. Métodos: Em estudo transversal com 101 pacientes, avaliaram-se a composição corporal e a DMO por meio da densitometria óssea, interpretando-a conforme a faixa etária e a população de referência. Foi considerado grupo de risco para baixa DMO valores de z-escore entre -1,1 e -1,9 no grupo dos menores de 20 anos. Compararam-se os valores da DMO com características clínicas, tratamento recebido e composição corporal. Foram utilizados os testes qui-quadrado, exato de Fisher, razão de verossimilhança e t de Student, com nível de significância de 5%. Resultados: Foram encontradas 2% de fraturas, 2% de osteonecrose e 2,9% de baixa DMO. No grupo de pacientes com menos de 20 anos, três apresentaram baixa DMO. Os 16 pacientes com risco para baixa DMO exibiram menores valores em vértebras lombares L1-L4 (p=0,01), corpo total (p=0,005) e valores mais baixos de massa magra (p=0,03). No grupo de 22 pacientes com mais de 20 anos, dez demonstraram osteopenia. Conclusões: O baixo impacto do tratamento sobre a DMO neste estudo ratifica o conceito de que o ganho de massa óssea ocorre com o aumento da idade e que o tratamento não influencia tal processo. A população de risco para baixa DMO demonstrou valores menores de massa óssea, podendo beneficiar-se de um acompanhamento em longo prazo para uma possível toxicidade óssea.

ABSTRACT Objective: To evaluate the impact of therapy on bone mineral density (BMD) and body composition in survivors of acute lymphoblastic leukemia (ALL) treated in accordance with Brazilian protocols by the Brazilian Cooperative Group of Treatment of Lymphoblastic Leukemia in Childhood (GBTLI) LLA-93 and LLA-99. Methods: A cross-sectional study with 101 patients was performed. BMD and body composition were evaluated using bone densitometry and were interpreted according to the age group and the reference population. Values between -1.1 and -1.9 in the group of children under 20 years were considered as risk group for low BMD z-scores. BMD values were compared to clinical characteristics, treatment received and body composition. A chi-square test, Fisher’s exact test, likelihood ratio and Student’s t-test were applied, with a 5% significance level. Results: The patients presented a frequency of fractures of 2%, of osteonecrosis, 2%, and of low BMD, 2.9%. In the group of 79 patients under 20 years of age, three had low BMD. The 16 that presented risk for low BMD, demonstrated lower valutes in lumbar vertebrae L1-L4 (p=0.01) and whole body (p=0.005), and smaller values of lean body mass (p=0.03). In the group of 22 patients over 20 years of age, ten had osteopenia. Conclusions: The low impact of treatment on BMD of this study confirms the concept that the bone mass gain occurs with increasing age and that the treatment does not influence the process. The population at risk for low BMD values presented lower bone mass values and could benefit from a long-term monitoring for possible bone toxicity.

Characteristics and clinical outcomes of elderly patients with acute lymphoblastic leukemia / 白血病·淋巴瘤

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.

Dasatinib for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia：report of ten cases and review of literature / 白血病·淋巴瘤

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.