Outcomes and survival predictors of Latin American older adults with acute myeloid leukemia: Data from a single center

ABSTRACT Introduction: Acute myeloid leukemia (AML) is most commonly presented in older adults; however, it appears 10 years earlier in Latin American countries. Clinical evolution in older adults from this populations has not been characterized. We analyzed outcomes and survival predictors. Methods: Patients ≥ 55 years old diagnosed with AML at a hematology referral center from 2005 to 2020 receiving intensive chemotherapy (IC), low-dose cytarabine (LDAC) and best supportive care (BSC) were included. Survival analysis included the Kaplan-Meier and Cox models and the cumulative incidence of relapse (CIR). Results: Seventy-five adults were included and the overall survival (OS) was 4.87, 1.67 and 1.16 months, using IC, LDAC and BSC, respectively. The IC led to a higher OS (p < 0.001) and was a protective factor for early death, at a cost of more days spent hospitalized and more non-fatal treatment complications; non-significant differences were found between the LDAC and BSC. Eight (10.7%) patients underwent hematopoietic cell transplantation, with a higher OS (p = 0.013). Twenty (26.7%) patients achieved complete remission; 12 (60%) relapsed with a 6-month CIR of 57.9% in those < 70 years old vs. 86.5% in those ≥ 70 years old, p = 0.034. Multivariate analysis showed the white blood cell count (WBC) and IC had a significant impact on the patient survival, whereas chronological age and the Charlson comorbidity index (CCI) did not. Conclusion: AML in low-middle income countries demands a different approach; the IC improves survival, even with a high incidence of relapse, and should be offered as first-line treatment. Eligibility criteria should include WBC and a multidimensional evaluation. The age per se and the CCI should not be exclusion criteria to consider IC.

Analysis of 7 cases of pediatric acute myeloid leukemia with DEK-NUP214 fusion gene / 中华儿科杂志

Objective: To investigate the clinical features, treatment regime, and outcome of pediatric acute myeloid leukemia (AML) with DEK-NUP214 fusion gene. Methods: The clinical data, genetic and molecular results, treatment process and survival status of 7 cases of DEK-NUP214 fusion gene positive AML children admitted to the Pediatric Blood Diseases Center of Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences from May 2015 to February 2022 were analyzed retrospectively. Results: DEK-NUP214 fusion gene positive AML accounted for 1.02% (7/683) of pediatric AML diagnosed in the same period, with 4 males and 3 females. The age of disease onset was 8.2 (7.5, 9.5) years. The blast percentage in bone marrow was 0.275 (0.225, 0.480), and 6 cases were M5 by FAB classification. Pathological hematopoiesis was observed in all cases except for one whose bone marrow morphology was unknown. Three cases carried FLT3-ITD mutations, 4 cases carried NRAS mutations, and 2 cases carried KRAS mutations. After diagnosis, 4 cases received IAE induction regimen (idarubicin, cytarabine and etoposide), 1 case received MAE induction regimen (mitoxantrone, cytarabine and etoposide), 1 case received DAH induction regimen (daunorubicin, cytarabine and homoharringtonine) and 1 case received DAE induction regimen (daunorubicin, cytarabine and etoposide). Complete remission was achieved in 3 cases after one course of induction. Four cases who did not achieved complete remission received CAG (aclarubicin, cytarabine and granulocyte colony-stimulating factor), IAH (idarubicin, cytarabine and homoharringtonine), CAG combined with cladribine, and HAG (homoharringtonine, cytarabine and granulocyte colony-stimulating factor) combined with cladribine reinduction therapy, respectively, all 4 cases reached complete remission. Six patients received hematopoietic stem cell transplantation (HSCT) after 1-2 sessions of intensive consolidation treatment, except that one case was lost to follow-up after complete remission. The time from diagnosis to HSCT was 143 (121, 174) days. Before HSCT, one case was positive for flow cytometry minimal residual disease and 3 cases were positive for DEK-NUP214 fusion gene. Three cases accepted haploid donors, 2 cases accepted unrelated cord blood donors, and 1 case accepted matched sibling donor. The follow-up time was 20.4 (12.9, 53.1) months, the overall survival and event free survival rates were all 100%. Conclusions: Pediatric AML with DEK-NUP214 fusion gene is a unique and rare subtype, often diagnosed in relatively older children. The disease is characterized with a low blast percentage in bone marrow, significant pathological hematopoiesis and a high mutation rate in FLT3-ITD and RAS genes. Low remission rate by chemotherapy only and very high recurrence rate indicate its high malignancy and poor prognosis. Early HSCT after the first complete remission can improve its prognosis.

A Retrospective Study on the Efficacy and Safety of Idarubicin Combined with High-Dose Cytarabine Consolidation in Patients with Acute Myeloid Leukemia over 60 Years of Age in First Remission / 中国实验血液学杂志

OBJECTIVE@#To evaluate the efficacy and safety of idarubicin combined with high-dose cytarabine as a post-remission therapy for elderly patients with acute myeloid leukemia (AML).@*METHODS@#From November 2017 to June 2021, 24 AML patients aged ≥60 years who were in complete remission for the first time were enrolled in consolidation chemotherapy with idarubicin (10 mg/m2 intravenously once for day 1) combined with high-dose cytarabine (1.5 g/m2 intravenously over 3 hours every 12 hours for day 1-3), and the efficacy and safety were observed.@*RESULTS@#Among the 24 patients, there were 12 males and 12 females, the median age was 65 (60-78) years old, and the median follow-up time was 23.3 (2-42.7) months. By the end of the follow-up, 15 patients relapsed and 11 patients died. The median disease-free survival (DFS) was 9 months and there were 3 cases of 2-year DFS. The median overall survival (OS) was 16.2 months, and there were 4 cases of 2-year OS. In terms of safety, 6 patients had grade 1-2 non-hematological adverse reactions, 12 patients had grade 3-4 hematological adverse reactions, and a total of 6 patients developed infection after consolidation chemotherapy. Multivariate analysis showed that two induction cycles and high-risk cytogenetic abnormalities were the adverse factors of DFS and OS in elderly patients with AML in this study.@*CONCLUSION@#For AML patients ≥60 years old in first complete remission, idarubicin combined with high-dose cytarabine as post-remission therapy has a better safety, but compared with other regimens does not improve the prognosis of elderly patients, which needs further exploration.

Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To evaluate the clinical efficacy and safety of decitabine combined with modified CAG regimen (D-CAG regimen) in patients aged ≥70 years with newly diagnosed acute myeloid leukemia (AML).@*METHODS@#The clinical data of 59 AML patients (≥70 years old) who were newly diagnosed and treated in the Hematology Department of the First Affiliated Hospital of Nanjing Medical University from November 2010 to June 2021 were retrospectively analyzed.@*RESULTS@#Among the 59 AML patients, 28 were males and 31 were females, with a median age of 74 (70-86) years. The complete remission (CR) rate was 69.4% (34/49), and the median duration of CR was 10.7 (0.6-125.4) months after 2 courses of D-CAG treatment. According to the British Medical Research Council (MRC) classification, there was only one patient in the favorable-risk group, and the CR rate was 71.8% (28/39) in the intermediate-risk group, and 55.6% (5/9) in the adverse-risk group, respectively. There was no statistical difference in the CR rate between the intermediate-risk and adverse-risk group. Referring to ELN 2017 genetic risk classification, CR rate was 88.2% (15/17) in the favorable-risk group, 45.5% (5/11) in the intermediate-risk group, and 66.7% (14/21) in the adverse-risk group. There was no significant difference in CR rate between the favorable-risk and adverse-risk categories, but both were significantly higher than that in the intermediate-risk group (P <0.05). Next-generation sequencing (NGS) analysis showed that 11 gene mutations with a frequency of more than 10%, including TET2 mutation (35.6%), ASXL1 mutation (30.5%), NPM1 mutation (28.8%), FLT3-ITD mutation (27.1%), DNMT3A mutation (22.0%), IDH1 mutation (15.3%), CEBPA single mutation (13.6%), TP53 mutation (13.6%), IDH2 mutation (11.9%), RUNX1 mutation (11.9%), and NRAS mutation (10.2%). There were no statistical differences in mutation frequency of these 11 genes between CR group and non-CR group. Compared with normal karyotypes, patients with complex karyotypes were more likely to develop TP53 mutations (P <0.001), while FLT3-ITD and DNMT3A mutations were more likely to occur in patients with normal karyotypes (P =0.04, P =0.047). The median follow-up, overall survival (OS), and event-free survival (EFS) of all the patients was 11.7 (1.5-128.2) months, 12.3 (1.5-128.2) months, and 8.5 (1.5-128.2) months, respectively. The median OS and EFS of CR patients were 19.8 and 13.3 months, respectively, which were significantly longer than 6.4 and 5.7 months in patients experiencing treatment failure (P < 0.001, P =0.009). In regard to genes with mutation frequency >10%, there were no statistical differences in CR rate, median OS, and median EFS between mutated and wild-type patients by Chi-square test and survival analysis. Univariate analysis showed that age, hemoglobin, lactate dehydrogenase, cytogenetics and CR were factors affecting prognosis, while multivariate analysis showed that only CR failure was an independent adverse prognostic factor for OS. The major adverse reactions to D-CAG regimen were grade 3-4 myelosuppression, pulmonary infection, and fever (infection focus was not identified).@*CONCLUSION@#D-CAG regimen is safe and effective in the treatment of AML patients ≥70 years old, and can partially improve the prognosis of elderly and high-risk patients.

The Effects and Regulatory Mechanism of Targeting CXC Chemokine Receptor 1/2 Combined with Ara-C on the Malignant Biological Behaviors of U937 Cells of Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate and analyze the effect of CXC chemokine receptor 1/2 (CXCR1/2) targeting inhibitor Reparixin combined with cytarabine (Ara-C) on the malignant biological behaviors of acute myeloid leukemia cells and its effect on the expression of the CXCR family, while exploring the accompanying molecular mechanism, providing scientific basis and reference for new molecular markers and targeted therapy for AML.@*METHODS@#Acute myeloid leukemia U937 cells were treated with different concentrations of Reparixin, Ara-C alone or in combination, and the cell morphology was observed under an inverted microscope; Wright-Giemsa staining was used to detect cell morphological changes; CCK-8 method was used to detect cell proliferation; the ability of cell invasion was detected by Transwell chamber method; the ability of colony formation was detected by colony formation assay; cell apoptosis was detected by Hoechst 33258 fluorescent staining and Annexin V/PI double-staining flow cytometry; monodansylcadaverine(MDC) staining was used to detect cell autophagy; the expression of apoptosis, autophagy and related signaling pathway proteins was detected by Western blot and the expression changes of CXCR family were detected by real-time quantitative polymerase chain reaction (qRT-PCR).@*RESULTS@#Reparixin could inhibit the proliferation, invasion, migration and clone formation ability of U937 cells. Compared with the single drug group, when U937 cells were intervened by Reparixin combined with Ara-C, the malignant biological behaviors such as proliferation, invasion and colony formation were significantly decreased, and the levels of apoptosis and autophagy were significantly increased (P<0.01). After Reparixin combined with Ara-C intervenes in U937 cells, it can up-regulate the expression of the pro-apoptotic protein Bax and significantly down-regulate the expression of the anti-apoptotic protein Bcl-2, and also hydrolyze and activate Caspase-3, thereby inducing cell apoptosis. Reparixin combined with Ara-C could up-regulate the expressions of LC3Ⅱ and Beclin-1 proteins in U937 cells, and the ratio of LC3Ⅱ/LC3Ⅰ in cells was significantly up-regulated compared with single drug or control group (P<0.01). MDC result showed that the green granules of vesicles increased significantly, and a large number of broken cells were seen (P<0.01). Reparixin combined with Ara-C can significantly inhibit the phosphorylation level of PI3K, AKT and NF-κB signaling molecule, inhibit the malignant biological behavior of cells by inhibiting the activation of PI3K/AKT/NF-κB pathway, and induce programmed cell death. Ara-C intervention in U937 cells had no effect on the expression of CXCR family (P>0.05). The expression of CXCR1, CXCR2, and CXCR4 mRNA could be down-regulated by Reparixin single-agent intervention in U937 cells (P<0.05), and the expression of CXCR2 was more significantly down-regulated than the control group and other CXCRs (P<0.01). When Reparixin and Ara-C intervened in combination, the down-regulated levels of CXCR1 and CXCR2 were more significant than those in the single-drug group (P<0.01), while the relative expressions of CXCR4 and CXCR7 mRNA had no significant difference compared with the single-drug group (P>0.05).@*CONCLUSION@#Reparixin combined with Ara-C can synergistically inhibit the malignant biological behaviors of U937 cells such as proliferation, invasion, migration and clone formation, and induce autophagy and apoptosis. The mechanism may be related to affecting the proteins expression of Bcl-2 family and down-regulating the proteins expression of CXCR family, while inhibiting the PI3K/AKT/NF-κB signaling pathway.

Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy, prognosis and safety of decitabine combined with modified EIAG regimen in the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).@*METHODS@#The clinical data of 44 patients with relapsed/refractory AML and high-risk MDS admitted to our hospital from January 2017 to December 2020 were analyzed retrospectively. The patients were equally divided into D-EIAG group (decitabine combined with EIAG regimen) and D-CAG group (decitabine combined with CAG regimen) according to clinical treatment regimen. The complete response (CR), CR with incomplete hematologic recover (CRi), morphologic leukemia-free state (MLFS), partial response (PR), overall response rate (ORR), modified composite complete response (mCRc), overall survival (OS) time, 1-year OS rate, myelosuppression and adverse reactions between the two groups were compared.@*RESULTS@#In D-EIAG group, 16 patients (72.7%) achieved mCRc (CR+CRi+MLFS), 3 patients (13.6%) achieved PR, and ORR (mCRc+PR) was 86.4%. In D-CAG group, 9 patients (40.9%) achieved mCRc, 6 patients (27.3%) achieved PR, and ORR was 68.2%. Difference was observed in mCRc rate between the two groups (P=0.035), but not in ORR (P>0.05). The median OS time of D-EIAG group and D-CAG group was 20 (2-38) months and 16 (3-32) months, and 1-year OS rate was 72.7% and 59.1%, respectively. There was no significant difference in 1-year OS rate between the two groups (P>0.05). After induction chemotherapy, the median time for absolute neutrophil count recovery to 0.5×109/L in D-EIAG group and D-CAG group was 14 (10-27) d and 12 (10-26) d, for platelet count recovery to 20×109/L was 15 (11-28) d and 14 (11-24)d, the median red blood cell suspension transfusion volume was 8 (6-12) U and 6 (6-12) U, and the median apheresis platelet transfusion volume was 4 (2-8) U and 3 (2-6) U, respectively. There were no statistically significant differences in comparison of the above indicators between the two groups (P>0.05). The hematological adverse reactions of patients were mainly myelosuppression. Grade III-IV hematological adverse events occurred in both groups (100%), with no increase in the incidence of non-hematological toxicities such as gastrointestinal reactions or liver function damage.@*CONCLUSION@#Decitabine combined with EIAG regimen in the treatment of relapsed/refractory AML and high-risk MDS can improve remission rate, provide an opportunity for subsequent therapies, and have no increase in adverse reactions compared with D-CAG regimen.

Effect of MXRA7 on the Biological Functions of Acute B Lymphoblastic Leukemia Cell Line REH / 中国实验血液学杂志

OBJECTIVE@#To discover the relationship between matrix remodeling associated 7 (MXRA7) and acute B lymphoblastic leukemia (B-ALL), and explore the effect of MXRA7 on the biological functions of B-ALL cell line REH.@*METHODS@#The expression of MXRA7 in blood diseases was searched and analyzed through BloodSpot database. Real-time qPCR was used to detect the expression level of MXRA7 in B-ALL cell line 697 and REH cells. Lentivirus-mediated shRNA interference technology was utilized to knock down the expression of MXRA7 in REH cells. The effects of MXRA7 on the biological functions of REH cells were studied by in vitro experiments. Cell proliferation was detected by CCK-8 assay, cell cycle was detected by PI staining, cell apoptosis was detected by Annexin V and 7-AAD staining, and the expression of apoptosis pathway related proteins was detected by Western blot.@*RESULTS@#Database analysis showed that MXRA7 was highly expressed in B-ALL patients, and real-time qPCR results showed that MXRA7 was also highly expressed in cell lines 697 and REH cells. Knockdown of MXRA7 in REH cells inhibited the cell proliferation and increased the percentage of G0/G1 phase cells. After treatment with cytarabine, the apoptotic ratio was increased in MXRA7-impaired REH cells, and the activation of caspase-3 and caspase-9 were also increased.@*CONCLUSION@#Knockdown of MXRA7 can reduce the malignancy of REH cells by inhibiting the cell proliferation and increasing the sensitivity of REH cells to cytarabine. These results indicate MXRA7 may be as a novel target for the treatment of B-ALL, and the potential usefulness of MXRA7 in B-ALL deserves further investigation.

Recurrent and Refractory Langerhans Cell Histiocytosis in Children Treated with the Combination of Cladribine and Cytarabine / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy and prognosis of cladribine (2-CdA) combined with cytarabine (Ara-C) regimen in the treatment of relapsed refractory Langerhans cell histiocytosis (LCH) in children.@*METHODS@#Nine patients with relapsed refractory LCH treated with the 2-CdA combined with Ara-C regimen in the Department of Hematology and Oncology of Wuhan Children's Hospital from July 2014 to February 2020 were retrospectively analyzed, and the efficacy and disease status were evaluated according to the Histiocyte Society Evaluation and Treatment Guidelines (2009) and the Disease Activity Score (DAS), the drug toxicity were evaluated according to the World Health Organization（WHO） grading criteria for chemotherapy. All patients were followed up for survival status and disease-related sequelae.@*RESULTS@#Before the treatment combining 2-CdA and Ara-C, 7 of 9 patients were evaluated as active disease worse (ADW), and 2 as active disease stable (ADS) with a median disease activity score of 8 (4-15). Of 9 patients, 6 cases achieved non active disease (NAD) and 3 achieved active disease better (ADB) with a median disease activity score of 0 (0 to 5) after 2-6 courses of therapy. All 9 patients experienced WHO grade IV hematologic toxicity and 3 patients had hepatobiliary adverse effects (WHO grade I～II) after treatment. The median follow-up time was 31(1 to 50) months with all 9 patients survived, 3 of the 9 patients experienced sequelae to the disease with 2 combined liver cirrhosis as well as cholestatic hepatitis and 1 with oral desmopressin acetate tablets for diabetes insipidus.@*CONCLUSION@#2-CdA combined with Ara-C is an effective regimen for the treatment of recurrent refractory LCH in children, and the main adverse effect is hematologic toxicity, which is mostly tolerated in children. Early treatment with this regimen may be considered for patients with multisystem LCH with risky organ involvement who have failed first-line therapy and for patients with relapse.

Establishment of Drug-Resistant Cell Lines of Acute Myeloid Leukemia and Correlation of Sirt1 and PGC-1α Expression Levels with Drug Resistance / 中国实验血液学杂志

OBJECTIVE@#To construct cytarabine-resistant acute myeloid leukemia (AML) cell lines, and explore the correlation between Sirt1, PGC-1α expression levels and drug resistance.@*METHODS@#Human acute promyelocytic leukemia Kasumi-1 cells were induced by the method of gradually increasing the concentration of Ara-C drug. The IC50 value of Kasumi-1 cells before and after drug addition was detected by CCK-8 method, so as to construct Ara-C resistant cell lines. The expression levels of Sirt1 and PGC-1α mRNA in Kasumi-1 drug-resistant cell lines and their parental cell lines were detected by real-time fluorescence quantitative PCR, and the expression levels of Sirt1 and PGC-1α protein in kasumi-1 drug-resistant cell lines and their parental cell lines were detected by Western blot.@*RESULTS@#The constructed Kasumi-1 cell line had common morphological characteristics of drug-resistant cell lines under microscope, and the drug resistance index was greater than 5, indicating that Kasumi-1 drug-resistant cells had good drug resistance after the construction. The RT-qPCR and Western blot assays showed that the expression levels of Sirt1 and PGC-1α mRNA and protein in the drug-resistant cell lines were higher than those of the parental cell lines (P<0.001).@*CONCLUSION@#AML cell lines resistant to Ara-C can be successfully induced by the method of gradually increasing the concentration, and the co-high expression of Sirt1 and PGC-1α may mediate the drug resistance of AML cells.

Research Advance of Gene Mutation and Targeted Drug Therapy in Childhood Acute Myeloid Leukemia --Review / 中国实验血液学杂志

The clinical therapeutic regimen for acute myeloid leukemia (AML) is not significantly different between adults and children, which is mostly based on IA (idarubicin and cytosine arabinoside) induction chemotherapy. With the rapid development of sequencing technique, people's understandings towards the molecular and biological abnormalities of AML are increasing, diverse AML gene mutation-based targeted drugs have been rapidly developed and applied. In this review, several commonly gene mutations in AML (such as FLT3, NPM1 and C/EBPA) was described, and the therapeutic effects and differences of targeted drugs that used in clinical treatment or had been reported (like tyrosine kinase inhibitor, IDH1 mutation inhibitor and epigenetic modification inhibitor) in child and adult AML patients were summrized.

Mechanism of miR-155 Promoting Drug Resistance in Childhood Acute Lymphoblastic Leukemia by Regulating Wnt/β-Catenin Signaling Pathway / 中国实验血液学杂志

OBJECTIVE@#To investigate the mechanism of miR-155 promoting drug resistance of children B-ALL to Ara-C by regulating Wnt/β-Catenin signaling pathway.@*METHODS@#The expression of miR-155 in bone marrow tissue and cell line of B-ALL was detected by PCR. The chemotherapy resistant strain REH/ Ara-C was constructed by using REH cells. REH/ Ara-C cells were transfected with miR-155 inhibitor. The proliferation of REH/Ara-C cells was detected by EdU. The apoptosis of REH/ Ara-C cells was detected by flow cytometry. The drug resistance of REH/Ara-C cells were analyzed by CCK-8 method and colony formation assay. The expression of Wnt/β-Catenin signaling pathway related proteins were determined by Western blot. MiR-155 inhibitor and Wnt activator agonist were used to transfect REH/Ara-C cells, and their effects on cell proliferation, apoptosis and drug resistance were determined.@*RESULTS@#Compared with normal tissues and cells, the expression level of miR-155 in B-ALL bone marrow tissue/cell line was increased (P<0.05); Compared with drug sensitive B-ALL tissues/cell lines, the expression level of miR-155 in drug resistant B-ALL tissues and cell lines was increased (P<0.05); Inhibition of miR-155 expression decreased the proliferation of REH/Ara-C cells (P<0.05), promoted apoptosis (P<0.05), enhanced the cytotoxicity of Ara-C (P<0.05), and inhibited Wnt/β-Catenin signaling pathway related protein and MDR1 gene expression (P<0.05), which could be reversed by activating Wnt expression (P<0.05).@*CONCLUSION@#The expression of miR-155 is up-regulated in bone marrow of children with B-ALL, which may be related to the activation of Wnt/β-Catenin signaling pathway promotes the proliferation of B-ALL cells and inhibits apoptosis, which leads to chemotherapy resistance.

Influence of Serum TGF-β1 and EGFR Levels on the Therapeutic Effect of High-Dose AraC in Patients with Acute Myeloid Leukemia Based on the Decision Curve / 中国实验血液学杂志

OBJECTIVE@#To analyze the influence of serum levels of transforming growth factor-β1 (TGF-β1) and epidermal growth factor receptor (EGFR) on the therapeutic effect of high-dose cytarabine (HD-AraC) in patients with acute myeloid leukemia (AML).@*METHODS@#98 patients with AML treated in our hospital from January 2019 to June 2020 were selected as the research subjects, all patients were treated with HD-AraC for 1 course of treatment every week. The effect of 2 groups were evaluated during after one course of treatment and divided into effective group and ineffective group, statistical table of baseline data was designed, the baseline data of 2 groups were counted in detail, the baseline data and serum levels of TGF-β1 and EGFR of 2 groups were compared, Logistic regression analysis was used to examine the relationship between the levels of serum TGF-β1, EGFR and the therapeutic effect of HD-AraC in patients with AML, the value of serum TGF-β1 and EGFR levels in predicting the therapeutic effect of HD-AraC in AML patients was analyzed based on ROC curve and decision curve.@*RESULTS@#After 1 course of treatment, among the 98 patients, 26 cases had complete remission, 38 cases had partially remission and 34 cases no remission, the total effective rate was 65.31% (64/98); after comparing data of 2 groups, Logistic regression analysis showed that the overexpression of serum EGFR before treatment might be a risk factor for the ineffective treatment of HD-AraC in AML patients (OR>1, P<0.05), overexpression of serum TGF-β1 before treatment might be a protective factor for the ineffective treatment of HD-AraC in AML patients (OR<1, P<0.05); the ROC curve results showed that the AUC of serum EGFR and TGF-β1 before treatment in predicting the risk of ineffective HD-AraC treatment in AML patients were >0.70, which had certain predictive value. The decision curve results showed that in the threshold range of 0.15-044, the prediction model combined with serum EGFR and TGF-β1 levels in predicting the net benefit rate of HD-AraC treatment in AML patients was better than that of serum EGFR or serum TGF-β1 alone.@*CONCLUSION@#The levels of serum TGF-β1 and EGFR affect the therapeutic effect of HD-AraC in patients with AML and increase the risk of ineffective treatment, serum TGF-β1 and EGFR can be used to predict the risk of ineffective HD-AraC treatment in AML patients, and the combined prediction of net benefit rate is higher.

Efficacy and safety of IAC regimen for relapse/refractory acute myeloid leukemia: a prospective randomized controlled study / 中华血液学杂志

Objective: To evaluate the efficacy and toxicity profiles of idarubicin, cytarabine, and cyclophosphamide (IAC) in relapse/refractory acute myeloid leukemia (AML) . Methods: This study was a prospective, randomized controlled clinical trial with the registration number NCT02937662. The patients were randomly divided into two groups. The experimental group was treated with an IAC regimen, and the regimen of the control group was selected by doctors according to medication experience. After salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was conducted as far as possible according to the situation of the patients. We aimed to observe the efficacy, safety, and toxicity of the IAC regimen in relapse/refractory AML and to explore which is the better regimen. Results: Forty-two patients were enrolled in the clinical trial, with a median age of 36 years (IAC group, 22 cases and control groups, 20 cases) . ①The objective response rate was 71.4% in the IAC group and 40.0% in the control group (P=0.062) ; the complete remission (CR) rate was 66.7% in the IAC group and 40.0% in the control group (P=0.121) . The median follow-up time of surviving patients was 10.5 (range:1.7-32.8) months; the median overall survival (OS) was 14.1 (range: 0.6-49.1) months in the IAC group and 9.9 (range: 2.0-53.8) months in the control group (P=0.305) . The 1-year OS was 54.5% (95%CI 33.7%-75.3%) in the IAC group and 48.2% (95%CI 25.9%-70.5%) in the control group (P=0.305) , with no significant difference between these two regimens. ②The main hematologic adverse events (AEs) were anemia, thrombocytopenia, and neutropenia. The incidence of grade 3-4 hematologic AEs in the two groups was 100% (22/22) in the IAC group and 95% (19/20) in the control group. The median time of neutropenia after chemotherapy in the IAC group and control group was 20 (IQR: 8-30) and 14 (IQR: 5-50) days, respectively (P=0.023) . ③The CR rate of the early relapse (relapse within 12 months) group was 46.7% and that of the late relapse (relapse after 12 months) group was 72.7% (P=0.17) . The median OS time of early recurrence was 9.9 (range:1.7-53.8) months, and that of late recurrence patients was 19.3 (range: 0.6-40.8) months (P=0.420) , with no significant differences between the two groups. The 1-year OS rates were 45.3% (95%CI 27.2%-63.3%) and 66.7% (95%CI 40.0%-93.4%) , respectively (P=0.420) . Survival analysis showed that the 1-year OS rates of the hematopoietic stem cell transplantation group and non-hematopoietic stem cell transplantation group were 87.5% (95%CI 71.2%-100%) and 6.3% (95%CI 5.7%-18.3%) , respectively. The OS rate of the hematopoietic stem cell transplantation group was significantly higher than that of the non-hematopoietic stem cell transplantation group (P<0.001) . Conclusion: The IAC regimen is a well-tolerated and effective regimen in relapsed/refractory AML; this regimen had similar efficacy and safety with the regimen selected according to the doctor's experience for treating relapsed/refractory AML. For relapsed/refractory patients with AML, allogeneic hematopoietic stem cell transplantation should be attempted as soon as possible to achieve long-term survival.

Comparison of the efficacy of IA and HAD induction regimens in the treatment of patients with newly diagnosed acute myeloid leukemia: a single-center study / 中华血液学杂志

Objective: To compare the efficacy of two induction regimens, namely, idarubicin combined with cytarabine (IA) versus the combination of homoharringtonine, daunorubicin, and cytarabine (HAD) , in adult patients with newly diagnosed de novo acute myeloid leukemia (AML) . Methods: From May 2014 to November 2019, 199 patients diagnosed with AML receiving either the IA or HAD regimens were assessed for overall survival (OS) , relapse-free survival (RFS) , as well as the CR rate and the MRD negative rate after induction therapy. The differences in prognosis between the two induction therapy groups was assessed according to factors, including age, white blood cell (WBC) count, NPM1 mutation, FLT3-ITD mutation, 2017 ELN risk stratification, CR(1) transplantation, and the use of high-dose cytarabine during consolidation therapy, etc. Results: Among the 199 patients, there were 104 males and 95 females, with a median age of 37 (15-61) years. Ninety patients received the IA regimen, and 109 received the HAD regimen. Comparing the efficacy of the IA and HAD regimens, the CR rates after the first induction therapy were 71.1% and 63.3%, respectively (P=0.245) , and the MRD negative rates after the first induction therapy were 53.3% and 48.6%, respectively (P=0.509) . One patient in the IA group and two in the HAD group died within 60 days after induction. The two-year OS was 61.5% and 70.6%, respectively (P=0.835) , and the two-year RFS was 51.6% and 57.8%, respectively (P=0.291) . There were no statistically significant differences between the two groups. Multivariate analysis showed that the ELN risk stratification was an independent risk factor in both induction groups; CR(1) HSCT was an independent prognostic factor for OS and RFS in the IA patients and for RFS in the HAD patients but not for OS in the HAD patients. Age, WBC level, NPM1 mutation, and FLT3-ITD mutation had no independent prognostic significance. Conclusion: The IA and HAD regimens were both effective induction regimens for AML patients.

Efficacy of Different Doses of Daunorubicin Induced Chemotherapy in Patients with Newly Diagnosed Primary Acute Myeloid Leukemia Under 65 Years Old / 中国实验血液学杂志

OBJECTIVE@#To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients.@*METHODS@#The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group ［75 mg/(m@*RESULTS@#Median follow-up time of all the patients was 15 months. The CR rate and MRD@*CONCLUSION@#The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.

Efficacy and Safety of Different Dosages of Decitabine in the Treatment of High-Risk Patients with Myelodysplastic Syndrome / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy of high-risk myelodysplastic syndrome (MDS) patients treated by different doses of decitabine (DAC) and its safety.@*METHODS@#Thirty patients with high-risk MDS were all treated by demethylation drug DAC. According to the doses of DAC, 30 patients were divided into 10-day regimen [6 mg/(m@*RESULTS@#The patients were followed up to May 2020, in the 10-day regimen group, 10 cases achieved complete remission (CR), 3 cases achieved partial remission (PR), and 2 cases were progressive disease (PD). Four cases died, including 1 case for heart failure, 2 cases for respiratory failure and 1 case for serious infection. In the 5-day regimen group, 11 cases achieved CR, 1 case achieved PR, 3 cases were PD. Five cases died, including 2 cases for heart failure and 3 for serious infection. The CR rate and ORR of the patients in the two groups were 66.67% vs 73.33%, 86.67% vs 80.00%, respectively, which showed no significant differences, and the efficacy also showed no significant difference. After treatment, the levels of WBC, NE, Hb and PLT of the patients in 10-day regimen group were higher than those in 5-day regimen. In the 10-day regimen group, there were 11 cases of pneumonia, 2 cases of bacteremia, 1 case of skin infection and 1 case of urinary tract infection. While in the 5-day regimen group, 13 cases of pneumonia, 5 cases bacteremia, 1 case of skin infection and 3 cases of urinary tract infection. There were 2 cases with mild gastrointestinal response in the 10-day regimen group, and 7 cases with obvious nausea and anorexia in the 5-day regimen group. The symptoms were relieved after the treatment of acid suppression, stomach protection and antiemetic. The liver, kidney and heart function were monitored. One case liver function damage and 2 cases cardiac insufficiency were observed in the 10-day regimen group. Seven cases regimen cardiac insufficiency and 4 cases regimen liver function damage were observed in the 5-day regimen group.@*CONCLUSION@#10-day regimen and 5-day regimen are equally effective, but 10-day regimen is less myelosuppressive and more safer, which can be applied in clinical.

Establishment of Cytarabine-resistant Acute Lymphoblastic Leukemia Cell Lines and Its Resistance Mechanism / 中国实验血液学杂志

OBJECTIVE@#To establish cytarabine-resistant acute lymphoblastic leukemia (ALL) cell lines and investigate its possible resistant mechanism.@*METHODS@#Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The cell viability was detected by CCK-8 assay, and the distribution of cell cycle was detected by flow cytometry. Real-time fluorescence quantitative PCR was used to detect the mRNA expression levels of multidrug resistant gene and Ara-C metabolic enzymes. The expression levels of cyclin were detected by Western blot.@*RESULTS@#Jurkat/Ara-C and Nalm-6/Ara-C drug-resistant cell lines were successfully established, the resistance index of which was 1 973.908±161.163 and 7 231.643± 1 190.624, respectively. Drug-resistant cell lines had no cross-resistance to commonly used chemotherapeutic drugs, such as doxorubicin. Flow cytometry showed that the ratio of G@*CONCLUSION@#Cytarabine-resistant ALL cell lines are successfully established by using low concentration continuous induction method, and its drug-resistant mechanism may be related to the deficiencies of DCK and cyclinB1.

The Relationship between Body Mass Index and Adult Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To analysis the relationship between different BMI (body mass index) and the clinical characteristics, laboratory examination indexes of newly diagnosed adult patients with acute myeloid leukemia (AML), so as to investigate the effects of BMI to the efficacy of first induction chemotherapy.@*METHODS@#The clinical data of 145 newly diagnosed adult AML patients treated in the First Hospital of Lanzhou University from August 2015 to August 2019 were retrospective analyzed. According to the guidelines for prevention and control of overweight and obesity in Chinese adults, the BMI (kg/m@*RESULTS@#Among the 145 newly diagnosed adult AML patients, there were 71 males and 74 females. The median age was 50 years old(range 18 to 82 years old). There were 21 patients in underweight group (14.5%), 79 patients in normal weight group (54.5%), and 45 patients in overweight and obese group (31.0%). The patients with higher BMI level showed the older in age（P=0.018）. There were significant differences in sex between the patients in each group(P=0.035). In overweight and obese patients, the number of male was significantly higher than female. There were no statistical differences in AML classification, comorbidities(Diabetes, hypertension, coronary heart disease), hospital days, whether secondary AML and FLT3 gene mutation among the patients in different BMI groups. There were significant differences in TG of the patients in the different groups, the overweight and obese patients were higher (P=0.007). There were no significant differences in WBC and Hb counts, ALB, TC, HDL, LDL, or LDH between the patients in each BMI group at newly diagnosed. The complete remission rate of the patients in the low body mass group or overweight and obese group were lower than that in the normal body weight group (P=0.035). The rate of documented infection during the first induction chemotherapy were significantly higher for the patients in low body mass group than those in normal weight group or overweight and obese group (P=0.038). There was no statistical difference in chemotherapy regimens, the number of chemotherapy until CR, febrile neutropenia, bleeding, and the time of neutropenia, liver and kidney toxicity among each BMI group. Multivariate analysis showed that overweight and obese (P=0.012) , FLT3 mutation (P=0.015) were the risk factors affecting the CR rate of the patients. And the patients with secondary AML, high-risk type, and newly diagnosed WBC ≥50×10@*CONCLUSION@#In newly diagnosed adult patients with AML, low body mass, overweight and obesity, and FLT3 mutations were the factors reducing the early efficacy of AML patients. There were more adverse reactions induced by chemotherapy in the low body mass group. Therefore, inappropriate BMI level can be a risk factor for assessing the prognosis of adults with newly diagnosed AML.