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  • 1
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    Molecular Mechanism Of Regulation Of Extramedullary Infiltration In AML1/ETO Positive Acute Myeloid Leukemia By APP/ERK/MMP-2
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3769-3769
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3769-3769
    Abstract: Amyloid precursor protein (APP) has been reported to be highly expressed in AML1/ETO positive acute myeloid leukemia (AML1/ETO+ AML), and we found it express even higher in those with extramedullary infiltration in our previous study. But it’s still unknown what role APP plays and how it works in AML1/ETO+ AML. This study was designed to investigate the effect of APP gene on the prognosis and its molecular mechanism of extramedullary infiltration in the patients with AML1/ETO+ AML. 44 cases of AML1/ETO+ AML patients with median age of 29 years old, who were admitted to our hospital from February, 2006 to February, 2012 and made the diagnosis according to WHO2008 diagnosis standard, and had completed conventional induction, consolidation and intensive therapy, were investigated in this study. They were divided into high expression group (n=22) and low one (n=22) according to APP mRNA median expression level from bone marrow cells before the first chemotherapy by QRT-PCR. Some of bone marrow samples were checked by Western Blot, and 5 biopsy specimens from extramedullary infiltration were tested by APP antibody immunohistochemistry staining. Incidence of extramedullary leukemia (EML), complete response (CR), overall survival (OS), and recurrence free survival (RFS) was differentiated between the two groups. Differences of cell ultrastructure, migration, proliferation, apoptosis and expression of ERK, MMP-2, MMP-9 and CXCR4 were studied on Kasumi-1 cell line between wild, negative control (NC) and si-APP group in which the expression levels of APP gene were down regulated with application of siRNA technology.Çå The incidence of EML was significantly different (45.5% versus 9.1%) in the two groups (P=0.007) and it was positively correlative with the expression levels of APP mRNA (rp=0.435, P=0.004). Extramedullary infiltration site also showed high expression of APP by immunohistochemistry, while the control group was negative. Not only CR rate after two courses of chemotherapy, but also OS and RFS with median follow-up of 28(4-70) months, of high expression group was all significantly lower than that of low expression group (Table 1). Compared with the wild and NC group, cell apoptosis of si-APP group was significantly increased (12.33 ± 0.75 vs 19.80 ± 1.51, P=0.000); the number of microvilli on the surface of the cell membrane significantly reduced; the ability of the cell migration by Tanswell chamber migration assay significantly decreased (P=0.004); and expression of P-ERK, c-MYC, MMP-2 decreased significantly which was confirmed by ERK and c-MYC blocker treatment (Figure 1). In sum, incidence of EML is significantly higher and the prognosis is poor in the patients with AML1/ETO+ AML with high expression of APP gene. We first describe that APP gene may mediate AML1/ETO+ leukemia cells in the development of extramedullary infiltration by up-regulation of the ERK/MMP-2 pathway. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3769.3769
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 2
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    APP Gene Is Correlated with C-KIT Mutations and Indicates Poor Disease Outcome in AML1-ETO-Positive Acute Myeloid Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 942-942
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 942-942
    Abstract: Amyloid precursor protein (APP) has been reported to be highly expressed in AML1-ETO-positive acute myeloid leukemia (AML1-ETO-positive AML), and we found it correlate with extramedullary infiltration regulated of by APP/ERK/MMP-2 signal pathway in our previous study. It is also known that C-KIT mutations highly expressed in AML1-ETO-positive AML and cooperates with full-length AML1-ETO to induce AML in mice. In this study we further described a close correlation of APP gene with C-KIT mutations, as well as APP related clinical and prognostic significance in 65 patients with AML1-ETO-positive AML. 65 cases of AML1-ETO-positive AML patients with median age of 30 years old, who were admitted to our hospital from February, 2006 to June, 2013 and made the diagnosis according to WHO2008 diagnosis standard, were enrolled into this study. APP expression in bone marrow cells before the first chemotherapy was assessed by quantitative reverse transcriptase (QRT)-PCR method. These cases were accordingly divided into APP-H group (n=33, with high level of APP by QRT-PCR) and APP-L group (n=32, with lower level of APP by QRT-PCR) according to median APP expression. Incidence of C-KIT mutations, clinical characteristics and prognosis including complete response (CR), overall survival (OS), and recurrence free survival (RFS) with median 35 (6-96) months followed-up was differentiated between the two groups. Furthermore, expression of APP and AML1/ETO fusion gene were simultaneously monitored at the time of 3, 6, 12 and 24 months or relapse after CR by QRT-PCR method. The incidence of C-KIT mutations was significantly increased in the APP-H group, as compared with the APP-L group (39.4% versus 12.5%) and it was positively correlative with APP expression (rp=0.435, P=0.004). Of the 17 patients harboring C-KIT mutations, 13 patients overexpressed APP gene (P=0.014) (Figure 1). Clinically, APP-H patients exhibited significantly elevated white blood cells count, increased extramedullary infiltration (P=0.039 and P=0.019, respectively). Moreover, APP overexpression was related to low rate of two-cycle CR, RFS and OS (P=0.020, P=0.001 and P=0.029, respectively) (Table 1). In addition, the change of APP expression was consistent with that of AML1-ETO fusion gene monitored by QRT-PCR method at different status of leukemia, though APP expressed differently in different patients with the same AML1-ETO expression. Taken together, these data suggest that APP gene is correlated with C-KIT mutations and indicates poor disease outcome and dynamic monitoring APP expression could be another choice of minimal residual disease monitoring in AML1-ETO-positive AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.942.942
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 3
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    The Clinical Characteristics and Efficacy of Chronic Myeloid Leukemia Patients with T315I Mutation
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5433-5433
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5433-5433
    Abstract: Background: The application of tyrosine kinase inhibitor (TKIs) has greatly improved the overall survival (OS) and quality of life of chronic myeloid leukemia (CML) patients.However, in the TKIs era, 10% to 25% of CML patients still develop TKIs resistance, and ABL kinase point mutations are the most common reason.Most of the ABL kinase region mutations resistant to imatinib could be alleviated by second generation TKIs, but the T315I mutation resistance to the first and second generation TKIs. Ponatinib is a multi-target tyrosine kinase inhibitor, which belongs to the third generation of TKI inhibitors,and is sensitive for CML or Ph postitive ALL patients with T315I mutation. But,how to apply ponatinib bridging graft or whether ponatinib preventive therapy is needed after transplantation is uncertainty. Methods: 18 CML patients with T315I mutation detected by ABL1 kinase region mutation in Southern Hospital from March 2013 to April 2018 were retrospectively analyzed.G-banding method was used for chromosome analysis and real-time quantitative PCR method was used to detect mutations in ABL1 kinase region by BCR-ABL1 fusion gene Sanger sequencer. Result:18 CML patients with T315I mutation :13 cases chronic phase (CP) ,2 cases in accelerated phase,3 cases in blastcrisis phase(BP); 9 cases in high risk group, 6 cases in middle risk group and 3 cases in low risk grou by Sokal score score system.15 patients by imatinib ,3 patients first-line treatment with dasatinib .In imatinib group, 13 cases conversed to dasatinib because of drug resistance or intolerance, and 5 cases (5 / 13) were converted to ponatinib because of T315I mutation.One case in dasatinib group converted to ponatinib because of T 315 I mutation.A total of 6 patients (6 / 18) were treated with ponatinib. 6 patients (6 / 18) treated by allogeneic hematopoietic stem cell transplantation (Allo-SCT).The median stage of T315I mutation was 12.5 m from the beginning of treatment to the detection of T 315I mutation in 18 patients.At the end of the follow-up, 8 cases died of recurrence and 10 survived: (CMR 2 cases, CHR 1 cases, PR 3 cases, NR 3 cases, 1 cases not regularly followed up, unable to evaluate the disease state), including 6 patients with PO treatment. Conclusion:The point of T315I mutation was detected in patients with CML resistance after long-term sequential therapy frequently. The recurrence rate was still high even if these patients experience allogeneic hematopoietic stem cell transplantation.However,these patients treatment with ponatinib before and after transplantation maybe reduce the recurrence rate and improve prognosis. Key words:Chronic myeloid leukemia;BCR-ABL;T315I;ponatinib. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-114113
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 4
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    De‐escalation or discontinuation of tyrosine kinase inhibitor in patients with chronic myeloid leukemia: A multicentral, open‐label, prospective trial in China
    Wiley ; 2022
    In:  eJHaem Vol. 3, No. 4 ( 2022-11), p. 1220-1230
    Details
    In: eJHaem, Wiley, Vol. 3, No. 4 ( 2022-11), p. 1220-1230
    Abstract: Background : Long‐term treatment‐free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). Optimizing dose of tyrosine kinase inhibitors (TKIs) in the CML treatment maybe a new challenge to maintain effective and improving patients’ quality of life. We hypothesized that administration of low‐dose TKIs does not compromise major molecular response (MMR) in patients with CML who have a deep molecular response (DMR). Methods : We did an open‐label, randomized trial at eight hospitals in China. Eligible CML‐CP patients (aged 18–70 years) had shown continuous response to TKI more than 5 years and maintained MR4.5 (BCR‐ABLIS ≤ 0.0032%) in recent 18 months. Patients were randomly assigned (1:1) to the TKI de‐escalation group or the discontinuation group. Randomization was done with permuted blocks (block size four) and implemented through an interactive web‐based randomization system. Recurrence was defined as the single sample with real time Quantitative PCR (RT‐qPCR) measurement greater than 0.1% (MMR). The primary endpoint was 12‐month MMR rate in patients who received de‐escalation or discontinuation of TKIs. This study was registered at ClinicalTrials.gov (NCT04143087). Results : Around 125 patients were enrolled between October 23, 2019 and October 31, 2020, 62 patients received dose de‐escalation of TKIs, while 63 patients in the discontinuation group. In the de‐escalation group, molecular recurrence‐free survival at 12 months was 88.32% (95% CI 79%–98%), whereas molecular recurrence‐free survival in the discontinuation group at 12 months was 59.98% (95% CI 47–73). No progressions occurred at the data cut‐off date. All 29 recurrence cases restart TKI treatment returned to MMR. Cytolytic NK cells as a proportion of lymphocyte cells were significantly increased from baseline after 6 months whether in the de‐escalation or TKIs cessation group ( P  = 0.048, 0.001, respectively); compared with the relapsing patients, Tregs proportion was decreased ( P  = 0.003), and higher proportion of NK cells were found in non‐relapsing patients whether in TKI de‐escalation or discontinuation group ( P  = 0.011, 0.007, respectively). We also found that the de‐escalation group showed better disease‐specific HRQOL in regards to its impact on emotional functioning, fatigue, pain, and financial difficulties. Conclusion : With 88.32% MMR in 12‐months follow‐up after de‐escalation TKIs’ treatment, dose‐halving could become a new treatment paradigm for CML patients who with DMR under continuing maintenance therapy with TKIs.
    Type of Medium: Online Resource
    ISSN: 2688-6146 , 2688-6146
    URL: Issue
    URL: Article
    DOI: 10.1002/jha2.v3.4
    DOI: 10.1002/jha2.550
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 5
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    A Novel Oral Histone Deacetylase Inhibitor Chidamide Is Highly Effective and Well-Tolerated in Adult Early T-Cell Precursor and Ph-like Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4011-4011
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4011-4011
    Abstract: Background Early T-cell precursor (ETP) lymphoblastic leukemia (ETP-ALL) is a neoplasm with an unique T-cell immunophenotype indicating limited early T differentiation. Ph-like ALL is a B-cell neoplasm which lack BCR-ABL1 translocation but similar expression-pattern of the BCR-ABL1-positive ALL. The optimal therapeutic approaches for ETP-ALL and Ph-like ALL are poorly characterized. Chidamide is a novel and orally active benzamide class of histone deacetylase inhibitor (HDACi) and approved for peripheral T-cell lymphoma (PTCL). Methods Based on the pediatric-inspired, PEG-L-asparaginase-intensified and MRD-directed PDT-ALL-2016 protocol, we designed two open-label, one-arm, multi-site trials, PDT-ETP-ALL (NCT03553238) and PDT-Ph-Like (NCT03564470), to evaluate the safety and effect of HDACi chidamide for adult ETP-ALL and Ph-Like-ALL group, respectively. The protocols were approved by Institutional Review Broad (IRB). Chidamide at a dose of 10mg/day will be added to ETP-ALL group from induction therapy to consolidation therapy according to PDT-ETP-ALL protocol. Chidamide and dasatinib will be added to HDACi cohort and TKI cohort, respectively, based on cytogenetics and next-generation-sequencing classification, according to PDT-Ph-Like protocol. Primary study endpoint is event-free survival and secondary study endpoints are complete remission (CR) and MRD after induction, adverse event and overall survival. Result Between FEB 2016 to DEC 2017, 24 patients with ETP-ALL were enrolled into PDT-ETP-ALL trial, 4 female patients and 20 male patients, a median age 22 years old (range, 14-22 years old). A total of 33 patients with Ph-like ALL has been enrolled into PDT-Ph-Like trial, 16 female patients and 17 male patients, a median age of 23 years old (range, 14-55 years old) 11 patients in TKI arm and 22 patients in HDACi arm. Ph-like ALL with CRLF2 high-expression, CRLF2/EPO/JAK2 rearrangement, JAK/STAT/IL-7R/SH2B3 mutation, will be assigned to HDACi arm. Targeted next-generation sequencing revealed ETP-ALL patients harbor high rates of mutations in factors involved in cytokine and JAK/STAT signaling pathway (62%), epigenetic regulation (52%) and hematopoietic development (35%). At the same time, we also performed NGS assessment with the same panel of Ph-like ALL patients. Of note, ETP-ALL and Ph-like ALL share the mutations involved in JAK/STAT signaling pathway (JAK1, JAK2, IL-7R) and histone modification (SETD2, KMT2A, EZH2, KMT2C), which might indicate the underlying mechanism of sensitivity of ETP-ALL and Ph-like ALL to HDACi chidamide. Chidadmide was well-tolerated in ETP-ALL and Ph-like ALL patients. Fatigue, nausea, vomit, neutropenia and thrombocytopenia are common chidamide-associated adverse events (AE) with Common Terminology Criteria for Adverse Events (CTCAE) grade I-II. Complete remission and Flow-MRD-negative rate after induction therapy for ETP-ALL and Ph-Like-ALL were 87% and 67%, 77% and 60%, respectively. Six patients with ETP-ALL (25%, 6/24) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and 11 patients with Ph-like ALL received allo-HSCT. With a median follow-up of 20 months (range, 7-31 months), estimated 2-year event-free-survival (EFS) of ETP-ALL and Ph-like ALL is 83%, 70%, respectively. Conclusion: Our preliminary data of PDT-ETP-ALL and PDT-Ph-like ALL trials suggest that a novel HDACi chidamide is effective and well-tolerated in adult ETP-ALL and Ph-like ALL, which deserve further extended clinical trial. Disclosures Zhou: CHIPSCREEN: Consultancy. Carter:novartis: Research Funding; AstraZeneca: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-113712
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
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  • 6
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    The Relationship between Clinical Feature, Complex Immunophenotype, Chromosome Karyotype, and Outcome of Patients with Acute Myeloid Leukemia in China
    Hindawi Limited ; 2015
    In:  Disease Markers Vol. 2015 ( 2015), p. 1-10
    Details
    In: Disease Markers, Hindawi Limited, Vol. 2015 ( 2015), p. 1-10
    Abstract: Mixed phenotype acute leukemia (MPAL) is a complex entity expressing both lymphoid and myeloid immunophenotyping. In the present study, 47 MPAL, 60 lymphoid antigen-positive acute myeloid leukemia (Ly + AML), and 90 acute myeloid leukemia with common myeloid immunophenotype (Ly − AML) patients were investigated. We found that, in MPAL patients, there were high proportions of blast cells in bone marrow and incidence of hepatosplenomegaly, lymphadenopathy, and Philadelphia chromosome. The overall survival (OS) and relapse-free survival (RFS) in MPAL patients were significantly shorter than those in Ly + AML and Ly − AML. With regard to the patients with normal karyotype only, the OS and RFS of MPAL were significantly lower than those of the Ly + AML and Ly − AML; but there were no significant differences in OS and RFS among the patients with complex karyotype. The OS rates of 3 groups with complex karyotype were lower than those of patients with normal karyotype. In Cox multivariate analysis, complex karyotype was an independent pejorative factor for both OS and RFS. Therefore, MPAL is confirmed to be a poor-risk disease while Ly + AML does not impact prognosis. Complex karyotype is an unfavorable prognosis factor in AML patients with different immunophenotype. Mixed immunophenotype and complex karyotype increase the adverse risk when they coexist.
    Type of Medium: Online Resource
    ISSN: 0278-0240 , 1875-8630
    URL: Article
    DOI: 10.1155/2015/382186
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2015
    detail.hit.zdb_id: 2033253-1
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  • 7
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    Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation For Patients With Chronic Myeloid Leukemia In Chronic Phase
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 5518-5518
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5518-5518
    Abstract: Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) scene in CML has changed dramatically. This retrospective cohort study was designed to compare medical outcomes of Imatinib mesylate and allo-HSCT for patients with CML in chronic phase. Patients and Methods From February 2002 to February 2012, 198 patients treated consecutively at the Nanfang Hospital,Southern Medical University were assigned to two groups according to treatment with imatinib or allo-HSCT. One hundred fifteen cases of imatinib group were given imatinib at an initial dose of 400mg daily and the dose was then adjusted according to the patient´s blood and therapy response. All the patients were evaluated for hematologic, cytogenetic and molecular response every 1-3months. Eighty-three cases of allo-HSCT group received myeloablative preconditioning regimen, and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease(GVHD), parts combined with mycophenolate mofetil (MMF) and antihuman thymocyte globulin(ATG). The primary end points of the study were complete cytogenetic response (CCyR), relapse rate, overall survival (OS) and progression-free survival (PFS) after therapy. Results In total, 59 (68.9%) patients treated over 12 months achieved a CCyR after 12 months in imatinib group, while 67 (95.7%) patients in allo-HSCT group. The relapse rates were 14.8% (n=17) in imatinib group and 10.8% (n=9) in allo-HSCT group (P=0.456). Ten-year cumulative OS rates were 93.9% in imatinib group and 77.1% in allo-HSCT group(P=0.015) and ten- year cumulative PFS rates of two groups were 86.1% vs.88.0%(P=0.508). For Sokal rating stratified analysis, the ten-year OS rates of two groups were 96.4% vs.68.0% (P = 0.049) for high-risk patients,92.6% vs. 57.1% (P = 0.019) for intermediate-risk patients , while the ten-year PFS rates of two groups were 89.3% vs. 88.0% for high-risk patients (P = 0.942), 70.4% vs. 85.7% for intermediate-risk patients (P = 0.405).The ten-year OS rates and PFS rates were not significant difference for low-risk patients. The cumulative OS rates of two groups were 94.7% vs. 73.5%(P=0.019)for the patients who were not less than 30 years old,and the cumulative PFS rates of two groups were 84.2% vs. 94.1% respectively (P=0.147). Conclusion Imatinib mesylate treatment is superior to allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.5518.5518
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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