RESUMO
The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto , Masculino , Feminino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Pessoa de Meia-Idade , Adolescente , Estudos Retrospectivos , Adulto Jovem , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Intervalo Livre de Doença , Transplante Homólogo , Aloenxertos , Taxa de SobrevidaRESUMO
INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.
Assuntos
Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transplante Homólogo , Humanos , Feminino , Masculino , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/líquido cefalorraquidiano , Leucemia Mieloide Aguda/mortalidade , Estudos Retrospectivos , Adulto , Prognóstico , Pessoa de Meia-Idade , Seguimentos , Adolescente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Taxa de Sobrevida , Adulto Jovem , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/líquido cefalorraquidiano , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Idoso , Criança , CitologiaRESUMO
To compare efficacy between homoharringtonine combined with cytarabine and aclarubicin (HAA) and idarubicin and cytarabine (IA) regimens as first induction chemotherapy in patients with core binding factor acute myeloid leukemia (CBF-AML). Cox regression model and propensity score matching (PSM) were used to identify the regimen associated with a better remission rate and outcomes. In total, 374 patients with CBF-AML (243 with RUNX1::RUXN1T1 and 131 with CBFB::MYH11) were included in this study. The patients received the HAA or IA regimen (187 each) as the first induction therapy. For patients with RUNX1::RUXN1T1, multivariate analyses showed that the HAA regimen was significantly associated with a higher CR/CRi rate after the first induction (hazard ratio [HR] = 5.3 [95% CI 2.3, 12.2]; p < 0.001) and more favorable relapse-free survival (RFS) (HR = 0.5 [0.3, 0.8], p = 0.01). In PSM analysis, the HAA regimen also had a higher CR/CRi rate (96% vs. 77%, p < 0.001), especially for those harboring wild-type KIT (KITWT) (96% vs. 83%, p = 0.02) or non-D816 KIT mutation (100% vs. 63%, p = 0.002), as well as more favorable RFS (p = 0.01), compared with the IA regimen. However, there was no difference in the remission rate or outcomes between the two regimens for patients with CBFB::MYH11. The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KITWT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.
Assuntos
Harringtoninas , Leucemia Mieloide Aguda , Humanos , Idarubicina/uso terapêutico , Mepesuccinato de Omacetaxina , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Citarabina/uso terapêutico , Aclarubicina , Quimioterapia de Indução , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Indução de RemissãoRESUMO
OBJECTIVE: To assess the value of fluorescence in situ hybridization (FISH) technique for the verification of the clonalities of non-clonal cytogenetic abnormalities (n-CCA) identified by conventional chromosome banding analysis (CBA) in patients with Myelodysplastic syndrome (MDS). METHODS: Clinical data and results of karyotyping and FISH assays for 91 patients of MDS with n-CCA identified by CBA were retrospectively analyzed. In total 94 non-clonal +8, 5q-, -7/7q- or 20q- were detected by CBA, among which 43 (45.7%) were verified to be clonal abnormalities by FISH. RESULTS: The detection rates for +8, 5q-, -7/7q- and 20q- by FISH were 47.6% (30/63), 25% (2/8), 41.7% (5/12), 40% (2/5) and 66.7% (4/6), respectively, with the positive cells accounting for 4% to 90% of all counted cells, with a median value of 7%. The 91 patients were divided into three groups including ≥ 20, 10 ~< 20 and < 10 based on the numbers of metaphase cells in CBA, and the detection rates by FISH for the three groups were 43.7% (31/71), 33.3% (3/9) and 63.6% (7/11), respectively, which showed no statistically difference (P > 0.05). Continuous CBA and FISH surveys were conducted for 26 patients who received supportive treatment, and the results revealed that 91.7% (11/12) of FISH-verified positive abnormalities had persisted, whereas 92.9% (13/14) of the n-CCA verified as negative by FISH was transient. CONCLUSION: Nearly half of the CBA identified n-CCA have been verified as clonal aberrations by FISH, and the FISH detection rate showed no correlation with the number of metaphase cells. FISH test is strongly recommended for verifying the clonalities of n-CCA detected by CBA, and continuous cytogenetic survey of the patients with MDS is necessary.
Assuntos
Aberrações Cromossômicas , Síndromes Mielodisplásicas , Humanos , Hibridização in Situ Fluorescente , Estudos Retrospectivos , Cariotipagem , Síndromes Mielodisplásicas/genéticaRESUMO
OBJECTIVE: To investigate the clinical and prognostic characteristics of primary acute myeloid leukemia (AML) with 11q23/KMT2A rearrangements. METHODS: Clinical data of 90 patients with primary AML and 11q23/KMT2A rearrangements were analyzed retrospectively. RESULTS: By karyotyping analysis, 80 of the 90 patients had translocations involving 11q23/KMT2A, with t(9;11)(p22;q23), t(6;11)(q27;q23), t(10;11)(p12;q23) and t(11;19)(q23;p13) being the most common ones, while 10 cases were found to have non-translocation abnormalities. The overall complete remission (CR) rate was 75.6%, and patients with t(6;11) had lower CR rate compared with non-t(6;11) patients (47.1% vs. 82.2%, P = 0.005). After a median follow-up of 24.5 months, the patients receiving allo-hematopoietic stem cell transplantation (allo-HSCT) had significantly higher 3-year overall survival (OS) (80.3% vs. 16.6%, P < 0.001) and 3-year event-free survival (EFS) (73.5% vs. 16.3%, P < 0.001) compared with non-transplant patients. Patients with t(6;11) had the lowest 3-year OS (11.8% vs. 56.0%, P < 0.001) and 3-year EFS (5.9% vs. 53.8%, P < 0.001) compared with other type of abnormalities. No significant difference was noted in the survival between patients with t(9;11) and non-t(9;11) regardless whether they had received HSCT. CONCLUSION: The clinical characteristics of primary AML with 11q23/KMT2A rearrangements are heterogeneous. Patients did not receive HSCT had poorer survival, particularly with the presence of t(6;11). Allo-HSCT could significantly improve the survival of such patients.
Assuntos
Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Translocação Genética , Rearranjo Gênico , PrognósticoRESUMO
Acute myeloid leukaemia (AML) patients with biallelic mutations of CEBPA (bi CEBPA) have a 30-50% relapse rate. This study established the value of mutations based on next-generation sequencing (NGS) and multiparameter flow cytometric measurable residual disease (MFC-MRD) detection and compared the outcomes. From 2014 to 2018, 124 newly diagnosed bi CEBPA AML patients were treated. The median age was 37·5 (16-69) years. The 3-year cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS) were 33·0%, 64·7% and 84·3%, respectively. Patients without additional mutations and with GATA2 mutations were defined as 'NGS low risk', which was the only favourable independent factor for CIR and RFS of pretreatment parameters. Patients with sustained positive MRD after two consolidation cycles and MRD negative losses at any time were defined as 'MRD high risk', which was the only poor independent factor for CIR, RFS and OS, including pretreatment and post-treatment parameters. In CR2 and non-remission patients who underwent allo-HSCT, superior OS was achieved. We conclude that NGS low risk was a favourable factor in the analysis of pretreatment parameters. MRD risk stratification was an independent prognostic factor in pretreatment and post-treatment parameters. Relapsed patients still have a favourable outcome followed by allo-HSCT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Estimuladoras de Ligação a CCAAT/genética , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda/patologia , Proteínas de Neoplasias/genética , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Idoso , Alelos , Aloenxertos , Antraciclinas/administração & dosagem , Terapia Combinada , Citarabina/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Idarubicina/administração & dosagem , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Recidiva , Medição de Risco , Adulto JovemRESUMO
To date, the research on dendritic cells (DCs) and their correlated neoplasms has not been clear. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and mature plasmacytoid dendritic cell proliferation (MPDCP) are two types of malignancies originating from plasmacytoid dendritic cells (pDCs). Some evidence has indicated the existence of other pDC neoplasms. In addition, cases of myeloid neoplasms (MNs), acute myeloblastic leukemia (AML), and myelodysplastic syndrome (MDS) with increased pDCs (AML/MDS-pDCs) seem to have immature DCs according to the vaguely consistent expression of markers among MNs and pDCs, which appear to fit the developmental pattern of normal DCs. We analyzed 14 AML/MDS-pDC cases mainly for their immunophenotype by flow cytometry and inferred their CD expression pattern. The patients' clinical information and other laboratory data were collected and reviewed. AML/MDS-pDCs show a different pattern of markers from BPDCN and MPDCP. Three maturation-involved stages were found in these AML/MDS-pDCs patients. Stage I was the most immature stage and displayed an expression profile of CD34+/st+ CD117+/st+ BDCA2- BDCA4- CD123+ HLA-DR+/st+ CD4- CD45dim+ ; Stage II was the more immature stage displayed a phenotype of CD34dim+ CD117dim+ BDCA2-/dim+ BDCA4-/dim+ CD123st+ HLA-DR+/st+ CD4- CD45+ ; and Stage III was the mature stage showed CD34- CD117- BDCA2+ /BDCA4+ CD123st+ HLA-DR+/st+ CD4+ CD45+/st+ . Three maturation-involved stages overlapped well with the phenotypes of normal DC progenitors in a continuously developmental process: granulocyte, monocyte, and DC progenitors (GMDPs) and/or monocyte and DC progenitors (MDPs), common DC progenitors (CDPs), pDCs, and/or pre-DCs. In this study, we considered AML/MDS-pDCs as entities that were distinct from BPDCN and MPDCP and correlated the components of this tumor with the normal DC differentiation pathway, which provides new evidence for understanding DC neoplasms. © 2019 International Society for Advancement of Cytometry.
Assuntos
Apresentação de Antígeno/fisiologia , Diferenciação Celular/fisiologia , Células Dendríticas/citologia , Leucemia Mieloide Aguda/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Dendríticas/imunologia , Feminino , Hematopoese/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
The pathogenesis of corticosteroid-resistant immune thrombocytopenia (ITP), a clinically challenging condition in which patients exhibit either no response to corticosteroids or are corticosteroid-dependent, remains poorly understood. Murine studies suggest that bone marrow (BM) endothelial progenitor cells (EPCs) play a crucial role in regulating megakaryocytopoiesis. However, little is known regarding the number and function of BM EPCs or how to improve impaired BM EPCs in corticosteroid-resistant ITP patients. In the current case-control study, we evaluated whether the BM EPCs in corticosteroid-resistant ITP differed from those in corticosteroid-sensitive ITP. Moreover, whether atorvastatin could enhance the number and function of BM EPCs derived from corticosteroid-resistant ITP patients was investigated in vitro and in vivo. Reduced and dysfunctional BM EPCs, characterized by decreased capacities of migration and angiogenesis as well as higher levels of reactive oxygen species and apoptosis, were observed in corticosteroid-resistant ITP patients. In vitro treatment with atorvastatin quantitatively and functionally improved BM EPCs derived from corticosteroid-resistant ITP patients by downregulating the p38 MAPK pathway and upregulating the Akt pathway, and rescued the impaired BM EPCs to support megakaryocytopoiesis. Subsequently, a pilot cohort study showed that atorvastatin was safe and effective in corticosteroid-resistant ITP patients. Taken together, these results indicate that reduced and dysfunctional BM EPCs play a role in the pathogenesis of corticosteroid-resistant ITP, and the impaired BM EPCs could be improved by atorvastatin both in vitro and in vivo. Although requiring further validation, our data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in corticosteroid-resistant ITP patients.
Assuntos
Corticosteroides/administração & dosagem , Atorvastatina/administração & dosagem , Células da Medula Óssea/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Células Endoteliais/metabolismo , Mielopoese/efeitos dos fármacos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Apoptose/efeitos dos fármacos , Células da Medula Óssea/patologia , Movimento Celular/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/metabolismo , Púrpura Trombocitopênica Idiopática/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Monosomal karyotype (MK) is associated with poor prognosis in patients with myeloid neoplasms; however, its prognostic significance in Philadelphia chromosome-negative (Ph-negative) acute lymphoblastic leukemia (ALL) remains unclear. Data of 323 patients with Ph-negative ALL treated at Peking University People's Hospital were retrospectively analyzed. MK was identified in 49 (14.8%) patients. The patients with MK had lower hemoglobin levels (P = 0.026), lower platelet count (P = 0.032), higher percentages of blasts in the peripheral blood at diagnosis (P = 0.008), and higher percentages of high-risk karyotypes (P < 0.001) compared with those without MK. The complete remission (CR) rate and the minimal residual disease negativity rate were not significantly different between patients with and without MK. In the multivariate analysis, MK was identified as an independent factor associated with higher cumulative incidence of relapse (CIR) (hazard ratio (HR), 2.07; 95% confidence interval (CI), 1.02, 4.21; P = 0.043), shorter disease-free survival (DFS) (HR, 2.80; 95% CI, 1.20, 6.54; P = 0.017) and shorter overall survival (OS) (HR, 5.75; 95% CI, 2.07, 16.03; P = 0.001) in the chemotherapy cohort; however, MK had no impact on outcomes in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) cohort. Mantel-Byar analysis showed that allo-HSCT was associated with lower CIR (P < 0.001), longer DFS (P < 0.001), and longer OS (P < 0.001) in CR patients with MK. In conclusion, our study showed that MK was an independent predictor of poor outcomes in patients with Ph-negative ALL receiving chemotherapy but not allo-HSCT, and allo-HSCT could improve the outcomes of patients with MK.
Assuntos
Antineoplásicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Idoso , Aloenxertos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos RetrospectivosRESUMO
Many studies have confirmed that overexpressed WT1 exists in leukemic cells, especially in AML. However, the immunophenotypic features of this sort of leukemic cells remain to be unclarified. We retrospectively analyzed the immunophenotype of 283 newly diagnosed AML patients with intermediated and poor cytogenetic risk to evaluate the correlation between phenotype and WT1 overexpression. EVI1 transcripts, KMT2A-PTD, FLT3-ITD, and NPM1 mutations were simultaneously assessed. Our results revealed that overexpressed WT1 was significantly associated with the expression of CD117, CD13, and CD123. Besides, leukemic cells with WT1 overexpression also lacked lymphoid and myeloid differentiation-related markers. FAB subtype M2 patients had higher WT1 levels, compared with other FAB subtype. Multivariate analysis was proved that NPM1 mutation, M2 subtype, and the expression of CD123 were independently associated with WT1 overexpression. These indicated that AML with overexpressed WT1 was proliferated and blocked in the early stage of AML development. It presumably provided some clues to detect overexpressed WT1 cells via multiparameter flow cytometry. CD123-targeted drugs might become one of the alternative treatments for patients with WT1 overexpression.
Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Proteínas WT1/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , Feminino , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Nucleofosmina , Fatores de Risco , Proteínas WT1/genéticaRESUMO
BACKGROUND: Currently, the prognostic stratification and therapeutic evaluation systems for multiple myeloma (MM) lack specific molecular indicators. OC-STAMP is a new gene and is also highly expressed in MM. METHODS: A total of 160 MM patients have been investigated with both quantitative reverse transcription PCR (RT-qPCR), flow cytometry (FCM) and cytogenetic FISH on the same mononuclear cells isolated from bone marrow specimens. RESULTS: We found that OC-STAMP mRNA levels were significantly higher in newly diagnosed cases of MM than in healthy donors (median, 0.52% vs. 0.02%, P < .001). Moreover, the changes in the OC-STAMP mRNA levels paralleled the disease stages and minimal residual disease, as detected by FCM. Furthermore, we found that patients with high OC-STAMP mRNA levels were more likely to develop ≥3 bone lesions, be diagnosed with Durie-Salmon stages III, and have the P53 (17p13) deletion. In addition, advanced stage patients with high OC-STAMP mRNA levels had a lower 4-year progression-free survival (5.6% vs. 22.9%, P = .0055) and a worse 4-year overall survival (25.8% vs. 48.8%, P = .0137) compared to patients with low mRNA levels of this indicator. CONCLUSIONS: OC-STAMP may be a promising molecular indicator to monitor treatment effects and participate in the prognostic stratification of MM.
Assuntos
Biomarcadores Tumorais , Proteínas de Membrana/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Medula Óssea/patologia , Linhagem Celular Tumoral , Aberrações Cromossômicas , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Imunofenotipagem , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Análise de Sobrevida , Translocação Genética , Proteína Supressora de Tumor p53/genéticaRESUMO
OBJECTIVE: To trace a rare case of chronic myeloid leukemia (CML) with a four-way Philadelphia chromosome variant by cytogenetic analysis in order to provide a basis for the selection of treatment. METHODS: Bone marrow morphology, chromosomal karyotyping, fluorescence in situ hybridization (FISH) and real-time quantitative PCR (RQ-PCR) were used for the diagnosis and staging of the disease. Point mutations in the tyrosine kinase domain of ABL1 gene were detected by Sanger sequencing. RESULTS: The patient was initially diagnosed as CML in chronic phase (CML-CP) with a chromosomal karyotype of 46,XX,t(5;9;22;6)(q13;q34;q11;q25), while FISH revealed presence of a variant Philadelphia chromosome translocation. Clonal evolution has occurred after 38 months of tyrosine kinase inhibitor (TKI) treatment, when cytogenetic analysis revealed coexisting t(5;9;22;6)(q13;q34;q11;q25) and t(5;9;22;6;17)(q13;q34;q11;q25;q11). After 57 months of TKIs treatment, only the t(5;9;22;6;17) clone was detected. Three months later, hyperdiploidy with additional abnormalities were detected in addition to t(5;9;22;6;17). Three mutations, including p.Tyr253Phe, p.Thr315Ile and p.Gly250Glu, were identified in the tyrosine kinase domain of the ABL1 gene during the course of disease. The patient did not attain cytogenetic and molecular response to TKIs. CONCLUSION: The four-way variant translocation may be genetically unstable. Clonal evolution and genetic mutations are likely to occur during TKIs treatment, resulting in poor response to drug therapy. This observation, however, needs to be confirmed by large-scale studies.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Translocação Genética , Inibidores Enzimáticos/uso terapêutico , Evolução Molecular , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação/genéticaRESUMO
Refinement of risk stratification in Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukaemia (ALL) might aid the identification of patients who are likely to relapse. Abnormal S100 calcium binding protein A16 (S100A16) has been implicated in various cancers, but its function remains unclear. We found S100A16 transcript levels were higher in 130 adults with newly-diagnosed Ph-negative B-cell ALL compared with 33 healthy controls. In 115 of 130 patients who achieved first complete remission, those with high S100A16 transcript levels displayed a lower 3-year cumulative incidence of relapse (CIR; 34% [21, 47%] vs. 40% [48, 72%]; P = 0·012) and higher 3-year relapse-free survival (RFS; 65% [53, 78%] vs. 35% [23, 46%]; P = 0·012), especially when receiving chemotherapy only. In multivariate analysis a low S100A16 transcript level was independently-associated with a higher CIR (Hazard ratio [HR] = 3·74 [1·01-13·82]; P = 0·048) and inferior RFS (HR = 5·78 [1·91, 17·84]; P < 0·001). Function analysis indicated that knockdown of S100A16 promoted proliferation and anti-apoptosis and reduced chemosensitivity. S100A16 over-expression revealed an opposite trend, especially in a xeno-transplant mouse model. Western blotting analysis showed upregulation of PI3K/AKT and ERK1/2 in S100A16-knockdown and S100A16-overexpression B-cell ALL cell lines respectively. Inhibition assays suggested these two signalling pathways participated in the S100A16-mediated proliferation and survival effects in B-cell ALL cell lines. Trial Registration: Registered in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940]; http://www.chictr.org.cn.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas S100/genética , Adolescente , Adulto , Idoso , Animais , Apoptose/fisiologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Estudos Retrospectivos , Proteínas S100/biossíntese , Análise de Sobrevida , Transcrição Gênica , Transfecção , Adulto JovemRESUMO
The prognostic significance of Wilms' tumor gene 1 (WT1) expression at diagnosis in adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly understood. A total of 257 adults with Ph-negative BCP-ALL who were consecutively diagnosed and received at least 1 course of induction therapy at our institute were retrospectively analyzed. The WT1 expression patterns were significantly different among the molecularly and cytogenetically defined groups (E2A-PBX1, TEL-AML1, and MLL rearrangements; high hyperdiploidy and B-other). By considering the WT1 expression pattern and the relapse status, 2 cutoff values, 1.8% and 7.2%, were arbitrarily selected to place patients into WT1-low, WT1-inter, and WT1-high groups. In the B-other patients who achieved complete remission (CR), WT1-low and WT1-high patients had similar 3-year relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS) rates, which were all significantly lower than those of WT1-inter patients. The combined WT1-low/high expression group (n = 132) had significantly lower 3-year RFS, DFS, and OS rates compared with the WT1-inter group (n = 63) of B-other patients (RFS and DFS all P < 0.0001; OS P = 0.0018 and 0.0008). WT1 low/high expression as well as treating with chemotherapy only was independent poor prognostic factors for RFS, DFS, and OS in the B-other patients who achieved CR. Therefore, the molecularly and cytogenetically defined adult Ph-negative BCP-ALL groups have characteristic WT1 expression patterns, and WT1 low/high expression at diagnosis predicts poor outcome in B-other patients.
Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Proteínas WT1/biossíntese , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Taxa de Sobrevida , Proteínas WT1/genéticaRESUMO
To explore the type, prevalence and outcomes in chronic myeloid leukaemia (CML) patients with uncommon BCR-ABL1 transcripts in the era of tyrosine kinase inhibitors (TKIs), uncommon BCR-ABL1 transcripts were screened in 4750 patients by multiplex polymerase chain reaction (PCR), and type-specific real-time quantitative PCR was regularly performed for molecular monitoring. A total of 19 uncommon transcripts, including e1a2, e1a3, e6a2, e8a2, e12a2, unusual e13a2, e13a3, unusual e14a2, e14a3 and e19a2 were identified in 83 (1·7%) patients. The three most frequent types were e19a2, e13a3/e14a3 and e1a2. Compared with the 571 newly diagnosed CML patients in chronic phase with common e13a2/e14a2 transcripts receiving frontline imatinib therapy, patients with the e19a2 (n = 16) and e1a2 (n = 11) transcripts had significantly reduced probabilities of 1-year complete cytogenetic response (CCyR, P = 0·0004 and 0·016) and major molecular response (MMR, P = 0·0018 and 0·0035), and patients with the e13a3/e14a3 transcript (n = 10) had significantly increased probabilities of 1-year CCyR (P = 0·0072) and MMR (P = 0·0073). Patients with the e19a2 transcript had low probabilities of 2-year event-free survival (EFS, P = 0·0004) and progression-free survival (P = 0·0067), and patients with the e1a2 transcript had low probability of 2-year EFS (P < 0·0001). Therefore, uncommon BCR-ABL1 fusion transcripts are rare and diverse in patients with CML and may be relevant for TKI therapy outcomes.
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Sequência de Bases , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Prevalência , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA Mensageiro/genéticaRESUMO
Relapse remains one of the major obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) even after allogeneic hematopoietic stem cell transplantation. The persistence of leukemia-propagating cells (LPCs) may lead to the recurrence of Ph+ALL. Using a xenograft assay, LPCs enrichment in the CD34+CD38-CD58- fraction in Ph+ALL was recently identified. A further cohort study indicated that the LPCs phenotype at diagnosis was an independent risk factor for relapse of Ph+ALL. However, little is known about the potential molecular mechanism of LPCs-mediated relapse. Therefore, the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL were investigated using RNA sequencing (RNA-Seq). Most of the differentially expressed genes between the LPCs and other cell fractions were related to the regulation of the cell cycle and metabolism, as identified by the gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Consistent with the RNA-Seq results, the mRNA levels of cell cycle-related genes, such as cyclin-dependent kinase 4, were significantly lower in the LPCs fraction than in other cell fractions. Moreover, the proportion of quiescent cells in LPCs was significantly higher than in other cell fractions. In summary, distinctive gene expression profiles and clusters, which were mostly related to the regulation of the cell cycle and metabolism, were demonstrated between LPCs and other cell fractions from patients with de novo Ph+ALL. Therefore, it would be beneficial to develop novel LPCs-based therapeutic strategies for Ph+ALL patients.
Assuntos
Perfilação da Expressão Gênica/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adulto , Estudos de Coortes , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Adulto JovemRESUMO
BACKGROUND Acute myeloid leukemia with intermediate cytogenetic risk (ICR-AML) needs to be stratified. The abnormal gene expression might be prognostic, and its cutoff value for patient grouping is pivotal. MATERIAL AND METHODS Ecotropic viral integration site 1 (EVI1) transcripts were assessed in 191 adult ICR-AML patients at diagnosis who received chemotherapy only. MLL-PTD, WT1 transcript levels, FLT3-ITD, and NPM1 mutations were simultaneously evaluated, and 27 normal bone marrow samples were tested to define normal threshold. RESULTS The normal upper limit of EVI1 transcript levels was 8.0%. Receiver operating characteristic curve analysis showed that 1.0% (a 0.9-log reduction from the normal limit) was the EVI1 optimal cutoff value for significantly differentiating relapse (P=0.049). A total of 23 patients (12%) had EVI1 levels ≥1.0%. EVI1 ≥1.0% had no effect on CR achievement, whereas it was significantly associated with lower 2-year relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS) rates in the entire cohort (P=0.0003, 0.0017, and 0.0009, respectively), patients with normal karyotypes (P=0.0032, 0.0047, and 0.0007, respectively), and FLT3-ITD (-) patients (all P<0.0001). Multivariate analysis showed that EVI1 ≥1.0% was an independent adverse prognostic factor for RFS, DFS, and OS in the entire cohort. In addition, patients with EVI1 transcript levels between 1.0% and 8.0% had 2-year RFS rates similar to those with EVI1 ≥8.0%, and they both had significantly lower RFS rates than those with EVI1 <1.0% (P=0.0005 and 0.027). CONCLUSIONS High EVI1 expression predicts poor outcome in ICR-AML patients receiving chemotherapy. The optimal cutoff value for patient stratification is different from the normal limit.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Adolescente , Adulto , Idoso , Medula Óssea/patologia , Estudos de Coortes , Citogenética , Intervalo Livre de Doença , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Curva ROC , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To report on a case of therapy-related acute monocytic leukemia(t-AML) with t(11;17) (q23;q21)/MLL-AF17q after successful treatment for acute promyelocytic leukemia(APL) with t(15;17) (q22;q21)/PML-RARα. METHODS: A MICM method (bone marrow morphology(M), immunophenotype(I), cytogenetics(C), and molecular biology(M)) was used for the diagnosis and classification of the disease at the time of onset and transformation. RESULTS: The patient was initially identified with typical morphology and immunophenotype of APL. She has carried t(15;17)(q22;q21) and PML-RARα fusion gene but was without t(11;17)(q23;q21) or MLL gene abnormalities. After 13 months of successful treatment, she has transformed to AML with typical morphology and immunophenotype. t(11;17)(q23;q21) and MLL-AF17q fusion gene were detected in her bone marrow sample, while no PLZF-RARα fusion gene was detected by real-time quantitative reverse-transcription PCR(RQ-PCR) and fluorescence in situ hybridization(FISH). CONCLUSION: t-AML is a serious complication after successful treatment of APL. t(11;17)(q23;q21) is not specific for the diagnosis of variant APL and can also be detected in t-AML. RQ-PCR and FISH are essential for the diagnosis of such patients.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 17 , Leucemia Monocítica Aguda/genética , Leucemia Promielocítica Aguda/genética , Segunda Neoplasia Primária/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-IdadeRESUMO
BACKGROUND: As one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34+CD38-CD58- fraction in human Ph+ALL. Additionally, a cohort study demonstrated that Ph+ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies. METHODS: RNA sequencing (RNA-Seq) and real-time quantitative polymerase chain reaction (qRT-PCR) were performed to analyze the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL. In order to assess the effects of the selective BCR-ABL and/or Janus kinase (JAK)2 inhibition therapy by the treatment with single agents or a combination of ruxolitinib and imatinib or nilotinib on Ph+ALL LPCs, drug-induced apoptosis of LPCs was investigated in vitro, as well as in vivo using sublethally irradiated and anti-CD122-conditioned NOD/SCID xenograft mouse assay. Moreover, western blot analyses were performed on the bone marrow cells harvested from the different groups of recipient mice. RESULTS: RNA-Seq and qRT-PCR demonstrated that JAK2 was more highly expressed in the sorted LPCs than in the other cell fractions in de novo Ph+ALL patients. Combination treatment with a selective JAK1/JAK2 inhibitor (ruxolitinib) and nilotinib more effectively eliminated LPCs than either therapy alone or both in vitro and in humanized Ph+ALL mice by reducing phospho-CrKL and phospho-JAK2 activities at the molecular level. CONCLUSIONS: In summary, this pre-clinical study provides a scientific rationale for simultaneously targeting BCR-ABL and JAK2 activities as a promising anti-LPCs therapeutic approach for patients with de novo Ph+ALL.