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1.
Anticancer Res ; 40(5): 2457-2465, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366389

RESUMEN

The introduction of tyrosine kinase inhibitors (TKIs) directed against the catalytic activity of the ABL tyrosine kinase has considerably improved the outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease. Indeed, these individuals currently show a life-expectancy comparable to those of healthy subjects. Currently, five TKIs (imatinib, dasatinib, nilotinib, bosutinib and ponatinib) are approved for the treatment of CML and can be used as first, second or further lines of treatment according to disease risk scores, patient comorbidities and the presence of known TKI resistance mechanisms. In fact, 15-20% of all CML patients fail to achieve optimal responses according to the current definitions of the European Leukemia Network and will require sequential TKI treatment to avoid disease progression. In this review, we present the state of art in several crucial areas of CML management by briefly: i) depicting the domain structure of the BCR-ABL1 oncoprotein; ii) describing pivotal data concerning TKI efficacy; iii) illustrating the diverse molecular mechanisms causing TKI resistance; and iv) summarizing new ABL1-directed therapeutic approaches that are presently under investigation.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-abl/genética , Resultado del Tratamiento
2.
Medicine (Baltimore) ; 99(19): e19962, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32384445

RESUMEN

INTRODUCTION: After tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 were introduced for the treatment of chronic myeloid leukemia, clinical outcomes have improved dramatically. However, together with the increase in the survival rate, a more frequent occurrence of secondary malignancies has been observed as well. TKIs have been demonstrated to be a risk factor of malignancies such as non-Hodgkin lymphoma, prostate cancer, and skin cancer. However, lymphoplasmacytic lymphoma (LPL) has never been reported as a secondary malignancy after TKI treatment in chronic myeloid leukemia (CML). PATIENT CONCERNS: An 81-year-old male patient diagnosed with CML and treated with TKIs for a long period (15 years) was admitted due to a chief complaint of abdominal pain. A large abdominal mass was detected by imaging that included computed tomography. DIAGNOSIS: LPL was confirmed from biopsies after ultrasonography and sigmoidoscopy. Serum IgM level was increased and M protein and monoclonal gammopathy, IgM_kappa light chain type were detected. INTERVENTIONS: The patient received six cycles of R-CHOP chemotherapy. OUTCOMES: After chemotherapy, he showed response. The sizes of the abdominal mass and lymph nodes decreased; moreover, serum M protein and IgM levels decreased, as well. CONCLUSION: Herein, for the first time, we describe a patient who developed LPL as a secondary malignancy after administration of TKIs for the treatment of CML. Our observations indicate the importance of awareness of this secondary malignancy that can develop in CML patients treated with TKIs.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Neoplasias Primarias Secundarias , Macroglobulinemia de Waldenström , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Biopsia/métodos , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Humanos , Inmunoglobulina M/sangre , Masculino , Neoplasias Primarias Secundarias/sangre , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/patología , Prednisona/administración & dosificación , Radiografía Abdominal/métodos , Rituximab/administración & dosificación , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Vincristina/administración & dosificación , Macroglobulinemia de Waldenström/sangre , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/etiología , Macroglobulinemia de Waldenström/patología
4.
Ann Hematol ; 99(5): 991-1006, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32253454

RESUMEN

Separase, a cysteine endopeptidase, is a key player in mitotic sister chromatid separation, replication fork dynamics, and DNA repair. Aberrant expression and/or altered separase proteolytic activity are associated with aneuploidy, tumorigenesis, and disease progression. Since genomic instability and clonal evolution are hallmarks of progressing chronic myeloid leukemia (CML), we have comparatively examined separase proteolytic activity in TKI-treated chronic phase CML. Separase proteolytic activity was analyzed on single cell level in 88 clinical samples and in 14 healthy controls by a flow cytometric assay. In parallel, BCR-ABL1 gene expression and replication fork velocity were measured by qRT-PCR and DNA fiber assays, respectively. The separase activity distribution (SAD) value indicating the occurrence of MNCs with elevated separase proteolytic activity within samples was found to positively correlate with BCR-ABL1 gene expression levels and loss of MMR (relapse) throughout routine BCR-ABL1 monitoring. Analyses of CD34+ cells and MNCs fractionized by flow cytometric cell sorting according to their separase activity levels (H- and L-fractions) revealed that CD34+ cells with elevated separase activity levels (H-fractions) displayed enhanced proliferation/viability when compared with cells with regular (L-fraction) separase activity (mean 3.3-fold, p = 0.0011). BCR-ABL1 gene expression positivity prevailed in MNC H-fractions over L-fractions (42% vs. 8%, respectively). Moreover, expanding CD34+ cells of H-fractions showed decreased replication fork velocity compared with cells of L-fractions (p < 0.0001). Our data suggests an association between high separase activity, residual BCR-ABL1 gene expression, and enhanced proliferative capacity in hematopoietic cells within the leukemic niche of TKI-treated chronic phase CML.


Asunto(s)
Antígenos CD34/metabolismo , Biomarcadores de Tumor/metabolismo , Proliferación Celular/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas/administración & dosificación , Separasa/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad
5.
Zhonghua Xue Ye Xue Za Zhi ; 41(2): 93-99, 2020 Feb 14.
Artículo en Chino | MEDLINE | ID: mdl-32135623

RESUMEN

Objective: To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) . Methods: From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed. Results: A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved

Asunto(s)
Dasatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva , Pirimidinas/uso terapéutico , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Estudios Retrospectivos , Resultado del Tratamiento
6.
Medicine (Baltimore) ; 99(9): e19256, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32118733

RESUMEN

INTRODUCTION: We report here the case of a patient with chronic myeloid leukemia (CML) in the chronic phase who was diagnosed 1 year after receiving a diagnosis of autoimmune hemolytic anemia (AIHA). The objective was to assess if the CML patient progressed from AIHA and explore the underlying factors of the poor outcome after the achievement of molecular complete remission (MCR). PATIENT CONCERNS: A patient with AIHA underwent splenectomy because of poor response to immune inhibitors. The spleen biopsy showed reactive hyperplasia. DIAGNOSIS: The patient was diagnosed with CML because of over-expression of the BCR-ABL (P210) gene in the bone marrow (BM), 1 year after receiving the diagnosis of AIHA. INTERVENTIONS: The splenectomy was performed as the patient was unresponsive to the standard treatments consisting of immunoglobulin and dexamethasone. The removed spleen was sent for pathological examination. After she was diagnosed with CML, she received imatinib treatment. OUTCOMES: The spleen biopsy confirmed the translocation of 22q11/9q34. No BCR-ABL kinase domain mutation was detected and there was no expression of the WT1 or EVI1 genes. After splenectomy, the number of peripheral white blood cells was consistently higher than normal during the total therapy time for CML even though she showed MCR. Two years after CML was diagnosed, the patient died from severe infection. The BM gene array analysis displayed 3 types of chromosomal abnormalities: gain (14q32.33), uniparental disomy (UPD) Xp11.22-p11.1), and UPD Xp11.1-q13.1. LESSONS: AIHA may be a clinical phase of CML progression in this patient. Both splenectomy and prolonged oral tyrosine kinase inhibitors may have contributed to the high risk of infection and her subsequent death. In addition, the gain of chromosome 14q32.33 may be related to her poor outcome.


Asunto(s)
Anemia Hemolítica Autoinmune , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Adolescente , Resultado Fatal , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Esplenectomía
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 136-140, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32027266

RESUMEN

OBJECTIVE: To analyze the relationship between cytogenetic changes and the progression in the patients with chronic myeloid leukemia (CML) during the treatment with tyrosine kinase inhibitor (TKI). METHODS: The chromosome G banding of 150 patients with CML treated in our hospital, was carried out to analyze the karyotype by the 24 h short-term culture or direct method of bone marrow cells, and the point mutation of the ABL kinase area was detected, the relationship between cytogenetic changes and the evolution of the disease course was analyzed. RESULTS: The indirect fluorescence in situ hybridization showed that the BCR-ABL fusion gene of 150 patients was positive, out of which 142 cases showed positive Philadelphia (Ph) (94.67%), 8 cases with Ph negative (5.33%). Among 142 cases with Ph positive on the first diagnosis, and 14 cases (9.86%) with additional chromosome abnormality (9.86%), 4 cases (2.82%) with mutation translocation with 124 cases (87.32%), standard translocation t (9; 22) (q34; Q11) were found. Out of the 14 patients with additional chromosomal abnormalities, 8 cases with "main pathmay" abnormalities, 2 case with -Y abnormalities, and 4 cases with "secondary pathway" abnormalities were observed. During TKI treatment, additional chromosomal abnormalities were found in 46 patients with standard translocation and abnormal number of chromosomes, and the incidence of disease progression and point mutation were higher (P<0.05). Compared with patients with the standard translocation, the disease-free survival rate of the patients diagnosed as CML at 1st visit and with additional chromosome abnormality was significantly decreased (P<0.05), but the overall survival rate showed no significantly different (P>0.05). Compared with patients without additional cvtogenetic aberrations, the disease free and overall survival rate of the patients with additional cytogenetic aberrations during the TKI treatment of CML in chronic phase were significantly decreased (P<0.05). CONCLUSION: Some CML patients may have additional chromosomal abnormalities during the onset and development of the disease, and these patients are at higher risk of disease progression.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/uso terapéutico , Aberraciones Cromosómicas , Análisis Citogenético , Citogenética , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Translocación Genética
8.
PLoS One ; 15(2): e0229104, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32106243

RESUMEN

Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34-/CD38-, BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and ß-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.


Asunto(s)
Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/farmacología , Células 3T3 , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Perfilación de la Expresión Génica , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ratones , Mutación/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos , Dominios Proteicos/genética , Inhibidores de Proteínas Quinasas/uso terapéutico
9.
Medicine (Baltimore) ; 99(3): e18888, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32011516

RESUMEN

RATIONALE: The success of tyrosine kinase inhibitor (TKI) therapy has greatly prolonged the survival time of patients with chronic myeloid leukemia (CML), harboring the characteristic Philadelphia (Ph) chromosome. However, a fraction of patients, achieving complete cytogenetic response after TKI therapy, develop a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with additional clonal chromosomal abnormalities in Philadelphia-negative cells (CCA/Ph-). PATIENT CONCERNS: A 56-year-old woman with AML, developing from Philadelphia-negative CML after TKI therapy. She showed 6 kinds of somatic variants-CEBPA, ATRX, WT1, CSMD1, IKZF1, and LRP1B mutation after diagnosed as AML. DIAGNOSIS: The patient was diagnosed with chronic phase CML that developed to AML after achieving durable complete cytogenetic response (CCR) and major molecular response (MMR). INTERVENTIONS: The patient was treated with TKI therapy at the period of CML. When diagnosed with AML, she received induction chemotherapy regimens, consolidation therapy, and allogeneic hematopoietic stem cell transplantation subsequently. OUTCOMES: The patient has been CCR and MMR for nearly 4 years, and has achieved complete remission after intervention related to AML. She is now preparing for allogeneic hematopoietic stem cell transplantation. LESSONS: These rare occurrences highlight the importance of exploring the relevant pathogenesis of AML developing from CML after TKI therapy. In addition to monitoring molecular changes in the course of CML, cytogenetic analysis, or next-generation sequencing of CML patients should be performed.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mieloide Aguda/etiología , Antineoplásicos/uso terapéutico , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Análisis Citogenético , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Translocación Genética
10.
Medicine (Baltimore) ; 99(5): e18811, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000382

RESUMEN

RATIONALE: Concurrent calreticulin (CALR) mutation and BCR-ABL1 fusion are extremely rare in chronic myelogenous leukemia; to date, only 12 cases have been reported. PATIENT CONCERNS: A 57-year-old male who had an 11-year history of essential thrombocytosis presented to our hospital with leukocytosis and marked splenomegaly for 3 months. DIAGNOSES: Chronic myelogenous leukemia with myeloid fibrosis arising on the background of essential thrombocytosis harboring both BCR-ABL1 fusion and type-1 like CALR mutation. INTERVENTIONS: Imatinib was started at 300 mg daily and increased to 400 mg daily after 3 months; interferon was added after 12 months. OUTCOMES: Partial cytogenetic response was achieved after 3 months of imatinib therapy and complete cytogenetic response was achieved after 1 year of treatment. However, CALR mutation was still present with a stable mutational allele burden. LESSONS: In this case report and review of additional 12 cases with simultaneous presence of CALR-mutation and BCR-ABL1 fusion, we highlighted the importance of integrating clinical, morphological, and molecular genetic data for classifying atypical myeloid neoplasms.


Asunto(s)
Calreticulina/genética , Proteínas de Fusión bcr-abl/genética , Genes abl , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Trombocitemia Esencial/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Trombocitemia Esencial/complicaciones
11.
Medicine (Baltimore) ; 99(7): e19150, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32049841

RESUMEN

Chronic myeloid leukemia (CML) is relatively rare in childhood and few studies have reported the clinical use of imatinib (IM) in pediatric CML. In this study, we evaluated the efficacy and tolerability of IM in children and adolescents with CML.We investigated 21 patients under 18 years of age with newly diagnosed CML and treated with IM in Children's Hospital of Chongqing Medical University between May 2014 and February 2018. The disease was staged according to the European LeukemiaNet criteria and the IM dose was determined based on the disease stage. Cumulative responses and survival probabilities were estimated according to the Kaplan-Meier method.The estimated complete hematologic response rate of chronic phase-chronic myeloid leukemia (CML-CP) was 89.5% at 3 months. The complete cytogenetic response rates increased with time, reaching 47.4%, 73.7%, and 80.3% at 6, 12, and 24 months, respectively. The cumulative major molecular response rates were 42.1% and 76.3% at 12 and 24 months, respectively. With a median follow-up time of 33.8 months (range, 3.2-61.7 months), the estimated 2-year overall survival (OS) rate for CML was 95.2% (95% confidence interval [CI], 70.7%-99.3%). None of the CML-CP patients progressed to the accelerated phase or had a blast crisis. The 2-year OS and progression-free survival rates for the CML-CP cohort were both 100%, while the estimated 2-year event-free survival rate was 68% (95% CI, 42.1%-84.2%). None of the patients in this group had treatment-related deaths or IM discontinuation due to drug toxicities, and only 1 patient had a grade III-IV nonhematologic adverse event. Overall, anemia was the most common adverse effect and 42.9% of patients had a decrease in bone mineral density.IM was effective and the adverse effects were well-tolerated throughout the follow-up period in Chinese CML patients under 18 years of age.


Asunto(s)
Antineoplásicos/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Adolescente , Niño , China/epidemiología , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
14.
Life Sci ; 243: 117255, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31923418

RESUMEN

BACKGROUND: The occurrence in drug resistance of chronic myeloid leukemia (CML) was accompanied by autophagy activation. Abnormal circular RNAs (circRNAs) participated in this progression. This study attempted to investigate the potential role of circ_0009910 in imatinib resistance of CML cells. METHODS: The expression of circ_0009910 and miR-34a-5p was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The characterization of circ_0009910 was investigated using oligo (dT)18 primers, Actinomycin D and RNase R. Cell viability (IC50 value) and apoptosis were assessed by Cell Counting Kit-8 (CCK8) assay and flow cytometry assay, respectively. The relative protein expression was quantified by western blot. The relationship among miR-34a-5p, circ_0009910 and ULK1 was predicted by online bioinformatics tool, and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP). RESULTS: The expression of circ_0009910 was up-regulated in the serum of imatinib-resistance CML patients and K562/R cells, and associated with unfavorable clinicopathologic features. Circ_0009910 in K562 and K562/R cells was mainly localized in the cytoplasm. Circ_0009910 knockdown inhibited cell proliferation and autophagy, but induced apoptosis in K562/R cells. Circ_0009910 targeted miR-34a-5p to regulate ULK1. MiR-34a-5p depression rescued the effects of circ_0009910 knockdown on apoptosis and autophagy in K562/R cells. CONCLUSION: Circ_0009910 accelerated imatinib-resistance in CML cells by modulating ULK1-induced autophagy via targeting miR-34a-5p, providing a potential target in imatinib resistance of CML.


Asunto(s)
Antineoplásicos/uso terapéutico , Homólogo de la Proteína 1 Relacionada con la Autofagia/fisiología , Autofagia/fisiología , Mesilato de Imatinib/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , MicroARNs/genética , Resistencia a Antineoplásicos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología
15.
Lancet Haematol ; 7(3): e218-e225, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31978329

RESUMEN

BACKGROUND: A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year. METHODS: The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099). FINDINGS: Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia. INTERPRETATION: Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed. FUNDING: Epidemiological and Clinical Research Information Network.


Asunto(s)
Dasatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Tasa de Supervivencia , Privación de Tratamiento
17.
Mini Rev Med Chem ; 20(1): 39-53, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-30854962

RESUMEN

Chronic Myeloid Leukemia (CML) represents 15-20% of all new cases of leukemia and is characterized by an uncontrolled proliferation of abnormal myeloid cells. Currently, the first-line of treatment involves Tyrosine Kinase Inhibitors (TKIs), which specifically inhibits the activity of the fusion protein BCR-ABL. However, resistance, mainly due to mutations, can occur. In the attempt to find more effective and less toxic therapies, several approaches are taken into consideration such as research of new anti-leukemic drugs and "combination chemotherapy" where different drugs that act by different mechanisms are used. Here, we reviewed the molecular mechanisms of CML, the main mechanisms of drug resistance and current strategies to enhance the therapeutic effect of TKIs in CML. Despite major advances in CML treatment, new, more potent anticancer drugs and with fewer side effects are needed. Marine organisms, and particularly seaweed, have a high diversity of bioactive compounds with some of them having anticancer activity in several in vitro and in vivo models. The state-of-art suggests that their use during cancer treatment may improve the outcome. We reviewed here the yet few data supporting anti-leukemic activity of some carotenoids and phlorotannins in some leukemia models. Also, strategies to overcome drug resistance are discussed, particularly the combination of conventional drugs with natural compounds.


Asunto(s)
Antineoplásicos/farmacología , Carotenoides/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Algas Marinas/química , Taninos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Carotenoides/química , Carotenoides/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Taninos/química , Taninos/uso terapéutico
18.
Bull Cancer ; 107(1): 113-128, 2020 Jan.
Artículo en Francés | MEDLINE | ID: mdl-31353136

RESUMEN

In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.


Asunto(s)
Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación Missense , Mutación Puntual , Antineoplásicos/uso terapéutico , Dominio Catalítico , Toma de Decisiones Clínicas , ADN de Neoplasias/análisis , Resistencia a Antineoplásicos/genética , Sustitución de Medicamentos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Biología Molecular , Dominios Proteicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Rol
19.
Chem Biol Interact ; 315: 108888, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31682805

RESUMEN

Relapse and drug resistance is still major challenges in the treatment of leukemia. Promethazine, an antihistaminic phenothiazine derivative, has been used to prevent chemotherapy-induced emesis, although there is no report about its antitumor potential. Thus, we evaluated the promethazine cytotoxicity against several leukemia cells and the underlying mechanisms were investigated. Promethazine exhibited potent and selective cytotoxicity against all leukemia cell types in vitro at clinically relevant concentrations. Philadelphia positive chronic myeloid leukemia (CML) K562 cells were the most sensitive cell line. The cytotoxicity of promethazine in these cells was triggered by the activation of AMPK and inhibition of PI3K/AKT/mTOR pathway. The subsequent downstream effects were NOXA increase, MCL-1 decrease, and Beclin-1 activation, resulting in autophagy-associated apoptosis. These data highlight targeting autophagy may represent an interesting strategy in CML therapy, and also the antitumor potential of promethazine by acting in AMPK and PI3K/AKT/mTOR signaling pathways. Since this drug is currently used with relative low side effects, its repurposing may represent a new therapeutic opportunity for leukemia treatment.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Beclina-1/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Prometazina/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Células Jurkat , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
20.
Ann Hematol ; 99(2): 359-361, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31872359
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