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1.
Zhonghua Xue Ye Xue Za Zhi ; 41(2): 93-99, 2020 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-32135623

RESUMO

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

Assuntos
Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva , Pirimidinas/uso terapêutico , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 18-23, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027247

RESUMO

OBJECTIVE: To investigate the clinical efficacy, related side-effectt and long-term survival condition of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients treated with second generation TKI dasatinib and chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Clinical data of 19 newly diagnosed as Ph+ ALL patients treated by dasatinib, chemotherapy and allo-HSCT from January 2012 to September 2018 were collectd and analyzed. RESULTS: There were 10 males and 9 females with median age of 29 years old. 14 patients were BCR/ABL P190 positive while 5 with BCR/ABL P210 positive. Three patients had complex karyotype, and 3 cases were confirmed to have central nervous system leukemia. All the patients received treatment with the induction chemotherapy regimen of VDCLP and consolidation regimens such as HD-MTX and MAE. 11 patients (57.9%) received dasatinib during induction chemotherapy, 3 patients (15.8%) received dasatinib after remission and 5 patients (26.3%) received dasatinib to replace imatinib. Side-effect appeared in 3 patients including rash, edema and nausea. All the patients got morphological remission and 7 patients(63.6%) got MMR after 4 weeks of induction chemotheraphy. 17 patients (89.5%) got MMR and 15 patients(78.9%) got CMR before allo-HSCT. All the patients received related bone marrow and peripheral hematopoietic stem cell transplantation from related donors, the median time of WBC and platelet engraftment were 12 d and 14 d after transplantation, respectively. The incidence rate of aGVHD and cGVHD were 42.1% and 57.9% respectivety. 13 patients received therapy of dasatinib after HSCT but 7 patients discontinued because of severe headache, vomiting and serious effusions. All the patients were followed-up for the median time of 42 months, the 3-year and 5-year OS both were 94.4%, and 3-year and 5-year RFS of 81.9% and 71.6%, respectively. CONCLUSION: First-line administration of dasatinib and chemotherapy followed by allo-HSCT for treatment of Ph+ALL is effective and patients can well-tolerate, the patients long-tern survival maybe superior to that of the patients treated with first generation TKI.


Assuntos
Dasatinibe/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Feminino , Humanos , Masculino , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases , Estudos Retrospectivos , Resultado do Tratamento
4.
Lancet Haematol ; 7(3): e218-e225, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978329

RESUMO

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.


Assuntos
Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Suspensão de Tratamento
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(1): 47-52, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31948524

RESUMO

OBJECTIVE: To study the influence of dasatinib treatment on body height in children with acute myeloid leukemia (AML). METHODS: A retrospective analysis was performed for the clinical data of 86 AML children aged <17 years. According to the treatment regimen, these children were divided into a conventional chemotherapy group and a dasatinib chemotherapy group. The 57 children in the conventional chemotherapy group were given conventional chemotherapy drugs without tyrosine kinase inhibitor, and the 29 children in the dasatinib chemotherapy group were given conventional chemotherapy drugs and dasatinib. The two groups were compared in terms of height standard deviation score (HtSDS) at the beginning of treatment and after treatment, as well as the change in HtSDS after 1 and 2 years of treatment. RESULTS: There was no significant difference in HtSDS between the conventional and dasatinib chemotherapy groups before treatment. Within the first two years of treatment, the dasatinib chemotherapy group had a similar change trend of HtSDS as the conventional chemotherapy group. Four children in the dasatinib chemotherapy group reached the final adult height during follow-up, which was significantly lower than the target height (P=0.044). In the conventional chemotherapy group, there was no significant difference between final adult height and target height. In the dasatinib chemotherapy group, the children in adolescence had a significant change in HtSDS after treatment (P=0.032). CONCLUSIONS: Dasatinib treatment may affect the final height of children with AML, and the use of dasatinib after the beginning of adolescence may lead to growth disorder, but dasatinib treatment has little effect on body height in the short-term treatment.


Assuntos
Estatura , Dasatinibe/uso terapêutico , Leucemia Mieloide Aguda , Adolescente , Criança , Transtornos do Crescimento , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Estudos Retrospectivos
6.
Medicine (Baltimore) ; 98(48): e18079, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770225

RESUMO

PURPOSE: The aim of this study was to evaluate the variables associated with patient-reported symptoms and the impact of symptoms on health-related quality-of-life (HRQoL) in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). METHODS: Anonymous Chinese-language questionnaires were distributed to adults with chronic-phase CML (CML-CP) receiving TKIs therapy >3 months regarding symptoms' incidence, severity, and HRQoL. The multivariate cumulative logistic regression model was built to identify variables associated with the symptoms. General Linear Model was used to model the relationship between symptoms and HRQoL using stepwise-forward algorithm. RESULTS: A total of 1142 respondents were included in this study. The top 10 common TKI-related symptoms were fatigue, periorbital and lower limb edema, chest distress and shortness of breath, memory deterioration, skin color change, alopecia, muscle cramp, weight gain and musculoskeletal pain, and itchy skin. One hundred forty-one (50%) females ≤50 years reported menstrual disorders. Female, married, therapy duration 1 to 3 years, and foreign generic TKIs were associated with increased symptoms' frequency and severity. In contrast, receiving nilotinib or dasatinib, and achieving a complete cytogenetic response but not complete molecular response were associated with fewer and milder symptoms. Chest distress and shortness of breath and loss of appetite were associated with both lower physical component summary (PCS) and mental component summary (MCS) scores; fatigue, musculoskeletal pain, dizziness and abdominal pain, were associated with lower PCS score; anxiety-depression, was associated with lower MCS score in multivariate analyses. CONCLUSIONS: Demographic and social variables, type of TKI-therapy, therapy duration, and depth of response were associated with patient-reported symptoms in persons with chronic phase CML. Certain symptoms have adverse impact on HRQoL.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dasatinibe/uso terapêutico , Feminino , Humanos , Leucemia Mieloide de Fase Crônica/patologia , Leucemia Mieloide de Fase Crônica/psicologia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Pirimidinas/uso terapêutico , Qualidade de Vida , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Prague Med Rep ; 120(2-3): 52-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31586504

RESUMO

Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by inhibiting key proteins included in CML development, predominantly Bcr-Abl and Src. Its advantage is that it shows activity in many cases where other agents bring no improvement due to resistance. Pharmacokinetics of dasatinib has specific characteristics that may play an important role in achieving sufficient exposure in patients. Therefore, the key pharmacokinetic properties are summarized in this report. For example, dasatinib absorption is significantly influenced by gastric pH and its modulation can be a source of serious interactions, as well as simultaneous administration of drugs affecting cytochrome P450.


Assuntos
Dasatinibe/farmacocinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sistema Enzimático do Citocromo P-450 , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Ácido Gástrico , Humanos , Concentração de Íons de Hidrogênio , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
8.
EBioMedicine ; 47: 446-456, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31542391

RESUMO

BACKGROUND: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. METHODS: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ±â€¯3·1 years old; 2 female; BMI:33·9 ±â€¯2·3 kg/m2; eGFR:27·0 ±â€¯2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. FINDINGS: D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated ß-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12. INTERPRETATION: "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.


Assuntos
Senescência Celular/efeitos dos fármacos , Dasatinibe/farmacologia , Nefropatias Diabéticas/metabolismo , Quercetina/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Idoso , Biomarcadores , Biópsia , Ensaios Clínicos Fase I como Assunto , Dasatinibe/uso terapêutico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Quimioterapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Testes de Função Renal , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Quercetina/uso terapêutico
9.
Indian J Med Res ; 149(5): 600-609, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31417027

RESUMO

Paediatric chronic myeloid leukaemia (CML) has biological and clinical differences from adult CML. Management of paediatric CML presents unique challenges in growing children, and there are no specific guidelines for paediatric CML. This review focusses on the clinical characteristics, diagnostic issues and management of paediatric CML. Major studies that provide the basis of managing paediatric CML are summerized here. Studies conducted on adult CML patients were used to guide the management of places where studies were lacking in paediatric CML. Recently, dasatinib and nilotinib have been approved for treatment of paediatric CML, and their role has been discussed in the current management perspective. Allogeneic transplant, fertility and vaccination in paediatric CML, have also been discussed.


Assuntos
Dasatinibe/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Tiazóis/uso terapêutico , Antineoplásicos/uso terapêutico , Criança , Análise Custo-Benefício , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Pediatria/tendências , Pirimidinas/uso terapêutico
10.
Anticancer Res ; 39(7): 3949-3954, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262926

RESUMO

We report the case of an 89-year-old male diagnosed with chronic-phase CML and expressing a rare e13a3 BCR-ABL1 fusion transcript. His cytogenetic analysis showed the t(9;22) translocation generating the Philadelphia chromosome (Ph), with a multiplex RT-PCR detecting an atypical fragment. Using two primers complementary to exon 10 of BCR and exon 4 of ABL1, a larger PCR product was observed, where after Sanger sequencing, an e13a3 BCR-ABL1 transcript was revealed. Given the diagnosis, the patient received 100 mg of dasatinib every other day and was then monitored by measuring both hematological and cytogenetic parameters, while his BCR-ABL1 transcripts were examined by PCR and semi-nested-PCR. According to the 2013 European Leukemia Network criteria, after six months of dasatinib the patient's response was classified as warning as he displayed 20% of Philadelphia-positive metaphases. Sequencing of the ABL1 catalytic domain did not detect point mutations. A complete cytogenetic response was achieved after one year of dasatinib. However, semi-nested-PCR confirmed the presence of the e13a3 BCR-ABL1 fusion transcript that has persisted up to the latest follow-up visit.


Assuntos
Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou mais , Humanos , Masculino , Translocação Genética , Resultado do Tratamento
11.
Clin Appl Thromb Hemost ; 25: 1076029619858409, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218883

RESUMO

Bleeding has been reported in patients with chronic myeloid leukemia (CML) using tyrosine kinase inhibitors (TKIs). In this study, we aimed to evaluate platelet functions and associated bleeding symptoms in patients with CML using TKIs. A standardized questionnaire that was developed for inherited bleeding disorders (ISTH/SSC Bleeding Assessment Tool) was used to score bleeding symptoms in 68 chronic phase patients with CML receiving imatinib (n = 47), dasatinib (n = 15), or nilotinib (n = 6). Light transmission aggregometry was used for platelet function testing. None of the patients had major bleeding (score > 3). Minor bleeding was observed in 25.6% and 20% of the patients in imatinib and dasatinib treatment groups. Impaired/decreased platelet aggregation was observed in 29.8% of imatinib treatment group, 50% of nilotinib group, and 40% of dasatinib group. A secondary aggregation abnormality compatible with the release defect was observed in 26% of patients with CML; 25.5%, 33.3%, and 16.7% of patients receiving imatinib, dasatinib, and nilotinib, respectively. No correlation was found between bleeding symptoms and the impaired platelet function. We can conclude that TKIs may impair in vitro platelet aggregation but this impairment is not associated with bleeding diathesis.


Assuntos
Transtornos Plaquetários/induzido quimicamente , Hemorragia/etiologia , Leucemia Mieloide de Fase Crônica/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Adolescente , Adulto , Idoso , Dasatinibe/uso terapêutico , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Pirimidinas/uso terapêutico
12.
Lancet Haematol ; 6(7): e375-e383, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31201085

RESUMO

BACKGROUND: All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission. METHODS: The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response [MMR]) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. FINDINGS: Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8-10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64-80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25-53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption. INTERPRETATION: Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR. FUNDING: Newcastle University and Bloodwise.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Dasatinibe/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Pirimidinas/uso terapêutico , Recidiva , Resultado do Tratamento
15.
Tumori ; 105(6): NP8-NP11, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30935343

RESUMO

BACKGROUND: Progression of chronic myeloid leukemia (CML) is frequently accompanied by cytogenetic evolution, with an extra copy of the Philadelphia chromosome, trisomy 8 and 19, and isochromosome (17p) commonly detected. Translocations involving 11q23 chromosomal region have been rarely reported in CML. The few reported patients with blast crisis (BC) of CML carrying an 11q rearrangement have insufficient responses to tyrosine kinase inhibitors (TKIs) and possess a poor prognosis. CASE REPORT: We report the case of a 30-year-old man with CML who had a fulminant myeloid BC 4 months after initiation of first-line therapy with the TKI dasatinib, despite showing an optimal response at the 3-month timepoint. Despite cytoreductive therapy with hydroxyurea and 3rd-generation TKI ponatinib, the patient died within 10 days after the diagnosis of BC. Cytogenetic analyses revealed additional genetic aberrations including trisomy 8 and t(9;11)(p21;q23) involving the mixed lineage leukemia (MLL) gene. CONCLUSION: The presence of 11q23 rearrangements in the relapse clone in BC of CML most likely accounts for the adverse clinical outcome. Thus, in the case of rapid and unexpected BC, the presence of 11q rearrangements should be tested together with other additional chromosomal alterations, and immediate addition of chemotherapy to the TKIs should be evaluated.


Assuntos
Antineoplásicos/uso terapêutico , Crise Blástica/genética , Cromossomos Humanos Par 11 , Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/uso terapêutico , Translocação Genética , Cariótipo Anormal , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biópsia , Medula Óssea/patologia , Aberrações Cromossômicas , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Humanos , Imunofenotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento
16.
Expert Opin Investig Drugs ; 28(5): 411-420, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30916583

RESUMO

INTRODUCTION: Acute lymphoblastic leukemia (ALL) with BCR-ABL1 translocation is an aggressive malignancy that is usually treated with intensive chemotherapy with the possibility of allogeneic stem cell transplantation. The encoded fusion protein may be important for leukemogenesis; clinical studies show that dasatinib has an antileukemic effect in combination with steroids alone or intensive chemotherapy. Areas covered: Relevant publications were identified through literature searches (the used terms being acute lymphoblastic leukemia plus dasatinib) in the PubMed database. We searched for original articles and reviews describing the pharmacology and clinical use of dasatinib in ALL with BCR-ABL1. The mechanism of action, pharmacology and clinical study findings are examined. Expert opinion: Dasatinib is associated with a high complete remission rate in ALL when used alone and in combination with steroids or intensive chemotherapy. However, mutations at T315 and F317 are associated with dasatinib resistance. Overall toxicity has been acceptable in these studies and no unexpected toxicity was observed. It is not known whether the antileukemic effect of dasatinib differs between subsets of BCR-ABL1+ patients or is attributed to inhibition of the fusion protein alone, or a combined effect on several kinases, and whether dasatinib-containing combination treatment should be preferred in these patients instead of other emerging strategies, e.g. monoclonal antibodies.


Assuntos
Dasatinibe/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dasatinibe/efeitos adversos , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Indução de Remissão
18.
Zhonghua Xue Ye Xue Za Zhi ; 40(2): 98-104, 2019 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-30831623

RESUMO

Objective: To investigate the efficiency and safety of domestic tyrosine kinase inhibitor (TKI) dasatinib (Yinishu) as second-line treatment for patients with chronic myeloid leukemia in chronic phase (CML-CP). Methods: A retrospective analysis of clinical data of CML-CP patients who received domestic dasatinib as second-line treatment in the CML collaborative group hospitals of Hubei province from March 2016 to July 2018 was performed. The optimal response rate, the cumulative complete cytogenetic response (CCyR), the cumulative major molecular responses (MMR), progression free survival (PFS), event free survival (EFS) and adverse effects (AEs) of the patients were assessed at 3, 6 and 12 months of treatment. Results: A total of 83 CML-CP patients were enrolled in this study. The median follow-up time was 23 months. The optimal response rates at 3, 6 and 12 months in 83 CML-CP patients treated with dasatinib were 77.5% (54/71), 72.6% (61/75) and 60.7% (51/69), respectively. By the end of follow-up, the cumulative CCyR and MMR rates were 65.5% (55/80) and 57.1% (48/73), respectively. The median time to achieving CCyR and MMR was 3 months. During follow-up time, the PFS rate was 94.0% (79/83) and the EFS rate was 77.4% (65/83). The most common non-hematological AEs of dasatinib were edema (32.5%), rash itching (18.1%) and fatigue (13.3%). The common hematological AEs of dasatinib were thrombocytopenia (31.3%), leukopenia (19.3%) and anemia (6.0%). Conclusion: Domestic dasatinib was effective and safe as the second-line treatment of CML-CP patients and it can be used as an option for CML-CP patients.


Assuntos
Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases , Estudos Retrospectivos , Resultado do Tratamento
20.
Comp Med ; 69(1): 22-28, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717820

RESUMO

Canine histiocytic sarcoma is a highly aggressive and metastatic hematopoietic neoplasm that responds poorly to currently available treatment regimens. Our goal was to establish a clinically relevant xenograft mouse model to assess the preclinical efficacy of novel cancer treatment protocols for histiocytic sarcoma. We developed an intrasplenic xenograft mouse model characterized by consistent tumor growth and development of metastasis to the liver and other abdominal organs. This model represents the metastatic or disseminated form of canine histiocytic sarcoma, which is considered the most clinically challenging form of the disease. Transfection of tumor cells with a luciferase vector supported the use of in vivo bioluminescence imaging to track tumor progression over time and to assess the response of this murine model to novel chemotherapeutic agents. Dasatinib treatment of the mice with intrasplenic xenografts decreased tumor growth and increased survival times, compared with mice treated with vehicle only. Our findings indicate the potential of dasatinib for the treatment of histiocytic sarcoma in dogs and for similar diseases in humans. These results warrant additional studies to clinically test the efficacy of dasatinib in dogs with histiocytic sarcoma.


Assuntos
Dasatinibe/uso terapêutico , Modelos Animais de Doenças , Doenças do Cão/tratamento farmacológico , Sarcoma Histiocítico/veterinária , Animais , Antineoplásicos/uso terapêutico , Doenças do Cão/diagnóstico por imagem , Cães , Xenoenxertos , Sarcoma Histiocítico/diagnóstico por imagem , Sarcoma Histiocítico/tratamento farmacológico , Camundongos
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