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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 395-402, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812405

RESUMO

OBJECTIVE: To investigate the effect of etoposide (ETO) on elimination of chronic myeloid leukemia (CML) stem cells by imatinib mesylate(IM) in vivo. METHODS: SCL-tTA/BCR-ABL mice were used as CML animal model. Flow cytometry was used to assess the effect of ETO alone or in combination with IM on the number of leukemia stem cell (LSC) in bone marrow and spleen, and peripheral blood neutrophils in CML mice and normal control FVB mice. RESULTS: The results showed that in CML mice, the number and proportion of LSC in bone marrow and the proportion of neutrophils in peripheral blood decreased significantly after ETO and IM combined treatment, and the degree of decrease was more significant than that of both alone. While in wild type FVB mice, the combination of ETO and IM showed no significant effect on the number and proportion of LSK cells in bone marrow and the proportion of neutrophils in spleen. CONCLUSION: ETO can selectively enhance elimination of CML LSC by IM in vivo.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Animais , Etoposídeo , Proteínas de Fusão bcr-abl , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Camundongos , Células-Tronco
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 456-461, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812415

RESUMO

OBJECTIVE: To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP). METHODS: Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment. RESULTS: Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABLIS≤10%, and 5 patients (10.2%) with major molecular response (MMR: BCR-ABLIS ≤ 0.1%). After 6 months of treatment, 49 patients underwent hematological examination, and 49 patients (100%) all achieved CHR. 49 patients underwent cytogenetic examined, of which 41 cases (83.7%) obtained MCyR and 31 cases (65.3%) obtained CCyR. 49 patients underwent the level of BCR-ABL test, among which 33 patients (67.4%) showed BCR-ABLIS≤1%, and 15 patients(30.6%) reached MMR. After 12 months of treatment, 45 patients underwent hematological examination, and all the patients (100%) got CHR. 45 patients underwent cytogenetic examined, of which 41 cases (91.1%) obtained MCyR and 35 cases (77.8%) obtained CCyR. 45 cases were tested for BCR-ABL level, and 24 cases (55.3%) reached MMR. The incidence of grade Ⅲ leukopenia, thrombocytopenia and anemia were 14.0%, 8.7% and 10.5%, respectively. Non-hematological adverse reactions were edema (64.9%), nausea (50.9%), vomiting (35.1%), rash (24.5%), fever (15.8%), bone and joint muscle pain (38.6%), diarrhea(17.6%) and liver function damage (3.5%). There were no grade IV hematological and non-hematological adverse reactions. CONCLUSION: In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , China , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas , Pirimidinas/uso terapêutico , Resultado do Tratamento
3.
Rinsho Ketsueki ; 62(3): 180-185, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33828011

RESUMO

We report the case of a 26-year-old male patient with chronic myelogenous leukemia in the chronic phase with the e13a3 (b2a3) variant of BCR-ABL1 fusion. Despite the presence of Philadelphia chromosome and fluorescence in situ hybridization-detectable BCR-ABL1 fusion signals, quantitative measurement of BCR-ABL1 on the ABL1 using a reverse primer in exon 2 of ABL1 failed to detect the fusion transcripts. PCR direct sequencing analysis with a sense primer for exon 13 of BCR and an antisense primer for exon 3 of ABL1 revealed the e13a3 variant of BCR-ABL1 fusion. The variant fusion transcript level was successfully monitored by the TaqMan assay using a forward primer and probe both in exon 13 of BCR and a reverse primer in exon 3 of ABL1. The patient responded extremely well to imatinib treatment, similar to previously reported e13a3 cases. The patient achieved a molecular response (undetectable e13a3 transcripts) after 12 months of treatment.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adulto , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Inibidores de Proteínas Quinases/uso terapêutico
4.
Rinsho Ketsueki ; 62(1): 47-50, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33551425

RESUMO

The prognosis of chronic myeloid leukemia (CML) has improved dramatically with the introduction of tyrosine kinase inhibitors. Although the use of second-generation tyrosine kinase inhibitors is now available for initial cases, a small number of patients with CML unfortunately still experience progression to the accelerated or blastic phase of the disease. We recently managed a patient with chronic-phase CML, who developed a T315 mutation early in the course of treatment with dasatinib and progressed to the lymphoid blastic phase. The patient responded quickly to ponatinib therapy in combination with hyper CVAD, leading to cord blood transplantation. We report here the first case of a patient with CML in the lymphoid blastic phase treated with ponatinib in combination with hyper CVAD, which was tolerable despite adverse events such as infection, bilirubin elevation, and hypertension, and who was able to proceed to transplantation after achieving a complete molecular response.


Assuntos
Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva , Piridazinas/uso terapêutico , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico
5.
Cancer Sci ; 112(3): 1150-1160, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33428808

RESUMO

This study focused on children as well as adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population-based cancer registry data from Osaka, Japan. The study subjects comprised 2254 children (0-14 years) and 2,905 AYAs (15-39 years) who were diagnosed with leukemia during 1975-2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed 5-year overall survival probability (5y-OS), using the Kaplan-Meier method and expressed time trends using the joinpoint regression model. For recently diagnosed (2006-2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y-OS, using age group, gender, and treatment hospital as covariates. Over the 37-year period, 5y-OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y-OS of ALL improved, especially after 2000 (65% in 2006-2011), when the pediatric regimen was introduced but was still lower than that among children (87% in 2006-2011, P < .001). Survival improvement was most remarkable in CML, and its 5y-OS was over 90% among both children and AYAs after the introduction of molecularly targeted therapy with tyrosine kinase inhibitors. Among patients with recently diagnosed AML, the risk of death was significantly higher for patients treated at nondesignated hospitals than those treated at designated cancer care hospitals. The changes in survival improvement coincided with the introduction of treatment regimens or molecularly targeted therapies. Patient centralization might be one option which would improve survival.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Adulto , Fatores Etários , Institutos de Câncer/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/estatística & dados numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Fatores Sexuais , Adulto Jovem
6.
Mol Pharmacol ; 99(3): 226-241, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33446509

RESUMO

An essential function of DNA topoisomerase IIα (TOP2α; 170 kDa, TOP2α/170) is to resolve DNA topologic entanglements during chromosome disjunction by introducing transient DNA double-stranded breaks. TOP2α/170 is an important target for DNA damage-stabilizing anticancer drugs, whose clinical efficacy is compromised by drug resistance often associated with decreased TOP2α/170 expression. We recently demonstrated that an etoposide-resistant K562 clonal subline, K/VP.5, with reduced levels of TOP2α/170, expresses high levels of a novel C-terminal truncated TOP2α isoform (90 kDa, TOP2α/90). TOP2α/90, the translation product of a TOP2α mRNA that retains a processed intron 19 (I19), heterodimerizes with TOP2α/170 and is a resistance determinant through a dominant-negative effect on drug activity. We hypothesized that genome editing to enhance I19 removal would provide a tractable strategy to circumvent acquired TOP2α-mediated drug resistance. To enhance I19 removal in K/VP.5 cells, CRISPR/Cas9 was used to make changes (GAG//GTAA AC →GAG//GTAA GT ) in the TOP2α gene's suboptimal exon 19/intron 19 5' splice site (E19/I19 5' SS). Gene-edited clones were identified by quantitative polymerase chain reaction and verified by sequencing. Characterization of a clone with all TOP2α alleles edited revealed improved I19 removal, decreased TOP2α/90 mRNA/protein, and increased TOP2α/170 mRNA/protein. Sensitivity to etoposide-induced DNA damage (γH2AX, Comet assays) and growth inhibition was restored to levels comparable to those in parental K562 cells. Together, the results indicate that our gene-editing strategy for optimizing the TOP2α E19/I19 5' SS in K/VP.5 cells circumvents resistance to etoposide and other TOP2α-targeted drugs. SIGNIFICANCE STATEMENT: Results presented here indicate that CRISPR/Cas9 gene editing of a suboptimal exon 19/intron 19 5' splice site in the DNA topoisomerase IIα (TOP2α) gene results in circumvention of acquired drug resistance to etoposide and other TOP2α-targeted drugs in a clonal K562 cell line by enhancing removal of intron 19 and thereby decreasing formation of a truncated TOP2α 90 kDa isoform and increasing expression of full-length TOP2α 170 kDa in these resistant cells. Results demonstrate the importance of RNA processing in acquired drug resistance to TOP2α-targeted drugs.


Assuntos
DNA Topoisomerases Tipo II/genética , Regulação para Baixo , Etoposídeo/farmacologia , Edição de Genes/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Sistemas CRISPR-Cas , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos , Humanos , Íntrons , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Sítios de Splice de RNA
7.
Ann Hematol ; 100(2): 481-485, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33415425

RESUMO

The introduction of tyrosine kinase inhibitors (TKIs) has improved the overall survival of chronic myeloid leukemia patients in chronic phase (CP-CML) and reduced the rate of disease-related mortality. Conflicting results have been however reported between data emerged from sponsored clinical trials and from population-based registries. Moreover, no data are so far available for patients treated with frontline second-generation TKIs, excluding those from sponsored studies. We analyzed the mortality rate of 2315 CP-CML patients treated with frontline second-generation TKIs through the Italian Medicines Agency (AIFA) registries and compared it with the ISTAT mortality rate of the general population. The estimated differences show that the increased rate of mortality in CP-CML patients is less than 1% for the class 0-29 years, stable around 2% for the intervals 30-44 years and 45-59 years, and 1.4% for the interval 60-74 years; interestingly this rate is reduced for patients aged 75 years and more as compared to the general population (- 0.65%). The difference between potential and estimated deaths is higher among women in the age classes between 30 and 74 years.


Assuntos
Bases de Dados Factuais , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases/administração & dosagem , Sistema de Registros , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Itália/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
8.
Gan To Kagaku Ryoho ; 48(1): 73-75, 2021 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-33468727

RESUMO

It is expected that the number of long-term breast cancer survivors will increase owing to the improvements in chemotherapy and irradiation, while the risk of double cancers, including secondary malignancy, may become an issue. There are many unclear points in the treatment policy with regard to when a secondary malignancy occurs or the primary cancer relapses during the management of a secondary malignancy. A 54-year-old woman who was diagnosed with ER/PgR-positive HER2 negative breast cancer Stage ⅢB received neoadjuvant chemotherapy FEC and docetaxel followed by breast surgery, adjuvant hormone therapy, and radiation therapy. Chronic myeloid leukemia diagnosed by the abnormal findings of leukocytosis and bone marrow aspiration emerged after 3 years of the diagnosis of the first breast cancer. After 3 years of imatinib therapy that achieved a major molecular response(MMR)of CML, a recurrence of sacral metastasis of breast cancer was revealed by MRI. The combination of imatinib and hormone or S-1 chemotherapy could be maintained without serious adverse events after the relapse of the primary cancer.


Assuntos
Neoplasias da Mama , Leucemia Mielogênica Crônica BCR-ABL Positiva , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Hormônios/uso terapêutico , Humanos , Incidência , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2 , Resultado do Tratamento
9.
Leukemia ; 35(2): 440-453, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33414482

RESUMO

In the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Feminino , Seguimentos , Humanos , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Pirimidinas/administração & dosagem , Taxa de Sobrevida
10.
BMJ Case Rep ; 14(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462050

RESUMO

Dasatinib, an oral tyrosine kinase inhibitor, is approved for therapy of chronic myeloid leukaemia (CML). Common adverse effects of this therapy include myelosuppression, fluid retention and diarrhoea. However, Clostridioides difficile infections (CDIs) in the context of dasatinib therapy, without a history of antecedent antibiotic use, has not been reported previously. We present here a case of a 36-year-old man diagnosed with accelerated phase of CML, who was started on treatment with dasatinib. Two months into therapy, he experienced profuse diarrhoea and abdominal pain. Colonoscopy revealed multiple confluent colonic mucosal ulcerations. Immunoassay study of stool revealed positive C. difficile toxin. The patient was started on oral metronidazole, with discontinuation of all other drugs, including dasatinib. He made a complete uneventful recovery following 2 weeks of antibiotic therapy. Chemotherapeutic agents, such as dasatinib, should be considered as possible etiological agents in the pathogenesis of CDI, even in absence of antibiotic use.


Assuntos
Antineoplásicos/efeitos adversos , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/etiologia , Dasatinibe/efeitos adversos , Diarreia/etiologia , Adulto , Infecções por Clostridium/terapia , Diarreia/diagnóstico , Diarreia/terapia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino
11.
Leuk Res ; 101: 106516, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33517185

RESUMO

BACKGROUND: Treatment-free survival (TFS) in chronic myeloid leukemia (CML) is a new goal. This prospective study aims to evaluate imatinib discontinuation's feasibility and safety in patients with deep molecular response MR4 (BCR-ABL1 < 0.01 % IS). METHODS: Study was approved by the ethical committee and registered at Clinicaltrials.gov (NCT03239886). Incluision criteria were: age ≥ 18y, chronic phase, first-line imatinib for 36 months, MR4 for 12 months, no previous transplant or resistance. Imatinib was resumed when two samples confirmed the loss of MMR. The primary endpoint was molecular recurrence-free survival (MRFS) at 24 months. Lymphocyte subpopulations were counted in peripheral blood before discontinuation. RESULTS: 31 patients were included from Dec/2016 until Oct/2017. Median age was 54years, 58 % male, 58 % low Sokal, 65 % b3a2 transcripts, and 61 % were in MR4.5. Imatinib therapy's median time was 9.7y (3-14.9 y), median time of MR4 was 6.9y (1.6-10.3y). MRFS at 24 months was 55 % (95 % CI 39-75). Thirteen patients relapsed, 46 % after six months of discontinuation, and all patients recovered MMR. Median time to recover MMR was one month. MR4.5 was the only factor associated with MRFS. NK cells proportion at baseline was lower in patients with only MR4 who relapsed after discontinuation. CONCLUSION: With a median duration of sustained MR4 above five years, as recommended by most TKI discontinuation guidelines, the TFS was similar to previous studies. Only MR4.5 was associated with lower risk of relapse. Further studies are needed to evaluate whether patients with only MR4 and low NK cell levels are suitable for discontinuation.


Assuntos
Mesilato de Imatinib/administração & dosagem , Células Matadoras Naturais/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Recidiva , Fatores de Tempo
13.
Ter Arkh ; 92(7): 90-94, 2020 Sep 01.
Artigo em Russo | MEDLINE | ID: mdl-33346450

RESUMO

Therapy with tyrosine kinase inhibitors (TKI) allows to achieve a deep molecular response in 6070% of patients with chronic myeloid leukemia (CML). According to the current guidelines CML patients receive a long-term treatment with TKI in standard dose. The frequently observed adverse effects (AE) of TKI therapy are mostly dose-dependent. A new treatment approach with TKI use in reduced dose is desirable for the CML patients with existing AE or with a high risk of AE occurrence. We report the two cases of successful long-term treatment of CML patients with reduced doses of second generation TKIs. The aim of the TKI dose reduction was to reduce the clinical manifestations of drug toxicities and to prevent the AE.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Dasatinibe , Características da Família , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos
14.
Medicine (Baltimore) ; 99(45): e22791, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157925

RESUMO

RATIONALE: Dasatinib associated lymphadenopathy (DAL) is a rare adverse event in chronic myeloid leukemia patients (CML). A case of voluminous lymphadenopathy in the context of DAL is presented. PATIENT CONCERNS: A 40-year-old male patient was diagnosed with BCR-ABL1 positive chronic stage CML 2 years ago and achieved complete molecular response on nilotinib, which was switched to dasatinib due to nilotinib intolerance. After 5 months on dasatinib, the patient presented with a large mass in the axillary region. DIAGNOSIS: Common infectious and autoimmune etiologies of lymphadenopathy were ruled out. The positron emission tomography/computed tomography (PET/CT) demonstrated a hypermetabolic lymphadenopathy highly suspicious of lymphoma. The subsequent biopsy excluded lymphoma or extramedullary blastic transformation of CML and revealed reactive lymphadenopathy with mixed (cortical and paracortical) pattern. Clinical history and clinicopathological correlation suggested the diagnosis of DAL. INTERVENTION: Dasatinib was discontinued and the patient remained in close follow-up. TKI treatment with nilotinib was reinitiated. OUTCOMES: Lymphadenopathy resolved clinically at 4 weeks and normalization of PET/CT findings was documented at 9 weeks after cessation of the drug. TKI treatment with nilotinib was reinitiated with good tolerance. LESSONS: DAL may present with voluminous lymphadenopathy consistent with malignancy in clinical and imaging workup. We describe the spectrum of lesions associated with DAL and identify common features with drug-induced lymphadenopathy.


Assuntos
Dasatinibe/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Linfadenopatia/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Biópsia , Humanos , Linfadenopatia/diagnóstico por imagem , Masculino
15.
Anticancer Res ; 40(9): 5313-5317, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878823

RESUMO

BACKGROUND/AIM: Imatinib (IM) is the standard-of-care treatment for most chronic myeloid leukemia (CML) patients in chronic phase (CP). However, some patients suffer from low-grade side-effects that, in the long run, severely affect the quality of life and require treatment discontinuation due to toxicities. Fortunately, there are several therapeutic alternatives for these patients. Among them, the second-generation tyrosine kinase inhibitor dasatinib (DAS), used as second-line treatment, has shown to be a valid option in patients with CP-CML after intolerance to prior IM. PATIENTS AND METHODS: Herein, we report on seven CP-CML patients who achieved a stable major molecular response (MMR) with IM-therapy, but were shifted to DAS treatment due to recurrent low-grade IM-intolerances (grades 1-2). RESULTS AND CONCLUSION: All patients received conventional DAS treatment with a median daily dose of 83.3 mg. Treatment was well tolerated and side-effects were mild. In addition, after a median follow-up of 25 months (range=24-43 months) a deep molecular response (DMR) (either MR4 or MR4.5) was achieved in all patients after 24 months of treatment. This finding, although limited to a small cohort of CP-CML patients, supports the view that a therapy switch from IM to DAS induces a reduction of symptom burden, improves patient compliance and shows clinical efficacy in achieving and sustaining deep molecular responses.


Assuntos
Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Cooperação do Paciente , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Retratamento , Resultado do Tratamento
16.
Medicine (Baltimore) ; 99(36): e22061, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899072

RESUMO

INTRODUCTION: Nilotinib is a selective inhibitor of the BCR-ABL tyrosine kinase receptor and is used in the management of chronic myelogenous leukemia (CML). Nilotinib therapy at high doses is associated with elevated serum bilirubin levels. If the serum bilirubin level exceeds 3 times the upper limit of normal, the recommendation is to either adjust nilotinib dosage or temporarily discontinue the treatment. However, it is unclear whether hyperbilirubinemia indicates obvious liver histology damage. PATIENT CONCERNS: A 24-year-old man with confirmed CML was treated with nilotinib therapy and developed hyperbilirubinemia after the treatment. Although the first remission of the hyperbilirubinemia was achieved after dose adjustment, the hematological parameters deteriorated. Thus, we initiated an antineoplastic therapy (at the standard dose) until complete remission of the CML was achieved. The pathogenic mechanism of hyperbilirubinemia may be related to the inhibition of uridine diphosphate-glucuronosyltransferase (UGT1A1) activity. Liver histological analysis revealed no significant liver damage. In addition, the patient had no family history of hyperbilirubinemia and liver disease. DIAGNOSIS: The patient was admitted to our hospital under the diagnosis of hyperbilirubinemia, and histopathology by liver biopsy showed no obvious damage. We also detected a UGT1A1 mutation [ex1 c.686C > A (p.Pro229Gln)] in the patient and his mother. INTERVENTIONS: When the nilotinib dose was decreased to 300 mg daily, the total bilirubin (TBIL) level decreased to 30 to 50 µmol/L for 1 month. However, because the Bcr-Abl/Abl ratio did not correspond to the major molecular response (MMR; <0.1%), the nilotinib dose was readjusted to 400 mg daily. One week later, the TBIL and indirect bilirubin levels increased to 89 and 79 µmol/L, respectively. The levels of alanine transaminase and other liver functional indicators were normal. OUTCOMES: A Naranjo Adverse Drug Reaction (ADR) Probability Scale score of 13 indicates that hyperbilirubinemia is attributed to ADR caused by nilotinib rather than by drug-induced liver injury. CONCLUSION: Although reducing the nilotinib dose can alleviate the occurrence of hyperbilirubinemia, the effect of MMR is also reduced. Treatment of CML without dose adjustment or discontinuation of nilotinib therapy may be more advantageous.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/diagnóstico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Idoso , Antineoplásicos/uso terapêutico , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , China/epidemiologia , Feminino , Glucuronosiltransferase/efeitos dos fármacos , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia/induzido quimicamente , Japão/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mães , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Indução de Remissão , Adulto Jovem
17.
Vnitr Lek ; 66(4): 214-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972178

RESUMO

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia that is characterised by Philadelphia chromosome (Ph1 chromosome) and/or fusion gene BCR-ABL1 in bone marrow. Interpheron α and bone marrow transplantation used to be the main treatment modalities for patients with CML 20 years ago. Due to the introduction of imatinib mesylate since the year 2000 the outcome of CML patients has dramatically improved. The survival of both younger and elderly patients in the case of an optimal response has been prolonged and currently is close to survival of healthy population. Although, one third of patients does not respond well to first line imatinib and needs to change the treatment to second line tyrosine kinase inhibitors (TKI: bosutinib, dasatinib and nilotinib). Younger patients without cardiologic and metabolic disorders and those with poor risk profile score may have benefit from TKI of 2nd generation as a 1st line treatment option with the aim of reaching deeper molecular response and the chance of treatment free remission (TFR) in future. By older patients with severe comorbidities and in patients with good risk profile score imatinib as a 1st line treatment option can be used. For patients who are resistant simultaneously to 2nd generation TKI and for patients with mutation T315I ponatinib - TKI of 3rd generation can be used effectively. Intolerance and toxicity of TKI´s are the main barriers of effective CML treatment. TKI selection for each patient should be individual. Patient´s cooperation with medical team is crucial and inevitable in long time treatment process. The chance for TFR has become feasible for approximately 40-60 % CML patients in deep and durable molecular remission and represents a further important milestone in the management of CML patients.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adulto , Idoso , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/uso terapêutico
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(7): 874-880, 2020 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879093

RESUMO

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and characterized by the formation of Philadelphia (Ph) chromosome. Recently, tyrosine kinase inhibitors (TKI) treatment greatly improved the prognosis of CML. However, the options may be limited when a patient develops traditional TKI resistance or gene mutation. Herein, we reported a case. A 38-year-old male CML patient developed a BCR-ABL1 gene mutation of T315I after 2.5 years of TKI treatment, including imatinib and dasatinib. We adjusted the treatment with the combined application of dasatinib and axitinib. BCR-ABL1 gene copies dropped down and achieved an early molecular response at 2 months later. Subsequently, he received hematopoietic stem cell transplantation. Axitinib and dasatinib were applied for another half year after the allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two years after the allo-HSCT, the BCR-ABL1 gene was still undetectable. It provided a successful example in treating CML patients carrying BCR-ABL1 T315I mutation via combination of axitinib with conditional TKI.


Assuntos
Axitinibe , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adulto , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
20.
Bull Cancer ; 107(9): 861-866, 2020 Sep.
Artigo em Francês | MEDLINE | ID: mdl-32863000

RESUMO

INTRODUCTION: The treatment of chronic myeloid leukemia (CML) has been revolutionized by the advent of tyrosine kinase inhibitors. The results of the IRIS trial demonstrated the efficacy and long-term safety profile of Imatinib. The objective of our work is to report the results at 15 years of treatment of CML in chronic phase with Imatinib in Morocco. PATIENTS AND METHODS: Retrospective study realized at the hematology unit of CHU d'Ibn-Rochd in Casablanca, from January 2003 to September 2018, including all CML patients in the chronic phase at diagnosis, were treated with Imatinib for a minimum duration of 6 months. RESULTS: In total, 318 patients were collected, the median age was 41.5 years, the sex ratio M/F was 0.7, the Sokal score was high in 56% of cases. The complete hematological response at 3 months was 92%, the complete cytogenetic response at 12 months and the cumulative response were obtained in 43% (29/67) and 55% (153/279) of the cases respectively, the molecular response was evaluated in 125 patients witch 85% were on major molecular response. On a median follow-up of 44 months, the OS and EFS at 10 years were 86% and 59%, respectively. DISCUSSION: Our profile is characterized by a young age of the patients, the female predominance and a high Sokal score. The rate of complete cytogenetic response remains lower compared to what is described, however the survival rates as well as the tolerance were similar to those of the literature.


Assuntos
Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Marrocos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
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