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2.
J Med Chem ; 63(24): 15279-15307, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33325699

RESUMO

Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Benzofuranos/química , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Dasatinibe/análogos & derivados , Dasatinibe/síntese química , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Reposicionamento de Medicamentos , Epigenômica , Humanos , Nanotecnologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resveratrol/química , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Terpenos/química , Terpenos/farmacologia , Terpenos/uso terapêutico
3.
Medicine (Baltimore) ; 99(50): e21948, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327223

RESUMO

INTRODUCTION: Systemic mastocytosis is a rare disease due to mast cell accumulation in various extracutaneous sites. Systemic mastocytosis with an associated clonal hematologic non-MC lineage disease is the second most common subtype of systemic mastocytosis. The most common mutation associated with both systemic mastocytosis and myeloid sarcoma is mutation in Kit. Here, we identified the novel KIT D816V and ARID1A G1254S mutations co-occurring in systemic mastocytosis with myeloid sarcoma. PATIENT CONCERNS: A 33-year old male patient presented multiple skin lesions for 10 years. Symptoms accelerated in 2017 with decreased body weight. Physical examination revealed enlarged lymph nodes in his neck, axilla and inguinal region; conjunctival hemorrhage; gingival hyperplasia. Skin biopsy showed mast cell infiltration. Flow cytometry detected CD2, CD25 and CD117 positive cells in lymph nodes. Codon 816 KIT mutation D816V and codon 1245 ARID1A mutation G1254S were found in peripheral blood. MPO, CD117, CD68 positive cells in lymph nodes indicated co-existing myeloid sarcoma. DIAGNOSIS: Systemic mastocytosis with an associated clonal hematologic non-MC lineage disease of myeloid sarcoma INTERVENTIONS:: Cytarabine and daunorubicin for myeloid sarcoma and dasatinib for systemic mastocytosis were initiated. Anti-histamine and anti-leukotrienes therapy were used to prevent NSAIDs-induced shock. Platelets were infused to treat bone marrow suppression. OUTCOMES: Patient was discharged after recovered from bone marrow suppression. Dasatinib continued on outpatient. CONCLUSION: This is the first case of patient with systemic mastocytosis and myeloid sarcoma simultaneously presenting extensive skin involvements. Mutations of Kit and Arid1a emphasis the importance to notice possibility of various tumors occurring in patients with multiple mutations. In addition, cysteine-leukotrienes-receptor antagonists should always be used to prevent anaphylactic shock due to mast cell activation.


Assuntos
Mastocitose Sistêmica/complicações , Proteínas Proto-Oncogênicas c-kit/genética , Sarcoma Mieloide/complicações , Pele/patologia , Adulto , Antibióticos Antineoplásicos , Antimetabólitos Antineoplásicos/uso terapêutico , Antígenos CD2/metabolismo , Citarabina/uso terapêutico , Proteínas de Ligação a DNA/genética , Dasatinibe/uso terapêutico , Daunorrubicina/uso terapêutico , Quimioterapia Combinada , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Antagonistas de Leucotrienos/uso terapêutico , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Mastocitose Sistêmica/tratamento farmacológico , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Mutação , Transfusão de Plaquetas/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma Mieloide/tratamento farmacológico , Sarcoma Mieloide/genética , Sarcoma Mieloide/patologia , Fatores de Transcrição/genética , Resultado do Tratamento
4.
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
5.
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
6.
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
10.
Wien Klin Wochenschr ; 132(15-16): 415-422, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32533444

RESUMO

BACKGROUND: Several clinical trials in chronic phase (CP) chronic myeloid leukemia (CML) showed that early response to tyrosine kinase inhibitor (TKI) treatment results in an improved long-term survival and progression-free survival. This study assessed whether patients achieving early treatment response (ETR; partial cytogenetic response or BCR-ABL1 mRNA ≤10% at 3 months) in daily practice also have a long-term survival benefit. METHODS: The Retrospective Evaluation of Early response in CML for long-term Treatment outcome (R-EFECT), a multicenter, retrospective chart review, documented patients with newly diagnosed CML-CP starting first-line TKI therapy in routine clinical practice. The primary aim was to assess the 5­year overall survival rate. RESULTS: Of the 211 patients from 12 centers across Austria (January 2004-May 2010), 176 (median age, 56 years) were included in the analysis. All patients received first-line therapy with imatinib. Overall, 136 patients (77.3%) achieved ETR (ETR+ group), whereas 40 (22.7%) did not reach ETR (ETR- group). The ETR+ group had higher 5­year overall survival (92.5% vs. 77.5%, P = 0.018) and progression-free survival (95.6% vs. 87.5%, P = 0.06) rates compared with the ETR- group. As expected, more patients in the ETR- group were switched to another TKI. At the last contact, 120 patients were still on imatinib and 44 had switched to another TKI (25 to nilotinib, 15 to dasatinib, and 4 to bosutinib). CONCLUSION: The data are in line with randomized trials demonstrating that ETR is associated with improved survival and thus confirmed these results in patients treated in daily clinical routine.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Áustria , Dasatinibe/uso terapêutico , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
12.
Cancer Immunol Immunother ; 69(11): 2223-2232, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32474769

RESUMO

Malignant cells can increase in number using immune escape mechanisms such as immune checkpoints. In this study, we evaluated the expression of an immune checkpoint programmed death 1 (PD-1) on T-cell subsets in chronic myeloid leukemia (CML). We obtained bone marrow aspirate samples from CML patients and from individuals without evidence of hematologic malignancies (controls). PD-1 expression on T-cell subsets was measured using flow cytometric analysis. PD-1 expression levels on CD8+ T-cells were significantly lower in complete hematologic response (CHR) than in controls, chronic phase, and blast phase (BP). In CML patients receiving imatinib and dasatinib, PD-1 expression levels on CD8+ T-cells were lower than that at diagnosis. PD-1 expression levels on CD8+ T-cells were positively correlated with quantitative levels of the BCR/ABL fusion gene. PD-1 expression levels on CD4+ T-cells were higher in BP than in CHR. PD-1 expression levels on CD4+ T-cells did not differ significantly according to different medications or quantitative BCR/ABL1 fusion gene levels. Low PD-1 expression on CD8+ T-cells might play a role in maintaining CHR in CML patients. Immune monitoring of PD-1 expression on CD8+ T-cells may predict the disease course. In cases of refractory disease or resistance to imatinib or dasatinib, the use of PD-1 inhibitors would be helpful.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Receptor de Morte Celular Programada 1/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Dasatinibe/uso terapêutico , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Pediatr Hematol Oncol ; 37(5): 375-379, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32347770

RESUMO

We report a patient who developed chronic myelogenous leukemia (CML) at 12 months of age. She was treated aggressively with stem cell transplant (SCT), interferon, donor lymphocytes and imatinib, with subsequent molecular progression. She received dasatinib, achieving a complete molecular response. Dasatinib was discontinued at 3 years but she had a molecular recurrence. Dasatinib was restarted and continued for 5 additional years with a second major molecular remission (MMR). While on dasatinib therapy she suffered growth failure and was treated with concurrent growth hormone (GH). After discontinuing dasatinib and GH, catch-up growth continues and she remains in MMR. Discontinuation of TKI therapy and the toxicity of long-term TKI therapy is discussed.


Assuntos
Desenvolvimento Infantil , Dasatinibe/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Dasatinibe/efeitos adversos , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Lactente , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/efeitos adversos , Indução de Remissão , Resultado do Tratamento , Suspensão de Tratamento
15.
Am J Clin Oncol ; 43(7): 517-525, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32304434

RESUMO

OBJECTIVE: To examine the association among tyrosine kinase inhibitor (TKI) out-of-pocket costs, adherence, and health care costs and utilization in a large group of commercially insured patients with chronic myeloid leukemia (CML). MATERIALS AND METHODS: Patients with CML aged 18 to 64 years were identified using IBM MarketScan Commercial Database between April 1, 2011 and December 31, 2014. Patients were required to be continuously enrolled 3 months before and 12 months after TKI (imatinib, dasatinib, or nilotinib) initiation. TKI adherence is estimated using the proportion of days covered (PDC), defined as the percentage of the PDC by the prescription fill during the 12-month study period (adherent patients have PDC ≥80%). Health care cost differences between adherent and nonadherent patients were estimated using generalized linear models. Health care utilization was compared using negative binomial regression models. All models were controlled for potential confounding factors. RESULTS: The study sample consisted of 863 patients, where 355 (41.1%) patients were classified as adherent. Over the study period, nonadherent patients incurred US$10,974 more in medical costs (P<0.001), and US$1663 more in non-TKI pharmacy costs (P<0.01). Adherent patients incurred US$28,184 more in TKI pharmacy costs (P<0.001) that resulted in US$18,305 more in overall total health care costs (P<0.001). Adherent patients, however, were estimated to be less likely to have all-cause hospitalizations (incidence rate ratio, 0.32; P<0.001), or CML-specific hospitalizations (incidence rate ratio, 0.31; P<0.01). CONCLUSIONS: Patients with CML with better adherence experienced fewer hospitalizations, resulting in medical service cost savings. These lower medical costs, however, were more than offset by higher TKI medication costs observed during the first year of TKI therapy.


Assuntos
Custos de Cuidados de Saúde , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde , Inibidores de Proteínas Quinases/economia , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Dasatinibe/economia , Dasatinibe/uso terapêutico , Feminino , Humanos , Mesilato de Imatinib/economia , Mesilato de Imatinib/uso terapêutico , Revisão da Utilização de Seguros , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Pirimidinas/economia , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Adulto Jovem
16.
Oncology ; 98(7): 445-451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348984

RESUMO

BACKGROUND: Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs. METHODS: A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with latest-generation TKI (nilotinib, dasatinib, and ponatinib), while group B included patients treated with first-generation TKI (imatinib). Cardiological evaluation included electrocardiogram, echocardiogram with global longitudinal strain of left ventricle (GLS), and carotid ultrasound scan with arterial stiffness measurement (pulse wave velocity, PWV). Adverse cardiovascular events were recorded in both groups. RESULTS: Statistical analysis showed that cardiovascular adverse events (myocardial ischemia, peripheral artery disease, deep vein thrombosis, and pleural effusion) were significantly more frequent in group A than group B (p value = 0.044). Moreover, there was a significant reduction in GLS and PWV in group A when compared to group B (respectively, p = 0.03 and p = 0.004). CONCLUSIONS: Our study confirms that imatinib is a relatively safe drug, while it reveals that the latest-generation TKIs may cause a burden of cardiovascular complications. GLS and PWV allow detection of early signs of cardiac and vascular toxicity in oncohematologic patients treated with TKI, and their use is advisable.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Doença da Artéria Coronariana/induzido quimicamente , Dasatinibe/efeitos adversos , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
17.
Leukemia ; 34(8): 2064-2073, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32265500

RESUMO

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.


Assuntos
Dasatinibe/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dasatinibe/efeitos adversos , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
18.
Leukemia ; 34(4): 966-984, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32127639

RESUMO

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Compostos de Anilina/uso terapêutico , Tomada de Decisão Clínica , Conferências de Consenso como Assunto , Dasatinibe/uso terapêutico , Gerenciamento Clínico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Expectativa de Vida/tendências , Monitorização Fisiológica , Nitrilos/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/uso terapêutico , Análise de Sobrevida
19.
Int J Hematol ; 111(6): 812-825, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32152876

RESUMO

We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54 years (range 22-88 years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1-99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4-94.8%) and 87.2% (95% CI 78.1-93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.


Assuntos
Dasatinibe/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Japão , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
20.
Int J Hematol ; 111(6): 826-832, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32152877

RESUMO

We evaluated the effect of proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) on the efficacy and safety of dasatinib for chronic-phase chronic myeloid leukemia (CP-CML). Retrospective analyses were performed for patients with CP-CML who received dasatinib at seven hospitals between April 2009 and December 2016. Seventy-three patients were identified, 16 of whom received PPIs or H2RAs concurrently with dasatinib. Major molecular response at 12 months was observed in 13 of 13 patients (100%) with concurrent PPIs or H2RAs (combination group), and in 23 of 51 patients (45.1%) who received only dasatinib (dasatinib-alone group; P < 0.001). Deep molecular response at 12 months was observed in four of six patients (66.7%) in the combination group, and seven of 38 patients (18.4%) in the dasatinib-alone group (P = 0.027). Dasatinib chemotherapy was stopped after 18 months for 25 patients (43.9%) from the dasatinib-alone group, but for none from the combination group. Combination treatment with PPIs or H2RAs did not reduce the efficacy of dasatinib. PPIs and H2RAs reduce the incidence of dasatinib discontinuation due to adverse events and increase the efficacy of dasatinib chemotherapy for patients.


Assuntos
Dasatinibe/uso terapêutico , Interações Medicamentosas , Antagonistas dos Receptores Histamínicos H2/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Dasatinibe/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Segurança , Resultado do Tratamento , Adulto Jovem
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