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1.
Blood ; 132(4): 393-404, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29567798

RESUMO

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Cromossomo Filadélfia , Piridazinas/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Segurança , Taxa de Sobrevida , Fatores de Tempo , Adulto Jovem
2.
Haematologica ; 105(1): 136-147, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31018977

RESUMO

The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries for leukemic cells. In murine chronic myeloid leukemia (CML) CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of CML-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in CML after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with CML via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1+ cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and proto-oncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as an indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human CML. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - which could be exploited therapeutically in the future.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Animais , Medula Óssea , Selectina E/genética , Células Endoteliais , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos , Proto-Oncogene Mas , Proteína 1 de Leucemia Linfocítica Aguda de Células T
3.
Lancet Oncol ; 19(6): 747-757, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29735299

RESUMO

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. METHODS: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. FINDINGS: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported. INTERPRETATION: Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. FUNDING: ELN Foundation and France National Cancer Institute.


Assuntos
Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Tomada de Decisão Clínica , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Medição de Risco , Fatores de Risco , Fatores de Tempo
4.
Blood ; 127(6): 703-12, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26603839

RESUMO

BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ~20% of total alleles (referred to as "low-level mutations"), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Imidazóis/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Mutação/fisiologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Substituição de Aminoácidos , Quimioterapia Adjuvante , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide de Fase Crônica/genética , Terapia Neoadjuvante
5.
Blood ; 126(1): 42-9, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-25918346

RESUMO

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Terapia Combinada , Comorbidade , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mesilato de Imatinib , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
6.
Blood ; 121(2): 378-84, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23175686

RESUMO

Molecular response to imatinib (IM) in chronic myeloid leukemia (CML) is associated with a biphasic but heterogeneous decline of BCR-ABL transcript levels. We analyzed this interindividual heterogeneity and provide a predictive mathematical model to prognosticate the long-term response and the individual risk of molecular relapse on treatment cessation. The parameters of the model were determined using 7-year follow-up data from a randomized clinical trial and validated by an independent dataset. Our model predicts that a subset of patients (14%) achieve complete leukemia eradication within less than 15 years and could therefore benefit from discontinuation of treatment. Furthermore, the model prognosticates that 31% of the patients will remain in deep molecular remission (MR(5.0)) after treatment cessation after a fixed period of 2 years in MR(5.0), whereas 69% are expected to relapse. As a major result, we propose a predictor that allows to assess the patient-specific risk of molecular relapse on treatment discontinuation and to identify patients for whom cessation of therapy would be an appropriate option. Application of the suggested rule for deciding about the time point of treatment cessation is predicted to result in a significant reduction in rate of molecular relapse.


Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Modelos Teóricos , Recidiva Local de Neoplasia/prevenção & controle , Benzamidas , Proteínas de Fusão bcr-abl/análise , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Mesilato de Imatinib , Piperazinas/administração & dosagem , Reação em Cadeia da Polimerase , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco
7.
Blood ; 121(4): 628-37, 2013 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-23223357

RESUMO

Although the prognosis of chronic myeloid leukemia (CML) patients treated with imatinib is good, many fail to develop an optimal response or lose one. This heterogeneity could be attributed to the presence of human organic cation transporter-1 (hOCT1) single nucleotide polymorphisms (SNPs). In the present study, we analyzed the effect of 23 hOCT1 SNPs on imatinib treatment outcome in newly diagnosed CML patients using MassARRAY sequencing and pyrosequencing. The only SNP associated with outcome was M420del (rs35191146), with patients with the M420del demonstrating an increased probability of imatinib treatment failure. In CML cell lines transfected with M420del and/or M408V, M420del significantly decreased imatinib uptake, but this effect was countered if the M408V (rs628031) SNP was also present. A similar effect was seen for the uptake of the hOCT1 substrates TEA(+) and ASP(+). Finally, apparent hOCT1 mRNA levels were studied using both our earlier primers covering the M420del and another set that did not. Different mRNA expression was observed, explaining the disparity in published data on the prognostic importance of hOCT1 mRNA and highlighting the importance of avoiding common SNP sites in primer design. These data demonstrate that the common M420del SNP can modulate the outcome of imatinib treatment.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Transportador 1 de Cátions Orgânicos/genética , Piperazinas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Antineoplásicos/farmacocinética , Benzamidas , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Genótipo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Transportador 1 de Cátions Orgânicos/química , Transportador 1 de Cátions Orgânicos/metabolismo , Piperazinas/farmacocinética , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Resultado do Tratamento , Adulto Jovem
8.
Blood ; 121(20): 4175-83, 2013 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-23543457

RESUMO

Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in BCR-ABL1 mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or additional chromosomal aberrations leading to disease relapse and/or malignant progression. TKI-naive and TKI-treated leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage. To determine the role of TKI-refractory LSCs in genomic instability, we used a murine model of CML-CP where ROS-induced oxidative DNA damage was elevated in LSCs, including quiescent LSCs, but not in LPCs. ROS-induced oxidative DNA damage in LSCs caused clinically relevant genomic instability in CML-CP-like mice, such as TKI-resistant BCR-ABL1 mutations (E255K, T315I, H396P), deletions in Ikzf1 and Trp53, and additions in Zfp423 and Idh1. Despite inhibition of BCR-ABL1 kinase, imatinib did not downregulate ROS and oxidative DNA damage in TKI-refractory LSCs to the levels detected in normal cells, and CML-CP-like mice treated with imatinib continued to accumulate clinically relevant genetic aberrations. Inhibition of class I p21-activated protein kinases by IPA3 downregulated ROS in TKI-naive and TKI-treated LSCs. Altogether, we postulate that genomic instability may originate in the most primitive TKI-refractory LSCs in TKI-naive and TKI-treated patients.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Instabilidade Genômica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Células-Tronco Neoplásicas/fisiologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/fisiologia , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
9.
Blood ; 122(6): 872-84, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23803709

RESUMO

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Dasatinibe , Europa (Continente) , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Prognóstico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante de Células-Tronco , Tiazóis/uso terapêutico , Resultado do Tratamento
10.
Ann Hematol ; 94 Suppl 2: S219-25, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25814088

RESUMO

Serial quantification of BCR-ABL1 messenger RNA (mRNA) is an important therapeutic indicator for patients with chronic myeloid leukemia, but historically, there has been substantial variation in results reported by different laboratories. To help improve the comparability of results, an international scale (IS) for BCR-ABL1 was proposed which is being implemented by testing laboratories worldwide. This is being achieved most commonly by the derivation of laboratory-specific conversion factors, but increasingly by the use of kits or reagents that are calibrated to the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL1 mRNA. Recent attention has focused on the need to define and validate levels of deeper molecular response (MR) within the context of the IS. While there has been substantial progress in the alignment of results, BCR-ABL1 measurement is technically challenging and standardization is an ongoing process.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , RNA Mensageiro/metabolismo , Antineoplásicos/efeitos adversos , Biomarcadores/sangue , Biomarcadores/metabolismo , Medula Óssea/metabolismo , Calibragem , Monitoramento de Medicamentos , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Terapia de Alvo Molecular/efeitos adversos , Prognóstico , Inibidores de Proteínas Quinases/efeitos adversos , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase em Tempo Real , Padrões de Referência
11.
Ann Hematol ; 94 Suppl 2: S227-39, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25814089

RESUMO

The assessment of response to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) does not only reflect tumor burden at a given time but has been shown to be linked to long-term survival outcomes as well. Therefore, the quantification of molecular or cytogenetic response as early as 3 months on treatment allows a prognostic stratification of a patient's individual risk. With competing TKI regimens available, a timely switch of treatment can be considered if unfavorable outcome has to be expected due to early response failure. Numerous studies have demonstrated the association of long-term outcome with early response for first-line treatment with imatinib, with second-generation TKI and for second-line TKI treatment as well.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Biomarcadores/metabolismo , Monitoramento de Medicamentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Guias de Prática Clínica como Assunto , Prognóstico , Indução de Remissão , Medição de Risco/métodos
12.
Ann Hematol ; 94(6): 919-27, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25465231

RESUMO

Multi-state models support prediction in medicine. With different states of disease, chronic myeloid leukaemia (CML) is particularly suited for the application of multi-state models. In this article, we tried to find a model for CML that allows predicting the prevalence of three different states (initial state of disease, remission and progression) in dependence on treatment, adjusted for age, sex and risk score. Based on the German CML Study IV, one of the largest randomised studies in CML, the model was able to represent the known effects of age and risk score on the probabilities of remission and progression. Patients achieving a major molecular remission had a better chance of surviving without progression, but this effect was not significant. Comparing treatments, patient of the high-dose arm had the greatest chance to be in the state "remission" at 5 years but did not seem to have an advantage considering "progression". The proposed illness-death model can be useful for predicting the course of CML based on the patient's individual covariates (trial registration: this is an explorative analysis of ClinicalTrials.gov Identifier: NCT00055874).


Assuntos
Progressão da Doença , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Modelos Teóricos , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Resultado do Tratamento
13.
Ann Hematol ; 94(12): 2015-24, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26385387

RESUMO

Major route additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukaemia (CML) indicate an increased risk of progression and shorter survival. Since major route ACA are almost always unbalanced, it is unclear whether other unbalanced ACA at diagnosis also confer an unfavourable prognosis. On the basis of 1348 Philadelphia chromosome-positive chronic phase patients of the randomized CML study IV, we examined the impact of unbalanced minor route ACA at diagnosis versus major route ACA on prognosis. At diagnosis, 1175 patients (87.2 %) had a translocation t(9;22)(q34;q11) and 74 (5.5 %) a variant translocation t(v;22) only, while a loss of the Y chromosome (-Y) was present in addition in 44 (3.3 %), balanced or unbalanced minor route ACA each in 17 (1.3 %) and major route ACA in 21 (1.6 %) cases. Patients with unbalanced minor route ACA had no significantly different cumulative incidences of complete cytogenetic remission or major molecular remission and no significantly different progression-free survival (PFS) or overall survival (OS) than patients with t(9;22), t(v;22), -Y and balanced minor route karyotypes. In contrast, patients with major route ACA had a shorter OS and PFS than all other groups (all pairwise comparisons to each of the other groups: p ≤ 0.015). Five-year survival probabilities were for t(9;22) 91.4 % (95 % CI 89.5-93.1), t(v; 22) 87 % (77.2-94.3), -Y 89.0 % (76.7-97.0), balanced 100 %, unbalanced minor route 92.3 % (72.4-100) and major route 52.2 % (28.2-75.5). We conclude that only major route, but not balanced or unbalanced minor route ACA at diagnosis, has a negative impact on prognosis of CML.


Assuntos
Cariótipo Anormal , Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
14.
Haematologica ; 99(9): 1441-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24837466

RESUMO

The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 × 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 × 10(9)/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier:00055874).


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , RNA Mensageiro/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Monitoramento de Medicamentos , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Genótipo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , RNA Mensageiro/metabolismo , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento
15.
Ann Hematol ; 93(1): 81-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24281161

RESUMO

The activating KIT D816V mutation plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). For improved and reliable identification of KIT D816V, we have developed an allele-specific quantitative real-time PCR (RQ-PCR) with an enhanced sensitivity of 0.01-0.1 %, which was superior to denaturing high-performance liquid chromatography (0.5-1 %) or conventional sequencing (10-20 %). Overall, KIT D816 mutations were identified in 146/147 (99 %) of patients (D816V, n = 142; D816H, n = 2; D816Y, n = 2) with SM, including indolent SM (ISM, n = 63, 43 %), smoldering SM (n = 8, 5 %), SM with associated hematological non-mast cell lineage disease (SM-AHNMD, n = 16, 11 %), and aggressive SM/mast cell leukemia ± AHNMD (ASM/MCL, n = 60, 41 %). If positive in BM, the KIT D816V mutation was found in PB of all patients with advanced SM (SM-AHNMD, ASM, and MCL) and in 46 % (23/50) of patients with ISM. There was a strong correlation between the KIT D816V expressed allele burden (KIT D816V EAB) with results obtained from DNA by genomic allele-specific PCR and also with disease activity (e.g., serum tryptase level), disease subtype (e.g., indolent vs. advanced SM) and survival. In terms of monitoring of residual disease, qualitative and quantitative assessment of KIT D816V and KIT D816V EAB was successfully used for sequential analysis after chemotherapy or allogeneic stem cell transplantation. We therefore conclude that RQ-PCR assays for KIT D816V are useful complimentary tools for diagnosis, disease monitoring, and evaluation of prognosis in patients with SM.


Assuntos
Alelos , Mastocitose Sistêmica/genética , Mutação de Sentido Incorreto , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Biomarcadores , Cromatografia Líquida de Alta Pressão , Diagnóstico Diferencial , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Humanos , Estimativa de Kaplan-Meier , Leucemia de Mastócitos/diagnóstico , Leucemia de Mastócitos/genética , Masculino , Mastocitose Sistêmica/sangue , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/mortalidade , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Análise de Sequência de DNA , Triptases/sangue
16.
Ann Hematol ; 93(7): 1167-76, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24658964

RESUMO

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874


Assuntos
Benzamidas/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
17.
Ann Hematol ; 93(1): 71-80, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24162333

RESUMO

Since the advent of tyrosine kinase inhibitors, the impact of age on outcome of chronic myeloid leukemia (CML) patients has changed. We therefore analyzed patients from the randomized CML study IV to investigate disease manifestations and outcome in different age groups. One thousand five hundred twenty-four patients with BCR-ABL-positive chronic phase CML were divided into four age groups: (1) 16-29 years, n = 120; (2) 30-44 years, n = 383; (3) 45-59 years, n = 495; and (4) ≥60 years, n = 526. Group 1 (adolescents and young adults (AYAs)) presented with more aggressive disease features (larger spleen size, more frequent symptoms of organomegaly, higher white blood count, higher percentage of peripheral blasts and lower hemoglobin levels) than the other age groups. In addition, a higher rate of patients with BCR-ABL transcript levels >10 % on the international scale (IS) at 3 months was observed. After a median observation time of 67.5 months, no inferior survival and no differences in cytogenetic and molecular remissions or progression rates were observed. We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome.


Assuntos
Leucemia Mieloide de Fase Crônica/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Citarabina/administração & dosagem , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/sangue , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Interferon-alfa/administração & dosagem , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Leucemia Mieloide de Fase Crônica/sangue , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , RNA Mensageiro/sangue , RNA Neoplásico/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Fatores de Risco , Esplenomegalia/etiologia , Resultado do Tratamento , Adulto Jovem
18.
Clin Chem ; 59(6): 938-48, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23471097

RESUMO

BACKGROUND: Current guidelines for managing Philadelphia-positive chronic myeloid leukemia include monitoring the expression of the BCR-ABL1 (breakpoint cluster region/c-abl oncogene 1, non-receptor tyrosine kinase) fusion gene by quantitative reverse-transcription PCR (RT-qPCR). Our goal was to establish and validate reference panels to mitigate the interlaboratory imprecision of quantitative BCR-ABL1 measurements and to facilitate global standardization on the international scale (IS). METHODS: Four-level secondary reference panels were manufactured under controlled and validated processes with synthetic Armored RNA Quant molecules (Asuragen) calibrated to reference standards from the WHO and the NIST. Performance was evaluated in IS reference laboratories and with non-IS-standardized RT-qPCR methods. RESULTS: For most methods, percent ratios for BCR-ABL1 e13a2 and e14a2 relative to ABL1 or BCR were robust at 4 different levels and linear over 3 logarithms, from 10% to 0.01% on the IS. The intraassay and interassay imprecision was <2-fold overall. Performance was stable across 3 consecutive lots, in multiple laboratories, and over a period of 18 months to date. International field trials demonstrated the commutability of the reagents and their accurate alignment to the IS within the intra- and interlaboratory imprecision of IS-standardized methods. CONCLUSIONS: The synthetic calibrator panels are robust, reproducibly manufactured, analytically calibrated to the WHO primary standards, and compatible with most BCR-ABL1 RT-qPCR assay designs. The broad availability of secondary reference reagents will further facilitate interlaboratory comparative studies and independent quality assessment programs, which are of paramount importance for worldwide standardization of BCR-ABL1 monitoring results and the optimization of current and new therapeutic approaches for chronic myeloid leukemia.


Assuntos
Genes abl , Testes Genéticos/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Índice de Gravidade de Doença , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Padrões de Referência
19.
Blood ; 118(5): 1208-15, 2011 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-21562040

RESUMO

Mutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Guias de Prática Clínica como Assunto , Inibidores de Proteínas Quinases/uso terapêutico , Redes Comunitárias , Europa (Continente) , Prova Pericial , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Fosfotransferases/genética , Estrutura Terciária de Proteína/genética , Sociedades Médicas/legislação & jurisprudência , Sociedades Médicas/organização & administração
20.
Blood ; 118(20): 5697-700, 2011 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-21926354

RESUMO

T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL(T315I) mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors.


Assuntos
Proteínas de Fusão bcr-abl/genética , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Idoso , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros/estatística & dados numéricos , Transplante Homólogo , Adulto Jovem
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