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 JovemRESUMO
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/métodosRESUMO
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 SobrevidaRESUMO
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 TratamentoRESUMO
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 JovemRESUMO
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 JovemRESUMO
The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome-positive (Ph(+)) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACAs except -Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P < .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Translocação Genética , Resultado do Tratamento , Trissomia , Adulto JovemRESUMO
In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens.
Assuntos
Biomarcadores Tumorais/genética , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Transativadores/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Regulador Transcricional ERG , Regulação para Cima/genética , Adulto JovemRESUMO
Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high-risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional (n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD-HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide.
Assuntos
Leucemia Promielocítica Aguda/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trióxido de Arsênio , Arsenicais/administração & dosagem , Medula Óssea/patologia , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Contagem de Leucócitos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Óxidos/administração & dosagem , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Indução de Remissão , Risco , Tioguanina/administração & dosagem , Resultado do Tratamento , Tretinoína/administração & dosagemRESUMO
To search for new copy number alterations (CNAs) in acute promyelocytic leukemia (APL), we analyzed DNA from leukemic blasts of 93 acute promyelocytic leukemia (APL) patients with Genome-Wide SNP 6.0 arrays (SNP-A). We identified 259 CNAs consisting of 170 heterozygous deletions, 82 amplifications, and 7 regions of copy number neutral loss of heterozygosity. One of the most common CNAs was a deletion on chromosomal subband 1q31.3 in 13 of 93 (14%) patients encompassing the coding regions for the microRNAs mir181a1/b1. In multivariable analysis with the covariates age, white blood cell count, platelet count, and FLT3-ITD/FLT3 D835 mutations we found that after adjustment for patients' age (P<0.0001), patients with 2 or more CNAs detected by SNP-A had a higher risk of death (hazard ratio=5.942, P=0.0015) than patients with 0 or 1 CNA. Deletions of 1q31.3 were associated with a higher number of CNAs (median 2 vs. 8, P<0.0001) and were a strong independent prognostic factor for an increased risk of relapse (hazard ratio=28.9, P=0.0031). This study presents a comprehensive assessment of new CNAs as pathomechanistically relevant targets and possible prognostic factors which could refine risk stratification of APL.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Deleção de Genes , Leucemia Promielocítica Aguda/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Criança , Variações do Número de Cópias de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Fatores de Risco , Estatísticas não Paramétricas , Translocação GenéticaRESUMO
SOCS-2 gene expression at diagnosis has been suggested as a predictor of clinical outcome in chronic myeloid leukemia (CML). In this study SOCS-2 and GUS expression levels were determined by real-time PCR in pretherapeutic samples at diagnosis. First, three patient groups were compared after assessment at 48 months: optimal molecular responders (n = 35), patients with resistance to imatinib (n = 28), and blast crisis patients (n = 27). A significant difference in SOCS-2 gene expression at diagnosis was observed comparing blast crisis vs. resistant patients (p = 0.042) and optimal responders (p = 0.010). Second, a validation sample of consecutively randomized patients (n = 123) was investigated. No discriminative SOCS-2 gene expression cutoff could be derived to predict molecular or cytogenetic response, progression-free or overall survival. Although SOCS-2 gene was differentially expressed at the time of diagnosis in blast crisis patients when compared to other groups, a prognostic impact in consecutively randomized patients was not observed.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Crise Blástica/diagnóstico , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Expressão Gênica , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Point mutations of the BCR-ABL tyrosine kinase domain are considered the predominant cause of imatinib resistance in chronic myeloid leukemia. The expansion of mutant BCR-ABL-positive clones under selective pressure of tyrosine kinase inhibition is referred to as clonal selection; there are few data on the reversibility of this phenomenon. DESIGN AND METHODS: The changes of expression of mutant BCR-ABL-positive alleles after cessation of tyrosine kinase inhibitor treatment were examined in 19 patients with chronic myeloid leukemia harboring different mutations in a longitudinal follow-up. The proportion of mutant alleles was quantified by amplification of rearranged ABL sequences followed by mutation-specific restriction digestion, electrophoresis and densitometry. The size of mutant clones was established as a measure of the absolute amount of mutant cells considering the proportion of mutant BCR-ABL transcripts and the total level of BCR-ABL obtained by quantitative reverse transcriptase polymerase chain reaction. RESULTS: The median proportion of mutant transcripts was 97% before and 8% after cessation of tyrosine kinase inhibitor treatment indicating a relative decline of 88% within a median of 6 months. The relative decrease in the size of the mutant clones was 86%. Repeated selection and deselection of the mutant clone after resumption and second cessation of tyrosine kinase inhibitor treatment was observed in individual patients. CONCLUSIONS: Deselection of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor treatment might be a common, rapid and reproducible phenomenon, although some patients harboring the T315I mutation showed no deselection. Cessation of tyrosine kinase inhibitor treatment may lead to the regression of T315I mutant clones to a level under the limit of detection, offering the therapeutic option of resumed tyrosine kinase inhibitor treatment under close surveillance of the mutation status.
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/administração & dosagem , Proteínas Tirosina Quinases/genética , Pirimidinas/administração & dosagem , Tiazóis/administração & dosagem , Protocolos Antineoplásicos , Benzamidas , Células Clonais/patologia , Dasatinibe , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Mutação Puntual , Reação em Cadeia da Polimerase , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/uso terapêutico , RNA Mensageiro/análise , Tiazóis/uso terapêutico , Suspensão de TratamentoRESUMO
The BCR-ABL K247R change is based on a rare single nucleotide polymorphism occurring likewise in healthy controls and non-hematologic cell types. Despite its juxtaposition to the P-loop, functional analysis showed no alteration compared to non-mutated BCR-ABL. We sought to investigate if other changes in the BCR-ABL kinase domain should be considered as single nucleotide polymorphisms rather than acquired mutations. A total of 911 chronic myeloid leukemia patients after failure or suboptimal response to imatinib were screened for BCR-ABL kinase domain mutations. Single nucleotide polymorphism analysis was based on the search for nucleotide changes in corresponding normal, non-translocated ABL alleles by ABL allele-specific PCR following mutation analysis. In addition to the K247R polymorphism we uncovered five new single nucleotide polymorphisms within the BCR-ABL kinase domain; two of them led to amino acid changes. Single nucleotide polymorphisms could theoretically contribute to primary but not to secondary resistance to tyrosine kinase inhibitors and must therefore be distinguished from acquired mutations. Novel point mutations should be confirmed by analyzing the normal ABL alleles to exclude polymorphisms.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/genética , Polimorfismo de Nucleotídeo Único/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Bases , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Tirosina Quinases/metabolismo , Análise de SequênciaRESUMO
To date risk stratification in acute promyelocytic leukemia (APL) is based on highly dynamic leukocyte and platelet counts only. To identify a more robust risk stratification model, a molecular risk score was developed based on expression levels of the genes BAALC, ERG and WT1. Hereby, the main focus was on prediction of relapse. The integrative risk score divided patients into two groups with highly significant differences in outcome. It discriminated a high risk group with a high incidence of relapse successfully from a low risk group with no APL-related events after achievement of first remission. Especially the concurrent presence of molecular risk factors showed to be a negative prognostic factor in APL. The molecular risk score might be a promising approach to guide monitoring of APL patients and therapeutic decisions in the future.
RESUMO
Wilms' tumor 1 gene (WT1) is known to be highly expressed in acute promyelocytic leukemia (APL) but information on its impact on prognosis is lacking. WT1 expression was analyzed in bone marrow samples of 79 patients with APL at initial diagnosis. Patients had a differing outcome according to their level of WT1 expression. In patients who achieved a complete remission (CR), low or high WT1 expression was significantly associated with inferior overall survival (OS) compared to intermediate WT1 expression (49% for WT1high vs. 63% for WT1low vs. 93% for WT1int; p=0.008). Moreover, there were significant differences in relapse-free survival (RFS) between the three expression groups (42% for WT1high vs. 63% for WT1low vs. 83% for WT1int; p=0.047). In multivariable analysis WT1 expression showed an independent prognostic impact on OS of responders to induction therapy. In conclusion, the level of WT1 expression can add prognostic information in APL risk stratification.
Assuntos
Expressão Gênica , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Proteínas WT1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Biópsia , Medula Óssea/patologia , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Indução de Remissão , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Imatinib mesylate (STI571) is a major therapeutic advance for the management of chronic myeloid leukaemia (CML), however, a proportion of patients are refractory to it, particularly those in more advanced phases of CML. Different mechanisms of resistance to imatinib are suggested, including point mutations within ABL-kinase domains. A point mutation leading to substitution at the ATP binding site of ABL-kinase and insensitivity to imatinib was detected in our patient treated with imatinib, who progressed to blast crisis. Additionally, clonal evolution could lead to BCR-ABL-independent proliferation. Early detection of ABL-kinase mutation could predict the progression of CML treated with imatinib.
Assuntos
Crise Blástica/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/uso terapêutico , Mutação Puntual/genética , Pirimidinas/uso terapêutico , Trifosfato de Adenosina/metabolismo , Adulto , Sequência de Aminoácidos , Sequência de Bases , Benzamidas , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Homologia de Sequência do Ácido NucleicoRESUMO
PURPOSE: Chronic myeloid leukemia (CML) patients are monitored by both cytogenetic and molecular assessments, although present guidelines appear to switch from cytogenetic to molecular criteria. Due to the increasing use of molecular measurements, it was the aim of this work to identify a BCR-ABL level according to the international scale (BCR-ABL(IS)) as an equivalent substitute for complete cytogenetic remission (CCyR). METHODS: In total, 1,329 paired data from 557 patients of the German CML-Study IV were evaluated. The data set was divided into a learning set and a validation set. The best cutoff was determined applying a minimal p value approach to the Fisher test. RESULTS: In the learning set, we found BCR-ABL(IS) values between 0.2 and 1.1 % were well suited for predicting a CCyR. In the validation set, the cutoff level of 1 % led to a mean concordance rate of 90.1 %. CONCLUSIONS: Our results suggest that there is no one-to-one cutoff for BCR-ABL(IS) representing CCyR, but we advise to use the 1 % BCR-ABL(IS) in order to avoid misclassification of CCyR patients.
Assuntos
Biomarcadores Tumorais/sangue , Proteínas de Fusão bcr-abl/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , RNA Mensageiro/sangue , Biomarcadores Tumorais/genética , Proteínas de Fusão bcr-abl/genética , Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Técnicas de Diagnóstico Molecular , RNA Mensageiro/genética , Indução de RemissãoRESUMO
PURPOSE: Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival. PATIENTS AND METHODS: Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival. RESULTS: Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression. CONCLUSION: MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Citarabina/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , 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 , Terapia de Alvo Molecular , Piperazinas/efeitos adversos , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
We evaluated the prognostic value of BAALC expression in 86 patients with acute promyelocytic leukemia (APL). At 10 years, the overall survival (OS) was 66% in all patients and 75% in patients who achieved a complete remission (CR). Patients in the BAALC(low) group showed an OS of 87% as compared to 60% in the BAALC(high) group (p=0.019). This difference was more pronounced in treatment responders (92% vs. 70%; p=0.035). In multivariate analyses low BAALC expression retained its prognostic relevance. In conclusion, BAALC expression analysis might be useful in further risk stratification in APL patients.
Assuntos
Expressão Gênica , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Recidiva , Sobrevida , Adulto , Idoso , Sequência de Bases , Primers do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Targeted treatment of chronic myelogenous leukemia using imatinib has dramatically improved patient outcome. However, residual disease can be detected in the majority of patients treated with imatinib. Compensatory activation of MAP kinases (MAPK1/2) in response to BCR-ABL-inhibitors has been reported as a potential cytokine-dependent resistance mechanism leading to the rescue of leukemic progenitor cells. METHODS: Differential MAPK-modulating activity of clinically approved tyrosine kinase inhibitors was assessed in vitro using BCR-ABL-transformed cells. CD34+-enriched progenitors of newly diagnosed chronic myelogenous leukemia patients were exposed to tyrosine kinase inhibitors. MAPK-signaling was studied by Western blot technique. Proliferation assays were used to analyze response to antileukemic treatment. RESULTS: The ABL-inhibitors imatinib and nilotinib activate MAPKs in CD34+ chronic myelogenous leukemia progenitor cells, whereas treatment with the SRC/ABL-inhibitor dasatinib does not affect MAPK-activation at clinically relevant concentrations. Similar results are seen in BCR-ABL-transformed cells in the presence of interleukin-3 (IL-3). Experiments using BCR-ABL-mutant T315I, a resistance mutation not amenable to tyrosine kinase inhibitor binding, demonstrate that ABL-inhibitor-induced MAPK-activation does not depend on BCR-ABL-inhibition and cannot be prevented by selective SRC-inhibition. However, BCR-ABL-T315I enhances MAPK-activation, suggesting a T315I-dependent positive feedback of MAPK-activation. An autocrine IL-3-loop as trigger for aberrant T315I-dependent MAPK-activation was excluded. CONCLUSIONS: Aberrant MAPK-activation triggered by ABL-inhibitors and positively regulated by BCR-ABL kinase mutation T315I might be an experimental explanation for the clinical observation that patients carrying high-resistance mutations show a highly aggressive course of their disease when tyrosine kinase inhibitor treatment is not discontinued in time.