RESUMO
BACKGROUND: Published criteria defining the accelerated phase in chronic myeloid leukemia are heterogeneous and little is known about predictors of poor outcome.METHODS: This is a retrospective study of 139 subjects in the accelerated phase of chronic myeloid leukemia treated with imatinib at a single center in Brazil. The objective was to identify risk factors for survival, major cytogenetic response and progression to blast phase in this population. The factors analyzed were: blasts 10-29%, basophils ≥ 20%, platelets > 1 × 106/µL or <1 × 105/µL and white blood cells > 1 × 105/µL in the peripheral blood, as well as clonal evolution, splenomegaly, hemoglobin < 10 g/dL, time between diagnosis of chronic myeloid leukemia and imatinib treatment, and hematologic toxicity.RESULTS: Risk factors for poor survival in multivariate analysis were Grades 3-4 hematologic toxicity (p-value = 0.001), blasts 10-29% (p-value = 0.023), and hemoglobin < 10 g/dL (p-value = 0.04). Risk factors for not achieving major cytogenetic response were blasts 10-29% (p-value = 0.007), hemoglobin < 10 g/dL (p-value = 0.001), and previous use of interferon (p-value = 0.032). Risk factors for progression to the blast phase were hemoglobin < 10 g/dL (p-value = 0.005), basophils ≥ 20% (p-value = 0.023), and time from diagnosis of chronic myeloid leukemia to imatinib treatment > 12 months (p-value = 0.030).CONCLUSION: These data indicate that patients with the above risk factors have a worse prognosis. This information can guide the therapy to be used.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Prognóstico , Leucemia Mieloide de Fase Acelerada , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mortalidade , Mesilato de ImatinibRESUMO
We performed whole-exome sequencing in samples representing accelerated phase (AP) and blastic crisis (BC) in a subject with chronic myeloid leukemia (CML). A total of 12.74 Gb clean data were generated, achieving a mean depth coverage of 64.45 and 69.53 for AP and BC samples, respectively, of the target region. A total of 148 somatic variants were detected, including 76 insertions and deletions (indels), 64 single-nucleotide variations (SNV), and 8 structural variations (SV). On the basis of annotation and functional prediction analysis, we identified 3 SNVs and 6 SVs that showed a potential association with CML progression. Among the genes that harbor the identified variants, GATA2 has previously been reported to play important roles in the progression from AP to BC in CML. Identification of these genes will allow us to gain a better understanding of the pathological mechanism of CML and represents a critical advance toward new molecular diagnostic tests for the development of potential therapies for CML.
Assuntos
Crise Blástica/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide de Fase Acelerada/patologia , Polimorfismo Genético , Adulto , Povo Asiático/genética , Crise Blástica/genética , Progressão da Doença , Exoma , Fator de Transcrição GATA2/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Acelerada/genética , Masculino , Mutação , Análise de Sequência de DNARESUMO
Pomolic acid (PA) is a pentacyclic triterpene which has been previously described as active in inhibiting the growth of K562 cell line-originated from chronic myeloid leukemia (CML) in blast crisis-and its vincristine-resistant derivative K562-Lucena1. In this work, cells from CML patients were treated with PA and the apoptotic index was compared with the multidrug resistance (MDR) profile and clinical status of the patients. Our findings show that PA 12.5 microg/ml at 24 h (p = 0.000), at 48 h (p = 0.012) and at 72 h (p = 0.005) has a potent apoptotic index in CML cells as compared to mononuclear cells from healthy donors. PA was capable to induce apoptosis in cells from CML patients exhibiting functional MDR phenotype but not in P-glycoprotein expression. In addition, PA was effective in chronic as well as in blast phase of CML. Moreover, similar apoptotic index induced by PA was observed in low, intermediate and high-risk Sokal score as well as in samples from the group of patients with clinical resistance to interferon and/or imatinib and non-treated patients. These results suggest that PA may be an effective agent for the treatment of CML.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Crise Blástica/tratamento farmacológico , Crise Blástica/patologia , Resistência a Múltiplos Medicamentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide de Fase Acelerada/tratamento farmacológico , Leucemia Mieloide de Fase Acelerada/patologia , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/patologia , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêuticoAssuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Benzamidas , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/enzimologia , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Acelerada/tratamento farmacológico , Leucemia Mieloide de Fase Acelerada/terapia , Estudos Multicêntricos como Assunto , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/enzimologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Cromossomo Filadélfia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Terapia de Salvação , Resultado do TratamentoAssuntos
Transplante de Medula Óssea , Leucemia Mieloide de Fase Acelerada/terapia , Adulto , Evolução Fatal , Hemorragia/patologia , Humanos , Leucemia Mieloide de Fase Acelerada/complicações , Leucemia Mieloide de Fase Acelerada/patologia , Pneumopatias/patologia , Masculino , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodosRESUMO
Chronic myelogenous leukemia (CML) is a clonal disorder that presents with a stable period followed by an accelarated phase. The most frequent chromosomal abnormality described is t(9;22). Alterations of chromosome 17, where p53 is located, have been described during transformation. We studied a 23-year-old male who presented with chronic myelogenous leukemia. The karyotype demonstrated 46,XY,t(9;22) (q34;qll) in 12 percent of mitoses and hyperdiploidy in 43 percent. Forty six months later the patient suffered a blast crisis characterized by absolute basophilia; the cytogenetic study demonstrated 48,XY,+8,t(9;22(q34;qll), +der(22)t(9;22)(q34;qll),+i(17)(q10) in 18 percent of the mitoses, 46,XY,t(9;22) (q34;qll) in 34 percent and hyperdiploidy in 23 percent. Since there was i(17)(q10) during this stage, a retrospective DNA study of the biopsy material before and after the transformacition was performed. In the chronic phase, p53 was present in normal amounts, during transformation there was loss of genetic material from the p53 region. The protein product of suppressor gene p53 normally works holding the proliferation of cells. When there is the formation of an isochromosome, genetic material is lost; thus, in this patient, p53 was delted upon the observation of i(17). Lastly, this case shows how DNA can be extracted from slides; this technique is novel and can be used for retrospective studies when parafin block or fresh tissue are not available
Assuntos
Humanos , Masculino , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 17/ultraestrutura , Genes p53 , Isocromossomos , Leucemia Mieloide de Fase Acelerada/genéticaRESUMO
The value of low-dose interferon (IFN) on the evolution of chronic myelogenous leukaemia was assessed in this study. Eleven patients previously treated with busulphan were analysed. Seven of them, in the chronic phase, received IFN 2 x 10(6) U/m2 subcutaneously three times a week; four patients in accelerated phase and two unresponsive to IFN were given a combination of IFN and hydroxyurea. Low-dose IFN proved capable of prolonging the remission period induced by busulphan. In the accelerated phase, the association of IFN and hydroxyurea protracted the evolution of the disease, although no conclusions can yet be drawn regarding the patients' survival. Ph1-chromosome negativity was attained in 28% of the cases. Minimal untoward effects were observed. It was concluded that low doses of IFN may induce scarce toxicity while preserving the therapeutic value.
Assuntos
Fatores Imunológicos/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mieloide de Fase Acelerada/terapia , Leucemia Mieloide de Fase Crônica/terapia , Adolescente , Adulto , Idoso , Bussulfano/uso terapêutico , Terapia Combinada , Feminino , Humanos , Hidroxiureia/uso terapêutico , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Leucemia Mieloide de Fase Acelerada/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Indução de Remissão , Trombocitopenia/induzido quimicamenteRESUMO
One hundred and ninety well-characterized acute and chronic leukaemias were studied for the expression of CD1a antigen by indirect immunofluorescence (IIF). CD1a was detected on 28 per cent of mature B cell lymphoproliferative disorders, 26 per cent of acute non-lymphoblastic leukaemias (ANLL), 21 per cent of chronic granulocytic leukaemias in blast crisis (CML-BC), 53 percent of T acute lymphocytic leukaemias (T-ALL) and in only one out of 35 common acute lymphoblastic leukaemias (c-ALL). In some cases the expression of the CD1a antigen on the surface of leukaemic cells showed a spontaneous fluctuation after a short period of incubation in vitro. CD1b and CD1c molecules were also detected on B cells and acute non-lymphoblastic leukaemias. The presence of CD1 antigens was confirmed using a dot blot assay (DBA) on the lysate of leukaemic cells.