Inclusion of molecular monitoring (BCR-ABL1) in the treatment of chronic myeloid leukemia in the Brazilian Public Health System (SUS): an urgent need for treatment management

ABSTRACT Introduction: Chronic Myeloid Leukemia (CML) is a myeloproliferative disease that affects mainly adults between 50 and 55 years. In Brazil, information from the Sistema Único de Saúde (SUS) Outpatient Information System indicates that 12,531 patients had the Autorização de Procedimento Ambulatorial (APAC) approved for the CML treatment in 2017. Disease monitoring through molecular response evaluation is critical to the care of CML patients. The quantitative PCR test (real-time polymerase chain reaction) provides adequate evaluation parameters that allow the health professional to intervene at the right moments in order to reduce the chance of progression of the disease, providing the best outcome to the patient, including the possibility of treatment discontinuation for eligible patients. Although the test is included in the Clinical Protocol and Therapeutic Guidelines (PCDT) of CML, it is not possible to monitor the molecular response within SUS since there is no reimbursement for this test. Objective: Obtain expert recommendations on the importance, financing, and reimbursement of molecular monitoring in SUS. Methods: Six CML experts with different perspectives participated in the panel. The discussion was based in the main publications about the quantitative PCR test in CML monitoring. Results: Experts' recommendations: Molecular monitoring should be part of the integral treatment of patients with CML to reduce the chances of disease progression and costs to the health system; The government should put into practice what is provided in the PCDT of Chronic Myeloid Leukemia in Brazil: performing the monitoring of the molecular response via quantitative PCR; The government should create a code with adequate nomenclature and reimbursement value in SIGTAP, so that the test is carried out and covered by the public health network, as it is contained in the PCDT of the disease and the existing APAC does not cover the operational costs for its performance; Patients with chronic phase CML should perform a quantitative PCR every 3 months and, after reaching the MMR, should perform the examination every 6 months, as recommended by international guidelines; Patients should be monitored in reference laboratories that are standardized according to the international scale; The laboratories that are within the reference public centers could absorb all the test demand in Brazil, and other centers could be qualified through an ABHH accreditation; Adequate molecular monitoring may allow some patients to stop taking drugs and selffinancing the molecular test for all SUS patients Conclusion: A solution for the molecular test (BCR-ABL1) funding is urgent to ensure the monitoring of CML patients in SUS. The savings that might be generated with patients that stop taking the medication when adequately monitored may finance the test.

Guidelines for therapy of patients with chronic myeloproliferative neoplasms during the novel coronavirus SARS-CoV2 pandemic

ABSTRACT The novel coronavirus has swept across the world in 2020 and ushered a new era. In the current scenario, it is not clear how patients with myeloproliferative neoplasms (including chronic myelogenous leukemia) should be managed, considering the risk of therapy, the need for social distancing and the risk of untimely therapy discontinuation of delay. This guideline aims to give providers a sense of direction in order to better take care of patients and prioritize care.

Aspectos clínicos, laboratoriais e tratamento da leucemia mieloide crônica em cão relato de caso / Clinical aspects, hematological changes and treatments of chronic myeloid leukemia in dog: case report

O objetivo deste relato é apresentar o caso clínico de uma cadela, sem raça definida, com cinco anos de idade, diagnosticada com leucemia mieloide crônica (LMC). As leucemias são neoplasias malignas que se originam de células precursoras da medula óssea e as consequências podem ser trombocitopenia, anemia, leucocitose persistente e presença de células neoplásicas no sangue. O tratamento de escolha envolve o uso de inibidores de tirosina quinase, porém este não pode ser usado neste caso. Dessa forma a cadela recebeu diferentes protocolos quimioterápicos que incluíram inicialmente hidroxiureia, citarabina, doxorrubicina e prednisona. Devido a remissão parcial dos sinais clínicos e a resposta terapêutica pouco duradoura a essas medicações o protocolo foi alterado para quimioterapia metronômica com clorambucil. O uso desses quimioterápicos não foram eficazes em reduzir a leucocitose e controlar a anemia e trombocitopenia da paciente, devido a ocorrência do surgimento de células imaturas no sangue e resistência aos quimioterápicos. Na ausência da crise e da possibilidade do uso dos inibidores de tirosina quinase, a hidroxiureia permanece sendo o quimioterápico de eleição. O animal apresentou sobrevida de 210 dias, devido a leucocitose e anemia severas pouco responsivas ao protocolo terapêutico utilizado e o surgimento no hemograma de precursores neutrofilicos que ocorreu 46 dias

The aim of this report is to present the clinical case of a five-year-old mixed breed female dog diagnosed with chronic myeloid leukemia (CML). Leukemias are malignant neoplasms that originate from bone marrow precursor cells and the consequences can be thrombocytopenia, anemia, persistent leukocytosis and the presence of neoplastic cells in the blood. The treatment of choice involves the use of tyrosine kinase inhibitors, but it cannot be used in this case. Thus, the dog received different chemotherapy protocols that initially included hydroxyurea, cytarabine, doxorubicin and prednisone. Due to the partial remission of clinical signs and the short-term therapeutic response to these medications, the protocol was changed to metronomic chemotherapy with chlorambucil. The use of these chemotherapeutic agents was not effective in reducing leukocytosis and controlling the patient’s anemia and thrombocytopenia, due to the occurrence of immature cells in the blood and resistance to chemotherapeutic agents. In the absence of the crisis and the possibility of using tyrosine kinase inhibitors, hydroxyurea remains the chemotherapy of choice. The animal had a 210-day survival, due to severe leukocytosis and anemia, which were not responsive to the therapeutic protocol used and the appearance in the blood count of neutrophilic precursors that occurred 46 days after the beginning of hydroxyurea treatment.

Patients' perceptions about diagnosis and treatment of chronic myeloid leukemia: a cross-sectional study among Brazilian patients / Percepções dos pacientes sobre diagnóstico e tratamento da leucemia mieloide crônica: estudo transversal entre pacientes brasileiros

CONTEXT AND OBJECTIVES: Chronic myeloid leukemia (CML) requires strict daily compliance with oral medication and regular blood and bone marrow control tests. The objective was to evaluate CML patients' perceptions about the disease, their access to information regarding the diagnosis, monitoring and treatment, adverse effects and associations of these variables with patients' demographics, region and healthcare access. DESIGN AND SETTING: Prospective cross-sectional study among CML patients registered with the Brazilian Lymphoma and Leukemia Association (ABRALE). METHODS: CML patients receiving treatment through the public healthcare system were interviewed by telephone. RESULTS: Among 1,102 patients interviewed, the symptoms most frequently leading them to seek medical care were weakness or fatigue. One third were diagnosed by means of routine tests. The time that elapsed between first symptoms and seeking medical care was 42.28 ± 154.21 days. Most patients had been tested at least once for Philadelphia chromosome, but 43.2% did not know the results. 64.8% had had polymerase chain reaction testing for the BCR/ABL gene every three months. 47% believed that CML could be controlled, but 33.1% believed that there was no treatment. About 24% reported occasionally stopping their medication. Imatinib was associated with nausea, cramps and muscle pain. Self-reported treatment adherence was significantly associated with normalized blood count, and positively associated with imatinib. CONCLUSIONS: There is a lack of information or understanding about disease monitoring tools among Brazilian CML patients; they are diagnosed quickly and have good access to treatment. Correct comprehension of CML control tools is impaired in Brazilian patients.

CONTEXTO E OBJETIVOS: Leucemia mieloide crônica (CML) exige estrita adesão à medicação oral e ao monitoramento do sangue e da medula. O objetivo foi avaliar percepções de pacientes com leucemia mieloide crônica (LMC) sobre a doença, seu acesso à informação sobre diagnóstico, monitoramento e tratamento, efeitos adversos e a associação destes com dados demográficos, geográficos e de acesso a tratamento. DESENHO E LOCAL: Estudo prospectivo transversal realizado com pacientes de LMC cadastrados na Associação Brasileira de Leucemia e Linfoma (Abrale). MÉTODOS: Pacientes com LMC recebendo tratamento do sistema público de saúde foram entrevistados por telefone. RESULTADOS: Entre os 1.102 pacientes entrevistados, os sintomas mais frequentemente levando à busca de consulta foram fraqueza e fadiga. Um terço foi diagnosticado por exames de rotina. O tempo entre sintoma inicial e procura por ajuda foi de 42,28 ± 154,21 dias. A maioria foi testada pelo menos uma vez para o cromossomo Filadélfia, mas 43,2% não sabiam os resultados. 64,8% fizeram exame de reação em cadeia da polimerase para o gene BCR/ABL a cada três meses. 47% acreditavam que LMC pode ser controlada, mas 33,1% acham que não há tratamento. Cerca de 24% disseram que ocasionalmente interrompem o tratamento. Imatinibe associou-se com náusea, câimbra e dor muscular. Aderência auto-reportada associou-se significativamente com hemograma normal e positivamente com uso de imatinibe. CONCLUSÕES: Falta informação ou compreensão sobre monitoramento entre pacientes com LMC; eles recebem diagnóstico rapidamente e têm bom acesso ao tratamento. A correta compreensão das ferramentas de controle em LMC está prejudicada entre eles.

Aspectos diagnósticos, evolutivos y terapéuticos de la leucemia mieloide crónica / Diagnostic, evolutive and therapeutic aspects of chronic myeloid leukemia

Introducción: la leucemia mieloide crónica (LMC) es un síndrome mieloproliferativo crónico caracterizado por la presencia de una alteración citogenética en las células proliferantes, el cromosoma Filadelfia (Ph), que da lugar a la formación de un gen híbrido BCR-ABL, fundamental en la patogénesis de la enfermedad. Objetivo: describir el comportamiento de esta enfermedad en los pacientes tratados en el Instituto de Hematología e Inmunología. Métodos: se estudiaron las características de esta enfermedad en sus aspectos diagnósticos, evolutivos y terapéuticos, en los pacientes atendidos desde marzo de 1974 hasta junio de 2012. Resultados: el grupo de edad que predominó para ambos sexos fue de 30 a 39 años. El 21 por ciento de los pacientes se encontraban asintomáticos en el momento del diagnóstico. La esplenomegalia fue el signo predominante en el 64 por ciento de los pacientes. Los hallazgos iniciales más significativos del hemograma consistieron en leucocitosis, basofilia y anemia. El 81 por ciento de los casos se encontraba en fase crónica al inicio de la enfermedad. La mayoría de los pacientes debutaron con niveles de LDH elevados. Se observó el cromosoma Filadelfia en el 68 por ciento de los pacientes a quienes se les realizó estudio citogenético. El estudio del reordenamiento del gen BCR/ABL se realizó en el 70 por ciento de los casos, siendo positivo en su totalidad. La media de supervivencia en relación con el tratamiento fue mayor en los pacientes tratados con mesilato de imatinib desde el momento del diagnóstico (11.7 años). La media de supervivencia global es de 11.44 años y la mediana es de 8.18 años. Conclusiones: todos los parámetros demográficos, clínicos, de laboratorio y terapéuticos coincidieron con lo descrito en la literatura, excepto la edad de aparición de la LMC que evidenció una disminución

Introduction: Chronic myeloid leukemia (CML) is a chronic myeloproliferative syndrome characterized by the presence of a citogenetic alteration in proliferant cells, the Philadelphia chromosome (Ph), giving rise the formation of a hybrid gene BCR-ABL, with a fundamental role in the pathogenesis of the disease. Objective: To describe the clinical behavior of the illness in patients treated at the Institute of Hematology and Immunology. Methods: Characteristics according to diagnose, evolution and therapeutic aspects of the patients treated at from March 1974 to June 2012 were studied. Results: The age group that prevailed for both sexes was 30-39 years; 21 percent of the patients were asintomatic at diagnosis. Splenomegaly was the predominant sign in 64 percent of the patients. The most significant initial discoveries on blood film were leucocytosis, basophillia and anemia; at debut 81 percent of the patients were in chronic phase. Most patients debuted with high levels of LDH. Ph chromosome was observed in 68 percent of individuals with cytogenetc studies. The BCR/ABL gene was detected in every patient with molecular studies. The mean of survival in relation to treatment was higher in patients treated with imatinib mesilate at diagnosis (11.7 years). The mean of global survival was 11.44 years with the median of 8.18 years. Conclusion: All demographic, clinical, laboratory and therapeutic parameters coincided with the literature with the exception of a lower age at onset of CML

Aderência dos pacientes com leucemia mielóide crônica à terapia com inibidores de tirosino quinase / Adherence to tyrosine kinase inhibitors treatment in patients with chronic myeloid leukemia

A leucemia mieloide crônica e uma doença clonal, caracterizada por uma translocação recíproca entre os cromossomos 9 e 22. A introdução do tratamento com inibidores de tirosino quinase, administrado por via oral, revolucionou e melhorou drasticamente o tratamento destes pacientes, porem a eficácia deste tratamento esta diretamente relacionada ao uso desta medicação a longo prazo. Pacientes e métodos: 137 pacientes com leucemia mieloide crônica, em uso de inibidores de tirosino quinase, tiveram a sua aderência avaliada em três diferentes momentos: seis meses retrospectivo, seis e doze meses prospectivos. Três diferentes métodos indiretos foram utilizados para a avaliação da aderência: o teste de Morisky, o diário de medicação e o índice de posse da medicação. Resultados: não houve diferença significante quando consideramos os três diferentes momentos em que avaliação foi realizada e o método considerado mais efetivo para a avaliação da aderência foi considerado o índice de posse da medicação (p=0.0001). Considerando as informações acima, o método utilizado para a avaliação da aderência foi o índice de posse da medicação avaliado apos, aproximadamente, 12 meses de analise. A mediana de aderência observada neste estudo foi de 96,5%. Os fatores que influenciaram a aderência foram: nível socioeconômico, qualidade de vida, tempo de uso dos inibidores de tirosino quinase e participação em protocolos de pesquisa clinica. Sendo que pacientes com níveis socioeconômicos mais elevados, com melhor qualidade de vida e que estavam inseridos em protocolos clínicos estavam relacionados com melhores índices de aderência (p=0.01, p=0.007 e p=0.02 respectivamente). Enquanto que pacientes com tempo mais prolongado de uso dos inibidores de tirosino quinase estavam relacionados a piores índices de aderência (p=0.03).

Chronic myeloid leukemia is a clonal disorder caused by the reciprocal translocation between cromossomes 9 and 22.The introduction of oral tyrosine kinase inhibitors has dramatically revolucioned and improved outcomes in these patients. However, treatment success is directly related to good long-term adherence and questions relating to adherence to prescribed therapy have become an important issue. Patient and Methods: adherence to tyrosine kinase inhibitors therapy was evaluated in 137 chronic myeloid leukemia patients in three different times: six months retrospective, six and twelve month prospectively. Three different methods were used to evaluate adherence: the Morisky Questionnaire, the medication diary and the medication possession ratio. Results: there was no difference between the three different time of evaluation and the medication possession ratio was the most effective method of assessing adherence (p=0.0001); the median adherence was 96.5%. Duration of tyrosine kinase inhibitors treatment was the variable that most impacted adherence (p=0.03); the medication possession ratio was inversely correlated to the duration of therapy. Additionally, participation in clinical trials, better quality of life as reported by patients and higher socioeconomic status were all related to better adherence (p=0.02, p=0.007 and p=0.01, respectively). For patients treated with imatinib for 24 to 48 months (n=22), individuals with major molecular response had a significantly better medication possession ratio than those who failed to achieve MMR (p=0.04). In this group the mean MPR was 87% for the population without apparent molecular response and 96% for those achieving major molecular response, however only 24% of the patients were completely adherent to tirosine kinase inhibitors treatment.

Bilateral proliferative retinopathy as the initial presentation of chronic myeloid leukemia

The authors report a rare case of a 48-year-old male with chronic myeloid leukemia [CML] who initially presented with a bilateral proliferative retinopathy. The patient complained of recent visual loss and floaters in both eyes [BE]. Ophthalmologic evaluation revealed a best corrected visual acuity [BCVA] of 20/50 in the right eye and 20/200 in the left eye [LE]. Fundoscopy showed the presence of bilateral peripheral capillary dropout with multiple retinal sea fan neovascularisations, which were confirmed on fluorescein angiography. Full blood count revealed hyperleukocytosis, thrombocytosis, anemia, and hyperuricemia. Bone marrow aspiration and biopsy showed the reciprocal chromosomal translocation t [9;22], diagnostic of CML. The patient was started on hydroxyurea, allopurinol and imatinib mesylate. He received bilateral panretinal laser photocoagulation and a vitrectomy was performed in the LE. The patient has been in complete hematologic, cytogenetic, and major molecular remission while on imatinib and his BCVA is 20/25 in BE

Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital

Background: In the last decade, there has been a revolution in chronic myeloid leukemia treatment with the introduction of tyrosine kinase inhibitors with imatinib mesylate becoming the frontline therapy. Objective: To evaluate the therapeutic efficacy of imatinib mesylate in treating chronic myeloid leukemia patients and to identify factors related to therapeutic efficacy. Methods: This retrospective study was based on information obtained from patients'records in the Hematology Service of Hospital Universitário Walter Cantídio of the Universidade Federal do Ceará (HUWC / UFC). All patients diagnosed with chronic myeloid leukemia that took imatinib mesylate for a minimum of 12 months in the period from January 2001 to January 2011 were included. From a population of 160 patients, 100 were eligible for analysis. Results: The study population consisted of 100 patients who were mostly male (51%) with ages rangingbetween 21 and 40 years (42%), from the countryside (59%), in the chronic phase (95%), with high-riskprognostic factors (40%); the prognosis of high risk was not associated with complete hematologic responseor complete cytogenetic response, but correlated to complete molecular response or major molecularresponse. Reticulin condensation was associated with complete hematologic response and completecytogenetic response. It was found that 53% of patients had greater than 90% adherence to treatment. Thehigh adherence was correlated to attaining complete cytogenetic response in less than 12 months. Moreover,20% of patients had good response. Conclusion: Significant changes are indispensable in the monitoring of patients with chronic myeloid leukemia. Thus, the multidisciplinary team is important as it provides access to the full treatment and not just to medications. .

Caracterización de los autoanticuerpos en la anemia hemolítica autoinmune secundaria al tratamiento con interferón alfa / Characterization of autoantibodies in autoimmune hemolytic anemia following treatment with interferon alfa

Se estudiaron 13 pacientes con leucemia mieloide crónica y anemia hemolítica autoinmune inducida por el interferón alfa, a quienes se les realizó la detección de inmunoproteínas y la caracterización de las subclases de IgG en los hematíes mediante la prueba de antiglobulina directa (PAD) y la técnica de microplacas. Se aplicó además un ELISA para la cuantificación de inmunoglobulinas en los hematíes. Se detectó la presencia de IgG y C3 en el 53,84 por ciento de los casos, IgG sola en el 23,07 por ciento y en el 15,38 por ciento se identificaron autoanticuerpos IgG e IgA. En 11 pacientes se demostró la presencia de IgG1 y en un caso se identificaron además autoanticuerpos de la subclase IgG3. El ELISA detectó autoanticuerpos en concentraciones de 183 moléculas de IgG por hematíe en un paciente con PAD negativa. En los pacientes con hemólisis de alto grado se encontró una concentración de autoanticuerpos entre 1 500 y 3 180 moléculas de IgG por hematíe, mientras que en los casos con hemólisis de bajo grado se comportó entre 183 y 1 000 moléculas. Se observó una correlación negativa entre las cifras de Hb y los valores de haptoglobina plasmática con el número de moléculas de IgG por hematíe y una correlación positiva entre este último con el conteo de reticulocitos

We studied 13 patients with chronic myeloid leukemia and autoimmune hemolytic anemia induced by interferon alfa. They underwent tests for immune protein detection and characterization of IgG subclasses in RBCs by direct antiglobulin test (PAD) and the microplate technique. Also they were applied ELISA test for quantifying immunoglobulins in the red blood cells. It was detected the presence of IgG and C3 in 53.84 percent of cases, IgG alone in 23.07 percent and in 15.38 percent were identified IgG and IgA autoantibodies. In 11 patients the presence of IgG1 was showed and also in one case the subclass IgG3 autoantibodies was identified. The ELISA detected antibodies at concentrations of 183 IgG molecules per erythrocyte in a patient with negative PAD. In high-grade hemolysis patients, it was found a concentration of autoantibodies between 1 500 and 3 180 molecules of IgG per erythrocyte, while in low-grade hemolysis patients it behaved between 183 and 1 000 molecules. There was a negative correlation between Hb and plasma haptoglobin values with the number of IgG molecules per erythrocyte and a positive correlation between the latter with the reticulocyte count

Probable asociación de los inhibidores de la tirosina quinasa con la persistencia de clones aberrantes con cromosoma Filadelfia negativo / Probable association of tyrosine kinase inhibitors with aberrant clones persistent Philadelphia chromosome negative

Paciente de 43 años diagnosticado con leucemia mieloide crónica en 1998, que fue tratado de forma inicial con interferón alfa. En la terapia posterior adquirió múltiples cambios citogenéticos clonales en células del cromosoma Filadelfia negativas, por lo que se describe el efecto de los inhibidores de la tirosina quinasa de segunda generación sobre esos clones celulares.

Assessment of fibrosis and vascularization of bone marrow stroma of chronic myeloid Leukemia patients treated with imatinib mesylate and their relationship with the cytogenetic response / Avaliação da fibrose e vascularização do estroma da medula óssea de pacientes com leucemia mielóide crônica tratados com mesilato de imatinibe e sua relação com a resposta citogenética

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the presence of the Philadelphia chromosome (translocation between chromosomes 9 and 22), resulting in the formation of the hybrid BCR-ABL protein. Currently, the treatment of CML patients is performed with imatinib mesylate (IM), which promotes the elimination of leukemic cells by inhibiting the kinase activity of BCR-ABL. This study evaluated the effectiveness of IM by monitoring 22 CML patients in a chronic phase treated at the CEPON/SC with IM for a minimum follow-up period of two years. Cytogenetic Response (CR) and bone marrow biopsies (BMB) were evaluated before and after IM treatment. BMB were evaluated by detection of reticulin degree and vascularization. The results were correlated to the CR. Mean time to achieve CR was 9 months and was attained by 77.27 percent of the patients. The results from the initial BMB analysis showed that 59.09 percent presented reticulin of between 2+ and 4+ whereas after treatment, only 27.17 percent presented this degree. With regard to vascularization of the initial sample, 90.91 percent were graded between II and IV, whereas after treatment, 40.91 percent had this degree. The results suggest a positive correlation of degree of reticulin and vascularization with CR.

A Leucemia Mielóide Crônica (LMC) é uma doença mieloproliferativa caracterizada pela presença do cromossomo Filadélfia (translocação entre os cromossomos 9 e 22), que resulta na formação da proteína híbrida BCR-ABL. Atualmente o tratamento de pacientes com LMC é realizado com mesilato de imatinibe (MI), o qual promove a eliminação das células leucêmicas pela inibição da atividade quinase de BCR-ABL. O presente estudo avaliou a eficácia do MI por meio do acompanhamento de pacientes portadores de LMC em fase crônica, atendidos no CEPON/SC tratados com MI pelo tempo mínimo de dois anos. Foram avaliadas a Resposta Citogenética (RC) e as biópsias de medula óssea (BMO) antes e após o tratamento com MI. As BMO foram avaliadas quanto ao grau de reticulina e vascularização. Os resultados correlacionaram-se com a RC cujo tempo médio para obtenção da RC foi de 9 meses, sendo atingida por 77.27 por cento dos pacientes. Na primeira BMO, 59.09 por cento dos pacientes apresentaram grau de reticulina entre 2+ e 4+ e após o tratamento, apenas 27.17 por cento apresentaram esta graduação. Quanto à vascularização da primeira amostra, 90.91 por cento foram graduadas entre II e IV e após o tratamento, 40.91 por cento apresentaram esta graduação. Os resultados sugerem uma correlação diretamente proporcional entre os graus de reticulina e vascularização com a RC.

Leucemia mieloide crônica: passado, presente, futuro: [revisão] / Chronic myeloid leukemia: past, present, future: [review]

The discovery of the Philadelphia chromosome in 1960, and of the BCR-ABL oncogene in 1984, enabled the development in subsequent years of a targeted therapy that revolutionized the treatment of chronic myeloid leukemia, thus changing its natural history. The use of imatinib resulted in a significant improvement of the prognosis and outcome of patients with chronic myeloid leukemia. However, the occurrence of mechanisms of resistance or intolerance precludes the eradication of the disease in some of the patients. Second-generation tyrosinekinase inhibitors are efficient in most of these patients, except for those with T315I mutation. We present an overall review of chronic myeloid leukemia, with emphasis on the progress in its treatment.

As descobertas do cromossomo Filadélfia, em 1960, e do oncogene BCR-ABL, em 1984, permitiram o desenvolvimento, nos anos subsequentes, de uma terapia-alvo que revolucionou o tratamento da leucemia mieloide crônica, mudando sua história natural. O uso do imatinibe resultou numa melhora expressiva do prognóstico e da evolução dos pacientes com leucemia mieloide crônica. Entretanto, surgiram mecanismos de resistência ou intolerância, que impedem a erradicação da doença numa parcela dos pacientes. Os inibidores de tirosina quinase de segunda geração mostram eficácia namaioria desses pacientes , exceto naqueles com mutação T315I. Aqui, foi realizada uma revisão global da leucemia mieloide crônica, destacando-se a evolução de seu tratamento.

Visual disturbance as the first symptom of chronic myeloid leukemia

Chronic myeloid leukemia [CML] is a well-studied entity and advances made in diagnosis and treatment have improved the disease outcome. Patients with ophthalmic manifestation of CML have been reported to have lower 5-year survival rates. Hence, recognizing the early fundus changes may improve outcome by allowing earlier diagnosis and treatment. We report a case of a previously healthy 30-year-old Myanmarese male, who presented with a minor visual disturbance, complaining of seeing a 'black dot' in his left visual field for the past 1 week. Fundoscopic examination revealed bilateral retinal blot hemorrhages, white-centered hemorrhage, and preretinal hemorrhage over the left fovea. The full blood count and peripheral blood film were abnormal, and bone marrow biopsy confirmed the diagnosis of CML. Cytoreduction therapy was promptly commenced and his symptoms resolved, with improvement in visual acuity. No complications were recorded at 1-year follow-up

[Growth inhibitory and apoptotic effects of carbenoxolone in human leukemia K562 cell line]

Leukemia is a malignant and progressive disorder in which genetic defects in hematopoietic cells lead to uncontrolled proliferation of blood cells. Different drugs have been proposed for the treatment of leukemia but none of them resulted in complete remission. Recently, anti-cancer effects of carbenoxolone [CBX], that is a 3- hemisuccinate, have been reported in several cell lines. In the present study we evaluated the effects of CBX on K562 cell line as an experimental model of chronic myeloid leukemia [CML]. K562 cells were cultured and treated for various time intervals with different concentrations of CBX [50-300 micro M]. Trypan blue exclusion test and tetrazolium salt absorption test [MTT] were used to evaluate the growth inhibitory and apoptotic effects of the drug. Fluorescence microscopy and DNA fragmentation assay were used to study apoptosis. The results of this study showed that CBX induced growth inhibition of K562 cells in a dose- and time- dependent manner. For example, growth inhibition rates after 48 hours treatment with concentrations of 50 micro m, 100 micro m, 150 micro m, 200 micro m and 300 micro m were 11%, 41%, 59%, 79% and 92%, respectively. Furthermore results of fluorescence microscopy and DNA fragmentation assays indicated that apoptosis, is the cause of cell death induced by CBX. Considering the growth inhibitory and apoptotic effects of CBX on human myeloid leukemia K562 cells, the drug can be considered as a potential candidate for further studies on CML treatment