RESUMO
The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.
Assuntos
Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva , Pioglitazona/administração & dosagem , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
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 ReferênciaRESUMO
The introduction of oral tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes in chronic myeloid leukemia (CML) patients. However, treatment success is directly related to good long-term adherence. Adherence to TKI therapy was evaluated in 137 CML patients over a period of 1 year. Three different methods were used to evaluate adherence: the Morisky questionnaire, a medication diary and the medication possession ratio (MPR). MPR was the most effective method of assessing adherence (median adherence 96.5%; p = 0.0001), duration of TKI treatment was the variable that most impacted adherence (p = 0.03), and the MPR 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 compliance (p = 0.02, 0.007 and 0.01, respectively). For patients treated with imatinib for 24-48 months (n = 22), individuals with major molecular response (MMR) had a significantly better MPR 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 MMR; however, only 24% of the patients were completely adherent to TKI treatment.
Assuntos
Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Criança , Estudos de Coortes , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE OF REVIEW: Chronic myeloid leukemia (CML) management in developing countries has improved in the last years, but the availability of therapeutic resources, monitoring, reimbursement, and financial issues may be a challenge and interfere with the best practices and results of CML treatment. This review points out the main challenges in CML management in South America. RECENT FINDINGS: In this review, we describe the access to tyrosine kinase inhibitors and monitoring in different countries of South America. We also address the ongoing discontinuation trials, the progress, and limitations of hematopoietic stem cell transplantation in the last years. There are still many challenges for achieving the best outcomes for CML patients in South America. The continuous efforts to provide continuous education, access to tyrosine kinase inhibitors, and monitoring, providing reference centers for CML management and hematopoietic stem cell transplantation may improve patients' outcomes.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Antineoplásicos/uso terapêutico , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , América do Sul/epidemiologiaRESUMO
This observational, multicenter study aimed to report the clinical evolution of COVID-19 in patients with chronic myeloid leukemia in Latin America. A total of 92 patients presented with COVID-19 between March and December 2020, 26% of whom were severe or critical. The median age at COVID-19 diagnosis was 48 years (22-79 years), 32% were 60 years or older, and 61% were male. Thirty-nine patients presented with at least one comorbidity (42.3%). Eighty-one patients recovered (88%), and 11 (11.9%) died from COVID-19. There was one case of reinfection. Patients with a major molecular response presented superior overall survival compared to patients with no major molecular response (91 vs. 61%, respectively; p = 0.004). Patients in treatment-free remission and receiving tyrosine kinase inhibitors showed higher survival rates than patients who underwent hematopoietic stem cell transplantation and those who did not receive tyrosine kinase inhibitors (100, 89, 50, and 33%, respectively; p < 0.001).
Assuntos
COVID-19 , Leucemia Mielogênica Crônica BCR-ABL Positiva , Teste para COVID-19 , Humanos , América Latina/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , SARS-CoV-2RESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the BCR-ABL1 tyrosine kinase (TK). The development of TK inhibitors (TKIs) revolutionized the treatment of CML patients. However, TKIs are not effective to those at advanced phases when amplified BCR-ABL1 levels and increased genomic instability lead to secondary oncogenic modifications. Wiskott-Aldrich syndrome protein (WASP) is an important regulator of signaling transduction in hematopoietic cells and was shown to be an endogenous inhibitor of the c-ABL TK. Here, we show that the expression of WASP decreases with the progression of CML, inversely correlates with the expression of BCR-ABL1 and is particularly low in blast crisis. Enforced expression of BCR-ABL1 negatively regulates the expression of WASP. Decreased expression of WASP is partially due to DNA methylation of the proximal WASP promoter. Importantly, lower levels of WASP in CML advanced phase patients correlate with poorer overall survival (OS) and is associated with TKI response. Interestingly, enforced expression of WASP in BCR-ABL1-positive K562 cells increases the susceptibility to apoptosis induced by TRAIL or chemotherapeutic drugs and negatively modulates BCR-ABL1-induced tumorigenesis in vitro and in vivo. Taken together, our data reveal a novel molecular mechanism that operates in BCR-ABL1-induced tumorigenesis that can be used to develop new strategies to help TKI-resistant, CML patients in blast crisis (BC).
Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Azacitidina/uso terapêutico , Carcinogênese/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Regiões Promotoras Genéticas/genética , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/biossíntese , Proteína da Síndrome de Wiskott-Aldrich/genéticaRESUMO
OBJECTIVE: To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib. METHODS: Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing. RESULTS: We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months. CONCLUSIONS: Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome for these patients is poor, the development of new therapies for resistant chronic myeloid leukemia patients is necessary.
Assuntos
Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Exame de Medula Óssea , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Dasatinib has demonstrated efficacy in patients with chronic-phase chronic myeloid leukemia (CML) who had resistance or intolerance to imatinib. However, some patients also develop resistance or intolerance to dasatinib. To identify potential molecular pathways involved in primary resistance to dasatinib in CML, we analyzed gene expression profiles of mononuclear cells of 7 imatinib-resistant patients, collected before and after 1-year dasatinib treatment. Large-scale gene expression was measured with Agilent microarrays covering protein-coding genes and long (>200 nt) noncoding RNAs (lncRNAs). Sets of genes and lncRNAs significantly differentially expressed (>1.5 fold-change; q value ≤10%) were identified. Ingenuity Pathway Analysis pointed to a number of functions, canonical pathways and gene networks that were significantly enriched with differentially expressed genes. In addition to protein-coding genes, lncRNAs have been recently implicated in pathways leading to tumorigenesis. Our data point to new possible regulatory elements involved in dasatinib resistance in CML.
Assuntos
Benzamidas/farmacologia , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Piperazinas/farmacologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Longo não Codificante/genética , Tiazóis/uso terapêutico , Adulto , Idoso , Dasatinibe , Resistencia a Medicamentos Antineoplásicos , Feminino , Perfilação da Expressão Gênica , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/sangue , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Tiazóis/efeitos adversosRESUMO
BACKGROUND: Acute promyelocytic leukemia is a cytogenetically well defined entity. Nevertheless, some features observed at diagnosis are related to a worse outcome of the patients. METHODS: In a prospective study, we analyzed peripheral (PB) leukocyte count, immunophenotype, methylation status of CDKN2B, CDKN2A and TP73; FLT3 and NPM1 mutations besides nuclear chromatin texture characteristics of the leukemic cells. We also examined the relation of these features with patient's outcome. RESULTS: Among 19 cases, 4 had a microgranular morphology, 7 presented PB leukocytes >10x109/l, 2 had FLT3-ITD and 3 had FLT3-TKD (all three presenting a methylated CDKN2B). NPM1 mutation was not observed. PB leukocyte count showed an inverse relation with standard deviation of gray levels, contrast, cluster prominence, and chromatin fractal dimension (FD). Cases with FLT3-ITD presented a microgranular morphology, PB leukocytosis and expression of HLA-DR, CD34 and CD11b. Concerning nuclear chromatin texture variables, these cases had a lower entropy, contrast, cluster prominence and FD, but higher local homogeneity, and R245, in keeping with more homogeneously distributed chromatin. In the univariate Cox analysis, a higher leukocyte count, FLT3-ITD mutation, microgranular morphology, methylation of CDKN2B, besides a higher local homogeneity of nuclear chromatin, a lower chromatin entropy and FD were associated to a worse outcome. All these features lost significance when the cases were stratified for FLT3-ITD mutation. Methylation status of CDNK2A and TP73 showed no relation to patient's survival. CONCLUSION: in APL, patients with FLT3-ITD mutation show different clinical characteristics and have blasts with a more homogeneous chromatin texture. Texture analysis demonstrated that FLTD-ITD was accompanied not only by different cytoplasmic features, but also by a change in chromatin structure in routine cytologic preparations. Yet we were not able to detect chromatin changes by nuclear texture analysis of patients with the FTLD-TKD or methylation of specific genes.
Assuntos
Biomarcadores Tumorais/genética , Montagem e Desmontagem da Cromatina , Cromatina/ultraestrutura , Metilação de DNA , Leucemia Promielocítica Aguda/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Fractais , Humanos , Imunofenotipagem , Leucemia Promielocítica Aguda/imunologia , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Nucleofosmina , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteína Tumoral p73 , Proteínas Supressoras de Tumor/genética , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
We analyzed the outcome of a series of 19 newly diagnosed patients with acute promyelocytic leukemia treated with AIDA modified protocol, using mitoxantrone in place of idarubicin. Eleven patients achieved morphologic CR (58%). The remaining 8 patients had induction failure due to death during induction. Ten of eleven patients in CR achieved molecular remission after induction therapy and all the 8 patients had molecular remission after consolidation. Eight patients completed the three consolidation courses as scheduled and then proceeded to maintenance therapy. After a median follow up of 52 months, no molecular or hematological relapse has occurred. The 4-year disease-free survival is 82%. The study showed the antileukemic efficacy of mitoxantrone and that it could be used as a reasonable option in anthracycline-based strategies in APL.
RESUMO
OBJECTIVE: To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib. METHODS: Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing. RESULTS: We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months. CONCLUSIONS: Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome ...
Assuntos
Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Exame de Medula Óssea , Intervalo Livre de Doença , Proteínas de Fusão bcr-abl/genética , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Resultado do TratamentoRESUMO
Point mutations within the ABL kinase domain are the most frequent mechanism for reactivation of kinase activity of the BCR-ABL gene and have been associated with clinical resistance to tyrosine kinase (TK) inhibitors in patients with CML, conferring a poor prognosis. T315I (Treonine-->Isoleucine) is a mutation in the exon 6 of BCR-ABL gene that makes the protein resistant to kinase inhibitors currently used for treating CML. Denaturing High-performance liquid chromatography (D-HPLC) allows for high throughput mutation screening. In this study, we screened mutations in exon 6 of the BCR-ABL gene in patients presenting failure or sub optimal response according to Leukemia Net criteria and correlated the presence of mutations with clinical outcome. Genomic DNA was extracted from peripheral blood samples from 93 patients with CML (5 intolerant and 88 resistant). The PCR product was analysed by D-HPLC, and the patients samples with abnormal D-HLPC profiles were submitted to automated sequencing, using specific primers. Overall survival (OS) was calculated from the date of mutation analysis, for the whole group and for both groups (mutation versus no mutation). We screened mutations in exon 6 of the BCR-ABL gene in 93 CML TKI - resistant patients. Twenty-three out of 93 samples (25%) showed an abnormal elution profile. Automated sequencing confirmed the presence of a nucleotide change in 19 out of 23 cases: one polymorphism, T315T, seven known point mutations: T315I, F317L, V339L, M351T, E355G and F359V and three novel mutations: C305R, D325D and I360S. OS for the whole group was 80% in a median observation time of 30 months. OS for patients without the mutation was 87% and with the mutation was 56%, in a median observation time of 37 and 10 months, respectively (p < 0.0001, RR = 68). D-HPLC is a practical and sensitive method for routine clinical monitoring for emergence of kinase domain mutations and may be useful for optimising therapy in CML. The screening of mutations in exon 6 is clinically relevant, once the presence of mutations confers a poor outcome. Early detection of emerging mutant clones may help in decision-making for alternative treatment.
Assuntos
Éxons , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida de Alta Pressão/métodos , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: We evaluate the effectiveness and toxicity of high-dose sequential chemotherapy (HDS) as salvage therapy in patients with advanced-stage Hodgkin lymphoma. PATIENTS AND METHODS: We performed a retrospective analysis on 77 patients receiving HDS between 1998 and 2006. Patients enrolled were in disease progression or relapsed disease, or did not achieve a complete remission after first-line treatment. HDS consisted of the sequential administration of cyclophosphamide and granulocyte colony-stimulating factor with stem cell harvesting, followed by methotrexate plus vincristine and etoposide. RESULTS: The majority of patients had stage III/IV (64%) and B symptoms (71.4%). Disease status improvement after HDS was observed in 24 of 57 patients (42%) previously in disease progression or relapse. HDS-related deaths occurred in 8 of 77 patients (10.4%). Four patients (5.2%) developed acute myeloid leukemia/myelodysplastic syndrome. Overall, disease-free and progression-free survival was 27%, 57%, and 25%, respectively. CONCLUSION: Despite the treatment-related mortality, HDS is feasible, with satisfactory response rates, even in patients with poor prognosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Transplante AutólogoRESUMO
Using the overall survival (OS), disease free survival (DFS) and progression free survival (PFS), as well as associated toxicity, the purpose of this work was to evaluate the effectiveness of HDS followed by ASCT as salvage therapy. A retrospective analysis was performed of 106 patients with high grade non-Hodgkin lymphoma receiving HDS followed by ASCT, between 1998 and 2006. Median age was 45 years (Range: 8-65), with 66 (62 percent) men. Histopathological classification was: 78 percent DLBCL patients, 12 percent T and anaplastic and 9 percent Mantle cell lymphomas; 87 percent had B cell and 12 percent T cell lymphomas; 83 percent were stage III-IV (Ann Arbor Staging), 63 percent had B symptoms, 32 percent had bone marrow involvement, 62 percent bulky disease and 42 percent high-intermediate or high risk IPI. After HDCY, 9 patients died, 7 from toxicity and 2 from sepsis. Eighty patients underwent ASCT, 47 percent were in complete remission (CR) and 15 percent died, all from toxicity. Their OS was 45 percent over 8 years. During the follow-up, another 35 patients died [4 CR, 1 partial response (PR), 2 relapsed disease (RD) and 28 disease progression (DP)], 11 (31 percent) had not performed ASCT. OS was 37 percent; DFS was 49 percent and PFS 28 percent. OS by diagnosis was 42 percent for DLBCL, 40 percent for T-cell (8 y) and 20 percent for Mantle Cell (6 y) (P=NS). OS by B symptom patients was 22 percent vs. 58 percent (P=0.002) and PFS was 23 percent vs. 37 percent (P=0.03). Patients who achieved CR after HDCY (38) had significantly better OS and PFS (38 percent and 17 percent) than patients who remained in DP (P<0.0001). Cox Regression demonstrated therapeutic lines before HDCY (Relative risk - RR = 1.41; CI 95 percent: 1.04-1.90; P= 0.02) and PD both before (RR = 2.70; CI 95 percent: 1.49-4.91, P<0.001) and after HDCY (RR = 5.38; 95 percent CI: 2.93-9.87; P<0.0001). Conclusions: Our study suggests HDS is an efficient treatment to ...
A proposta deste trabalho foi avaliar a eficácia da HDS seguida do transplante autólogo como terapia de salvamento através da sobrevida global, livre de doença e livre de progressão bem como sua toxicidade. Realizou-se estudo retrospectivo com 106 pacientes com LNH de alto grau de malignidade entre 1998 e 2006. A mediana de idade foi 45 anos (8-65); 62 por cento homens; DLBCL, 78 por cento; 12 por cento, T e anaplásico e 9 por cento, linfoma da zona do manto; 87 por cento, células B; 83 por cento estádios III-IV; 63 por cento com sintomas B; 32 por cento com infiltração da medula óssea ao diagnóstico; 62 por cento com grande massa e 42 por cento com IPI de alto risco ou intermediário. Após alta dose de ciclofosfamida (HDCY), nove pacientes faleceram. Oitenta pacientes realizaram o transplante, sendo que 47 por cento estavam em RC e 15 por cento faleceram devido à toxicidade. A sobrevida global foi de 45 por cento em oito anos para estes pacientes. Trinta e cinco pacientes não realizaram o transplante por causas diversas. Sobrevida global para todos os pacientes foi de 42 por cento, DLBCL, 40 por cento; T-cell, 40 por cento e zona do manto, 20 por cento (P=NS). Pacientes que obtiveram RC após HDCY tiveram melhor sobrevida global e livre de progressão (38 por cento e 17 por cento, respectivamente) do que os que permaneceram em PD (P<0.0001). O modelo de Cox resultou que o número de linhas terapêuticas antes da HDCY (RR 1.41 IC 95 por cento: 1.04-1.90, P=0.02) e PD antes da HDCY (RR 2.70, IC 95 por cento: 1.49-4.91, P<0.001) e após HDCY (RR 5.38, IC 95 por cento: 2.93-9.87, P<0.0001). Nosso estudo sugere que HDS é um método eficiente de tratamento para melhorar o status e reduzir a massa tumoral. Em relação à toxicidade, é factível, especialmente em pacientes de prognóstico ruim
Assuntos
Transplante Autólogo , Brasil , Terapia de Salvação , LinfomaRESUMO
Inactivation of tumor suppressor genes, whose products exert an inhibitory influence on cell cycle progression, can lead to neoplastic transformation. In acute myeloid leukemia (AML), the frequency of p53 gene mutations ranges from 4 to 15% in populations from USA and Europe. In an attempt to investigate the frequency of point mutations in the p53 gene in AML Brazilian patients, DNA samples of 35 patients were studied using PCR-SSCP techniques, screening exons 4-10. Mutations were identified in bone marrow DNA in 5 of the 35 AML patients (14.3%), a frequency similar to those reported for Northern American and European populations. The overall survival of patients with mutations in the p53 gene was significantly shorter than for patients without mutations.
Assuntos
Genes p53/genética , Leucemia Mieloide/genética , Mutação/genética , Doença Aguda , Medula Óssea , Brasil/epidemiologia , Análise Mutacional de DNA , Éxons , Frequência do Gene , Humanos , Leucemia Mieloide/epidemiologia , Leucemia Mieloide/mortalidade , Mutação/fisiologia , Prognóstico , Análise de SobrevidaRESUMO
O mesilato de imatinibe (MI) é atualmente o tratamento de escolha da Leucemoa Mielóide Crônica (LMC), mas, apesar dos excelentes resultados, não é capaz de erradicar completamente a doença, podendo ocorrer resistência ao tratamento. O mecanismo mais conhecido de resistência é o desenvolvimento de mutações do BCR-ABL, que impedem a ação ligação adequada do imatinibe à quinase, além de amplificação gênica e evolução clonal. No entanto, há uma série de outros mecanismos envolvidos e ainda pouco estudados, como alterações na absorção, efluxo e influxo de droga para o interior das células. Devem-se também considerar outros fatores, como aderência ao tratamento e uso de medicamentos concomitantes que podem interferir com imatinibe, diminuindo sua ação. O entendimento desses mecanismos poderá contribuir no desenvolvimento de novas estratégias para o tratamento dos casos resistentes.
Imatinib is currently the treatment of choice of CML, but despite of the excellent results, it is not able to completely eradicate the disease and resistance may occur. The most studied mechanism is the presence of ABL kinase mutations that interfere with imatinib binding and action, gene amplification and clonal evolution. However, there are other mechanisms involved and less studied such as drug absorption and influx and efflux of imatinib. Besides the true causes of resistance, compliance is always a concern and also drug interaction should be checked. An understanding of these mechanisms will certainly contribute to develop new strategies for the treatment of resistant cases.
Assuntos
Humanos , Incompatibilidade de Medicamentos , Resistência a Medicamentos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mesilatos , Mutação , Proteínas Tirosina QuinasesRESUMO
Os linfomas não-Hodgkin (LNH) agressivos constituemum grupo heterogêneo de neoplasias hematológicas.Os LNH difusos de grandes células B compreendem cercade 20-25% dos LNH. O tratamento quimioterápico podecurar apenas 40%-50% dos pacientes adultos com linfomasagressivos. São considerados indicadores prognósticos:idade, número de sítios extranodais, LDH, performancestatus e estadiamento clínico.Além desses fatores, anormalidades das proteínasreguladoras do ciclo celular e da apoptose parecem ser umimportante mecanismo de desenvolvimento de neoplasiase podem ter um papel no prognóstico dos linfomas agressivos.A expressão das proteínas reguladoras do ciclo celular,p...Avaliamos também a expressão de proteínas reguladorasda apoptose (p53, Bcl-2, Bax, Bak e Mcl-1) de 33pacientes com LNH difusos de grandes células B e analisamosa relação entre a expressão dessas proteínas comdados clínicos e resposta à quimioterapia.Nossos resultados mostraram que a expressão dap53 foi considerada um parâmetro imunohistoquímico independenterelacionado a um pior prognóstico nesseslinfomas. Apesar da alta expressão observada das proteínasBcl-2, Bax, Bak e Mcl-1, não foi encontrado associaçãocom prognóstico ou resposta ao tratamento.
Aggressive non-Hodgkins lymphomas (NHL) forma heterogeneous group in terms of clinical presentation,histology, immunophenotype, response to treatment andprognosis. Diffuse large B-cell NHL (DLCL) constitute upto 20-25% of NHL in many series. Combinationchemotherapy may cure 40-50% of adult patients. Severalclinical prognostic factors have been described to predictclinical outcome, as age, LDH, performance status andstage and are useful for identifying high-risk patients, whowould benefit from a more intensive approach.Abnormalities of cell cycle and apoptosis regulatingproteins seem to be an important mechanism oftumorigenesis and may play a role in the prognosis ofaggressive NHL.The expression of p53, p21/WAF-1, Mdm2 , c-Mycand proliferating cell nuclear antigen (PCNA) proteins wereexamined by the immunohistochemistry of paraffinembedded samples of 113 high grade non-Hodgkinslymphomas (NHL) and in 62 patients with aggressive NHLcorrelated to clinical data. Expression of p53, ....NHL patients with a hyper-expression of p53 protein(n=17). DNA extraction was performed in 15 patients andPCR amplification of exons 5-9 was possible in 7 cases.We found a point mutation in exon 6 (Val→Glu;T→A), ina patient with a p53 hyper-expression and p21 negativeexpression.We also evaluated the expression of apoptosisregulatingproteins (p53, Bcl-2, Bax, Bak and Mcl-1) ofparaffin-embedded samples of 33 patients with diffuse largeB-cell NHL, and assessed the relationship of these proteinsto clinical outcome and response to chemotherapy.Our results showed that p53 expression was anindependent immunohistochemical parameter related to apoor prognosis in these lymphomas. Bcl-2, Bax, Bak andMcl-1 proteins, though highly expressed in almost all caseswere not associated with prognosis or response totreatment.
Assuntos
Humanos , Proteína de Suscetibilidade a Apoptose Celular , Linfoma não Hodgkin , Linfoma não Hodgkin/terapiaRESUMO
Imunodeficiência humoral é uma característica intrínseca da leucemia linfocítica crônica B. A quimioterapia, principalmente quando o paciente é politratado, e em especial os análogos da purina, ampliam o espectro de susceptibilidade destes pacientes a agentes infecciosos oportunistas devido ao efeito imunossupressor celular destas drogas. Relatamos um paciente com leucemia linfocítica crônica submetido a várias linhas de quimioterapia, inclusive o 2-CdA, que apresentou múltiplas complicações infecciosas associadas a grave imunodeficiência celular.
Hypogamaglobulinemia is frequently associatedwith B-CLL rendering the patients prone to bacterialinfections. The use of purine analogs that causedepletion of T lymphocytes in the treatment of thisdisease, increases the spectrum of susceptibility ofthese patients to oportunistic agents. We report acase of a young B-CLL patient treated with 2-CdA,who presented multiple infectious complicationsduring the course of his disease associated with asevere cellular immune deficiency.