RESUMO
The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Compostos de Anilina/uso terapêutico , Tomada de Decisão Clínica , Conferências de Consenso como Assunto , Dasatinibe/uso terapêutico , Gerenciamento Clínico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Expectativa de Vida/tendências , Monitorização Fisiológica , Nitrilas/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/uso terapêutico , Análise de SobrevidaRESUMO
The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/psicologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Qualidade de VidaRESUMO
Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.
Assuntos
Proteínas de Fusão bcr-abl/análise , Calibragem , Proteínas de Fusão bcr-abl/normas , Genes abl , Humanos , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcr/genética , Padrões de Referência , Organização Mundial da SaúdeRESUMO
Measurable ('minimal') residual disease (MRD) before or after hematopoietic cell transplantation (HCT) identifies adults with AML at risk of poor outcomes. Here, we studied whether peri-transplant MRD dynamics can refine risk assessment. We analyzed 279 adults receiving myeloablative allogeneic HCT in first or second remission who survived at least 35 days and underwent 10-color multiparametric flow cytometry (MFC) analyses of marrow aspirates before and 28±7 days after transplantation. MFC-detectable MRD before (n=63) or after (n=16) transplantation identified patients with high relapse risk and poor survival. Forty-nine patients cleared MRD with HCT conditioning, whereas two patients developed new evidence of disease. The 214 MRD(neg)/MRD(neg) patients had excellent outcomes, whereas both MRD(neg)/MRD(pos) patients died within 100 days following transplantation. For patients with pre-HCT MRD, outcomes were poor regardless of post-HCT MRD status, although survival beyond 3 years was only observed among the 58 patients with decreasing but not the seven patients with increasing peri-HCT MRD levels. In multivariable models, pre-HCT but not post-HCT MRD was independently associated with overall survival and risk of relapse. These data indicate that MRD(pos) patients before transplantation have a high relapse risk regardless of whether or not they clear MFC-detectable disease with conditioning and should be considered for pre-emptive therapeutic strategies.
Assuntos
Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/patologia , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Idoso , Exame de Medula Óssea , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasia Residual/mortalidade , Período Pós-Operatório , Período Pré-Operatório , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto JovemRESUMO
The ability to correlate single-cell genetic information to cellular phenotypes will provide the kind of detailed insight into human physiology and disease pathways that is not possible to infer from bulk cell analysis. Microfluidic technologies are attractive for single-cell manipulation due to precise handling and low risk of contamination. Additionally, microfluidic single-cell techniques can allow for high-throughput and detailed genetic analyses that increase accuracy and decrease reagent cost compared to bulk techniques. Incorporating these microfluidic platforms into research and clinical laboratory workflows can fill an unmet need in biology, delivering the highly accurate, highly informative data necessary to develop new therapies and monitor patient outcomes. In this perspective, we describe the current and potential future uses of microfluidics at all stages of single-cell genetic analysis, including cell enrichment and capture, single-cell compartmentalization and manipulation, and detection and analyses.
Assuntos
Microfluídica/métodos , Análise de Sequência/métodos , Análise de Célula Única , Genoma Humano , Humanos , Reação em Cadeia da PolimeraseAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , DNA (Citosina-5-)-Metiltransferases/genética , Éxons/genética , Leucemia Mieloide Aguda/mortalidade , Mutação/genética , Idoso , Idoso de 80 Anos ou mais , Citarabina/administração & dosagem , DNA Metiltransferase 3A , Daunorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
Nilotinib (Tasigna) is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to imatinib. The 48-month follow-up data for patients with CML-CP treated with nilotinib after imatinib resistance or intolerance on an international phase II study were analyzed. Overall, 59% of patients achieved major cytogenetic response; 45% achieved complete cytogenetic response while on study. The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively. Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months. Of the 321 patients initially enrolled in the study, 98 (31%) were treated for at least 48 months. Discontinuations were primarily due to disease progression (30%) or adverse events (21%). Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to imatinib. Further significant improvements in therapy are required for patients who are resistant or intolerant to imatinib.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Terapia de Salvação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Agências Internacionais , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
The purpose was to assess predictive factors for outcome in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) treated with nilotinib after imatinib failure. Imatinib-resistant and -intolerant patients with CML-CP (n=321) were treated with nilotinib 400 mg twice daily. Of 19 baseline patient and disease characteristics and two response end points analyzed, 10 independent prognostic factors were associated with progression-free survival (PFS). In the multivariate analysis, major cytogenetic response (MCyR) within 12 months, baseline hemoglobin ≥ 120 g/l, baseline basophils <4%, and absence of baseline mutations with low sensitivity to nilotinib were associated with PFS. A prognostic score was created to stratify patients into five groups (best group: 0 of 3 unfavorable risk factors and MCyR by 12 months; worst group: 3 of 3 unfavorable risk factors and no MCyR by 12 months). Estimated 24-month PFS rates were 90%, 79%, 67% and 37% for patients with prognostic scores of 0, 1, 2 and 3, respectively, (no patients with score of 4). Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Adulto JovemRESUMO
MOTIVATION: Selecting a small number of signature genes for accurate classification of samples is essential for the development of diagnostic tests. However, many genes are highly correlated in gene expression data, and hence, many possible sets of genes are potential classifiers. Because treatment outcomes are poor in advanced chronic myeloid leukemia (CML), we hypothesized that expression of classifiers of advanced phase CML when detected in early CML [chronic phase (CP) CML], correlates with subsequent poorer therapeutic outcome. RESULTS: We developed a method that integrates gene expression data with expert knowledge and predicted functional relationships using iterative Bayesian model averaging. Applying our integrated method to CML, we identified small sets of signature genes that are highly predictive of disease phases and that are more robust and stable than using expression data alone. The accuracy of our algorithm was evaluated using cross-validation on the gene expression data. We then tested the hypothesis that gene sets associated with advanced phase CML would predict relapse after allogeneic transplantation in 176 independent CP CML cases. Our gene signatures of advanced phase CML are predictive of relapse even after adjustment for known risk factors associated with transplant outcomes.
Assuntos
Algoritmos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Teorema de Bayes , Progressão da Doença , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide de Fase Crônica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , RecidivaRESUMO
Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.
Assuntos
Biomarcadores Tumorais/genética , Códon/genética , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Cariotipagem , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Nucleofosmina , Prevalência , Prognóstico , Sequências de Repetição em Tandem/genética , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Dasatinib is a highly potent BCR-ABL inhibitor that has shown durable efficacy in patients with chronic phase (CP) chronic myeloid leukemia (CML) after resistance, suboptimal response, or intolerance to prior imatinib. In patients with CML, BCR-ABL transcript measurement is the most sensitive method for assessing minimal residual disease. Here, molecular responses were analyzed in 1067 patients with CML-CP treated with dasatinib during phase II/III trials. After 3, 6, 12, and 24 months of follow-up, a major molecular response (MMR) was achieved by 12, 22, 35, and 40% of patients, respectively. The 24-month MMR rate was 34% in patients with resistance or suboptimal response to imatinib (n=829) and 63% in imatinib-intolerant patients (n=238). Among patients who had achieved a complete cytogenetic response (CCyR), 72% also achieved MMR. Responses with dasatinib 100 mg once daily were similar to other doses. In landmark analyses, 24-month progression-free survival was higher in patients who had achieved MMR or CCyR at 12 months than in those without MMR or CCyR at 12 months. MMR at 12 months was associated with a longer duration of CCyR. Overall, this analysis shows that dasatinib treatment results in high MMR rates in patients with CML-CP after imatinib failure.
Assuntos
Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Reparo de Erro de Pareamento de DNA , Dasatinibe , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Falha de TratamentoRESUMO
A large fraction of the carbon dioxide added to the atmosphere by human activity enters the sea, causing ocean acidification. We show that otoliths (aragonite ear bones) of young fish grown under high CO2 (low pH) conditions are larger than normal, contrary to expectation. We hypothesize that CO2 moves freely through the epithelium around the otoliths in young fish, accelerating otolith growth while the local pH is controlled. This is the converse of the effect commonly reported for structural biominerals.
Assuntos
Bass/crescimento & desenvolvimento , Dióxido de Carbono/análise , Membrana dos Otólitos/crescimento & desenvolvimento , Água do Mar/química , Animais , Bass/metabolismo , Calcificação Fisiológica , Carbonato de Cálcio/metabolismo , Dióxido de Carbono/metabolismo , Concentração de Íons de Hidrogênio , Larva/crescimento & desenvolvimento , Microscopia Eletrônica de Varredura , Membrana dos Otólitos/ultraestrutura , Óvulo/crescimento & desenvolvimentoRESUMO
Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Benzamidas , Progressão da Doença , Seguimentos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Segunda Neoplasia Primária/induzido quimicamente , Piperazinas/toxicidade , Pirimidinas/toxicidade , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoAssuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Nanotecnologia/instrumentação , Mutação Puntual , Reação em Cadeia da Polimerase/métodos , Humanos , Técnicas Analíticas Microfluídicas/instrumentação , Reação em Cadeia da Polimerase/normas , Sensibilidade e EspecificidadeAssuntos
Envelhecimento , Células-Tronco Hematopoéticas/química , Fatores Reguladores de Interferon/análise , ADP-Ribosil Ciclase 1 , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Antígenos CD34 , Humanos , Fatores Reguladores de Interferon/genética , Camundongos , Pessoa de Meia-Idade , Adulto JovemAssuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Transtornos Mieloproliferativos/genética , Doença Crônica , Ensaios Clínicos como Assunto , Instabilidade Genômica , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapiaRESUMO
Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03-20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in Assuntos
Crise Blástica/tratamento farmacológico
, Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
, Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
, Inibidores de Proteínas Quinases/administração & dosagem
, Pirimidinas/administração & dosagem
, Tiazóis/administração & dosagem
, Administração Oral
, Adolescente
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Antineoplásicos
, Benzamidas
, Terapia Combinada
, Dasatinibe
, Intervalo Livre de Doença
, Resistencia a Medicamentos Antineoplásicos
, Feminino
, Genes abl/genética
, Transplante de Células-Tronco Hematopoéticas
, Humanos
, Mesilato de Imatinib
, Leucemia Mielogênica Crônica BCR-ABL Positiva/genética
, Masculino
, Pessoa de Meia-Idade
, Piperazinas
, Inibidores de Proteínas Quinases/efeitos adversos
, Pirimidinas/efeitos adversos
, Tiazóis/efeitos adversos
, Resultado do Tratamento
, Adulto Jovem
RESUMO
Minimal residual disease (MRD) can be detected in many patients with leukemia who have achieved complete remission as defined by conventional pathology examination. The detection of MRD, be it by flow cytometry or by polymerase chain reaction assays, has now been found to be associated with subsequent relapses in most leukemia subtypes, either following chemotherapy or following hematopoietic stem cell transplantation. These assays are now increasingly used in clinical trial design to optimize therapy and provide a novel way to assess treatment efficacy.
Assuntos
Leucemia Linfocítica Crônica de Células B/diagnóstico , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Citometria de Fluxo , Humanos , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Neoplasia Residual/patologia , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologiaRESUMO
Molecular monitoring for patients with chronic myeloid leukaemia (CML) has become an important practice in the era of imatinib therapy. For successful widespread introduction into the mainstream patient monitoring schedule, many procedural aspects of the complex real-time quantitative polymerase chain reaction (RQ-PCR) technique for measuring BCR-ABL transcripts require optimization. Recommendations for harmonizing the differing methodologies have recently been proposed. These recommendations were designed to maximize reliability of analysis for clinical decision making and proposed the adoption of an International Scale of measurement. The purpose of this review is to present the evidence and supporting data for specific recommendations. These recommendations include use of the same source of cells, either blood or marrow, for analysis; for validation of equal PCR amplification efficiencies of cDNA and standards when using a plasmid to construct standard curves and for ensuring ongoing high-level performance by undertaking a quality assurance programme. Clinicians must know the measurement reliability of an RQ-PCR assay to be able to determine the significance of a change in BCR-ABL level. An assay with poor precision limits the clinical usefulness of results. International harmonization should establish RQ-PCR measurement of BCR-ABL as the best method for monitoring treatment response for patients with CML.
Assuntos
Monitoramento de Medicamentos/métodos , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Reação em Cadeia da Polimerase/métodos , Humanos , Reação em Cadeia da Polimerase/normas , Controle de Qualidade , RNA Mensageiro/análise , Reprodutibilidade dos TestesRESUMO
A total of 24 patients (median age 58; range, 27-71 years) with chronic myeloid leukemia (CML) in first chronic (CP1) (n=14), second chronic (n=4), or accelerated phase (n=6) who were not candidates for conventional hematopoietic cell transplantation (HCT), received nonmyeloablative HCT from HLA-matched siblings a median of 28.5 (range, 11-271) months after diagnosis. They were conditioned with 2 Gy total body irradiation (TBI) alone (n=8) or combined with fludarabine, 90 mg/m(2) (n=16). Postgrafting immunosuppression included cyclosporine and mycophenolate mofetil. All patients initially engrafted. However, 4 of 8 patients not given fludarabine experienced nonfatal rejection while all others had sustained engraftment. With a median follow-up of 36 (range, 4-49) months, 13 of 24 patients (54%) were alive and in complete remission. There were five (21%) deaths from nonrelapse mortality, one (4%) during the first 100 days after transplant. The proportions of grade II, III, and IV acute GVHD were 38, 4, and 8%, respectively. The 2-year estimate of chronic GVHD was 32%. The 2-year survival estimates for patients in CP1 (n=14) and beyond CP1 (n=10) were 70 and 56%, respectively. This study shows encouraging remission rates for patients with CML not eligible for conventional allografting.