RESUMO
Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.
Assuntos
Mastocitose Sistêmica , Humanos , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/terapia , Gerenciamento Clínico , Oncologia/normas , Oncologia/métodosRESUMO
Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).
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Citarabina , Leucemia Mieloide Aguda , Humanos , Vorinostat/uso terapêutico , Daunorrubicina , Idarubicina/uso terapêutico , Indução de Remissão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. PATIENTS AND METHODS: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. RESULTS: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. CONCLUSIONS: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.
Assuntos
Inibidores de Janus Quinases , Mielofibrose Primária , Humanos , Idoso , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Fosfatidilinositol 3-Quinases , Pirimidinas/uso terapêutico , Nitrilas/uso terapêutico , Inibidores de Janus Quinases/uso terapêuticoRESUMO
Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34+ MF cells. The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of pro-apoptotic Bcl-2 family proteins. Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/refractory MF. The randomized phase III BOREAS study compares the efficacy and safety of navtemadlin to best available therapy in patients with MF that is relapsed/refractory to JAK inhibitor treatment.
Myelofibrosis (MF) is a rare blood cancer that disrupts normal blood cell production and causes fibrosis (tissue thickening/scarring) in bone marrow, reduced red blood cells in the circulation, and an enlarged spleen. Although currently approved treatments can help relieve some effects, they have limited impact on the underlying cause of the disease. Navtemadlin is a new therapy that inhibits a protein frequently overexpressed in cancer cells found in MF patients called murine double minute 2 (MDM2), which regulates a common tumor suppressor protein called p53. By inhibiting MDM2, navtemadlin restores normal p53 function and its ability to kill MF cancer cells. BOREAS is a large clinical study of navtemadlin for MF patients whose disease is not responding to current therapy.
RESUMO
The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Adulto , Humanos , Oncologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/terapia , Policitemia Vera/diagnóstico , Mielofibrose Primária/diagnóstico , Trombocitemia Essencial/diagnósticoRESUMO
We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Humanos , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Mutação , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Transplante de Células-Tronco , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.
Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Oncologia/história , Neoplasias/tratamento farmacológico , Editoração/tendências , Análise de Rede Social , Algoritmos , Autoria , Feminino , História do Século XX , História do Século XXI , Humanos , Masculino , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , PesquisadoresRESUMO
Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.
Assuntos
Eosinofilia , Transtornos Mieloproliferativos , Neoplasias , Eosinofilia/diagnóstico , Eosinofilia/genética , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Proteínas de Fusão Oncogênica/genéticaRESUMO
For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Terapia de Salvação , Sulfonamidas/administração & dosagem , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 (P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Transplante HomólogoRESUMO
Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.
Assuntos
Anafilaxia/terapia , Mastocitose Sistêmica/terapia , Oncologia/normas , Equipe de Assistência ao Paciente/normas , Anafilaxia/diagnóstico , Anafilaxia/imunologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biópsia , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/normas , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Imunofenotipagem/métodos , Imunofenotipagem/normas , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/imunologia , Oncologia/métodos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/normas , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Sociedades Médicas/normas , Transplante Homólogo/métodos , Transplante Homólogo/normas , Resultado do Tratamento , Fatores de Poliadenilação e Clivagem de mRNA/genéticaRESUMO
The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KITwt); and AML with normal cytogenetics and mutations in NPM1 (NPM1mut); or biallelic mutations in CEBPA (CEBPAmut/mut), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPAmut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1mut AML and CEBPAmut/mut AML show significantly reduced overall survival in comparison with CBF-KITwt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management.
Assuntos
Genótipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Adulto , Fatores Etários , Idoso , Proteínas Estimuladoras de Ligação a CCAAT/genética , Fatores de Ligação ao Core/genética , Feminino , Ordem dos Genes , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Estudos Retrospectivos , Medição de Risco , Resultado do TratamentoRESUMO
Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.
Assuntos
Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/terapia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Humanos , Medição de Risco , Resultado do TratamentoRESUMO
Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.
Assuntos
Oncologia/normas , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Calreticulina/genética , Calreticulina/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Cromossomo Filadélfia , Policitemia Vera/diagnóstico , Policitemia Vera/epidemiologia , Policitemia Vera/genética , Policitemia Vera/terapia , Prevalência , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/epidemiologia , Mielofibrose Primária/genética , Mielofibrose Primária/terapia , Qualidade de Vida , Receptores de Trombopoetina/genética , Receptores de Trombopoetina/metabolismo , Medição de Risco , Transdução de Sinais , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/epidemiologia , Trombocitemia Essencial/genética , Trombocitemia Essencial/terapiaRESUMO
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Assuntos
RNA Polimerases Dirigidas por DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/genética , Translocação Genética , Antineoplásicos/farmacologia , Azepinas/farmacologia , Linhagem Celular Tumoral , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , RNA Polimerases Dirigidas por DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Elementos Facilitadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Família Multigênica , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Regiões Promotoras Genéticas , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transcrição Gênica , Triazóis/farmacologiaRESUMO
PURPOSE OF REVIEW: Acute myeloid leukemia (AML) is an immensely heterogeneous disease based on the presence of varying combinations of morphologic, immunophenotypic, genetic, and molecular characteristics identified among those diagnosed with this disease. Although current therapeutic strategies provide a reasonable likelihood of achieving a complete remission for the majority of patients, relapse rates and subsequent disease-related mortality remain unacceptably high. Improved methods of risk stratification are needed to better identify patients at considerable risk of relapse in hopes of allowing for early therapeutic intervention and/or intensification that may lead to a higher likelihood of cure. The current status of risk stratification of AML and emerging technologies with potential to improve prognostic classification and outcomes are summarized in this review. RECENT FINDINGS: Refinement of our understanding of the impact of current pretreatment AML cytogenetic, immunophenotypic, and molecular aberrations to predict outcomes and guide therapeutic decision-making is ongoing. Emerging data suggest that incorporation of the degree of posttreatment response and/or the detection of minimal residual disease can improve the accuracy of risk stratification for individual patients. SUMMARY: Although pretreatment disease characteristics remain the hallmark of prognostication for AML patients, posttreatment parameters such as minimal residual disease assessment and degree of response to therapy possess the ability to further refine our identification of patients with unfavorable disease and thereby influence decisions regarding therapeutic planning.
Assuntos
Leucemia Mieloide Aguda/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Tomada de Decisão Clínica , Testes Genéticos , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Neoplasia Residual , Prognóstico , Indução de Remissão , Risco , Resultado do TratamentoRESUMO
Treatment outcomes have significantly improved for children with acute lymphoblastic leukemia (ALL), a relatively common childhood cancer, with 5-year survival rates over 80%. However, survival rates for adolescents and young adults (AYAs) with ALL are lower than that for their younger counterparts. Despite marked heterogeneity in the biology of ALL, advancing age appears to be associated with an increased incidence of prognostically unfavorable cytogenetic abnormalities and a decreased incidence of favorable cytogenetic abnormalities. Retrospective analyses indicate that AYAs display superior remission and survival rates when treated with a pediatric rather than an adult protocol. This is thought to, in part, reflect differences in drug selection and dose intensity, with typical pediatric treatment regimens incorporating higher total doses of vincristine, l-asparaginase, and glucocorticoids than adult regimens, which tend to use more myelosuppressive agents. The tolerability and efficacy of intensive pediatric regimens are being tested prospectively in the AYA population. This review will describe the biology, treatment approaches, and therapy-related toxicities for AYAs with ALL.
RESUMO
BACKGROUND: T-cell large granular lymphocytic leukemia is a clonal proliferation of cytotoxic T-lymphocytes which often results in severe cytopenia. Current treatment options favor chronic immunosuppression. Alemtuzumab, a humanized monoclonal antibody against glycophosphatidylinositol-anchored CD52, is approved for patients refractory to therapy in other lymphoid malignancies. DESIGN AND METHODS: We retrospectively examined treatment outcomes in 59 patients with CD8+ T-cell large granular lymphocytic leukemia, 41 of whom required therapy. Eight patients with severe refractory cytopenia despite multiple treatment regimens had been treated with subcutaneous alemtuzumab as salvage therapy. Flow cytometry was used to monitor expression of glycophosphatidylinositol-anchored CD52, CD55, and CD59 as well as to characterize T-cell clonal expansions by T-cell receptor variable beta-chain (Vbeta) repertoire. RESULTS: Analysis of the effects of alemtuzumab revealed remissions with restoration of platelets in one of one patient, red blood cell transfusion independence in three of five patients and improvement of neutropenia in one of three, resulting in an overall response rate of 50% (4/8 patients). Clonal large granular lymphocytes exhibited decreased CD52 expression post-therapy in patients refractory to treatment. Samples of large granular lymphocytes collected prior to therapy also unexpectedly had a significant proportion of CD52-negative cells while a healthy control population had no such CD52 deficiency (p=0.026). CONCLUSIONS: While alemtuzumab may be highly effective in large granular lymphocytic leukemia, prospective serial monitoring for the presence of CD52-deficient clonal cytotoxic T-lymphocytes should be a component of clinical trials investigating the efficacy of this drug. CD52 deficiency may explain lack of response to alemtuzumab, and such therapy may confer a survival advantage to glycophosphatidylinositol-negative clonal cytotoxic T-lymphocytes.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antígenos CD/biossíntese , Antígenos de Neoplasias/biossíntese , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/biossíntese , Leucemia Linfocítica Granular Grande/sangue , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Linfócitos T Citotóxicos/metabolismo , Idoso , Alemtuzumab , Anticorpos Monoclonais Humanizados , Antígeno CD52 , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Estudos de Coortes , Feminino , Humanos , Leucemia Linfocítica Granular Grande/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T Citotóxicos/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: T-cell large granular lymphocyte leukemia is a chronic clonal lymphoproliferation of cytotoxic T cells often associated with immune-mediated cytopenias. The pathophysiology of cytopenias includes cytokine effects and direct antigen-specific cytotoxicity to hematopoietic precursors. This review will address the diagnostic challenges of and therapeutic options for T-cell large granular lymphocyte leukemia. RECENT FINDINGS: Immunosuppressive therapy, with cyclosporine, methotrexate, and oral cyclophosphamide, is often used, but formal trials have not been performed and response rates are poorly established. In refractory cases, alternative regimens such as antithymocyte globulin or monoclonal antibody therapy have exhibited hematologic response. SUMMARY: T-cell large granular lymphocyte leukemia may assume an indolent course but sometimes manifests with significant cytopenias. A majority of patients will ultimately require immunosuppressive therapy due to symptomatic neutropenia or anemia. In these cases, a variety of agents maybe used successfully though chronic therapy is often necessary.