RESUMO
For several decades, the treatment for acute myeloid leukemia (AML) has been a dichotomous choice between intensive chemotherapy strategies with curative intent and non-intensive options including supportive care. Patients' age and fitness, as well as comorbidities, primarily influenced this choice. However, the therapeutic armamentarium is evolving, so that there are highly effective and increasingly specific drugs, fitting the mutational profile of a patient's leukemia. There is now a spectrum of treatment options that are less intense and can be administered in an outpatient setting and to a substantial extent are equally or even more effective than standard intensive therapy. We are, therefore, witnessing a radical change in the treatment landscape of AML. In this review, we examine the current treatment options for patients with AML, considering the molecular spectrum of the disease on the background of patient-related factors.
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Leucemia Mieloide Aguda , Humanos , Adulto , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Exercício Físico , MutaçãoRESUMO
PURPOSE OF REVIEW: Until recently, improvement in terms of survival for patients with acute myeloid leukemia (AML) was achieved mostly in younger patients with dose intensification of conventional chemotherapy and a broadening use of allogeneic hematopoietic cell transplantation (allo-HCT) whereas the results remained dismal and very stable in patients older than 60 years. The current review highlights the recent developments in standard intensive post-remission chemotherapy, evidence for the use of recently approved agents, and discusses the relevance of measurable residual disease (MRD) measurement in treatment adaptation. RECENT FINDINGS: Current approvals of midostaurin, venetoclax, gemtuzumab ozogamicin, VYXEOS, ivosidenib, enasidenib, glasdegib, and CC-486 have changed the structure, aim, and schedule of consolidation therapy, and new, well-tolerated agents are being evaluated as maintenance therapies. Furthermore, MRD assessment has been implemented to guide the duration and type of consolidation and maintenance therapy as well as indicate the optimal timing of allo-HCT. Novel therapies have changed the structure and perspective of post-remission therapy in AML for both young and elderly patients. In addition, MRD assessment could guide the type, duration, and intensity of consolidation and maintenance therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide/terapia , Neoplasia Residual/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Indução de Remissão , Análise de Sobrevida , Transplante HomólogoRESUMO
Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.
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Leucemia Linfocítica Crônica de Células B , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/epidemiologia , Mutação , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosAssuntos
Aminoglicosídeos , Protocolos de Quimioterapia Combinada Antineoplásica , Gemtuzumab , Leucemia Mieloide Aguda , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aminoglicosídeos/uso terapêutico , Aminoglicosídeos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis , Método Duplo-Cego , Gemtuzumab/uso terapêutico , Gemtuzumab/administração & dosagem , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Compostos de Fenilureia , Indução de Remissão , Resultado do TratamentoAssuntos
Quimioterapia de Consolidação , Leucemia Mieloide Aguda , Animais , Everolimo , Nozes , Sirolimo , Serina-Treonina Quinases TOR , Reino UnidoRESUMO
BACKGROUND: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. METHODS: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. CONCLUSION: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.
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Leucemia Mieloide Aguda , Mitoxantrona , Humanos , Mitoxantrona/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/efeitos adversos , Doença Crônica , Citarabina/efeitos adversos , Tirosina Quinase 3 Semelhante a fms/genéticaAssuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Homeostase do Telômero/genética , Telômero/genética , Aberrações Cromossômicas , Ensaios Clínicos Fase II como Assunto , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Estudos Multicêntricos como Assunto , Mutação , Prognóstico , Encurtamento do Telômero , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND: The strength, assistance walking, rise from a chair, climb stairs, and falls (SARC-F) questionnaire is a well-established instrument for screening of sarcopenia and sarcopenia-related functional impairments. As it is based on self-reporting, its use precludes patients who are unable to answer the questionnaire as a consequence of severe acute diseases or cognitive impairment. Therefore, we aimed to validate a proxy-reported version of the SARC-F for both ad-hoc as well as retrospective screening for severe sarcopenia-related functional impairments. METHODS: Patients aged ≥60 years completed the SARC-F and performed the short physical performance battery (SPPB) at baseline (T1). Proxies in Cohort A gave a simultaneous assessment of the patients' functional status with the proxy-reported SARC-F at T1 and again, retrospectively, after 3 months (T2). Proxies in Cohort B only completed the SARC-F retrospectively at T2. The questionnaires' performances were assessed through sensitivity/specificity analyses and receiver operating characteristic (ROC) curves. For non-inferiority analyses, results of both the patient-reported and proxy-reported SARC-F were correlated with the SPPB total score as well as the results of the chair-rise test subcategory; the respective correlation coefficients were tested against each other. RESULTS: One hundred and four patients and 135 proxies participated. Using a SPPB score < 9 points as the reference standard, the proxy-reported SARC-F identified patients at high risk for sarcopenia-related functional impairment with a sensitivity of 0.81 (ad-hoc), 0.88 (retrospective Cohort A), and 0.87 (retrospective Cohort B) as well as a specificity of 0.89 (ad-hoc), 0.78 (retrospective Cohort A), and 0.64 (retrospective Cohort B). Areas under the ROC curves were ≥ 0.9 for the ad-hoc proxy-reported SARC-F and the retrospective proxy-reported SARC-F in both cohorts. The proxy-reported SARC-F showed a non-inferior correlation with the SPPB compared with the patient-reported SARC-F for ad-hoc (P = <0.001) as well as retrospective screening for severe sarcopenia-related functional impairment in both Cohorts A (P = 0.007) and B (P = 0.026). CONCLUSIONS: Proxy-reported SARC-F is a valid instrument for both ad-hoc as well as retrospective screening for sarcopenia-related functional impairment and could become the standard tool for evaluating this risk in older adults with severe acute disease, for example, in patients with quickly evolving haematological conditions.
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Sarcopenia , Idoso , Estudos Transversais , Humanos , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcopenia/diagnóstico , Sarcopenia/etiologia , Inquéritos e QuestionáriosRESUMO
Measurable residual disease (MRD) detected by multiparametric flow cytometry (MFC) is associated with unfavorable outcome in patients with AML. A simple, broadly applicable eight-color panel was implemented and analyzed utilizing a hierarchical gating strategy with fixed gates to develop a clear-cut LAIP-based DfN approach. In total, 32 subpopulations with aberrant phenotypes with/without expression of markers of immaturity were monitored in 246 AML patients after completion of induction chemotherapy. Reference values were established utilizing 90 leukemia-free controls. Overall, 73% of patients achieved a response by cytomorphology. In responders, the overall survival was shorter for MRDpos patients (HR 3.8, p = 0.006). Overall survival of MRDneg non-responders was comparable to MRDneg responders. The inter-rater-reliability for MRD detection was high with a Krippendorffs α of 0.860. The mean time requirement for MRD analyses at follow-up was very short with 04:31 minutes. The proposed one-tube MFC approach for detection of MRD allows a high level of standardization leading to a promising inter-observer-reliability with a fast turnover. MRD defined by this strategy provides relevant prognostic information and establishes aberrancies outside of cell populations with markers of immaturity as an independent risk feature. Our results imply that this strategy may provide the base for multicentric immunophenotypic MRD assessment.
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Leucemia Mieloide Aguda , Citometria de Fluxo , Humanos , Imunofenotipagem , Neoplasia Residual , Prognóstico , Reprodutibilidade dos TestesRESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive T-cell malignancy. Chemotherapy alone cures only 25-45% of the cases, thus, novel treatment agents and strategies are urgently needed. We assessed the efficacy of ruxolitinib in a patient with a cutaneous relapse after allogeneic blood cell transplantation of a refractory T-ALL with a Janus kinase 3 (JAK3) mutation. In this case report, we were able to show the potential benefit of the JAK inhibitor ruxolitinib in JAK3-mutated refractory T-ALL and emphasize the importance of integrating molecular markers in current treatment decision making for patients with T-ALL.
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BACKGROUND: Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial. METHODS/DESIGN: This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL STATUS: Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st. TRIAL REGISTRATION: ClinicalTrials.gov NCT04093505 ; EudraCT 2019-003913-32. Registered on October 30, 2018.
Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Idoso , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis , Gemtuzumab , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Compostos de FenilureiaRESUMO
Intensive induction chemotherapy followed by postremission treatment with either high-dose cytarabine-based regimens, autologous or allogeneic hematopoietic stem cell transplantation is still recognized as the main road toward cure in acute myeloid leukemia (AML). Pretreatment risk classification remains a key determinant of type and intensity of post-remission therapy. Still, high-dose cytarabine-based consolidation therapy is a cornerstone of postremission therapy with some recent adjustments regarding dosage and schedule. Current approvals of midostaurin, gemtuzumab ozogamicin, CPX-351, and ivosidenib as well as enasidenib comprise induction as well as consolidation therapy. In recent years measurable residual disease assessment is increasingly used to dynamically fine tune treatment during postremission treatment.
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Quimioterapia de Consolidação/métodos , Leucemia Mieloide Aguda/terapia , Idoso , Feminino , Humanos , MasculinoRESUMO
In addition to previously studied immunological variables, the relative expression of IFNGR2, IFNAR1, CD18, and CD275 (all encoded in chromosome 21) on circulating leucocytes and multifunctional T cells (evaluated by an intracellular cytokine/proliferation assay) were compared between children with Down syndrome (DS) and healthy controls (HC). As previously reported, numbers of lymphocytes, CD4(+) T cells, Treg cells, B cells, and levels of serum IgM were decreased, and levels of IgG and IgA were increased in children with DS. Moreover, the relative expression of CD18 on T and B cells (previously and not previously reported, respectively) were elevated in DS children (p⩽0.01). Age and numbers of B and Treg cells moderately correlated with retrospectively identified infection related hospitalizations (rho: 0.300-0.460, p⩽0.003). Age and the numbers of Treg cells also correlated with prospectively identified infection related hospitalizations. Future studies are necessary to clarify the role of these parameters in the immunity of DS patients.
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Linfócitos B/imunologia , Cromossomos Humanos Par 21/genética , Síndrome de Down/imunologia , Hospitalização/estatística & dados numéricos , Infecções/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Antígenos CD18/metabolismo , Proliferação de Células , Criança , Pré-Escolar , Citocinas/metabolismo , Síndrome de Down/complicações , Síndrome de Down/epidemiologia , Feminino , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Lactente , Infecções/complicações , Infecções/epidemiologia , Ativação Linfocitária , Masculino , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismoRESUMO
The role of a parent with a disabled child can be highly demanding. There are few publications concerning parental emotional exhaustion in Latin America. The present prevalent case-controlled study evaluated the frequency of emotional exhaustion in 103 parental couples of parents of children with Down Syndrome (DS); likewise the study explores the rate of emotionally exhausted and depressed mothers in comparison with the fathers. This outcome was measured using a modified and validated version of the Maslach Burnout Inventory. The results showed a prevalence of emotional exhaustion of 52.64%. In the matched-pair analysis we found a higher chance of exhaustion in mothers in comparison with their partners.
El trabajo de un padre con un hijo con discapacidad puede llegar a ser muy exigente. Existen pocas publicaciones que hacen referencia al agotamiento emocional de los padres de niños con discapacidades en América Latina. El presente estudio de casos y controles prevalentes describe la frecuencia de agotamiento emocional en 103 parejas de padres de niños con síndrome de Down. También describe las diferencias en el agotamiento emocional y depresión entre padres y madres. Este resultado se midió usando una versión modificada y validada del Maslach Burnout Inventory. Los resultados mostraron una prevalencia de agotamiento emocional del 52,64%. En el análisis apareado encontramos una mayor probabilidad de agotamiento en las madres en comparación con sus parejas.
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Los elementos anatómicos que al atravesar la fosa retroclavicular son susceptibles de ser comprimidos y generar sintomatología son la arteria y vena subclavias y el plexo braquial. Por la disposición anatómica de esta región que conforma el desfiladero torácico superior, puede suscitarse compresión en los siguientes niveles: canal costo clavicular, desfiladero intercosto escalénico; y, la angulada inserción del músculo pectoral menor en la apófisis coracoides, túnel subpectoral. Cada uno genera un cuadro característico de acuerdo a la estructura y nivel comprometido, con síntomas neurológicos somáticos, simpáticos o síntomas vasculares arteriales o venosos. Esto síntomas se nos revelarán en la historia durante el examen físico...