RESUMO
BACKGROUND: Sweet syndrome is a neutrophilic dermatosis that may be categorized into classic, malignancy-associated, and drug-induced subtypes. Few studies have systematically analyzed this rare disorder. OBJECTIVE: To describe the clinicopathologic characteristics and treatment of Sweet syndrome and identify characteristics associated with concurrent malignancy. METHODS: We retrospectively reviewed patients with Sweet syndrome at the University of Pennsylvania from 2005 to 2015. RESULTS: We identified 83 patients (mean age, 57 years; 51% male) with Sweet syndrome: 30% with the classic form, 44% with the malignancy-associated form, 24% with the drug-induced form in the setting of malignancy, and 2% with the drug-induced form. Acute myeloid leukemia was the most common malignancy (in 24 of 83 patients [29%]). Filgrastim was the most common medication (used in 8 of 83 patients [10%]). Leukopenia (P < .001), anemia (P = .002), thrombocytopenia (P < .001), absence of arthralgia (P < .001), and histiocytoid or subcutaneous histopathology (P = .024) were associated with malignancy (χ2 test). LIMITATIONS: This was a retrospective study that represents patients from a single tertiary academic referral center, which may limit its generalizability to other settings. CONCLUSION: When caring for patients with Sweet syndrome, dermatologists should be aware of the potential association of leukopenia, anemia, thrombocytopenia, absence of arthralgia, and histiocytoid or subcutaneous histopathology with malignancy.
Assuntos
Leucemia Mieloide Aguda/genética , Neoplasias/complicações , Síndrome de Sweet/tratamento farmacológico , Síndrome de Sweet/etiologia , Centros Médicos Acadêmicos , Corticosteroides/uso terapêutico , Adulto , Idoso , Anemia/etiologia , Artralgia/etiologia , Colchicina/uso terapêutico , Dapsona/uso terapêutico , Feminino , Filgrastim/efeitos adversos , Antagonistas do Ácido Fólico/uso terapêutico , Fármacos Hematológicos/efeitos adversos , Humanos , Inflamação/complicações , Leucemia Mieloide Aguda/complicações , Leucopenia/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Iodeto de Potássio/uso terapêutico , Estudos Retrospectivos , Síndrome de Sweet/patologia , Centros de Atenção Terciária , Trombocitopenia/etiologia , Moduladores de Tubulina/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
PURPOSE: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A-rearranged (KMT2Ar) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. METHODS: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 (NPM1) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar. The separate NPM1 cohort of the trial is ongoing. RESULTS: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% (P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. CONCLUSION: Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.
RESUMO
Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients. To determine the molecular underpinnings of the host defense defects in MDS patients, we investigated the MDS-associated spliceosome mutation U2AF1-S34F using a transgenic mouse model that expresses this mutant gene. We found that U2AF1-S34F causes a profound host defense defect in these mice, likely by inducing a significant neutrophil chemotaxis defect. Studies in human neutrophils suggest that this effect of U2AF1-S34F likely extends to MDS patients as well. RNA-seq analysis suggests that the expression of multiple genes that mediate cell migration are affected by this spliceosome mutation and therefore are likely drivers of this neutrophil dysfunction.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Animais , Humanos , Camundongos , Quimiotaxia , Leucemia Mieloide Aguda/genética , Camundongos Transgênicos , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Neutrófilos/metabolismo , Splicing de RNA , Fator de Processamento U2AF/genéticaRESUMO
The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens. SIGNIFICANCE: These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass. This article is featured in Selected Articles from This Issue, p. 1949.
Assuntos
Leucemia Mieloide Aguda , Humanos , Antígenos CD34/metabolismo , Antígenos CD34/uso terapêutico , Leucemia Mieloide Aguda/genética , Células-Tronco Neoplásicas/metabolismo , Progressão da DoençaRESUMO
PURPOSE: There are currently limited objective criteria to help assist physicians in determining whether an individual patient with acute myeloid leukemia (AML) is likely to do better with induction with either standard 7 + 3 chemotherapy or targeted therapy with venetoclax plus azacitidine. The study goal was to address this need by developing exploratory clinical decision support methods. PATIENTS AND METHODS: Univariable and multivariable analysis as well as comparison of a range of machine learning (ML) predictors were performed using cohorts of 120 newly diagnosed 7 + 3-treated AML patients compared with 101 venetoclax plus azacitidine-treated patients. RESULTS: A variety of features in the two patient cohorts were identified that may potentially correlate with short- and long-term outcomes, toxicities, and other considerations. A subset of these diagnostic features was then used to develop ML-based predictors with relatively high areas under the curve of short- and long-term outcomes, hospital stays, transfusion requirements, and toxicities for individual patients treated with either venetoclax/azacitidine or 7 + 3. CONCLUSION: Potential ML-based approaches to clinical decision support to help guide individual patients with newly diagnosed AML to either 7 + 3 or venetoclax plus azacitidine induction therapy were identified. Larger cohorts with separate test and validation studies are necessary to confirm these initial findings.
Assuntos
Sistemas de Apoio a Decisões Clínicas , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Aprendizado de Máquina , Sulfonamidas , Resultado do TratamentoRESUMO
Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 109/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.
Assuntos
Leucemia Mieloide Aguda/terapia , Leucocitose/terapia , Adulto , Idoso , Feminino , Humanos , Leucaférese/métodos , Contagem de Leucócitos/métodos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Indução de Remissão , Estudos RetrospectivosRESUMO
PURPOSE OF REVIEW: Patients with relapsed T cell acute lymphoblastic leukemia (T-ALL) have limited therapeutic options and a poor prognosis. Although a variety of salvage chemotherapy regimens may be used, response rates are unsatisfactory. This article summarizes current approaches and promising emerging strategies for the treatment of relapsed T-ALL. RECENT FINDINGS: Although nelarabine is the only agent approved specifically for T-ALL, recent studies have identified a variety of genetic alterations and signaling pathways that are critical in its pathogenesis. Based on these findings, a number of small-molecule inhibitors and other targeted therapies are being studied for relapsed T-ALL, including gamma-secretase inhibitors, BCL-2 inhibitors, cyclin-dependent kinase inhibitors, and mTOR inhibitors. In addition, pre-clinical studies of chimeric antigen receptor T cells targeting CD5 and CD7 as well as the monoclonal antibody daratumumab have shown promising results for T-ALL. Relapsed T-ALL currently remains challenging to treat, but recent pre-clinical studies of targeted and immunotherapeutic agents have shown encouraging results. A number of clinical trials investigating these approaches for T-ALL are currently underway.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Vincristina/uso terapêutico , Antineoplásicos/uso terapêutico , Humanos , Lipossomos/química , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Terapia de Salvação/métodos , Vincristina/químicaRESUMO
Relapse remains the primary obstacle to long-term survival in patients with acute myeloid leukemia (AML) who achieve a remission following standard induction and consolidation therapy. Although allogeneic hematopoietic stem cell transplantation decreases the risk of relapse for many patients, relapse is common even among these patients. A number of approaches to maintenance therapy for AML have been studied with the goal of finding an agent with a tolerable side effect profile that may be given to patients in remission, typically for a prolonged period of time, in order to decrease the risk of relapse. Numerous trials that evaluated cytotoxic agents as maintenance therapy did not find any improvement in survival, but more recent studies of alternative approaches to maintenance including immunomodulation, epigenetic reprogramming, and targeted agents have been much more promising. In this article, we review the current evidence for various maintenance strategies for AML including immunotherapy, hypomethylating agents, and targeted therapies, particularly FLT3 inhibitors. We also discuss promising emerging approaches to maintenance for AML, including the incorporation of measurable residual disease assessment.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia/métodos , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Humanos , Leucemia Mieloide Aguda/patologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Primary refractory acute myeloid leukemia (AML), or primary induction failure, represents a continued challenge in clinical management. This review presents an overview of primary refractory disease and a discussion of risk factors for induction failure, including current evidence regarding the impact of karyotype and molecular mutation status on responsiveness to chemotherapy. We review the evidence for various treatment options for refractory AML including salvage chemotherapy regimens, allogeneic hematopoietic stem cell transplantation, targeted agents, and non-intensive therapies such as hypomethylating agents. A therapeutic approach to this patient population is presented, and several new and emerging therapies are reviewed.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Gerenciamento Clínico , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Retratamento , Fatores de Risco , Resultado do TratamentoRESUMO
Introduction: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). FLT3-internal tandem duplication mutations are associated with an increased risk of relapse, and a number of small molecule inhibitors of FLT3 have been developed. The highly potent and selective FLT3 kinase inhibitor gilteritinib is the first tyrosine kinase inhibitor approved as monotherapy for the treatment of relapsed and/or refractory FLT3-mutated AML. Areas covered: We review the biology and prognostic significance of FLT3 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of gilteritinib. We also summarize important differences among the various FLT3 inhibitors that are currently approved or under development and highlight areas of ongoing research. Expert opinion: Gilteritinib has been shown to improve survival compared to salvage chemotherapy in relapsed and/or refractory FLT3-mutated AML. Gilteritinib is orally available with a favorable toxicity profile and as such is quickly becoming the standard of care for this patient population. Ongoing clinical trials are evaluating gilteritinib in combination with frontline chemotherapy, in combination with other agents such as venetoclax and azacitidine for patients who are ineligible for standard induction therapy, and as a maintenance agent.
Assuntos
Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Pirazinas/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Recidiva , Sobrevida , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983.
Assuntos
Evolução Clonal/genética , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Proteínas ras/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Análise de Célula Única , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
The development of thrombocytopenia is common in hospitalized patients and is associated with increased mortality. Frequent and important causes of thrombocytopenia in hospitalized patients include etiologies related to the underlying illness for which the patient is admitted, such as infection and disseminated intravascular coagulation, and iatrogenic etiologies such as drug-induced immune thrombocytopenia, heparin-induced thrombocytopenia, posttransfusion purpura, hemodilution, major surgery, and extracorporeal circuitry. This review presents a brief discussion of the pathophysiology, distinguishing clinical features, and management of these etiologies, and provides a diagnostic approach to hospital-acquired thrombocytopenia that considers the timing and severity of the platelet count fall, the presence of hemorrhage or thrombosis, the clinical context, and the peripheral blood smear. This approach may offer guidance to clinicians in distinguishing among the various causes of hospital-acquired thrombocytopenia and providing management appropriate to the etiology.
Assuntos
Trombocitopenia/etiologia , Hospitalização , Humanos , Infecções/complicações , Contagem de Plaquetas , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologiaAssuntos
Compostos de Anilina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pirazinas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/metabolismo , Compostos de Anilina/farmacologia , Diferenciação Celular , Humanos , Pirazinas/farmacologia , RecidivaRESUMO
Autofluorescence spectroscopy is a powerful imaging technique that exploits endogenous fluorophores. The endogenous fluorophores NADH and flavin adenine dinucleotide (FAD) are two of the principal electron donors and acceptors in cellular metabolism, respectively. The optical oxidation-reduction (redox) ratio is a measure of cellular metabolism and can be determined by the ratio of NADH/FAD. We hypothesized that there would be a significant difference in the optical redox ratio of normal mammary epithelial cells compared with breast tumor cell lines and that estrogen receptor (ER)-positive cells would have a higher redox ratio than ER-negative cells. To test our hypothesis, the optical redox ratio was determined by collecting the fluorescence emission for NADH and FAD via confocal microscopy. We observed a statistically significant increase in the optical redox ratio of cancer compared with normal cell lines (P < 0.05). Additionally, we observed a statistically significant increase in the optical redox ratio of ER(+) breast cancer cell lines. The level of ESR1 expression, determined by real-time PCR, directly correlated with the optical redox ratio (Pearson's correlation coefficient = 0.8122, P = 0.0024). Furthermore, treatment with tamoxifen and ICI 182,870 statistically decreased the optical redox ratio of only ER(+) breast cancer cell lines. The results of this study raise the important possibility that fluorescence spectroscopy can be used to identify subtypes of breast cancer based on receptor status, monitor response to therapy, or potentially predict response to therapy. This source of optical contrast could be a potentially useful tool for drug screening in preclinical models.