RESUMEN
Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.
Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/patología , Compuestos Bicíclicos Heterocíclicos con Puentes , Sulfonamidas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Anciano , Calidad de Vida , Estudios Prospectivos , Inducción de Remisión , Leucemia Mieloide Aguda/terapia , Estudios RetrospectivosRESUMEN
Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
Asunto(s)
Cuidados Críticos , Leucemia Mieloide Aguda , Calidad de Vida , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Standard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA sequencing test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management. METHODS: This prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24 hours of fever onset (T1) and every 2 to 3 days. KT results were compared with blood culture (BC) and standard microbiological testing (SMT) results. RESULTS: Positive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45), respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N = 0); definite (N = 12): KT identified ≥1 organism also found by SMT within 7 days; probable (N = 19): KT result was compatible with a clinical diagnosis; possible (N = 10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable, and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%), and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases. CLINICAL TRIALS REGISTRATION: NCT02912117. CONCLUSION: KT shows promise in the diagnosis and treatment optimization of FN.
Asunto(s)
Ácidos Nucleicos Libres de Células , Neutropenia Febril , Antibacterianos/uso terapéutico , Neutropenia Febril/diagnóstico , Neutropenia Febril/tratamiento farmacológico , Neutropenia Febril/etiología , Fiebre/etiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estudios ProspectivosRESUMEN
Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
Asunto(s)
Duplicación de Gen , Predisposición Genética a la Enfermedad , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Secuencias Repetidas en Tándem/genética , Tirosina Quinasa 3 Similar a fms/genética , Europa (Continente) , Femenino , Genotipo , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Nucleofosmina , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Resultado del TratamientoRESUMEN
Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5-15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25-7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).
Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Fatiga/inducido químicamente , Humanos , Dosis Máxima Tolerada , Náusea/inducido químicamente , Neoplasias/metabolismoRESUMEN
Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare and heterogeneous myeloid disorders. There is strong morphologic resemblance among these distinct diagnostic entities as well as a lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole-exome and RNA sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not cosegregation, of clinical and genetic disease features with transcriptional clusters. In conclusion, these groups of diseases represent a continuum of related diseases rather than discrete diagnostic entities.
Asunto(s)
Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Leucemia Neutrofílica Crónica/diagnóstico , Leucemia Neutrofílica Crónica/genética , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Estudios de Cohortes , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Perfilación de la Expresión Génica , Genómica , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , PronósticoRESUMEN
BACKGROUND: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Estaurosporina/administración & dosificación , Estaurosporina/efectos adversos , Adulto JovenRESUMEN
Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apoptosis/efectos de los fármacos , Quimioterapia de Inducción , Leucemia Mieloide Aguda , Mitocondrias/metabolismo , Adulto , Anciano , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Lenalidomida/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mitocondrias/patología , Mitoxantrona/administración & dosificaciónRESUMEN
Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Combinación de Medicamentos , Neoplasias Hematológicas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Mieloide Aguda/metabolismo , Mutación/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismoRESUMEN
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in â¼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.
Asunto(s)
Aminopiridinas/uso terapéutico , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Triazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Aminopiridinas/efectos adversos , Aminopiridinas/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Triazinas/efectos adversos , Triazinas/farmacocinética , Adulto JovenRESUMEN
Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population. OBJECTIVES AND METHODS: We used the comprehensive Danish National Acute Leukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and long-term clinical outcome in APL between 2000 and 2014. RESULTS: Twenty-two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04-0.86, P = 0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz-score were independent prognostic variables. CONCLUSIONS: The very low EDR for on-trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL.
Asunto(s)
Leucemia Promielocítica Aguda/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Terapia Combinada , Dinamarca/epidemiología , Manejo de la Enfermedad , Femenino , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/etiología , Leucemia Promielocítica Aguda/terapia , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Modelos de Riesgos Proporcionales , Mejoramiento de la Calidad , Sistema de Registros , Translocación Genética , Adulto JovenRESUMEN
Optimization of post-remission therapies to maintain complete remission and prevent relapse is a major challenge in treating patients with acute myeloid leukemia (AML). Monitoring patients for measurable residual disease (MRD) is helpful to identify those at risk for relapse. Hypomethylating agents are being investigated as post-remission therapy. Identification of recurrent genetic alterations that drive disease progression has enabled the design of new, personalized approaches to therapy for patients with AML. Emerging data suggest that targeted post-remission therapy, alone or in combination with chemotherapy, may improve outcomes. Results of ongoing clinical trials will further define potential clinical benefits.
Asunto(s)
Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Inducción de Remisión , Humanos , Neoplasia Residual , RecurrenciaRESUMEN
To examine the outcomes of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared with chemotherapy alone in a population-based setting, we identified a cohort of patients with acute myeloid leukemia (AML) aged 15 to 70 years diagnosed between 2000 and 2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival (OS) between patients with unfavorable cytogenetic features receiving postremission therapy with conventional chemotherapy only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of allogeneic HSCT as a time-dependent covariate, and stratified the results by age (<60 or ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with a lower relapse rate (24% versus 49%) despite a similar median time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower and both RFS and OS were superior in recipients of HSCT (OS, adjusted mortality ratios: all patients, .54 [95% confidence interval (CI), .42-.71]; patients age <60 years, .58 [95% CI, .42-.81]; patients age ≥60 years, .42 [95% CI, .26-.69]; patients with intermediate-risk cytogenetics, .63 [95% CI, .43-.87]; patients with adverse-risk cytogenetics, .40 [95% CI, .24-.67]). In conclusion, in this population-based nationwide cohort study, HSCT was associated with improved survival in both younger and older patients and in patients with both intermediate and adverse cytogenetic risk.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Factores de Edad , Anciano , Estudios de Cohortes , Citogenética , Dinamarca , Femenino , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Previous studies reported increased risk of acute myeloid leukaemia (AML) in individuals with inflammatory conditions. However, it is unclear whether this association is explained by preceding cytotoxic therapy or haematological diseases. We conducted a nationwide case-control study that included 3053 AML patients, diagnosed in Denmark between 2000 and 2013, and 30 530 sex- and age-matched population controls. We retrieved information on autoimmune disease, infections, and use of antibiotics and computed odds ratios for AML (conditional logistic regression). Results were stratified by AML type, sex, and age. Autoimmune diseases were associated with an overall increased risk of AML {odds ratio [OR] 1·3 [95% confidence interval (CI) = 1·1-1·5]}. However, the risk was confined to patients with previous haematological disease or cytotoxic therapy exposure [secondary/therapy-related AML (sAML/tAML0) OR 2·0 (95% CI = 1·6-2·6)] and not de novo AML [OR 1·1 (95% CI = 0·9-1·3)]. Similarly, any prior infection requiring hospitalization was associated with a higher risk of AML [OR 1·3 (95% CI = 1·1-1·4)]. Again, this association was evident for sAML/tAML [OR 1·8 (95% CI = 1·5-2·2)], and not de novo AML [OR 1·1 (95% CI = 1·0-1·2)]. In conclusion, autoimmune diseases and infections were associated with an increased AML risk only in subjects with prior haematological disease and/or cytotoxic treatment. These observations suggest, that inflammation plays - if any - a minor role for the development of de novo AML.
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Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Enfermedades Autoinmunes , Infecciones , Leucemia Mieloide Aguda , Anciano , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/epidemiología , Estudios de Casos y Controles , Dinamarca/epidemiología , Femenino , Humanos , Infecciones/tratamiento farmacológico , Infecciones/epidemiología , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.
Asunto(s)
ARN Helicasas DEAD-box/genética , Mutación de Línea Germinal , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Técnica del Anticuerpo Fluorescente , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase II trial compared safety and efficacy of three therapeutic strategies in patients 65 years or over with newly-diagnosed acute myeloid leukemia: 1) continuous high-dose lenalidomide (n=15); 2) sequential azacitidine and lenalidomide (n=39); and 3) azacitidine only (n=34). The efficacy end point was 1-year survival. Median age was 76 years (range 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%) had adverse cytogenetics. One-year survival was 21% [95% confidence interval (CI): 0, 43%] with high-dose lenalidomide, 44% (95%CI: 28, 60%) with sequential azacitidine and lenalidomide, and 52% (95%CI: 35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early therapy discontinuations. Hazard of death in the first four months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential azacitidine and lenalidomide over the conventional dose and schedule of azacitidine only in patients aged 65 years or over with newly-diagnosed acute myeloid leukemia. (clinicaltrials.gov identifier: 01358734).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/uso terapéutico , Lenalidomida/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Lenalidomida/administración & dosificación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
Cancer is widely characterized by the sequential acquisition of genetic lesions in a single lineage of cells. Our previous studies have shown that, in acute myeloid leukemia (AML), mutation acquisition occurs in functionally normal hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, of the mutations found in the leukemic cells. We report here the identification of patterns of mutation acquisition in human AML. Our findings support a model in which mutations in "landscaping" genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, whereas mutations in "proliferative" genes occur late. Additionally, we analyze the persistence of preleukemic mutations in patients in remission and find CD34+ progenitor cells and various mature cells that harbor preleukemic mutations. These findings indicate that preleukemic HSCs can survive induction chemotherapy, identifying these cells as a reservoir for the reevolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease and show that some of these patterns are consistent with involvement of preleukemic HSCs. These findings provide key insights into the monitoring of minimal residual disease and the identification of therapeutic targets in human AML.
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Evolución Clonal/genética , Epigénesis Genética/genética , Células Madre Hematopoyéticas/química , Leucemia Mieloide Aguda/genética , Modelos Biológicos , Preleucemia/genética , Antígenos CD34/metabolismo , Secuencia de Bases , Exoma/genética , Citometría de Flujo , Genotipo , Humanos , Datos de Secuencia Molecular , Mutación/genética , Análisis de Secuencia de ADNRESUMEN
The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed.
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Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Cariotipo , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Resultado del Tratamiento , Adulto JovenRESUMEN
Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.