RESUMEN
DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide and cytarabine following 'priming' with 5-10 days of decitabine (dec/MEC) in 52 adults (median age 55 (range: 19-72) years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6-12 patients, all dose levels were well tolerated. As response rates appeared similar with 7 and 10 days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D). Among 46 patients treated at/above the RP2D, 10 (22%) achieved a complete remission (CR), 8 without measurable residual disease; five additional patients achieved CR with incomplete platelet recovery, for an overall response rate of 33%. Seven patients (15%) died within 28 days of treatment initiation. Infection/neutropenic fever, nausea and mucositis were the most common adverse events. While the CR rate compared favorably to a matched historic control population (observed/expected CR ratio=1.77), CR rate and survival were similar to two contemporary salvage regimens used at our institution (G-CLAC (granulocyte colony-stimulating factor (G-CSF); clofarabine; cytarabine) and G-CLAM (G-CSF; cladribine; cytarabine; mitoxantrone)). Thus, while meeting the prespecified efficacy goal, we found no evidence that dec/MEC is substantially better than other cytarabine-based regimens currently used for relapsed/refractory AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/uso terapéutico , Biomarcadores , Citarabina , Decitabina , Resistencia a Antineoplásicos , Etopósido , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mitoxantrona , Clasificación del Tumor , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.
Asunto(s)
Arsenicales/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Óxidos/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trióxido de Arsénico , Femenino , Humanos , Leucemia Promielocítica Aguda/etiología , Leucemia Promielocítica Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/genética , Inducción de Remisión , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
This corrects the article DOI: 10.1038/leu.2016.303.
RESUMEN
PR1, an HLA-A2-restricted peptide derived from both proteinase 3 and neutrophil elastase, is recognized on myeloid leukemia cells by cytotoxic T lymphocytes (CTLs) that preferentially kill leukemia and contribute to cytogenetic remission. To evaluate safety, immunogenicity and clinical activity of PR1 vaccination, a phase I/II trial was conducted. Sixty-six HLA-A2+ patients with acute myeloid leukemia (AML: 42), chronic myeloid leukemia (CML: 13) or myelodysplastic syndrome (MDS: 11) received three to six PR1 peptide vaccinations, administered subcutaneously every 3 weeks at dose levels of 0.25, 0.5 or 1.0 mg. Patients were randomized to the three dose levels after establishing the safety of the highest dose level. Primary end points were safety and immune response, assessed by doubling of PR1/HLA-A2 tetramer-specific CTL, and the secondary end point was clinical response. Immune responses were noted in 35 of 66 (53%) patients. Of the 53 evaluable patients with active disease, 12 (24%) had objective clinical responses (complete: 8; partial: 1 and hematological improvement: 3). PR1-specific immune response was seen in 9 of 25 clinical responders versus 3 of 28 clinical non-responders (P=0.03). In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Antígeno HLA-A2/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Péptidos/inmunología , Biomarcadores , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Epítopos de Linfocito T/inmunología , Femenino , Antígeno HLA-A2/química , Humanos , Memoria Inmunológica , Inmunofenotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Péptidos/administración & dosificación , Péptidos/efectos adversos , Análisis de Supervivencia , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , VacunaciónRESUMEN
Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.5-5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Médula Ósea/patología , Aberraciones Cromosómicas , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Resultado del TratamientoAsunto(s)
Leucemia Mieloide Aguda/patología , Neoplasia Residual , Adulto , Humanos , Recurrencia , Análisis de SupervivenciaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adhesión a Directriz/estadística & datos numéricos , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Humanos , Idarrubicina/administración & dosificación , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como AsuntoRESUMEN
Measurable ('minimal') residual disease (MRD) before or after hematopoietic cell transplantation (HCT) identifies adults with AML at risk of poor outcomes. Here, we studied whether peri-transplant MRD dynamics can refine risk assessment. We analyzed 279 adults receiving myeloablative allogeneic HCT in first or second remission who survived at least 35 days and underwent 10-color multiparametric flow cytometry (MFC) analyses of marrow aspirates before and 28±7 days after transplantation. MFC-detectable MRD before (n=63) or after (n=16) transplantation identified patients with high relapse risk and poor survival. Forty-nine patients cleared MRD with HCT conditioning, whereas two patients developed new evidence of disease. The 214 MRD(neg)/MRD(neg) patients had excellent outcomes, whereas both MRD(neg)/MRD(pos) patients died within 100 days following transplantation. For patients with pre-HCT MRD, outcomes were poor regardless of post-HCT MRD status, although survival beyond 3 years was only observed among the 58 patients with decreasing but not the seven patients with increasing peri-HCT MRD levels. In multivariable models, pre-HCT but not post-HCT MRD was independently associated with overall survival and risk of relapse. These data indicate that MRD(pos) patients before transplantation have a high relapse risk regardless of whether or not they clear MFC-detectable disease with conditioning and should be considered for pre-emptive therapeutic strategies.
Asunto(s)
Citometría de Flujo/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/patología , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Anciano , Examen de la Médula Ósea , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasia Residual/mortalidad , Periodo Posoperatorio , Periodo Preoperatorio , Recurrencia , Estudios Retrospectivos , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Resultado del Tratamiento , Adulto JovenRESUMEN
Decitabine may open the chromatin structure of leukemia cells making them accessible to the calicheamicin epitope of gemtuzumab ozogamicin (GO). A total of 110 patients (median age 70 years; range 27-89 years) were treated with decitabine and GO in a trial designed on model-based futility to accommodate subject heterogeneity: group 1: relapsed/refractory acute myeloid leukemia (AML) with complete remission duration (CRD) <1 year (N=28, 25%); group 2: relapsed/refractory AML with CRD ⩾1 year (N=5, 5%); group 3: untreated AML unfit for intensive chemotherapy or untreated myelodysplastic syndrome (MDS) or untreated myelofibrosis (MF; N=57, 52%); and group 4: AML evolving from MDS or relapsed/refractory MDS or MF (N=20, 18%). Treatment consisted of decitabine 20 mg/m(2) daily for 5 days and GO 3 mg/m(2) on day 5. Post-induction therapy included five cycles of decitabine+GO followed by decitabine alone. Complete remission (CR)/CR with incomplete count recovery was achieved in 39 (35%) patients; group 1= 5/28 (17%), group 2=3/5 (60%), group 3=24/57 (42%) and group 4=7/20 (35%). The 8-week mortality in groups 3 and 4 was 16% and 10%, respectively. Common drug-related adverse events included nausea, mucositis and hemorrhage. Decitabine and GO improved the response rate but not overall survival compared with historical outcomes in untreated AML ⩾60 years.
Asunto(s)
Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Decitabina , Femenino , Gemtuzumab , Humanos , Masculino , Persona de Mediana Edad , Lectina 3 Similar a Ig de Unión al Ácido Siálico/análisisAsunto(s)
Biomarcadores Farmacológicos/análisis , Trasplante de Médula Ósea , Aprobación de Drogas/legislación & jurisprudencia , Drogas en Investigación/uso terapéutico , Leucemia Mieloide Aguda/terapia , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Expresión Génica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Neoplasia Residual , Pronóstico , Calidad de Vida , Inducción de Remisión , Análisis de Supervivencia , Estados UnidosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Adolescente , Adulto , Estudios de Cohortes , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/patología , Células de la Médula Ósea/citología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Recuento de Plaquetas , Pronóstico , Inducción de RemisiónAsunto(s)
Quimioterapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/mortalidad , Leucemia Mieloide Aguda/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/patologíaRESUMEN
Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch-Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ('primary refractoriness'). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML.
Asunto(s)
Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Neoplasia Residual , Nucleofosmina , Pronóstico , Análisis de Regresión , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) is primarily a disease of older adults, for whom optimal treatment strategies remain controversial. Because of the concern for therapeutic resistance and, in particular, excessive toxicity or even treatment-related mortality, many older or medically unfit patients do not receive AML-directed therapy. Yet, evidence suggests that outcomes are improved if essentially all of these patients are offered AML therapy, ideally at a specialized cancer center. Medical fitness for tolerating intensive chemotherapy can be estimated relatively accurately with multiparameter assessment tools; this information should serve as basis for the assignment to intensive or non-intensive therapy. Until our accuracy in predicting the success of individual therapies improves, all patients should be considered for participation in a randomized controlled trial. Comparisons between individual trials will be facilitated once standardized, improved response criteria are developed, and standard treatment approaches have been defined against which novel therapies can be tested.
Asunto(s)
Antineoplásicos/uso terapéutico , Manejo de la Enfermedad , Monitoreo de Drogas/normas , Leucemia Mieloide Aguda/tratamiento farmacológico , Selección de Paciente/ética , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Estado de Salud , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de SupervivenciaRESUMEN
Less-intense remission induction regimens for adults with newly diagnosed acute myeloid leukemia (AML) aim to reduce treatment-related mortality (TRM), here defined as death within 4 weeks after starting induction therapy. This assumes that TRM rates are similar to the 15-20% observed 20 years ago. Herein we test this assumption. We examined TRM rates in 1409 patients treated on SWOG (Southwest Oncology Group) trials and 1942 patients treated at MD Anderson (MDA) from 1991 to 2009. Eighty-eight percent of SWOG patients received '3+7' or regimens of similar intensity while 92% of the MDA patients received ara-C at 1.5-2.0 g/m(2) daily × 3-5 days+other cytotoxic agents. We examined the relationship between time and TRM rates after accounting for other covariates. TRM rates between 1991 and 2009 decreased from 18-3% in SWOG and 16-4% at MDA. Multivariate analyses showed a significant decrease in TRM over time (P=0.001). The decrease in TRM was not limited to younger patients, those with a better performance status or a lower white blood cell count. Though our observations are limited to patients treated with intensive therapy at SWOG institutions and MDA, the decrease in TRM with time emphasizes the problem with historical controls and could be considered when selecting AML induction therapy.