RESUMEN
The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
Asunto(s)
Azepinas/farmacología , Descubrimiento de Drogas , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Megacariocitos/metabolismo , Poliploidía , Pirimidinas/farmacología , Bibliotecas de Moléculas Pequeñas , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Aurora Quinasa A , Aurora Quinasas , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Leucemia Megacarioblástica Aguda/genética , Megacariocitos/citología , Megacariocitos/patología , Ratones , Ratones Endogámicos C57BL , Mapas de Interacción de Proteínas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
Five-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT], chemotherapy with cranial radiation [chemo + CRT], chemotherapy only [chemo-only]), and diagnosis decade. Self-reported health status was compared across treatments, diagnosis decade, and with siblings. Among 856 survivors (median diagnosis age, 7.1 years; median age at last follow-up, 29.4 years), 20-year late mortality cumulative incidence was highest after HCT (13.9%; 95% confidence interval [CI], 10.0%-17.8%; chemo + CRT, 7.6%; 95% CI, 2.2%-13.1%; chemo-only, 5.1%; 95% CI, 2.8%-7.4%). Cumulative incidence of mortality for HCT survivors diagnosed in the 1990s (8.5%; 95% CI, 4.1%-12.8%) was lower vs those diagnosed in the 1970s (38.9%; 95% CI, 16.4%-61.4%). Most survivors did not experience any grade 3 to 5 CHC after 20 years (HCT, 45.8%; chemo + CRT, 23.7%; chemo-only, 27.0%). Furthermore, a temporal reduction in CHC cumulative incidence was seen after HCT (1970s, 76.1%; 1990s, 38.3%; P = .02), mirroring reduced use of total body irradiation. Self-reported health status was good to excellent for 88.2% of survivors; however, this was lower than that for siblings (94.8%; P < .0001). Although HCT is associated with greater long-term morbidity and mortality than chemotherapy-based treatment, gaps have narrowed, and all treatment groups report favorable health status.
Asunto(s)
Supervivientes de Cáncer , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Humanos , Niño , Adulto , Evaluación de Resultado en la Atención de Salud , Estado de Salud , Leucemia Mieloide Aguda/terapia , Enfermedad CrónicaRESUMEN
Biallelic CEBPA mutations are associated with favorable outcomes in acute myeloid leukemia (AML). We evaluated the clinical and biologic implications of CEBPA-basic leucine zipper (CEBPA-bZip) mutations in children and young adults with newly diagnosed AML. CEBPA-bZip mutation status was determined in 2958 patients with AML enrolled on Children's Oncology Group trials (NCT00003790, NCT0007174, NCT00372593, NCT01379181). Next-generation sequencing (NGS) was performed in 1863 patients (107 with CEBPA mutations) to characterize the co-occurring mutations. CEBPA mutational status was correlated with disease characteristics and clinical outcomes. CEBPA-bZip mutations were identified in 160 (5.4%) of 2958 patients, with 132 (82.5%) harboring a second CEBPA mutation (CEBPA-double-mutated [CEBPA-dm]) and 28 (17.5%) had a single CEBPA-bZip only mutation. The clinical and laboratory features of the 2 CEBPA cohorts were very similar. Patients with CEBPA-dm and CEBPA-bZip experienced identical event-free survival (EFS) of 64% and similar overall survival (OS) of 81% and 89%, respectively (P = .259); this compared favorably to EFS of 46% and OS of 61% in patients with CEBPA-wild-type (CEBPA-WT) (both P < .001). Transcriptome analysis demonstrated similar expression profiles for patients with CEBPA-bZip and CEBPA-dm. Comprehensive NGS of patients with CEBPA mutations identified co-occurring CSF3R mutations in 13.1% of patients and GATA2 mutations in 21.5% of patients. Patients with dual CEBPA and CSF3R mutations had an EFS of 17% vs 63% for patients with CEBPA-mutant or CSF3R-WT (P < .001) with a corresponding relapse rate (RR) of 83% vs 22%, respectively (P < .001); GATA2 co-occurrence did not have an impact on outcome. CEBPA-bZip domain mutations are associated with favorable clinical outcomes, regardless of monoallelic or biallelic status. Co-occurring CSF3R and CEBPA mutations are associated with a high RR that nullifies the favorable prognostic impact of CEBPA mutations.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/diagnóstico , Masculino , Mutación , Pronóstico , Transcriptoma , Adulto JovenRESUMEN
BACKGROUND: High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531. METHODS: Patients on AAML0531 received cytarabine (1600 mg/m2 )/daunorubicin (150 mg/m2 )/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48 mg/m2 )/cytarabine (8000 mg/m2 ) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE. RESULTS: MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p = .87; measurable residual disease [MRD]+: 57% vs. 46%, p = .34); or intensification I response (CR: 79% vs. 94%, p = .27; MRD+: 27% vs. 20%, p = 1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p = .63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p = .66). MA was associated with slower neutrophil recovery (median 34 vs. 27 days, p = .007) and platelet recovery (median 29 vs. 24.5 days, p = .04) and longer hospital stay (32 vs. 28 days, p = .01) during induction II. CONCLUSION: Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).
Asunto(s)
Quimioterapia de Inducción , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Busulfano/uso terapéutico , Niño , Ensayos Clínicos como Asunto , Citarabina/uso terapéutico , Supervivencia sin Enfermedad , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/etiología , Neoplasia Residual/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification. METHODS: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL. RESULTS: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21). CONCLUSIONS: The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Bifenotípica Aguda/epidemiología , Leucemia Bifenotípica Aguda/terapia , Pronóstico , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunofenotipificación/métodos , Lactante , Leucemia Bifenotípica Aguda/patología , Masculino , Pediatría/tendencias , Organización Mundial de la Salud , Adulto JovenRESUMEN
BACKGROUND: Treatment-related morbidity and mortality occur frequently in childhood acute myeloid leukemia (AML) induction. Yet the contributions of respiratory adverse events (AEs) within this population are poorly understood. Furthermore, the roles of fluid overload (FO) and infection in AML pulmonary complications have been inadequately examined. OBJECTIVES: To describe the incidence, categories, and grades of respiratory AEs and to assess the associations of FO and infection on respiratory AE development in childhood AML induction. METHODS: We retrospectively examined the induction courses of a cohort of de novo pediatric AML patients for any NCI CTCAE grade 2 to 5 respiratory AE, FO, and systemic/pulmonary infection occurrence. Demographic, disease, and treatment-related data were abstracted. Descriptive, univariate, survival, and multivariable analyses were conducted. RESULTS: Among 105 eligible subjects from 2009 to 2016, 49.5% (n = 52) experienced 63 discrete respiratory AEs. FO occurred in 28.6% of subjects (n = 30), with half occurring within 24 hours of hospitalization. Positive FO status < 10 days (aHR 5.5, 95% CI 2.3-12.8), ≥ 10 days (aHR 13, 95% CI 4.1-41.8), and positive infection status ≥ 10 days into treatment (aHR 14.9, 5.4-41.6) were each independently associated with AE development. CONCLUSIONS: We describe a higher incidence of respiratory AEs during childhood AML induction than previously illustrated. FO occurs frequently and early in this course. Late infections and FO at any time frame were strongly associated with AE development. Interventions focused on the prevention and management of FO and infectious respiratory complications could be instrumental in reducing preventable treatment-related morbidity and mortality.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Edema/complicaciones , Quimioterapia de Inducción/efectos adversos , Infecciones/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Enfermedades Respiratorias/patología , Desequilibrio Hidroelectrolítico/complicaciones , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/patología , Masculino , Pronóstico , Enfermedades Respiratorias/etiología , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children's Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (>5 WBC with blasts or CNS symptoms) disease at diagnosis. METHODS: We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy. RESULTS: Young age (P = 0.003), hyperleukocytosis (P < 0.001), and the presence of inversion 16 (P < 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P < 0.001). From diagnosis, event-free survival (EFS) for patients with CNS involvement was significantly worse (P < 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease-free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P < 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome. CONCLUSIONS: CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.
Asunto(s)
Enfermedades del Sistema Nervioso Central/etiología , Leucemia Mieloide Aguda/complicaciones , Humanos , Lactante , Pronóstico , Resultado del TratamientoRESUMEN
Survival rates for children with Down syndrome (DS) and acute myeloid leukemia (AML) are high; however, little is known regarding the health-related quality of life (HR-QOL) of these survivors. Individuals who survived ≥5 years following diagnosis of childhood AML were invited to complete parent or patient-report surveys measuring HR-QOL and chronic health conditions. In total, 26 individuals with DS had a median age at diagnosis of 1.8 years (range, 0.77 to 10.9 y) and median age at interview of 15 years (range, 8.3 to 27.6 y). Participants with DS and AML were compared with AML survivors without DS whose caregiver completed a HR-QOL survey (CHQ-PF50). In total, 77% of survivors with DS reported ≥1 chronic health condition compared with 50% of AML survivors without DS (P=0.07). Mean physical and psychosocial QOL scores for children with DS and AML were statistically lower than the population mean, though not discrepant from AML survivors without DS. Although the overall prevalence of chronic health conditions in survivors with DS is higher than in survivors without DS, prior studies of children with DS have reported similarly high rates of chronic health conditions, suggesting that AML therapy may not substantially increase this risk.
Asunto(s)
Síndrome de Down/complicaciones , Leucemia Mieloide Aguda/etiología , Calidad de Vida , Sobrevivientes , Adolescente , Niño , Preescolar , Enfermedad Crónica/epidemiología , Síndrome de Down/psicología , Estudios de Seguimiento , Indicadores de Salud , Humanos , Hipotiroidismo/epidemiología , Hipotiroidismo/etiología , Lactante , Leucemia Mieloide Aguda/psicología , Leucemia Mieloide Aguda/terapia , Sobrevivientes/psicología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Leucemia Bifenotípica Aguda/genética , Leucemia Bifenotípica Aguda/mortalidad , Peroxidasa/genética , Enfermedad Aguda , Adolescente , Linfocitos B/patología , Niño , Preescolar , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Lactante , Recién Nacido , Leucemia Bifenotípica Aguda/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Fenotipo , Estudios RetrospectivosRESUMEN
Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a rare subtype associated with FLT3-internal tandem duplication (ITD) and poor outcomes. The clinical outcomes of paediatric patients with t(6;9) with and without FLT3-ITD treated on six consecutive cooperative trails were evaluated. In contrast to patients without t(6;9), those with t(6;9) had a significantly lower complete remission rate, higher relapse rate (RR), and poor overall survival (OS). Within t(6;9) patients, those with and without FLT3-ITD had an OS of 40% and 27% respectively (P > 0·9), demonstrating that t(6;9) is a high-risk cytogenetic feature in paediatric AML and its clinical impact is independent of the presence of FLT3-ITD.
Asunto(s)
Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 9/genética , Leucemia Mieloide Aguda/genética , Translocación Genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Duplicación de Gen , Genes Relacionados con las Neoplasias , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/terapia , Masculino , Proteínas de Neoplasias/genética , Pronóstico , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Secuencias Repetidas en Tándem , Resultado del TratamientoRESUMEN
BACKGROUND: We sought to better define the role of hematopoietic cell transplantation (HCT) in first remission (CR1) for high-risk pediatric acute myeloid leukemia (AML). PROCEDURES: Outcomes were compared among patients aged less than 21 years with cytogenetically defined poor-risk AML treated with chemotherapy, matched related (MRD), or unrelated donor (URD) transplantation in CR1. Poor-risk cytogenetics was defined as monosomy 7/del7q, monosomy 5/del 5q, abnormalities of 3q, t(6;9)(p23;q34), or complex karyotype. Included are patients treated on Children's Oncology Group trials or reported to the Center for International Blood and Marrow Transplant Research from 1989 to 2006. RESULTS: Of the 233 patients, 123 received chemotherapy, 55 received MRD HCT, and 55 received URD HCT. The 5-year overall survival from the time of consolidation chemotherapy or transplant conditioning was similar: chemotherapy (43% ± 9%), MRD (46% ± 14%), or URD (50% ± 14%), P = 0.99. Similarly, multivariate analysis demonstrated no significant differences in survival [(reference group = chemotherapy); MRD HR 1.08, P = 0.76; URD HR 1.13, P = 0.67] despite lower relapse risk with URD HCT (HR = 0.43, P = 0.01). CONCLUSIONS: Our findings do not provide support for the preferential use of HCT over chemotherapy alone for children with cytogenetically defined poor-risk AML in CR1.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aberraciones Cromosómicas , Selección de Donante , Enfermedad Injerto contra Huésped/diagnóstico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/mortalidad , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Análisis Citogenético , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/terapia , Donadores Vivos , Masculino , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Trasplante Autólogo , Donante no Emparentado , Adulto JovenRESUMEN
BACKGROUND: Therapy for childhood acute myeloid leukemia (AML) has historically included chemotherapy with or without autologous bone marrow transplant (autoBMT) or allogeneic hematopoietic stem cell transplantation (alloBMT). We sought to compare health-related quality-of-life (HRQOL) outcomes between these treatment groups. PROCEDURE: Five-year survivors of AML diagnosed before age 21 and enrolled and treated from 1979 to 1995 on one of 4 national protocols were interviewed. These survivors or proxy caregivers completed a health questionnaire and an HRQOL measure. RESULTS: Of 180 survivors, 100 were treated with chemotherapy only, 26 with chemotherapy followed by autoBMT, and 54 with chemotherapy followed by alloBMT. Median age at interview was 20 years (range 8-39). Twenty-one percent reported a severe or life-threatening chronic health condition (chemotherapy-only 16% vs. autoBMT 21% vs. alloBMT 33%; P = 0.02 for chemotherapy-only vs. alloBMT). Nearly all (95%) reported excellent, very good or good health. Reports of cancer-related pain and anxiety did not vary between groups. HRQOL scores among 136 participants ≥14 years of age were similar among groups and to the normative population, though alloBMT survivors had a lower physical mean summary score (49.1 alloBMT vs. 52.2 chemotherapy-only; P = 0.03). Multivariate analyses showed the presence of severe chronic health conditions to be a strong predictor of physical but not mental mean summary scores. CONCLUSIONS: Overall HRQOL scores were similar among treatment groups, although survivors reporting more health conditions or cancer-related pain had diminished HRQOL. Attention to chronic health conditions and management of cancer-related pain may improve QOL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Estado de Salud , Leucemia Mieloide Aguda/terapia , Calidad de Vida , Sobrevivientes , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Estadificación de Neoplasias , Pronóstico , Encuestas y Cuestionarios , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Studies comparing survival of adolescent and young adult (AYA) patients to that of younger patients with newly diagnosed acute myeloid leukemia (AML) have yielded conflicting results. In order to more accurately characterize relative survival and other outcomes of AYA patients, a cross-study analysis was conducted using data from recent trials conducted by the Children's Cancer Group (CCG) and Children's Oncology Group (COG). METHODS: Data were combined from the CCG-2891, CCG-2941, CCG-2961, and AAML03P1 trials. The data set included 1840 patients, comprising 238 AYA and 1602 younger patients. RESULTS: Overall survival was not significantly different in the 2 groups (AYA, 49% ± 7% versus younger, 54% ± 3% (± 2 standard errors), P = .058). Relapse was lower in AYA patients (30% ± 7% versus 41% ± 3%, P = .002), but treatment-related mortality (TRM) was higher (25% ± 6% versus 12% ± 2%, P < .001). After adjustment for other factors, older age remained strongly associated with TRM (hazard ratio = 2.30, 95% CI = 1.59-3.33, P < .001). Infection accounted for the excess TRM in AYA patients. CONCLUSIONS: Survival in AYA and younger patients with newly diagnosed AML is similar; however, older patients are at higher risk for TRM. More effective strategies for preventing mortality from infection in AYA patients are needed.
Asunto(s)
Leucemia Mieloide Aguda/mortalidad , Adolescente , Factores de Edad , Niño , Femenino , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Adulto JovenRESUMEN
BACKGROUND: A retrospective meta-analysis of adolescents and young adults (AYAs) with acute myeloid leukemia (AML) was performed to determine if differences in outcome exist following treatment on pediatric versus adult oncology treatment regimens. METHODS: Outcomes were compared of 517 AYAs with AML aged 16 to 21 years who were treated on Children's Oncology Group (COG), Cancer and Leukemia Group B (CALGB), and Southwest Oncology Group (SWOG) frontline AML trials from 1986 to 2008. RESULTS: There was a significant age difference between AYA cohorts in the COG, CALGB, and SWOG trials (median, 17.2 versus 20.1 versus 19.8 years, P < .001). The 10-year event-free survival of the COG cohort was superior to the combined adult cohorts (38% ± 6% versus 23% ± 6%, log-rank P = .006) as was overall survival (45% ± 6% versus 34% ± 7%), with a 10-year estimate comparison of P = .026. However, the younger age of the COG cohort is confounding, with all patients aged 16 to 18 years doing better than those aged 19 to 21 years. Although the 10-year relapse rate was lower for the COG patients (29% ± 6% versus 57% ± 8%, Gray's P < .001), this was offset by a higher postremission treatment-related mortality of 26% ± 6% versus 12% ± 6% (Gray's P < .001). Significant improvements in 10-year event-free survival and overall survival were observed for the entire cohort in later studies. CONCLUSIONS: Patients treated on pediatric trials had better outcomes than those treated on adult trials, but age is a major confounding variable, making it difficult to compare outcomes by cooperative group.
Asunto(s)
Leucemia Mieloide Aguda/mortalidad , Adolescente , Adulto , Factores de Edad , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Abnormalities of chromosome 5q (-5/5q-) are associated with poor prognosis in adults with acute myeloid leukemia (AML). However, there are no large studies on outcomes of children with -5/5q- AML. To determine the disease correlates of this group, we retrospectively analyzed cytogenetic data from five studies of childhood AML. PROCEDURE: Data from patients whose cytogenetic clones included -5/5q-, with the exception of those with acute promyelocytic leukemia or Down syndrome, were included. RESULTS: Of the 2,240 patients with cytogenetic data available, 26 (1.2%) had -5 or 5q-. A significant number of these patients were age 11-21 (61.5%, P = 0.031) and had M0 morphology compared with patients without -5/5q- (24.0% vs. 2.8%, P < 0.001). Twenty-two of the 26 patients had a complete remission (CR) response to induction chemotherapy. The 5-year overall survival (OS) from the time of diagnosis for the -5/5q- patients was significantly lower than for patients without -5/5q- (27 ± 17% vs. 50 ± 2%, P = 0.027). Similarly, from induction CR, patients with -5/5q- had significantly worse disease free survival, OS and relapse risk than those without this abnormality (27 ± 19% vs. 46 ± 2%, P = 0.035, 32 ± 20% vs. 57 ± 2%, P = 0.025, 68 ± 21% vs. 45 ± 2%, P = 0.01, respectively). CONCLUSIONS: Pediatric patients with AML and -5/5q- had a very poor outcome. These findings support the need for new or novel therapies for these patients.
Asunto(s)
Cromosomas Humanos Par 5/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Eliminación de Gen , Humanos , Lactante , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard-timing regimen of dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891). METHODS: COG A2971 was a multi-institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41). RESULTS: The median follow-up was 4.8 years (range, 0.8-8.6 years), the median age at diagnosis was 1.7 years (range, 0.3-13.6 years), and the median white blood cell count was 6200/µL (range, 900-164,900/µL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5-year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease-free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day-14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5-year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0-4 years [median, 1.7 years; n = 126]; P = .001). CONCLUSIONS: The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Síndrome de Down/complicaciones , Leucemia Mieloide/tratamiento farmacológico , Adolescente , Trasplante de Médula Ósea , Niño , Preescolar , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Leucemia Mieloide/complicaciones , Leucemia Mieloide/cirugía , Masculino , Tioguanina/administración & dosificación , Resultado del TratamientoRESUMEN
KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML). However, their prevalence and prognostic significance in pediatric CBF AML is not well established. We performed KIT mutational analysis (exon 8 and exon 17) on diagnostic specimens from 203 pediatric patients with CBF AML enrolled on 4 pediatric AML protocols. KIT mutations were detected in 38 (19%) of 203 (95% CI, 14%-25%) patient samples of which 20 (52.5%) of 38 (95% CI, 36%-69%) involved exon 8, 17 (45%) of 38 (95% CI, 29%-62%) involved exon 17, and 1 (2.5%; 95% CI, 0%-14%) involved both locations. Patients with KIT mutations had a 5-year event-free survival of 55% (+/- 17%) compared with 59% (+/- 9%) for patients with wild-type KIT (P = .86). Rates of complete remission, overall survival, disease-free survival, or relapse were not significantly different for patients with or without KIT mutations. Location of the KIT mutation and analysis by cytogenetic subtype [t(8;21) vs inv(16)] also lacked prognostic significance. Our study shows that KIT mutations lack prognostic significance in a large series of pediatric patients with CBF AML. This finding, which differs from adult series and a previously published pediatric study, may reflect variations in therapeutic approaches and/or biologic heterogeneity within CBF AML. Two of 4 studies included in this analysis are registered at http://clinicaltrials.gov as NCT00002798 (CCG-2961) and NCT00070174 (COG AAML03P1).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-kit/genética , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Exones/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Mutación , Prevalencia , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Translocación Genética , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Extramedullary leukemia (EML) is common in pediatric acute myeloid leukemia (AML) and occurs as leukemia cells within the cerebrospinal fluid (CSF) or as a solid tumor (myeloid sarcoma-MS). The effect of MS on survival is unknown. METHODS: Patients on CCG protocols 2861, 2891, 2941, and 2961 being treated for AML with intensive-timing chemotherapy were classified for the presence of EML (CSF leukemia, CNS-MS, orbital-MS, or non-CNS MS). CSF leukemia was classified as CNS3 (>5 WBC in the CSF with blasts) and non-CSF leukemia as CNS1/2 (<5 WBC in the CSF with or without blasts). Characteristics and outcomes of these patients were compared. RESULTS: Of the 1,459 total patients, 1,206 (82%) had no EML, 154 (11%) had CSF leukemia, 19 (1%) had CNS-MS, 23 (2%) had orbital-MS, and 57 (4%) had non-CNS MS. The CR rate was significantly higher in patients with orbital-MS and CNS-MS than in those with non-MS and non-CNS MS (96% and 95% vs. 78% and 78%, P = 0.034). Patients with orbital-MS and CNS-MS had significantly higher overall survival than patients with non-CNS MS (92% and 73% vs. 38%, P < 0.001), CNS3 patients (92% and 73% vs. 51, P < 0.001), and CNS1/2 patients (92% and 73% vs. 50%, P < 0.001). Patients with orbital-MS had a significantly lower relapse rate. CONCLUSION: Patients with MS involving orbital and CNS sites had a significantly better survival than patients with non-CNS MS, with CSF leukemia, or with no EML.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Nervioso Central , Leucemia Mieloide Aguda , Neoplasias Primarias Secundarias , Neoplasias Orbitales , Sarcoma Mieloide , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/mortalidad , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/clasificación , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Orbitales/clasificación , Neoplasias Orbitales/tratamiento farmacológico , Neoplasias Orbitales/mortalidad , Sarcoma Mieloide/clasificación , Sarcoma Mieloide/tratamiento farmacológico , Sarcoma Mieloide/mortalidad , Tasa de SupervivenciaRESUMEN
Investigations of long-term outcomes have been instrumental in designing safer and more effective contemporary therapies for pediatric hematological malignancies. Despite the significant therapeutic changes that have occurred over the last five decades, therapy modifications largely represent refinements of treatment protocols using agents and modalities that have been available for more than 30 years. This review summarizes major trends in the evolution of treatment of pediatric hematological malignancies since 1960 to support the relevance of the study of late effects of historical therapeutic approaches to the design and evaluation of contemporary treatment protocols and the follow-up of present-day survivors.
Asunto(s)
Protocolos Antineoplásicos , Neoplasias Hematológicas/terapia , Niño , Terapia Combinada/tendencias , Enfermedad de Hodgkin/terapia , Humanos , Leucemia Mieloide Aguda/terapia , Linfoma no Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sobrevivientes , Resultado del TratamientoRESUMEN
BACKGROUND: FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL). PROCEDURE: Diagnostic specimens from 104 pediatric APL patients were screened for FLT3/Mut (FLT3/ITD or FLT3/ALM). FLT3/Mut status was correlated with disease characteristics and clinical outcome for patients treated on CALGB C9710 (n = 50). RESULTS: Forty-two of the 104 patients (40%) had either FLT3/ITD (n = 28, 27%) or FLT3/ALM (n = 15, 14%). Median diagnostic WBC count was 23,400 cells/µl vs. 3,600 cells/µl for those with and without FLT3/Mut (P < 0.001), and similar results for the cohort of 50 patients treated on C9710 (P < 0.001). In patients treated on C9710, presence of a FLT3 mutation was highly correlated with diagnostic WBC count >10,000 (P = 0.004), microgranular variant histology (P = 0.035), and a lower remission rate (P = 0.009). In patients who received ATRA (C9710 or CCG-2911, n = 8), those with FLT3/Mut had an induction death rate of 30% (7/23) compared to 3% (1/35) in FLT3/WT patients (P = 0.005). In patients with high WBC counts (>10,000), those with FLT3/Mut had a significantly higher risk of induction death versus FLT3/WT patients (47% vs. 0%, P = 0.05). FLT3/Mut was not associated with adverse outcome in those who survived induction therapy. CONCLUSIONS: FLT3/Mut are prevalent in pediatric APL and are associated with high WBC count and increased induction death. This study provides further evidence for testing APL patients for FLT3/Mut and the potential role for FLT3 inhibitors in this disease.