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
BACKGROUND: A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization. PROCEDURE: A single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive. RESULTS: Nine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response. CONCLUSION: Oxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA.
Asunto(s)
Anabolizantes/administración & dosificación , Anemia de Fanconi/complicaciones , Hemoglobinuria Paroxística/tratamiento farmacológico , Oxandrolona/administración & dosificación , Anabolizantes/efectos adversos , Anemia Aplásica , Enfermedades de la Médula Ósea , Trastornos de Fallo de la Médula Ósea , Niño , Femenino , Hemoglobinuria Paroxística/etiología , Humanos , Masculino , Oxandrolona/efectos adversosRESUMEN
BACKGROUND: This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment. PROCEDURE: Patients with <400 mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12 mg/m(2) days 1-3) and low-dose cytarabine (100 mg/m(2) days 1-7) (Arm A). Patients with ≥400 mg/m(2) prior anthracycline received bortezomib with etoposide (100 mg/m(2) on days 1-5) and high-dose cytarabine (1 g/m(2) every 12 hours for 10 doses) (Arm B). RESULTS: Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3 mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR + CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39 ± 15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response. CONCLUSION: Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Animales , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/efectos adversos , Bortezomib , Niño , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Lactante , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Conejos , Terapia Recuperativa/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL.
Asunto(s)
Síndrome de Down/complicaciones , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Adolescente , Adulto , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Niño , Preescolar , Terapia Combinada , Ciclosporina/efectos adversos , Ciclosporina/uso terapéutico , Supervivencia sin Enfermedad , Predisposición Genética a la Enfermedad , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Lactante , Estimación de Kaplan-Meier , Donadores Vivos , Agonistas Mieloablativos/efectos adversos , Agonistas Mieloablativos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recurrencia , Sistema de Registros , Inducción de Remisión , Estudios Retrospectivos , Terapia Recuperativa , Tacrolimus/efectos adversos , Tacrolimus/uso terapéutico , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento , Irradiación Corporal Total/efectos adversosRESUMEN
Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Médula Ósea , Síndrome de Down/terapia , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Adolescente , Niño , Preescolar , Síndrome de Down/complicaciones , Síndrome de Down/inmunología , Síndrome de Down/mortalidad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Masculino , Recurrencia , Inducción de Remisión , Factores de Riesgo , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.
Asunto(s)
Citarabina/uso terapéutico , Síndrome de Down/complicaciones , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Enfermedad Aguda , Antimetabolitos Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Leucemia Megacarioblástica Aguda/complicaciones , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Mieloide/diagnóstico , Masculino , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/diagnóstico , Pronóstico , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Reordenamiento Génico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Niño , Preescolar , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 8 , Estudios de Cohortes , Análisis Citogenético , Femenino , Estudios de Asociación Genética , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Translocación Genética , TrisomíaRESUMEN
BACKGROUND: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML. METHODS: AAML03P1 enrolled 350 children with previously untreated AML. Patients with a matched family donor received 3 courses of chemotherapy followed by hematopoietic stem cell transplantation; those without a matched family donor received 5 courses of chemotherapy. Gemtuzumab ozogamicin 3 mg/m(2)/dose was administered on Day 6 of Course 1 and Day 7 of Course 4. RESULTS: Toxicities observed in all courses of therapy were typical of AML chemotherapy regimens, with infection being most common. Patients achieved a complete remission rate of 83% after 1 course and 87% after 2 courses. The mortality rate was 1.5% after the first gemtuzumab ozogamicin-containing induction course and 2.6% after 2 induction courses. The 3-year event-free survival and overall survival rates were 53 ± 6% and 66 ± 5%, respectively. CONCLUSIONS: This trial determined that it is safe and feasible to include gemtuzumab ozogamicin in combination with intensive chemotherapy. The survival rates compare favorably with the recently published results of clinical trials worldwide.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Adolescente , Adulto , Aminoglicósidos/administración & dosificación , Amsacrina/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Niño , Preescolar , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Gemtuzumab , Humanos , Lactante , Recién Nacido , Masculino , Estadificación de Neoplasias , Proyectos Piloto , Pronóstico , Tasa de Supervivencia , 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
Children with trisomy 21 have a unique predisposition to develop a megakaryoblastic proliferative disease of varying severity during their first 3 months of life. This disorder exists in no other children or adults without the presence of trisomy 21 and only occurs in the fetal or neonatal period of life. Its spontaneous resolution in most cases further delineates it from otherwise indistinguishable neonatal leukaemias. The identification that GATA1 mutations are the leukaemogenic source along with three recently reported prospective clinical trials now provide a clearer understanding of this haematopoietic disorder. These recent advances in this enigmatic disorder, now known as Transient Myeloproliferative Disorder, are reviewed here in order to bring clarity to the breadth of organ involvement, the range of severity, the risk factors for mortality, the therapeutic options for severe manifestations, the natural course of spontaneous resolution regardless of therapy, and the elucidation of the subsequent risk for myeloid leukaemia.
Asunto(s)
Síndrome de Down/complicaciones , Trastornos Mieloproliferativos/etiología , Niño , Preescolar , Humanos , Incidencia , Leucemia/etiología , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/terapia , Factores de RiesgoRESUMEN
Almost a decade ago, Gillil and proposed a model of leukemogenesis for acute myeloid leukemia (AML). In this model, AML results from activating mutations in genes that confer increased proliferation and survival capabilities (class I mutations) acting in concert with chromosomal abnormalities or gene mutations that block differentiation and subsequent apoptosis (class II mutations). In this issue of Blood, Bach as and colleagues present data that clearly demonstrate mutational shifts in class I/II genes that occur between diagnosis and relapse in children with AML. The authors suggest that these findings may allow for personalized treatment.
RESUMEN
BACKGROUND: The importance of matching at the HLA C locus has not been well defined for unrelated umbilical-cord blood transplantation. The selection algorithm for umbilical-cord blood units generally considers intermediate resolution HLA typing at A and B and allele-level typing at DRB1. We aimed to establish the relative importance of additional matching at HLA C. METHODS: We used Cox regression to assess retrospectively the effect of donor-recipient HLA matching on outcomes of single umbilical-cord blood transplantations for leukaemia and myelodysplastic syndrome. Our primary endpoint was transplant-related mortality. HLA typing was done with molecular techniques with a minimum of intermediate resolution for HLA A, B, and C, and at the allele-level for DRB1. FINDINGS: The median age of our study population was 10 years (range <1-62) and 552 (69%) of 803 patients were aged 16 years or younger at transplantation. Compared with transplantations matched at HLA A, B, C, and DRB1 (n=69), transplant-related mortality risk was higher after transplantations matched at HLA A, B, and DRB1 and mismatched at HLA C (n=23; HR 3·97, 95% CI 1·27-12·40; p=0·018). Transplant-related mortality risk was also higher after transplantations with a single mismatch at HLA A, B, or DRB1 and mismatched at HLA C (n=234; 1·70, 1·06-2·74; p=0·029) compared with transplantations matched at HLA C with a single mismatch at HLA A, B, or DRB1 (n=127). Assessing the overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (n=259; 3·27, 1·42-7·54; p=0·006), three (n=253; 3·34, 1·45-7·71; p=0·005), or four (n=75; 3·51, 1·44-8·58; p=0·006) loci compared with matched units (n=69). INTERPRETATION: Our data suggest that the present strategy for umbilical-cord blood unit selection should be reassessed; matching at HLA C for units that are matched at HLA A, B, or DRB1 or in the presence of a single locus mismatch at HLA A, B, or DRB1 should be included to minimise mortality risks. FUNDING: National Cancer Institute, National Heart Lung and Blood Institute, National Institute for Allergy and Infectious Diseases, Leukemia and Lymphoma Society, US Department of the Navy, Children's Leukemia Research Association, and INSERM.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Antígenos HLA/inmunología , Prueba de Histocompatibilidad , Histocompatibilidad , Leucemia/cirugía , Síndromes Mielodisplásicos/cirugía , Adolescente , Adulto , Algoritmos , Niño , Preescolar , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/mortalidad , Europa (Continente) , Femenino , Antígenos HLA/genética , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Antígenos HLA-C/inmunología , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Humanos , Lactante , Estimación de Kaplan-Meier , Leucemia/inmunología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Selección de Paciente , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.
Asunto(s)
Cromosomas Humanos Par 11/genética , Reordenamiento Génico , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Translocación Genética , Niño , Mapeo Cromosómico , Cromosomas Humanos Par 9/genética , Supervivencia sin Enfermedad , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Agencias Internacionales , Cariotipificación , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Conflicting data exist regarding whether low bone mineral density (BMD) is associated with Fanconi anemia (FA). The current study identified the frequency of low BMD in FA, expecting low BMD even in childhood and before HCT. PROCEDURE: Thirty-seven FA patients (18 prior HCT, 19 no prior HCT), participating in an IRB-approved database, had clinical assessment of DXA of lumbar spine BMD. Four had used androgens, one later underwent HCT. Most had used glucocorticoids after HCT (prolonged in five), and one more with no HCT. BMD [in standard deviation units from mean for age (SD), gender, and ethnicity (BMD Z-score)] was then adjusted for height age, and separately for bone maturation (BA). Data were collected for height SD, pubertal stage, and duration since HCT. RESULTS: BMD Z-score (without adjustment) was <-1 SD in half of FA children. BA-adjusted BMD Z-score was similar. (BA was not usually delayed, although most patients were short.) In contrast, height age-adjusted BMD Z-score was normal in most with FA (only below -2.0 in one child after prolonged glucocorticoids). Mean duration after HCT until DXA test was 6.2 years (median 4.2 years, range 1-18 years). CONCLUSIONS: Children and adolescents with FA have normal BMD prior to and after HCT, when DXA results are adjusted for bone size/height age. In contrast, BA-adjustment of BMD was not useful in this population. Individual BMD results may be influenced by gonadal function, transplantation status, and prolonged glucocorticoid therapy.
Asunto(s)
Densidad Ósea , Anemia de Fanconi/metabolismo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Based on its potential role in adult myelodysplastic syndrome (MDS), the Children's Oncology Group (COG) embarked on a phase II study using amifostine in pediatric MDS (WHO 2001 criteria) patients. Responses were evaluated after two cycles. Ten patients were enrolled; five were deemed ineligible, and four withdrew after the first course. Only one patient completed two courses, and was found to be in complete remission. The study was closed after being open for 2 years due to slow accrual. Studying a rare disease like MDS may pose insurmountable obstacles even in a large clinical trials group such as COG, in part because of the changing definitions of MDS and the rarity of adult type MDS in children. The role of amifostine in pediatric MDS was not known at the time of study.
Asunto(s)
Amifostina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Protectores contra Radiación/uso terapéutico , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proyectos de InvestigaciónRESUMEN
PURPOSE: To determine the efficacy of imatinib in children with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML). METHODS: This was an open label, multi-center phase II clinical trial. Courses were defined as consecutive 28-day intervals. Oral imatinib was administered daily at 340 mg/m² without interruption in the absence of toxicity. RESULTS: Fifty-one children received 978 28-day courses of imatinib. The most common toxicities encountered were hematologic. Forty-one patients (80%) achieved a complete hematologic response by the end of course 2. Nineteen children (38%) obtained a complete cytogenetic response (CCyR) at the end of course 3. Overall, 72% achieved CCyR at a median time of 5.6 months. The rate of complete molecular response (>3 log reduction) was 27%. Progression-free and overall survival at 3 years were 72% ± 6.4% and 92% ± 3.9%, respectively. CONCLUSIONS: Daily oral imatinib at a dose of 340 mg/m² is well tolerated in children. In addition, imatinib therapy is effective in inducing a high percent of hematologic, cytogenetic and molecular responses, comparable to adults with CML. (This study was registered at ClinicalTrials.gov under identifier NCT00030394.).
Asunto(s)
Antineoplásicos/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Administración Oral , Adolescente , Adulto , Antineoplásicos/efectos adversos , Benzamidas , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Piperazinas/efectos adversos , Pirimidinas/efectos adversos , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
Previous studies showed that Fanconi anemia (FA) murine stem cells have defective reconstitution after bone marrow (BM) transplantation. The mechanism underlying this defect is not known. Here, we report defective homing of FA patient BM progenitors transplanted into mouse models. Using cells from patients carrying mutations in FA complementation group A (FA-A), we show that when transplanted into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) recipient mice, FA-A BM cells exhibited impaired homing activity. FA-A cells also showed defects in both cell-cell and cell-matrix adhesion. Complementation of FA-A deficiency by reexpression of FANCA readily restored adhesion of FA-A cells. A significant decrease in the activity of the Rho GTPase Cdc42 was found associated with these defective functions in patient-derived cells, and expression of a constitutively active Cdc42 mutant was able to rescue the adhesion defect of FA-A cells. These results provide the first evidence that FA proteins influence human BM progenitor homing and adhesion via the small GTPase Cdc42-regulated signaling pathway.
Asunto(s)
Células de la Médula Ósea/metabolismo , Anemia de Fanconi/metabolismo , Proteína de Unión al GTP cdc42/metabolismo , Adolescente , Adulto , Animales , Células de la Médula Ósea/patología , Trasplante de Médula Ósea , Estudios de Casos y Controles , Adhesión Celular , Movimiento Celular , Niño , Ensayo de Unidades Formadoras de Colonias , Anemia de Fanconi/patología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante HeterólogoRESUMEN
BACKGROUND: Children with Down syndrome (DS) have about a 20-fold increased risk of developing leukemia. Early childhood infections may protect against acute lymphoid leukemia (ALL) in children with and without DS. We examined whether maternal infections and health conditions during pregnancy were associated with acute leukemia in children with DS. PROCEDURE: We conducted a case-control study of 158 children with DS and leukemia (including 97 cases with acute lymphoblastic leukemia (ALL) and 61 cases with acute myeloid leukemia (AML)) and 173 children with DS during the period 1997-2002. Maternal interview included information about 14 maternal conditions during gestation that are likely to induce an inflammatory response. We evaluated their prevalence in cases and controls. Five of these were common enough to allow analyses by leukemia subtype. RESULTS: Vaginal bleeding was the most frequent (18% cases, 25% controls) and was associated with a reduced risk (odds ratio (OR) = 0.57; 95% confidence interval (CI) = 0.33-0.99) for all cases combined. Other variables, while showing a potential trend toward reduced risk had effect estimates, which were imprecise and not statistically significant. In contrast, amniocentesis was marginally associated with an increased risk of AML (OR = 2.06, 95% CI = 0.90-4.69). CONCLUSIONS: Data from this exploratory investigation suggest that some health conditions during pregnancy may be relevant in childhood leukemogenesis. Larger epidemiological studies and other model systems (animal, clinical studies) may provide a clearer picture of the potential association and mechanisms.
Asunto(s)
Síndrome de Down/complicaciones , Síndrome de Down/epidemiología , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/epidemiología , Bienestar Materno/estadística & datos numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Masculino , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND: Children with Fanconi anemia (FA) tend to have short stature, mild thyrotropin (TSH) elevation, and borderline low free thyroxine (FT4). Objective was to examine whether thyroid hormone therapy improves linear growth in children with FA and borderline thyroid function tests PROCEDURE: Thyroid function tests were performed in 63 children with FA. Eight subjects participated in a random order, double-blind, cross-over treatment for 7 months with levothyroxine and for 7 months with placebo. Monitoring included growth measurements and laboratory assays at 1, 4 and 7 months of each phase. A 1 month lead in/wash out period was excluded from analysis of each treatment phase. RESULTS: The majority (63%) of FA children had borderline thyroid function tests. All eight FA subjects enrolled in the treatment study had FT4 in the lowest third of the normal range of 0.8-1.8 ng/dL (10.3-23.2 pmol/L) [FT4 0.9 +/- 0.1 ng/dL (mean +/- SD), range 0.8-1.2 ng/dL (10.3-15.4 pmol/L)]. TSH (optimal range 0.5-3 mU/L) was borderline elevated in six of eight subjects (4.0 +/- 1.5 mU/L, 1.9-7.3 mU/L). Growth velocity was slow at baseline and improved significantly during the thyroid phase compared to the placebo phase (2.1 +/- 1.2 cm/year vs. 5.4 +/- 1.7 cm/year, P < 0.05). CONCLUSIONS: Thyroid hormone therapy is safe and may improve linear growth velocity in children with FA who have borderline thyroid function. Subtle hypothyroidism has importance for growth in children. Whether thyroid hormone treatment improves adult height in these children remains to be elucidated.