RESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil , Adulto , Azacitidina/efeitos adversos , Criança , Metilação de DNA , Humanos , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Leucemia Mielomonocítica Juvenil/genética , MutaçãoRESUMO
PURPOSE: Known clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML on the basis of DNA methylation patterns are lacking. We, therefore, sought to define an international consensus for DNA methylation subgroups in JMML and develop classification methods for clinical implementation. EXPERIMENTAL DESIGN: Published DNA methylation data from 255 patients with JMML were used to develop and internally validate a classifier model. Accuracy across platforms (EPIC-arrays and MethylSeq) was tested using a technical validation cohort (32 patients). The suitability of both methods for single-patient classification was demonstrated using an independent cohort (47 patients). RESULTS: Analysis of pooled, published data established three DNA methylation subgroups as a de facto standard. Unfavorable prognostic parameters (PTPN11 mutation, elevated fetal hemoglobin, and older age) were significantly enriched in the high methylation (HM) subgroup. A classifier was then developed that predicted subgroups with 98% accuracy across different technological platforms. Applying the classifier to an independent validation cohort confirmed an association of HM with secondary mutations, high relapse incidence, and inferior overall survival (OS), while the low methylation subgroup was associated with a favorable disease course. Multivariable analysis established DNA methylation subgroups as the only significant factor predicting OS. CONCLUSIONS: This study provides an international consensus definition for DNA methylation subgroups in JMML. We developed and validated methods which will facilitate the design of risk-stratified clinical trials in JMML.
Assuntos
Consenso , Metilação de DNA , Leucemia Mielomonocítica Juvenil/mortalidade , Adolescente , Criança , Pré-Escolar , Ilhas de CpG/genética , Conjuntos de Dados como Assunto , Epigênese Genética , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/genética , Masculino , Prognóstico , Medição de Risco/métodos , Medição de Risco/normasRESUMO
BACKGROUND: The occurrence of prior, concurrent and subsequent neoplasms (SN) represents a serious problem in children and adolescents with soft tissue sarcomas. Pathogenic germline variants contribute to the diagnosis of multiple neoplasms in sarcoma survivors. MATERIALS AND METHODS: The records of 748 children and adolescents, diagnosed with soft tissue sarcomas and registered in trials/registries by the cooperative soft tissue sarcoma (Cooperative Weichteilsarkom Studie) group, were reviewed for the occurrence of SNs. Reference histology review was available for all cases; the presence of oncogenic fusions known at the time of diagnosis was confirmed for fusion-positive (F+) entities. RESULTS: Concurrent or subsequent SNs developed in 13 of 473 survivors of fusion-negative (F-) sarcomas, for an 8-year cumulative SN incidence of 5% in survivors of F- sarcomas. In contrast, only 1 of 278 survivors of F+ sarcoma developed an SN. Twenty of 748 patients with soft tissue sarcomas had a history of prior neoplasms. Six of 14 patients who developed SNs after their index sarcomas met Chompret criteria for Li-Fraumeni syndrome. Nine of 20 patients who had tumors before their index sarcoma diagnosis had neurofibromatosis type 1 or neurofibromatosis type 1 spectrum tumors. CONCLUSION: Sarcoma phenotype/genotype and the sequence and nature of prior and subsequent neoplasms provide a window into underlying germline genetic susceptibilities in children and adolescents with soft tissue sarcomas.
Assuntos
Biomarcadores Tumorais/genética , Sobreviventes de Câncer/estatística & dados numéricos , Mutação em Linhagem Germinativa , Segunda Neoplasia Primária/epidemiologia , Proteínas de Fusão Oncogênica/genética , Sistema de Registros/estatística & dados numéricos , Sarcoma/mortalidade , Adolescente , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Terapia Combinada , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Lactente , Masculino , Segunda Neoplasia Primária/classificação , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Prognóstico , Fatores de Risco , Sarcoma/genética , Sarcoma/patologia , Sarcoma/terapia , Taxa de SobrevidaRESUMO
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.
Assuntos
Metilação de DNA , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Antineoplásicos/uso terapêutico , Biópsia , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Análise Mutacional de DNA , Epigenômica , Feminino , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/patologia , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Mutação , Síndrome de Noonan/patologia , Prognóstico , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-cbl , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Regulação para Cima , DNA Metiltransferase 3BRESUMO
BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm of childhood whose clinical heterogeneity is only poorly represented by gene sequence alterations. It was previously shown that aberrant DNA methylation of distinct target genes defines a more aggressive variant of JMML, but only few significant targets are known so far. To get a broader picture of disturbed CpG methylation patterns in JMML, we carried out a methylation screen of 34 candidate genes in 45 patients using quantitative mass spectrometry. FINDINGS: Five of 34 candidate genes analyzed showed recurrent hypermethylation in JMML. cAMP-responsive element-binding protein-binding protein (CREBBP) was the most frequent target of epigenetic modification (77 % of cases). However, no pathogenic mutations of CREBBP were identified in a genetic analysis of 64 patients. CREBBP hypermethylation correlated with clinical parameters known to predict poor outcome. CONCLUSIONS: This study supports the relevance of epigenetic aberrations in JMML pathophysiology. Our data confirm that DNA hypermethylation in JMML is highly target-specific and associated with higher-risk features. These findings encourage the development of prognostic markers based on epigenetic alterations, which will be helpful in the difficult clinical management of this heterogeneous disease.
Assuntos
Proteína de Ligação a CREB/genética , Metilação de DNA , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , Ilhas de CpG , Epigênese Genética , Humanos , Espectrometria de Massas/métodos , PrognósticoRESUMO
A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative high-resolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., α, ß, and γ) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples. The AKAP12α promoter shows DNA hypermethylation in JMML samples, which is associated with decreased AKAP12α expression. Promoter methylation of AKAP12α correlates with older age at diagnosis, elevated levels of fetal hemoglobin and poor prognosis. In silico screening for transcription factor binding motifs around the sites of most pronounced methylation changes in the AKAP12α promoter revealed highly significant scores for GATA-2/-1 sequence motifs. Both transcription factors are known to be involved in the haematopoietic differentiation process. Methylation of a reporter construct containing this region resulted in strong suppression of AKAP12 promoter activity, suggesting that DNA methylation might be involved in the aberrant silencing of the AKAP12 promoter in JMML. Exposure to DNMT- and HDAC-inhibitors reactivates AKAP12α expression in vitro, which could potentially be a mechanism underlying clinical treatment responses upon demethylating therapy. Together, these data provide evidence for epigenetic silencing of AKAP12α in JMML and further emphasize the importance of dysregulated RAS signaling in JMML pathogenesis.
Assuntos
Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ciclo Celular/genética , Metilação de DNA , Inativação Gênica , Leucemia Mielomonocítica Juvenil/genética , Regiões Promotoras Genéticas , Linhagem Celular Tumoral , Pré-Escolar , Feminino , Genes ras , Humanos , Lactente , Masculino , Transdução de SinaisRESUMO
Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.
Assuntos
Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Leucemia Mielomonocítica Juvenil/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 7 , Ilhas de CpG , Feminino , Inativação Gênica , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Monossomia , Mutação , Prognóstico , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality.
Assuntos
Anemia Aplástica/terapia , Transplante de Medula Óssea , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Anemia Aplástica/imunologia , Anemia Aplástica/mortalidade , Anemia Aplástica/patologia , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Ciclofosfamida/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Antígenos HLA/imunologia , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Melfalan/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Índice de Gravidade de Doença , Irmãos , Análise de Sobrevida , Transplante HomólogoRESUMO
Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090).
Assuntos
Soro Antilinfocitário/uso terapêutico , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Pancitopenia/tratamento farmacológico , Adolescente , Animais , Soro Antilinfocitário/administração & dosagem , Criança , Pré-Escolar , Feminino , Cavalos , Humanos , Imunossupressores/administração & dosagem , Lactente , Masculino , Pancitopenia/diagnóstico , Coelhos , Recidiva , Fatores de Risco , Resultado do TratamentoRESUMO
Aberrant DNA methylation contributes to the malignant phenotype in virtually all types of cancer, including myeloid leukemia. We hypothesized that CpG island hypermethylation also occurs in juvenile myelomonocytic leukemia (JMML) and investigated whether it is associated with clinical, hematologic, or prognostic features. Based on quantitative measurements of DNA methylation in 127 JMML cases using mass spectrometry (MassARRAY), we identified 4 gene CpG islands with frequent hypermethylation: BMP4 (36% of patients), CALCA (54%), CDKN2B (22%), and RARB (13%). Hypermethylation was significantly associated with poor prognosis: when the methylation data were transformed into prognostic scores using a LASSO Cox regression model, the 5-year overall survival was 0.41 for patients in the top tertile of scores versus 0.72 in the lowest score tertile (P = .002). Among patients given allogeneic hematopoietic stem cell transplantation, the 5-year cumulative incidence of relapse was 0.52 in the highest versus 0.10 in the lowest score tertile (P = .007). In multivariate models, DNA methylation retained prognostic value independently of other clinical risk factors. Longitudinal analyses indicated that some cases acquired a more extensively methylated phenotype at relapse. In conclusion, our data suggest that a high-methylation phenotype characterizes an aggressive biologic variant of JMML and is an important molecular predictor of outcome.
Assuntos
Metilação de DNA , Leucemia Mielomonocítica Juvenil/genética , Proteína Morfogenética Óssea 4/genética , Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Ilhas de CpG , Inibidor de Quinase Dependente de Ciclina p15/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Prognóstico , Precursores de Proteínas/genética , Receptores do Ácido Retinoico/genética , Fatores de Risco , Resultado do TratamentoRESUMO
It is currently unknown whether immunosuppressive therapy or hematopoietic stem cell transplantation is the most appropriate treatment strategy for children with refractory cytopenia and normal karyotype or trisomy 8. We report on 31 children with hypoplastic refractory cytopenia treated with immunosuppressive therapy consisting of antithymocyte globulin and cyclosporine. At 6 months, 22 of 29 evaluable patients had a complete or partial response; a total of ten patients achieved a complete response at varying time points. Six patients subsequently received a transplant because of non-response, progression to advanced myelodysplastic syndrome or evolution of monosomy 7. Overall and failure-free survival rates at 3 years were 88% and 57%, respectively.
Assuntos
Soro Antilinfocitário/uso terapêutico , Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Transfusão de Sangue , Criança , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/cirurgia , Prednisona/uso terapêutico , Estudos Prospectivos , Recidiva , Indução de Remissão , Estatísticas não Paramétricas , Linfócitos T , Resultado do TratamentoRESUMO
Chimaerism analysis was performed by polymerase chain reaction amplification of short-tandem repeat markers in 30 children following haematopoietic stem cell transplantation for juvenile myelomonocytic leukaemia (JMML). Fourteen patients always had complete chimaerism (CC); one of them relapsed after the discontinuation of the study and 13 continued in complete remission (CR). Mixed chimaerism (MC) was noted in 16 patients. Of those 12 patients demonstrated increasing MC (i-MC); 10 relapsed and two achieved CC following discontinuation of immunosuppressive therapy (IST). Four other patients demonstrating only transient MC are alive in CR. MC with up to 20% of autologous cells could be successfully eradicated without induction of severe graft-versus-host disease when IST was reduced or discontinued directly after the first demonstration of MC. At the same time, MC with up to 10% of autologous cells could disappear without intervention. The interval between MC and relapse ranged from 0-320 d (median 38 d). Donor leucocyte infusion was given to six patients with i-MC, but only one patient responded. Peripheral blood seems as valuable as bone marrow for chimaerism studies. In conclusion, serial quantitative chimaerism studies can identify patients with i-MC who are at high risk for relapse of JMML. Immediate withdrawal of IST is advised in these patients.
Assuntos
Leucemia Mielomonocítica Aguda/cirurgia , Transplante de Células-Tronco , Quimeras de Transplante/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Marcadores Genéticos , Efeito Enxerto vs Leucemia , Humanos , Lactente , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/imunologia , Transfusão de Leucócitos , Masculino , Reação em Cadeia da Polimerase/métodos , Estudos Prospectivos , Indução de Remissão , Taxa de Sobrevida , Sequências de Repetição em TandemRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide/patologia , Leucemia Mieloide/cirurgia , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Europa (Continente) , Feminino , Seguimentos , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Leucemia Mieloide/imunologia , Masculino , Recidiva , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Primary myelodysplasia (MDS) without an increased number of blasts is a rare finding in childhood. We performed a retrospective analysis of 67 children with a diagnosis of primary MDS to determine the clinical and hematologic course of the disease. The median age at diagnosis was 8.3 years (range, 0.3-18.1 years). In contrast to refractory anemia in adults, 44% of patients had hemoglobin levels greater than 10 g/100 mL. The median white blood cell count and the absolute neutrophil count were 3.6 x 109/L and 0.9 x 109/L, respectively. Seventy-five percent of patients had thrombocytopenia. Bone marrow was hypocellular in 43% of the patients. Results of cytogenetic analysis showed monosomy 7 in 49%, trisomy 8 in 9%, and other abnormalities in 9% of the patients. The probability of survival 10 years after diagnosis was 0.48 (standard error [SE] = 0.10). Patients with monosomy 7 had significantly higher estimated probabilities of progression to advanced MDS than did patients with other chromosomal anomalies or normal karyotype. Of the 67 children, 41 underwent allogeneic stem cell transplantation (SCT). Patients whose disease did not progress to advanced MDS before SCT had significantly greater probability of survival than patients who experienced progression (0.76 [SE = 0.09] vs 0.36 [SE = 0.16]). SCT improved the outcomes for patients with monosomy 7 and should be offered early in the course of the disease. Recommendations for best treatment options for children with other chromosomal abnormalities or normal karyotype may have to await results of prospective clinical trials.