[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLA-matched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n=53), RAEB in transformation (RAEB-T, n=29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n=15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n=57) or alternative family donor (n=1). Stem cell source was bone marrow (n=69) or peripheral blood (n=28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2011; 25(3):455-62. · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify cytogenetic risk factors predicting outcome in children with advanced myelodysplastic syndrome, overall survival of 192 children prospectively enrolled in European Working Group of Myelodysplastic Syndrome in Childhood studies was evaluated with regard to karyotypic complexity. Structurally complex constitutes a new definition of complex karyotype characterized by more than or equal to 3 chromosomal aberrations, including at least one structural aberration. Five-year overall survival in patients with more than or equal to 3 clonal aberrations, which were not structurally complex, did not differ from that observed in patients with normal karyotype. Cox regression analysis revealed the presence of a monosomal and structurally complex karyotype to be strongly associated with poor prognosis (hazard ratio = 4.6, P < .01). Notably, a structurally complex karyotype without a monosomy was associated with a very short 2-year overall survival probability of only 14% (hazard ratio = 14.5; P < .01). The presence of a structurally complex karyotype was the strongest independent prognostic marker predicting poor outcome in children with advanced myelodysplastic syndrome.
[Show abstract][Hide abstract] ABSTRACT: Subcutaneous (sc) administration of anti-D seems to offer the same efficacy as intravenous administration but with less side effects. Here we report our experience with sc anti-D for pediatric immune thrombocytopenia (ITP). A total of 12 children with a median age of 11.2 years had been treated by sc anti-D. They received a median of 2 sc anti-D applications (range 1-31) with a dosage of 250-375 IE/kg body weight. Only in one out of a total of 102 single applications, a minimal and self-limited side effect (chills) had been observed. The mean platelet count was almost doubled after sc anti-D (p < 0.0001). After a median follow-up of 11.4 months, all patients are alive without major bleeding and stay well. We conclude that sc anti-D: is not only an efficient means of treating ITP in children but is also a safe and convenient one.
Annals of Hematology 10/2009; 89(4):415-8. · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extramedullary plasmacytomas are extremely rarely diagnosed in children. We report two cases of extramedullary plasmacytoma detected coincidentally in the adenoidectomy specimens of children younger than 4 years. We show that these children are disease-free after local excision as the only treatment. Surgical treatment without anti-neoplastic therapy in pediatric plasma cell dyscrasias of the pharyngeal lymphoid tissue may be a sufficient curative therapy.
Pediatric Blood & Cancer 04/2007; 48(3):361-2. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the clinical course and outcome of infants with Langerhans cell histiocytosis (LCH) involving skin and to estimate the incidence of progression to multi-system (M-S) disease in those with isolated skin involvement.
A retrospective review was conducted on 22 LCH patients who were younger than 12 months at the onset of their skin eruption.
Twelve patients had isolated skin involvement at diagnosis and 10 were evaluable for progression. Four of the 10 (40%) evaluable patients progressed to multi-system (M-S) disease. Of the 10 patients with M-S disease at diagnosis, 5 had a history of a preceding skin eruption 2 to 13 months prior to diagnosis. Eleven of the 14 (79%) patients with M-S disease had risk organ involvement. The mortality rate of M-S disease was 50%.
It is important for primary caregivers to recognize that isolated cutaneous LCH in infants is not always a benign disorder. The diagnosis of self-healing cutaneous LCH should only be made in retrospect. Careful, albeit non-invasive, follow-up is recommended to monitor for disease progression and development of long-term complications.
Pediatric Blood & Cancer 02/2006; 46(1):66-71. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The coincidence of T-cell acute lymphoblastic leukemia (T-ALL) and histiocytic disorders, including hemophagocytic lymphohistiocytosis (T-ALL/HLH) and Langerhans cell histiocytosis (T-ALL/LCH), is very seldom and is usually associated with a dismal prognosis. Retrospective statistical analysis of all T-ALL patients, who have been registered in the BFM-ALL trials from 1981 - 2001 and who have subsequently developed a LCH/HLH, in order to identify any common risk factors pre-disposing to the synchronous occurrence of both disorders. Six out of 971 T-ALL patients had either HLH or LCH ( approximately 0.03% of treated T-ALL/year). The mean age at diagnosis of T-ALL/HLH/LCH was significantly lower than in the remaining T-ALL group (4.05 +/- 0.59 vs 8.82 +/- 0.14 years; p = 0.000). The mean initial leukocyte count was higher than in the non-HLH/LCH group (270,700 +/- 60,677 microl(-1) vs 134,141 +/- 5,663 microl(-1); p = 0.074). No hemophagocytosis was seen in the initial bone marrow (BM) smears. Five of 6 patients obtained a good prednisone response (GPR) at day 8 in peripheral blood with <5% blasts at day 15 in BM and all cases were in complete remission (CR) at day 33. The mean time until development of the histiocytosis was 17.95 months (range 2.5 - 33 months). Four patients developed a HLH and 2 a LCH. All patients with HLH showed a multi-organ involvement, while the LCH patients had only local disease. Only the LCH patients survived, while all patients with HLH died. The authors recommend a close follow-up for at least 3 years after diagnosis in younger T-ALL patients with high initial leukocyte count.
Leukemia and Lymphoma 12/2005; 46(12):1735-41. · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: The International Prognostic Scoring System (IPSS) for myelodysplastic syndrome (MDS) is based upon weighted data on bone marrow (BM) blast percentage, cytopenia, and cytogenetics, separating patients into four prognostic groups. We analyzed the value of the IPSS in 142 children with de novo MDS and 166 children with juvenile myelomonocytic leukemia (JMML) enrolled in retro- and prospective studies of the European Working Group on childhood MDS (EWOG-MDS). Survivals in MDS and JMML were analyzed separately. Among the criteria considered by the IPSS score, only BM blasts <5% and platelets >100 x 10(9)/l were significantly associated with a superior survival in MDS. In JMML, better survival was associated with platelets >40 x 10(9)/l, but not with any other IPSS factors including cytogenetics. In conclusion, the IPSS is of limited value in both pediatric MDS and JMML. The results reflect the differences between myelodysplastic and myeloproliferative diseases in children and adults.