Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the ...hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications.
One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 × 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant.
Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.
Despite advances in the treatment of childhood acute lymphoblastic leukemia (ALL), the risk of relapse remains about 30 percent. Studies have shown that the presence or absence of residual disease, ...as assessed by the polymerase-chain-reaction (PCR) assay, can serve as a prognostic factor in patients with ALL,
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and threshold levels of residual leukemic cells have been proposed for predicting relapse.
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However, many of the studies have been retrospective analyses
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or have involved a small number of patients who were sometimes treated with different protocols. Furthermore, the course of residual disease has varied considerably in some studies. . . .
The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy>50 chromosomes (HD>50), a group of B-cell precursor acute lymphoblastic ...leukemia with favorable outcome. The 541 HD>50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error SE = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P < .0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI < 1.16/≥1.16-<1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728.
•Patients with 58-66 chromosomes have 99% event-free survival and 100% overall survival in the 58951 EORTC-CLG study.•The higher the ploidy, the better the prognosis in the 58951 EORTC-CLG study.
Abstract Aim of the study To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing’s sarcoma. Methods Standard risk tumours (SR, good ...histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was <50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5–30% residual cells or large unresected tumours >100 ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue. Results From 1993 to 1999, 214 patients were enrolled. 5y-EFS and OS were 60% (95% confidence interval (CI), 53–66) and 69% (95% CI, 63–75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30–60) and 20% (95% CI, 7–43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours. Conclusion These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.
The European Organisation for Research and Treatment of Cancer 58951 trial for children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) addressed 3 randomized questions, ...including the evaluation of dexamethasone (DEX) versus prednisolone (PRED) in induction and, for average-risk patients, the evaluation of vincristine and corticosteroid pulses during continuation therapy. The corticosteroid used in the pulses was that assigned at induction. Overall, 411 patients were randomly assigned: 202 initially randomly assigned to PRED (60 mg/m2/d), 201 to DEX (6 mg/m2/d), and 8 nonrandomly assigned to PRED. At a median follow-up of 6.3 years, there were 19 versus 34 events for pulses versus no pulses; 6-year disease-free survival (DFS) rate was 90.6% (standard error SE, 2.1%) and 82.8% (SE, 2.8%), respectively (hazard ratio HR = 0.54; 95% confidence interval, 0.31-0.94; P = .027). The effect of pulses was similar in the PRED (HR = 0.56) and DEX groups (HR = 0.59) but more pronounced in girls (HR = 0.24) than in boys (HR = 0.71). Grade 3 to 4 hepatic toxicity was 30% versus 40% in pulses versus no pulses group and grade 2 to 3 osteonecrosis was 4.4% versus 2%. For average-risk patients treated according to Berlin-Frankfurt-Muenster–based protocols, pulses should become a standard component of therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.
AP-HP, Paris, France.
BACKGROUND AND OBJECTIVES: Deletion and methylation of the 9p21 chromosomal region are frequent in childhood acute lymphoblastic leukemia (ALL) but the prognostic significance ...is controversial. They inactivate CDKN2A, a gene encoding both p16INKa and p14ARF and, in some cases, contiguous genes that may influence chemosensitivity, such as CDKN2B encoding p15INKb or MTAP encoding methylthioadenosine phosphorylase. DESIGN AND METHODS: CDKN2A inactivation by deletion or methylation was studied using gene dosage and methyl-specific polymerase chain reaction. RESULTS: Bi-allelic and mono-allelic inactivation were found in, respectively, 38 (17%) and 31 (14%) of 227 children with B-lineage ALL enrolled in EORTC trials. Although CDKN2A inactivation was more often associated with poor prognostic features in B-lineage ALL, it failed to influence the outcome of the patients significantly. Bi-allelic CDKN2B and MTAP co-inactivation were found in 36 (16%) and 24 (11%) of patients, respectively, and did not influence the 6-year event-free survival rate either, even when the analysis was restricted to CDKN2A inactivated ALL. INTERPRETATION AND CONCLUSIONS: In this study of 227 cases of childhood B-lineage ALL, inactivation of CDKN2A, CDKN2B and MTAP did not influences the patients' outcome.
The objective of the present study was to investigate the role of early common infections and perinatal characteristics in the aetiology of childhood common leukaemia. A case-control study was ...conducted from 1995 to 1998 in France, and included 473 incident cases of acute leukaemia (AL) (408 acute lymphoblastic leukaemia (ALL), 65 acute myeloid leukaemia (AML) age-, sex- and region-matched with 567 population-based controls. Data on the medical history of the child and his/her environment were collected using self-administered questionnaires. Analyses were conducted using nonconditional logistic regression. A slight negative association with early infections was observed (OR=0.8; 95% CI (0.6-1.0)). The association was stronger for early gastrointestinal infections. Early day-care was found to be associated with a decreased risk of AL (OR=0.6; 95% CI (0.4-0.8) and OR=0.8; 95% CI (0.5-1.2) for day-care starting before age 3 months and between 3 and 6 months, respectively). No association with breast-feeding was observed, irrespective of its duration. A birth order of 4 or more was associated with a significantly increased risk of AL (OR=2.0; 95% CI (1.1-3.7) with ALL). A history of asthma was associated with a decreased risk of ALL (OR 0.5; 95% CI (0.3-0.90). Although the results regarding birth order and breast-feeding do not fit with Greaves' hypothesis, the study supports the hypothesis that early common infections may play a protective role in the aetiology of childhood leukaemia, although this effect was not more marked for common ALL.
In a series of 153 children with T-cell malignancies enrolled in 2 consecutive European Organization for Research and Treatment of Cancer (EORTC) trials, we assessed the HOX11L2 expression and/or the ...presence of a t(5;14)(q35;q32). Additionally, in 138 of these patients, HOX11 expression and SIL-TAL rearrangement were also assessed. These alterations were mutually exclusive, and their frequency was 23% (n = 35), 7% (n = 10), and 12% (n = 17), respectively. HOX11L2/t(5;14) positivity was more frequent in acute lymphoblastic leukemia (ALL) with cortical T immunophenotype and in children aged between 6 and 9 years. In contrast with previously reported data, patients positive and negative for HOX11L2/t(5;14) were comparable with regard to clinical outcome as well as to the response to a 7-day prephase treatment or to residual disease at completion of induction therapy. The 3-year event-free survival (EFS) rate (± SE percentage) for patients positive and negative for HOX11L2/t(5;14) was 75.5% (± 8.1%) and 68.3% (± 5.0%), respectively; the hazard ratio was 0.84 (95% confidence interval, 0.40-1.80). Patients with HOX11-high expression and those with SIL-TAL fusion had low levels of residual disease at the end of induction and a favorable prognosis: the 3-year EFS rate was 83.3% (± 8.5%) and 75.3% (± 12.6%), respectively. The results obtained in HOX11L2/t(5;14) patients in this study do not confirm the unfavorable prognosis reported in previous studies.
Abstract Purpose Many cooperative groups have reported on the chemo-sensitivity of rhabdomyosarcoma (RMS). Doxorubicin has been tested but remains a controversial treatment option. We report here the ...results of the up-front evaluation of the efficacy of doxorubicin in children and adolescents with high-risk metastatic RMS. Patients and methods Patients younger than 18 years of age (>6 months) with newly diagnosed, histologically confirmed high-risk metastatic RMS were required to have measurable disease, to have undergone no prior chemotherapy or radiation therapy and to have normal liver, renal and cardiac function before treatment. Doxorubicin was administered intravenously over 48 h to a total dose of 60 mg/m2 . Two courses were given separated by a 21 day interval. Response to therapy was assessed by diagnostic imaging after the second course. The study was designed as a two-stage procedure according to the multistep plan described by Fleming. Results Twenty patients were eligible for analysis. Median age at diagnosis was 9.8 years (range from 2 to 16). Thirteen of the 20 patients treated in the first step responded to treatment, corresponding to an overall response to doxorubicin of 65% 95% confidence interval (CI), 44–85%. The rates of CR and PR were 5% 95% CI, 0–14% and 60% 95% CI, 39–81%, respectively. Four (20%) patients had progressive disease, corresponding to a progression rate of 20% 95% CI, 2–38%. Conclusion This window study provides the definitive demonstration of the efficacy of doxorubicin in untreated RMS. Given the inconclusive results obtained from previous studies using differing schedules chemotherapy incorporating doxorubicin, the next step should be a randomised study testing dose intensity in high-risk localised RMS. This issue is being addressed in a current European study (EpSSG RMS 2005).
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