The prognosis of patients with relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a ...long-term, follow-up retrospective study to address the outcome of patients with ETV6/RUNX1-positive leukemia relapses.
Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified in the low or intermediate risk groups. The median follow-up after relapse was 54.2 months. All but three received second-line salvage therapy and 16 underwent allogeneic transplantation.
ETV6/RUNX1 had a strong effect on overall survival after relapse (3-year survival= 64.7% for positive cases versus 46.5% for negative cases) (P=0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (P=0.04). In 81.4% of cases the relapses were late, early combined or isolated extramedullary relapses. The 5-year survival rate of patients with ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.8% when the relapse occurred after 36 months (versus 31.2% when the relapse occurred earlier). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome.
We found an excellent outcome for patients with ETV6/RUNX1-positive leukemia relapses that occurred more than 36 months after diagnosis. The duration of first complete remission may, therefore, be a guide to define the treatment strategy for patients with relapsed ETV6/RUNX1- positive leukemia.
Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the ...discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10−4, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 109/L, gHiR classifier, and MRD ≥10−4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 109/L, gLoR classifier, and MRD <10−4 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 109/L, it identifies a significant subgroup of patients with a low risk of relapse.
•In pediatric T-ALL, oncogenetic markers, MRD, and WBC count are independent predictors of outcome.•These factors should be used together for individual treatment stratification.
We explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL) in a study of the effect of early features on prognosis in children. Here we report the ...long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors.
Between 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling.
Complete remission (CR) was observed in 26 children (72%), of which 13 underwent allogeneic bone marrow transplantation (BMT). Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1). Overall five-year disease-free survival (DFS) was 42 +/- 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age<10, leukocyte count <100,000/mm3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival EFS: 57%, overall survival OS: 79%), than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27%) (p < 0.005). We also observed a non statistically significant difference (p = 0.14) in outcome between these groups for transplanted patients (5-year DFS: 83 +/- 14% and 33 +/- 15%, respectively).
Age, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.
Summary
Childhood autoimmune haemolytic anaemia (AIHA) requires second‐line immunosuppressive therapy in 30–50% of cases. It appears that rituximab is indicated in such circumstances. This ...prospective national study reports the practice, efficacy and tolerance of rituximab in children with isolated AIHA and AIHA in the setting of Evans syndrome (ES). Sixty‐one children were given rituximab between 2000 and 2014. The median interval from diagnosis to rituximab was 9·9 interquartile range (IQR) 1·6–28·5 months. Forty‐six patients responded (75%) and the 6‐year relapse‐free survival (RFS) was 48%. Twenty patients relapsed at a median interval of 10·8 (IQR 3·9–18·7) months, rituximab allowed steroid withdrawal in 44/61 (72%) of children. In isolated AIHA, complete response and 6‐year RFS were significantly higher than in ES (P < 0·05). Ten out of 61 patients were infants, seven of who responded with a 6‐year RFS of 71%. Among patients without immunoglobulin substitution before rituximab, 4 are still receiving substitutions. Five patients died, including one potentially attributable to rituximab. This large observational series of childhood AIHA established the rituximab benefit‐risk ratio, allowing steroid withdrawal, with 37% of long‐term responders, mainly in isolated AIHA. All subgroups of patients drew benefit. Our long‐term results indicate the baseline to be challenged by new treatment approaches.
Abstract Purpose To examine whether three cycles of a low-intensity chemotherapy consisting of cyclophosphamide 500 mg/m2 – day 1, vinblastine 6 mg/m2 – days 1 and 8 and prednisolone 40 mg/m2 – days ...1–7 (CVP) is safe and therapeutically effective in children and adolescents with early stage nodular lymphocyte predominant Hodgkin lymphoma nLPHL. Patients and methods Fifty-five children and adolescents with early stage nLPHL median age 13 years, range 4–17 years diagnosed between June 2005 and October 2010 in the UK and France are the subjects of this report. Staging investigations included conventional cross sectional as well as 18 fluro-deoxyglucose FDG PET imaging. Histology was confirmed as nLPHL by an expert pathology panel. Results Of the 45 patients, who received CVP as first line treatment, 36 80%, 95% Confidence Interval CI: (68; 92) either achieved a complete remission CR or CR unconfirmed CRu, the remaining nine patients achieved a partial response. All nine subsequently achieved CR with salvage chemotherapy n = 7 or radiotherapy n = 2. Ten patients received CVP at relapse after primary treatment that consisted of surgery alone and all achieved CR. To date, only three patients have relapsed after CVP chemotherapy and all had received CVP as first line treatment at initial diagnosis. The 40-month freedom from treatment failure and overall survival for the entire cohort were 75.4% (SE ± 6%) and 100%, respectively. No significant early toxicity was observed. Conclusions Our results show that CVP is an effective chemotherapy regimen in children and adolescents with early stage nLPHL that is well tolerated with minimal acute toxicity.
In many countries, nitrous oxide is used in a gas mixture (EMONO) for short-term analgesia. Cases of addiction, with significant misuse, have been reported in hospitalized patients. Patients ...suffering from sickle cell disease (SCD) could represent a high-risk population for substance use disorder (SUD) due to their significant pain crisis and repeated use of EMONO. The objective of the PHEDRE study was to assess the prevalence of SUD for EMONO in French SCD patients.
A total of 993 patients were included. Among 339 EMONO consumers, only 38 (11%) had a SUD, with very few criteria, corresponding mainly to a mild SUD due to a use higher than expected (in quantity or duration) and relational tensions with the care teams. Almost all patients (99.7%) were looking for an analgesic effect, but 68% of patients were also looking for other effects. The independent risks factors associated with at least one SUD criterion were: the feeling of effects different from the expected therapeutic effects of EMONO, at least one hospitalization for vaso occlusive crisis in the past 12 months and the presence of a SUD for at least one other analgesic drug.
The use of EMONO was not problematic for the majority of patients. Manifestations of SUD that led to tensions with healthcare teams should alert and lead to an evaluation, to distinguish a true addiction from a pseudoaddiction which may be linked to an insufficient analgesic treatment related to an underestimation of pain in SCD patients.
Clinical Trials, NCT02580565. Registered 16 October 2015, https://clinicaltrials.gov/.
Morbidity and mortality are high in young children with medulloblastoma who receive craniospinal radiotherapy. We aimed to assess whether adjuvant treatment with protracted chemotherapy alone could ...replace radiotherapy.
We enrolled 79 children aged younger than 5 years who had had surgical resection of medulloblastoma onto a multicentre trial. Patients were treated with combination chemotherapy, which did not include methotrexate, for more than 16 months irrespective of the extent of disease. Early postoperative imaging defined three groups: R0M0 (no residual disease, no metastasis), R1M0 (radiological residual disease alone), and RXM+ (presence of metastases). Patients who did not relapse did not receive radiotherapy. Patients who relapsed or had disease progression received salvage treatment, which consisted of high-dose chemotherapy and stem-cell transplantation followed by local or craniospinal radiotherapy. For children classified as R0M0, the primary endpoint was 5-year overall survival and the secondary endpoint was 5-year progression-free survival. For children classified as R1M0 or RXM+, the primary endpoint was best radiological response and the secondary endpoints were 5-year overall survival and 5-year progression-free survival. Analyses were done by intention to treat.
Two of 15 patients classified as RXM+ and four of 17 patients classified as R1M0 had a complete radiological response. 5-year progression-free survival was 29% (95% CI 18–44) in the R0M0 group, 6% (1–27) in the R1M0 group, and 13% (4–38) in the RXM+ group. 5-year overall survival was 73% (59–84) in the R0M0 group, 41% (22–64) in the R1M0 group, and 13% (4–38) in the RXM+ group. In the R0M0 group, 5-year progression-free survival was 41% (26–58) for the 34 patients who underwent gross total resection compared with 0% for the 13 patients who had subtotal resection (relative risk 2·7 1·3–5·6, p=0·0065).
Conventional chemotherapy alone can be used to cure children with non-metastatic medulloblastoma who have gross total resection confirmed by early radiological assessment, but is not sufficient for treatment of those with metastatic or incompletely resected medulloblastoma. Salvage treatment followed by posterior-fossa radiotherapy can effectively treat local relapses or progression.
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.