Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive ...long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IM). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 years (range, 6.8-50.0 years) and the median follow-up period was 11.3 years (range, 5.1-38.0 years). At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM). A wide range of cIM occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IM. The number of cIM was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio 1.4, 95% Confidence Interval: 1.15-1.60, P=0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 years (range, 1.7-31.5 years), and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, long-term outcomes of pES showed remission of cytopenias but frequent IM linked to high second-line treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French ...patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.
Abstract BACKGROUND High Risk medulloblastoma (MB) treatment strategy is based on an intensive multimodal treatment including surgery, chemotherapy and radiotherapy. French adapted PNET HR +5 is ...based on high-dose chemotherapy and age-stratified (18 Gy < 3 yo, 23 for 3-5 yo, 36 Gy for > 5 yo) craniospinal dose irradiation to reduce long-term side-effects of radiotherapy. METHODS To estimate progression-free (PFS) in a national multi-institutional retrospective study, we enrolled children younger than 5 yo with newly diagnosed high-risk MB treated according to adapted PNET HR +5 trial. RESULTS Thirty-seven children from 15 French hospitals (median age, 3.4 yo; range, 0.7-4.8) with confirmed high-risk MB were included. 15 patients (39%) were less than 3 years old. 29 patients (81%) had metastatic disease. Group 3 was the most represented molecular subgroup. 5-year PFS and OS was 59 % and 77 %, respectively. According to dose of craniospinal irradiation, PFS for 18 Gy, 23.4 Gy and 36 Gy patient groups were 100 %, 75 % and 45%, respectively. Treatment was well tolerated. One toxic death was declared. Analysis of longitudinal neurocognitive performance is ongoing. CONCLUSIONS the French strategy comprising high-dose chemotherapy and age-adapted craniospinal irradiation is promising with a high rate of survival in young children and must be confirmed by a prospective trial.
Abstract
Splenectomy is effective in ∼70% to 80% of pediatric chronic immune thrombocytopenia (cITP) cases, and few data exist about it in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). ...Because of the irreversibility of the procedure and the lack of predictions regarding long-term outcomes, the decision to undertake splenectomy is difficult in children. We report here factors associated with splenectomy outcomes from the OBS’CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP, n = 120; AIHA, n = 19; ES, n = 22) with a median (minimum-maximum) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio HR, 0.39; 95% confidence interval CI, 0.21-0.72, P = .003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR, 0.22; 95% CI, 0.12-0.39; P = 2.8 × 10−7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes.
Abstract
Acute Lymphoblastic Leukemia (ALL) is the main neoplastic disease in children. Treatment is based on chemotherapy associated or not to bone marrow transplantation. The 5-year survival rate ...in European children is reported as 86% but long term survival data are not available. We investigated the 20 year Overall Survival (OS) and Net survival (NS) of the patients diagnosed in the population of the Côte d'Or area in France. 162 cases were diagnosed in the population of the Côte d'Or area between 1970 and 2015. Cases diagnosed between 1970 and 1979 (n=29) were not formally registered in the registry database but data were available through the unique regional, reference hematology laboratory. All cases were followed until 01 01 2017. The treatment regimens that were used were as follows in chronological order (from the earliest to the most recent); LAL 76 and 80; the FRALLE 83, 87 and 89 until 1993; the FRALLE 93 from 1993 to 2001 and then the FRALLE 2000. The 20-y OS and NS of ALL was respectively 66% and 67%. It was 59% in boys but 75% in girls (p=0.04). No statistical difference was found according to age. According to lineage subtype, the 20-y NS was 82% in B-ALL, 65% in T-ALL and 34% in ALL, not otherwise specified (p<0.001). According to treatment regimen, the 20-y-NS was 51% before the use of the FRALLE 93, compared to 71% for cases treated by the FRALLE 93 regimen and 95% for those treated with the FRALLE 2000 regimen (p<0.001). The survival was 95% irrespective of the time of diagnosis following introduction of the FRALLE 2000 regimen. Data on long term survival of ALL in children are scarce. Our results show 1) a very high 20 year survival rate indicating the efficacy and safety of the treatment regimens used, 2) the utility of randomized clinical trials to define new standards of care.
Citation Format: Sophie Gauthier, Morgane Mounier, Stéphanie Girard, Claire Briandet, Paule Marie Carli, Marc Maynadie. Long-term survival of children with acute lymphoblastic leukemia, according to treatment regimen, in a regional French population abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1205.
Abstract Purpose: The study of cell-free DNA (cfDNA) enables sequential analysis of tumor cell–specific genetic alterations in patients with neuroblastoma. Experimental Design: Eighteen patients with ...relapsing neuroblastoma having received lorlatinib, a third-generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for nine patients and sequentially for five patients (blood/bone marrow plasma) by performing whole-genome sequencing library construction followed by ALK-targeted ddPCR of the hotspot mutations F1174L, R1275Q, and I1170N; variant allele fraction (VAF) detection limit 0.1% and whole-exome sequencing (WES) to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES. Results: Overall response rate to lorlatinib was 33% (CI, 13%–59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF < 0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples. Conclusions: We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in patients with neuroblastoma receiving ALK-targeted therapy.
•SLE occurs in 22% of children with ANA-associated AIC.•Children of age >10 years and ANA titer >1/160 must be monitored long-term, for progression to SLE.
Display omitted
Autoimmune cytopenia (AIC) ...in children may be associated with positive antinuclear antibodies (ANA) and may progress to systemic lupus erythematosus (SLE). We evaluated the risk of progression to SLE of childhood-onset ANA-associated AIC. In the French national prospective OBS’CEREVANCE cohort, the long-term outcome of children with ANA-associated AIC (ANA titer ≥1/160) and a subgroup of children who developed SLE were described. ANA were positive in 355 of 1803 (20%) children with AIC. With a median follow-up of 5.8 (range, 0.1-29.6) years, 79 of 355 (22%) patients developed SLE at a median age of 14.5 (1.1-21.4) years; 20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome. None of the patients with ANA-negative test developed SLE. Severe manifestations of SLE were observed in 21 patients, and 2 patients died. In multivariate analysis including patients with positive ANA within the first 3 months after AIC diagnosis, age >10 years at AIC diagnosis (relative risk RR, 3.67; 95% confidence interval CI, 1.18-11.4; P = .024) and ANA titer >1/160 (RR, 5.28; 95% CI, 1.20-23.17; P = .027) were associated with the occurrence of SLE after AIC diagnosis. ANA-associated AIC is a risk factor for progression to SLE, especially in children with an initial ANA titer >1/160 and an age >10 years at AIC diagnosis. ANA screening should be recommended in children with AIC, and patients with ANA should be monitored long-term for SLE, with special attention to the transition period. This trial was registered at www.ClinicalTrials.gov as #NCT05937828.
A minority of patients presenting as children with chronic autoimmune cytopenia (AIC), manifesting as immune thrombocytopenic purpura or autoimmune hemolytic anemia, will subsequently develop systemic lupus erythematosus (SLE), but which ones? In a prospective cohort study, Granel and colleagues identified a 22% incidence rate of SLE after diagnosis of AIC if the antinuclear antibody (ANA) was ever positive, with the highest risk in children diagnosed after 10 years of age and where the ANA titer exceeded 160. The authors’ work identified a subgroup of patients needing long-term monitoring for later emergence of SLE.
Objective
To describe characteristics and outcome of pediatric ovarian immature teratomas (IT) to better define the place of chemotherapy.
Methods
Children with ovarian IT enrolled in TGM95 and ...TGM2013 studies were analyzed. Norris grading and International Federation of Gynecology and Obstetrics staging system were used.
Results
Thirty‐six cases were identified with a median age of 11 years (range = 1‐18): 35 of 36 stage I (17 stage IA, 13 stage IC, and 5 stage IX), including seven patients with gliomatosis peritonei (GP), and 1 stage IIIB (IT peritoneal implants). Centrally reviewed Norris grading was performed in 31 cases: 14 grade I and 17 grade II/III tumors. All patients underwent upfront surgery: 19 unilateral oophorectomy, 14 unilateral adnexectomy, 2 unilateral cystectomy, and 1 bilateral cystectomy. No extensive GP surgery was performed. Six patients received adjuvant vinblastin, bleomycin, and cisplatinum because of tumor rupture (n = 5, including two patients with GP) or stage III (n = 1). After a median follow‐up of 39.5 months (range = 6‐238), two events occurred 10 and 11 months after diagnosis: one bilateralization (initial stage IX, grade I) and one IT peritoneal relapse (initial stage IA, grade II), respectively. Both were successfully rescued by platinum‐based chemotherapy and delayed surgery. No stage IC patients treated without adjuvant chemotherapy relapsed (four grade I and three grade III). None of the seven patients with GP progressed. Five‐year event‐free survival and overall survival were 94% (95% CI = 81‐98%) and 100%.
Conclusions
The current series confirms the excellent prognosis of pediatric ovarian IT, arguing for conservative surgical approach in GP and against systematic adjuvant chemotherapy, even in ruptured tumors.
PDF
