Summary
There is little data available regarding children and adolescents with Hodgkin lymphoma (HL) who relapse after combined‐modality treatment, even though they have a substantial chance of cure. ...The purpose of this national retrospective study was to evaluate the outcome of patients with recurrent/refractory HL and determine adverse prognostic factors. From 1990 to 2006, 70 patients (median age 13·9 years) with refractory (n = 31) or first relapse (n = 39) HL were identified. Median time from end of treatment to relapse was 6 months (3–56). Relapses occurred in irradiated areas in 43/70 patients. Salvage therapy consisted of chemotherapy and 50 patients received high‐dose chemotherapy with autologous stem cell transplantation. Radiotherapy was performed in 29 cases, tandem autologous transplantation in five and allograft in three. With a median follow‐up of 40 months (2–140), significant prognostic factors were time to progression/relapse and response to therapy before autograft. Event‐free survival and overall survival in patients with refractory disease, early relapse and late relapse were 35 ± 9%, 67 ± 11%, 76 ± 10% and 48 ± 11%, 89 ± 7% and 80 ± 10%, respectively. As progression <3 months was a major adverse prognostic factor, novel therapeutic approaches are needed for this group of patients. By contrast, patients have substantial chance of long term second remission in case of relapse >3 months.
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.
From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This ...intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60+/-4 and 48+/-4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52+/-4% for non-allografted patients and 57+/-7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT-) than in patients randomized for MT (77.6+/-8 vs 59+/-8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.
Ecthyma gangrenosum is characterized by necrotic ulcerations surrounded by an erythematous halo. It is secondary to Pseudomonas aeruginosa infection. Most lesions are located in the anogenital and ...axillary areas, but the route of infection is generally difficult to establish.
We report six children with perineal ecthyma gangrenosum and discuss predisposing factors, origin, and route of infection.
This was a retrospective clinical study.
Three children had blood cultures positive for P. aeruginosa, and one died. Predisposing factors were present in all cases; two had received chemotherapy (neuroblastoma, acute lymphoblastic leukemia), and two had idiopathic granulocytopenia. The last two patients previously had received treatment with systemic antibiotics and had abnormal granulocyte killing several months later.
Septicemic ecthyma gangrenosum can be rapidly fatal in young children and requires aggressive antibiotic therapy. Benign ecthyma gangrenosum in healthy infants may result from a modification of bowel microflora after antibiotic therapy in conjunction with maceration in the diaper area. However, careful evaluation and long-term follow-up must be done to detect neutropenia, functional abnormalities of granulocytes, or a possible immune deficiency.
Abstract 1508
The long term prognosis of ETV6/RUNX1 -positive acute lymphoblastic leukemia (ALL) remains to be evaluated with regard to the frequency of late relapses and the possible existence of a ...preleukemic stem cell. We performed a retrospective study based on a long-term follow up of the FRALLE 93 ALL relapses to address the issue of the outcome of ETV6/RUNX1 -positive ones.
1395 patients aged 0 to 20 years with untreated ALL (except L3) were included between 01-Jan-1993 and 31-Dec-1999. From 1995, children were systematically screened for four fusion transcripts (ETV6-RUNX1, BCR-ABL, E2A-PBX1, MLL-AF4). The FRALLE 93 study population was stratified into three groups (low-risk LR, intermediate-risk IR, and high-risk HR) based on the following prognostic factors: age, white-cell count at diagnosis, haemoglobin level, immunophenotype, karyotype, and response to steroids. Patients received an initial treatment comprised of a prednisone prophase and a triple-drug intrathecal injection. Induction treatment then included prednisone, vincristine, L-asparaginase, daunorubicin (except for the LR group), and one or two more triple-drug intrathecal injections (TIT). The main treatment features of the SR and IR protocol were induction, consolidation, delayed intensification, and maintenance (total treatment duration of 26 and 38 months for girls and boys respectively). Treatment of the HR patients consisted of induction, consolidation, two delayed intensifications, and maintenance with a total treatment time of 2 years. Depending on subgroups, CNS-directed therapy included intrathecal injections +/− high-dose methotrexate +/− cranial irradiation. Following factors influencing survival after first relapse were analyzed: age, leukocytosis, gender, duration of first remission (CR1), risk groups defined in the REZ-BFM 95/96 study, sites of relapse and post CR2 consolidation treatment (AlloSCT or not).
Results. ETV6/RUNX1 status was defined for 724 patients B lineage ALL. Overall, 162 of the 713 children who reached CR1 (45 % of boys) relapsed, including 43 with t(12;21). Cumulative incidence of relapses did not differ between ETV6/RUNX1 -positive and negative ALL (p=0.94), with a 5-year estimate at 19.4% and 19.9%, respectively nor according to gender and type of relapse. Nevertheless, 11 out of 26 relapses in the ETV6/RUNX1 -positive ALL males (43%) were testicular (4 testis isolated) versus 16 out of 70 (23%) in ETV6/RUNX1 -negative ALL cases (p= 0.04). Thirty three (77%) had been stratified as LR (n=6) or IR (n=27) group and 32 displayed good early response at initial diagnosis. Thirty five (81.4%) patients were classified as S1/S2 and 8 (18.6%) as S3/S4. All but three received second line salvage therapy (37/40 were included in the COOPRALL 97) and 16 underwent an AlloSCT (6 S3/S4). Based on univariate analyses, the overall survival of ETV6-RUNX1 -positive ALL after relapse was significantly affected by the duration of the first remission with a OS that was significantly improved when relapse occurred after 36 months (5-year OS: 80.6+/−7.9% versus 34.7+/− 12.3, p=0.002). Female gender was also associated with a poor survival (p= 0.015), whereas the site of relapse (p= 0.13), age at initial diagnosis (p= 0.81), leukocytosis (p=0.42), and consolidation strategy (p=0.18) had no affect on survival. In multivariate Cox-regression analysis, only the duration of first remission remained associated with the outcome (Figure 1).
We found a high rate of testicular relapse without any increase of other extramedullary sites and an excellent outcome for ETV6/RUNX1 -positive leukemia relapses occurring over 36 months post-diagnosis. These findings highlight the interest of a primary treatment able to cross the testicular barrier. They also support the hypothesis that ETV6/RUNX1 “late relapses” are due to a novel leukemic clone, sensitive to a novel cycle of ALL chemotherapy. Display omitted
No relevant conflicts of interest to declare.
Abstract▪2227▪This icon denotes a clinically relevant abstract
While splenectomy is the gold standard treatment for adult's refractory primary immune thrombocytopenia (ITP), its place remains debated ...in children. The Rare Disease Plan gave us the opportunity to conduct a French collaborative work aiming to study efficiency, tolerance and prognostic factors associated with success of this procedure in childhood ITP.
A retrospective study was conducted in France, of less than 18 years old children and adolescents who underwent a splenectomy for ITP during a 9-year period (2000–2009). Data from both the CEREVANCE national cohort and systematic requests to 30 paediatric units were reviewed. Medical data and procedures were checked from patients’ medical records. Complete remission (CR) was defined by platelet count of more than 100 G/L, continuous complete remission (CCR) was defined as CR with no relapse or treatment for at least one year (Aladjidi et al, Haematologica 2011). Relapse-free survival was assessed by Kaplan Meier method.
For 78 children in 16 units, the median ages at diagnosis of ITP and at splenectomy were respectively 9.6 (0.8–16.5) and 12.4 (3.5–17.4) years. The median duration of ITP before splenectomy was 24 months (1–162), 62 children had chronic ITP of more than 12 months duration. The surgical procedure was laparoscopy in 81% of children. Four patients experienced post-operative complications: 1 severe intra-abdominal hemorrhage requiring open surgery twelve hours after laparoscopy, 1 pleural and peritoneal hemorrhage after laparotomy, 1 mesenteric and splenic thrombosis and 1 pulmonary atelectasia. With a median follow up of 41 months (1–109), CR and CCR were achieved respectively for 83% and 75% of 62 children with chronic ITP. No overwhelming sepsis was reported during the follow-up. Isotopic platelet studies were available in 10 of the 16 units and assessed in 30 of the 44 concerned children. CR was obtained in 77% of 26 cases with predominant splenic destruction, and in 0% of 2 cases with non splenic destruction. Five-year relapse-free survival was 35% in children of less than 10 years old and 81% in children of more than 10 years old at initial diagnosis of ITP (p=0.0002).
This collaborative national study confirms the excellent benefit-risk ratio of splenectomy for refractory chronic ITP, especially in older children. Even if our own results are limited by the small number of patients, prior isotopic platelet studies is useful when locally available. Long term respect of anti-infectious measures is recommended.
Acknoledgements to the Association Française pour le Syndrome d’Evans (AFSE), the GIS - Institut des Maladies Rares - INSERM, and the French Health Ministry (Programme Hospitalier de Recherche Clinique 2005, Rare Diseases Plan 2007).
No relevant conflicts of interest to declare.
Abstract▪2100▪This icon denotes a clinically relevant abstract
Autoimmune hemolytic anemia (AIHA) in children is in more than half cases characterized by a severe course, with prolonged need of ...immunosuppressive therapy. Rituximab is a chimeric anti-CD20 monoclonal antibody increasingly used for treating severe autoimmune diseases. Paediatric experience in AIHA is only made of case reports and short series. The Rare Disease Plan gave us the opportunity to conduct national studies on those rare pediatric diseases.
At the end point of August 1, 2011, data from the CEREVANCE French national prospective cohort of auto-immune cytopenia were extracted, and a retrospective study of children who underwent rituximab for isolated AIHA was conducted. Patients with post bone marrow transplantation AIHA or underlying characterised primitive immune deficiency were excluded. Medical data and procedures were checked from patients' medical records. Complete remission (CR) was defined by haemoglobin count of more than 11 g/dL and reticulocytes count of less than 120 G/L, continuous complete remission (CCR) was defined as CR with no relapse or treatment for at least one year (Aladjidi et al, Haematologica 2011). Efficiency, safety and immunologic tests were evaluated after therapy.
Rituximab was administered in 42 children with isolated AIHA between 1999 and 2010. Associated immunologic disorders were noticed in 16 children before AIHA or during the follow-up. The median age at rituximab initiation was 5.4 years (0.1 to 17.5), with 15 children being younger than 2. The median duration of AIHA before rituximab was 6.2 months (0.1 to 74). The number of lines of treatments before rituximab varied from 1 (steroids alone for 23 children) to 5. Nineteen children received 4 weekly doses of 375 mg/m2, 6 received less than 4 courses and 7 received more than 4 courses (6 to 12). Rituximab allowed CR obtention in 85% of evaluable children, and all immunosuppressive treatment cessation in 67%. For failure or relapse, 21 children required 1 to 3 further lines of treatments. Systematic intravenous immunoglobulin (IVIg) substitution was administered in 55% of children, for a median duration of 18 months (1–140). Rituximab was well tolerated and severe neutropenia with sepsis happened in one child 6 months after rituximab. With a median follow-up of 3.6 years (0.2 to 11.3) after rituximab treatment, 22 children were in CCR, 7 children were in CR without treatment, 10 children were in CR with continuous treatment, 2 children were not in remission, 1 child died from associated giant cell hepatitis. Six children still required IgIV substitution at the last follow up, mainly younger and heavily treated children.
Comparisons with rituximab efficiency and tolerance in chronic ITP and in AIHA/Evans syndrome are available from this national cohort.
This collaborative national study confirms the excellent benefit-risk ratio of rituximab for childhood refractory AIHA. Early introduction could allow avoiding prolonged steroid treatments. However, the benefit of more than 4 courses was not demonstrated in this cohort. AIHA and chronic ITP are different diseases: the prolonged IVIg substitution required in 14% of children imposes to carefully search prior underlying immune deficiency before beginning an anti-CD20 treatment.
Acknowledgments to the Association Française pour le Syndrome d’Evans (AFSE), the GIS-Institut des Maladies Rares-INSERM, and the French Health Ministry (Programme Hospitalier de Recherche Clinique 2005, Rare Diseases Plan 2007).
No relevant conflicts of interest to declare.
Abstract 3017
Poster Board II-993
Autoimmune haemolytic anemia (AIHA) of children is a rare and severe condition. Early retrospective series provided the first descriptions, but knowledge is still ...less than satisfactory. Under a national clinical and biological network, the French Society of Hematology and Immunology (SHIP), in partnership with families (AFSE), conducted from 2004 an observational study of non selected children with AIHA. The aim was to refine epidemiological, clinical and biological data and to identify putative prognostic factors.
Parents gave written informed consent for anonymous data collection. Inclusion criteria were age <18, hemoglobin <11 g/dl, positive Coombs test and haemolysis. Standardized work-up was proposed at initial diagnosis. ES was defined by the synchrone or metachrone association of AIHA and ITP, whatever underlying context was. Dysimmunity was defined by immune deficiency, autoimmune disease, ES or miscellaneousmanifestations. A subclassification heeding familial and personal dysimmunity was proposed. Treatments were prospectively registered. Status of the disease was described as non response (NR), partial response (PR), complete response (CR), and continuous complete response without specific treatment for more than one year (CCR). Kaplan-Meyer method was applied to estimate survival rates in CCR. Potential prognostic variables were assessed using a Cox model. The first 268 patients are described.
The first 268 children of this cohort, whose AIHA was diagnosed between 1986 and 2007, are described. For the 2003-2007 period, the number of new diagnosis per year ranged from 15 to 35. Median age at diagnosis was 3.8 years. Median hemoglobin level on the first blood count was 6 g/dl. Coombs test was of IgG/IgG+C3b type in 75% of cases. Consanguinity was reported in 8%, first degree familial dysimmunity in 12%, prematurity in 9% of cases. For 53 children, AIHA initial diagnosis was concomitant to a documented infection, mainly EBV (n=11), mycoplasma (n=9), parvovirus (n=6), CMV (n=6). Dysimmunity preceded AIHA in 22% of children, and was diagnosed from the diagnosis of AIHA or in the follow-up in 45% of children. ES was diagnosed in 101 children (37%) : AIHA/ES and isolated AIHA without ITP presentation and outcome significantly differed. In the end of the follow up, all 268 AIHA were subclassified in purely post-infectious in 10%, dysimmune in 52% of cases and primitive in 38%. 92% of children received steroids as first-line therapy.In the end of the first month of disease, CR was obtained for 57% of children. Steroid resistance or high level of steroid dependence led 49% of treated children to receive a median number of 2 (1 to 7) further multimodal therapy, for a median period time of 1.2 years (0 to 21.3). With a 3 year (0.1–21.2) median follow-up, 4% of children died, 30% of alive children were treatment dependant, and AIHA was in PR in 6%, in CR in 50% and in CCR in 40% of cases. In multivariate analysis, Coombs test of IgG/IgG+C3b type was of pejorative value on CCR survival (figure 1).
The present nationwide French cohort is the first large prospective study of non selected children with AIHA reported so far. Heterogeneity of the disease is highlighted, and urge for the need of an etiologic classification dissociating isolated AIHA from AIHA/ES, and the subgroup of AIHA with immune genetic predisposition. Regarding outcome, the only independant prognostic factor is Coombs test type. Chronic course of the disease is not a rare event and warants long term multidisciplinary follow-up. Therapeutic trials should now focus on risk-adjusted sparing steroids and quality of life.
Display omitted
No relevant conflicts of interest to declare.
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