Sandrine Girard

NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951

Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH+ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH+ patients showed a better early response to chemotherapy as compared with NOTCH− patients, according to the rate of poor pre-phase ‘responders’ (25% versus 44%; P=0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P=0.01) at completion of induction. However, the outcome of NOTCH+ patients was similar to that of NOTCH− patients, with a 5-year event-free survival (EFS) of 73% and 70% (P=0.82), and 5-year overall survival of 82% and 79% (P=0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH+) versus 42% (NOTCH−), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH+) versus 78% (NOTCH−). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1+ patients (8.3%), which could be related to a higher propensity of NOTCH+ leukemic blasts to target the CNS.

Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30×109/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.

An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions.

Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk stratification. However, a significant number of BCP-ALL patients are still genetically unassigned. Using array-comparative genomic hybridization in a selected BCP-ALL cohort, we characterized a recurrent V(D)J-mediated intragenic deletion of the ERG gene (ERGdel). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1–17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERGdel was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERGdel was associated with higher age (median 7.0 vs 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs 3.7%, P<0.001) and frequent IKZF1 Δ4-7 deletions (37.9% vs 5.3%, P<0.001). However, ERGdel patients had a very good outcome, with an 8-year event-free survival (8-y EFS) and an 8-year overall survival of 86.4% and 95.6%, respectively, suggesting that the IKZF1 deletion had no impact on prognosis in this genetic subtype. Accordingly, within patients with an IKZF1 Δ4-7 deletion, those with ERGdel had a better outcome (8-y EFS: 85.7% vs 51.3%; hazard ratio: 0.16; 95% confidence interval: 0.02–1.20; P=0.04). These findings have implications for further stratification including IKZF1 status.

Clinical presentation, evolution, and prognosis of precursor B-cell lymphoblastic lymphoma in trials LMT96, EORTC 58881, and EORTC 58951

In children, lymphoblastic lymphomas represent 30% of Non‐Hodgkin lymphomas (NHL), and approximately 15% are precursor B‐cell lymphomas (PBLL). Our study evaluated their main clinical characteristics, evolution, and prognosis in three trials. From 1989 to 2008, 53 children with PBLL (median age 7·75 years) were included in three protocols: Malignant Lymphoma Therapy (LMT) 96, European Organization for Research and Treatment of Cancer (EORTC) 58881, and EORTC 58951 using Berlin‐Frankfürt‐Münster‐derived acute lymphoblastic leukaemia (ALL) therapy. There were 10 stage I disease, 9 stage II, 9 stage III and 25 stage IV. Clinical presentation was heterogeneous with a majority of bone lesions and cutaneous or subcutaneous manifestations. At diagnosis 23 patients had bone marrow involvement, and only three had central nervous system involvement. The median follow‐up was 74 months. At last follow‐up, 45 patients were in continuous complete remission, whereas eight had progressed or had relapsed (7 Stages IV and 1 Stage III) and died. Two patients had a secondary neoplasia, and are still alive. Disease stage was a major prognostic factor, with better overall survival (OS) and event‐free survival (EFS) (P < 0·05) rates observed in patients with Stage I to III as compared to those with Stage IV. Treatment with protocols derived from ALL therapy are efficient with an 82% EFS and an 85% OS at 5 years.

Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial.

Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this “superiority” of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m2/day) to prednisolone (60 mg/m2/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3–4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m2/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results.

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) Childrens 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.

IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951

The added value of IKZF1 gene deletion (IKZF1del) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1del in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1del had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75–3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1del remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1del increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19–5.55; P=0.013) and in ‘B-other‘ ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45–3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1del-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3–99.0 versus 42.1; 95% CI=20.4–62.5). Thus, IKZF1del retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in ‘B-other‘ ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1del patients in preventing relapses.

La maladie de Biermer : une cause possible d'anémie microcytaire chez l'adolescent

Resume Nous rapportons l’observation d’un adolescent qui s’est presente avec un tableau d’anemie microcytaire ferriprive. La gastroscopie a retrouve une gastrite atrophique fundique, orientant vers une entite rare en pediatrie : la maladie de Biermer ou anemie pernicieuse. Sur le plan hematologique, l’anemie est classiquement macrocytaire. La forme microcytaire ferriprive est decrite principalement chez les sujets jeunes.

Hemophagocytic Syndrome Revealing Primary HHV-6 Infection

Figure. Bone marrow smears during hemophagocytic syndrome concurrent to HHV-6 primary infection. A, Hemophagocytosis of 7 red blood cells into a single macrophage. B, Activated macrophages and lymphocytes destroying red blood cells (lymphohistiocytosis). O n day 7 after a course of vincristin-actinomycin for bilateral nephroblastomatosis, a 14-monthold girl with Wiedemann-Beckwith syndrome presented at our hospital with pyrexia, asthenia, and hepatomegaly. She had severe pancytopenia (hemoglobin, 58 g/L; lymphopenia, 1.7 g/L; thrombocytopenia, 21 g/L), but she also had acute hepatic insufficiency (prothrombin time, 19.8 seconds; factor V, 40%; ALAT, 1922 UI/L; ASAT, 3327 UI/L; LDH, 7465 UI/L) without cholestasis. She had a high serum ferritin level (1237 mg/L) and low serum triglyceride level (0.75g/L) at admission (2.96 g/L 7 days later). Serum C-reactive protein level was 28 mg/L. Abdominal ultrasound examination found a normal biliary tract and heterogeneous hepatomegaly with moderate ascites but normal Doppler on both portal and sushepatic veins. The suspicion of hemophagocytic syndrome was confirmed on bone marrow smears (Figure). She received transfusion of platelets and red blood cells and methylprednisolone at 1 mg/kg twice a day. Clinical and biological examinations resolved within 48 hours. No septicemia could be documented. Legionella urinary antigens were negative, as was the PCR for search of Mycoplasma pneumoniae. Antigenemia for Cryptococcus was negative. On day 1 of the episode, human herpes virus (HHV)-6 serologies were negative for both immunoglobulin (Ig)M and IgG. On day 3, PCR HHV6 was positive, whereas IgM was negative and IgG positive, with a weak intensity. On day 7, PCR, IgM, and IgG were positive for HHV6. Three weeks later, IgM HHV6 became negative and IgG had a stronger positivity, and PCR was still positive. All other virus searches remained negative (hepatitis A, B, C, E; human immunodeficiency virus; cytomegalovirus; herpes simplex virus; varicella-zoster virus; Epstein-Barr virus; HHV8; parvovirus B19; influenza A, B; rhinoviruses), except for Respiratory Syncytial Virus (positive on PCR and cultures of nasal secretions). Despite the high rate of HHV-6 primary infection in childhood, it is a rare cause of hemophagocytic syndromes in children. n

Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia: results of the EORTC CLG 58881 and 58951 trials

Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia: results of the EORTC CLG 58881 and 58951 trials