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This article describes the survival after childhood acute leukaemia (AL) and non-Hodgkin's lymphoma (NHL) of French population aged less than 15 years. The French National Registry of Childhood Leukaemia and Lymphoma recorded 3995 cases of acute lymphoblastic leukaemia (ALL), 812 of acute myeloid leukaemia (AML) and 1137 of NHL over the period from 1990 to 2000. Overall survival rates at 5 years were 82% (95% CI 80-83), 58% (95% CI 54-61) and 87% (95% CI 85-89) for ALL, AML and NHL, respectively. Survival after AL increased from 77% (95% CI 75-80) in 1990-1992 to 85% (95% CI 83-87) in 1997-2000 for ALL and from 47% (95% CI 41-54) to 61% (95% CI 55-67) for AML. Among AL cases, children aged 1-4 years had the most favourable prognosis. Down's syndrome was associated with poor survival after ALL. No gender-related variations in survival were in evidence. The results reported herein are similar to those reported by other European registries and clinical trials. [ABSTRACT FROM AUTHOR]

Presents information on acute leukemia from citations and notes of clinicians. Treatment for adolescents with acute lymphoblastic leukemia; Multicenter case-control study on myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma; Discussion on gemtuzumab, fludarabine, cytarabine and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes.

Background: The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month., Methods: We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups., Results: Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30-793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4-236]), neutrophils < 2 × 10 9 /L (regression coefficient: 3.9, OR 50 [95%CI: 4.3-58]), and platelets < 300 × 10 9 /L (regression coefficient: 2.6, OR 14 [95%CI: 2.3-83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93-0.99])., Conclusions: Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 10 9 /L or platelets < 300 × 10 9 /L.

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.

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 (ERG(del)). 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. ERG(del) 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. ERG(del) 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, ERG(del) 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 ERG(del) 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.

Background: 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., Design and Methods: 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., Results: 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., Conclusions: 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.

Childhood acute lymphoblastic leukemia is a model in oncology. The outcome was dismal 40 years ago but is now generally excellent, owing to the recent advent of new drugs. These advances were made possible by the creation of specialized units, better supportive care (transfusions, antibiotics and pain control) and intense biological and clinical research coordinated by national and international cooperative groups, allowing the use of available drugs to be optimized. The current aims are to de-escalate treatment for better-defined low-risk groups, and to develop the use of new drugs and targeted therapies for high-risk groups, based on genome-wide analysis of the patient and the leukemic cell.

Background: 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., Methods: 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., Results: 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)., Conclusion: 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.

Background: The prognostic value of the ectopic activation of TLX3 gene expression, a major oncogenetic event associated with pediatric T-cell acute lymphoblastic leukemia, is controversial. Likewise, the frequency and the prognostic significance in pediatric T-cell acute lymphoblastic leukemia of the newly characterized NUP214-ABL1 fusion transcript is not yet clear., Design and Methods: Two hundred children with T-cell acute lymphoblastic leukemia were treated in the French FRALLE-93 study from 1993 to 1999. The expression of TLX3, TLX1 and SILTAL1 genes was analyzed in samples from 92 patients by real-time quantitative reverse transcriptase polymerase chain reaction. Most of these samples were further studied for NUP214-ABL1 and CALM-AF10 fusion transcripts., Results: The median follow-up was 7.9 years. At 5 years the overall survival (+/- standard deviation, %) was 62 (+/-3%) and leukemia-free survival was 58 (+/-3%). Patients with T-cell acute lymphoblastic leukemia positive for TLX3 had a poorer survival compared to those with T-ALL negative for TLX3 (overall survival: 45+/-11% vs. 57+/-5%, p=0.049). In multivariate analysis, TLX3 expression was an independent adverse risk factor predicting relapse with a hazard ratio of 2.44 (p=0.017) and an overall survival with a hazard ratio of 3.7 (p=0.001). NUP214-ABL1 was expressed in 16.6% of patients with TLX3-positive T-ALL (3 of 18); all of the patients with this association died before completion of the treatment. SILTAL expression did not significantly affect the prognosis of patients with T-cell acute lymphoblastic leukemia. Only three of 92 patients expressed the TLX1 gene and all three are alive., Conclusions: TLX3 gene expression is an independent risk factor predicting poor survival in childhood T-cell acute lymphoblastic leukemia. When co-expressed with TLX3, NUP214-ABL1 transcripts may increase the risk of poor survival.

Background: In 2002, a poster alerted the French health authorities to the possibility that the risk of childhood leukaemia might be increased by hepatitis B vaccination. Elucidating the role of vaccination in the aetiology of childhood acute leukaemia (AL) was therefore included in the objectives of an ongoing national study., Methods: The ESCALE study was a French national population-based case-control study conducted in France in 2003 and 2004 in order to investigate the role of infectious, environmental and genetic factors in four childhood neoplastic diseases (leukaemia, lymphoma, neuroblastoma and brain tumour). The controls were randomly selected from the French population and age and gender frequency matched with the cases. A total of 776 cases of AL (91% of the eligible cases) and 1681 controls (71% of the eligible controls) were included. In a specific standardized telephone interview, which was the same for both the cases and controls, each mother was asked to read out her child's complete vaccination record., Results: No association between vaccination and the risk of childhood AL: acute lymphoblastic leukaemia or acute myeloblastic leukaemia was observed. No relationship between the risk of leukaemia and the type of vaccine, number of doses of each vaccine, total number of injections, total number of vaccine doses or number of early vaccinations was evidenced. No confounding factor was observed., Conclusion: The study did not show any evidence of a role of vaccination in the aetiology of childhood leukaemia.

The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)+/-high-dose methotrexate (HD MTX) in children with acute lymphoblastic leukemia (ALL). 1395 children were enrolled on FRALLE 93 protocol from 1993 to 1999. Lower-risk group (LR, n=182) were randomized to weekly low-dose MTX at 25 mg/m(2)/week (LD MTX, n=81) or HD MTX at 1.5 g/m(2)/2 weeks x 6 (n=77). Intermediate-risk group (IR, n=672) were randomized to LD MTX (n=290) or HD MTX at 8 g/m(2)/2 weeks x 4 (n=316). Higher-risk group (HR, n=541) prednisone-responder patients received LD MTX and cranial radiotherapy. HR group steroid resistant cases were grafted (autologous or allogenic). TIT (MTX, cytarabine and methylprednisolone) was given every 2 weeks during 16-18 weeks and every 3 months during maintenance therapy in LR and IR patients. 52 patients (3.7%) developed neurotoxicity. Isolated seizures: n=15 (1.1%), peripheral and spinal neuropathy: n=17 (1.2%) and encephalopathy: n=20 (1.4%). Age >10 years was significantly associated with neurotoxicity (P=0.01) and use of HD MTX is associated with encephalopathy (P=0.03). Sequels are reported respectively in 60 and 33% of spinal neuropathy and encephalopathy cases. Current strategies tailoring risk of neurological sequels has to be defined.

Aim: To analyse the association between potential environmental exposure to hydrocarbons and the risk of acute childhood leukaemia., Methods: A hospital based multicentre case control study, stratified on centre, age, and sex, with 280 leukaemia cases and 285 controls was carried out. Data were collected by a standardised interview of the mothers., Results: No clear association was seen between maternal occupational exposure to hydrocarbons during pregnancy and leukaemia, or between residential traffic density and leukaemia. There was an association between dwellings neighbouring a petrol station or a repair garage during childhood and the risk of childhood leukaemia (OR 4.0, 95% CI 1.5 to 10.3), with a duration trend. The association, which appeared particularly strong for acute non-lymphocytic leukaemia (OR 7.7, 95% CI 1.7 to 34.3), was not altered by adjustment for potential confounding factors., Conclusions: Results showed an association between acute childhood leukaemia and dwellings neighbouring auto repair garages and petrol stations, which are benzene emitting sources. These findings could be due to chance, although the strength of the association and the duration trend are arguments for a causal association.

Additional chromosomal aberrations occur frequently in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) of childhood. The treatment outcome of these patients is heterogeneous. This study assessed whether such clinical heterogeneity could be partially explained by the presence and characteristics of additional chromosomal abnormalities. Cytogenetic descriptions were available for 249 of 326 children with Ph+ ALL, diagnosed and treated by 10 different study groups/large single institutions from 1986 to 1996. Secondary aberrations were present in 61% of the cases. Chromosomes 9, 22, 7, 14, and 8 were most frequently abnormal. Most (93%) karyotypes were unbalanced. Three main cytogenetic subgroups were identified: no secondary aberrations, gain of a second Ph and/or >50 chromosomes, or loss of chromosome 7, 7p, and/or 9p, while other secondary aberrations were grouped as combinations of gain and loss or others. Of the three main cytogenetic subgroups, the loss group had the worst event-free survival (P=0.124) and disease-free survival (P=0.013). However, statistical significance was not maintained when adjusted for other prognostic factors and treatment. Karyotypic analysis is valuable in subsets of patients identified by molecular screening, to assess the role of additional chromosomal abnormalities and their correlation with clinical heterogeneity, with possible therapeutic implications.

The French National Registry of Childhood Leukaemia and Lymphoma (NRCL) covers the whole French mainland population aged less than 15 years (approximately 11 million children) for all childhood haematopoietic tumours since 1 January 1990, except Hodgkin's disease, which has been registered since 1 January 1999. During the period from 1990 to 1999, 5757 cases of leukaemia, lymphoma and myelodysplastic syndrome were registered in the NRCL, with an average of 2.5 sources per case. The age-standardized incidence rates per million per year were 43.1 for leukaemia (34.3 for acute lymphoblastic leukaemia, 7.1 for acute myeloblastic leukaemia, 0.6 for chronic myeloid leukaemia and 0.5 for chronic myelomonocytic leukaemia), 8.9 for non-Hodgkin's lymphomas and 6.7 for Hodgkin's disease. Down's syndrome was present in 110 cases of acute leukaemia (2.5%) and three cases of non-Hodgkin's lymphoma (0.3%). The incidence of acute lymphoblastic leukaemia showed a typical peak at age 2 years for girls and 3 years for boys. The incidence rates of leukaemia and non-Hodgkin's lymphoma did not show any temporal trends over the 10 year period.

Purpose: In a previous randomized study, the authors reported that granulocyte colony-stimulating factor (G-CSF) increased the chemotherapy dose-intensity delivered during the consolidation therapy of high-risk childhood acute lymphoblastic leukemia (ALL). The aim of the current study was to perform an economic evaluation in the same cohort., Methods: In this open-label multicenter randomized trial, prophylactic G-CSF was administered after consolidation therapy courses. Economic data were retrospectively quantified for each patient: hospital stays, drugs, and blood products., Results: Sixty-seven children were enrolled in the very high-risk branch of the FRALLE 93 protocol. Chemotherapy dose-intensity was significantly increased (105 +/- 5% in the G-CSF group vs. 91 +/- 4% in the non-G-CSF group, P < 0.001). The mean total costs per child were not statistically different: 32,309 dollars in the G-CSF group versus 31,569 dollars in the non-G-CSF group. Further analysis per child and per course (R3 or COPADM) demonstrated that the mean cost of hospitalization and the mean cost of intravenous antibiotics were significantly decreased in the G-CSF group after R3 courses (3,857 dollars vs. 4,993.80 dollars, P < 0.001; 171.40 dollars vs. 306.20 dollars, P = 0.029, respectively), but the cost of platelet transfusion was significantly increased (P = 0.03). Conversely, post-COPADM costs were similar. Finally, mean costs per course in the two randomized groups were not significantly different: 5,848.80 dollars versus 6,181 dollars and 7,388.10 dollars versus 6,475.70 dollars for R3 and COPADM, respectively. The 3-year probability of event-free survival between the two groups was not different., Conclusions: G-CSF can increase chemotherapy dose-intensity in very high-risk ALL without raising costs, but event-free survival was not improved. The cost benefit of prophylactic treatment by G-CSF relies on the chemotherapeutic regimen given prior to G-CSF administration.

Purpose: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents., Patients and Methods: From June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving complete remission (CR) and event-free survival (EFS)., Results: Patients were younger in the FRALLE-93 than in the LALA-94 protocol (median age, 15.9 v 17.9 years, respectively), but other characteristics were similar, including median WBC count (18 x 10(9) cells/L v 16 x 10(9) cells/L), B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45 chromosomes: 6% v 5%). The CR rate depended on WBC count (P =.005) and trial (94% v 83% in FRALLE-93 and LALA-94, respectively; P =.04). Univariate analysis showed that unfavorable prognostic factors for EFS were as follows: the trial (estimated 5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P <.0001), an increasing WBC count (P <.0001), poor-risk cytogenetics (P =.005), and T-lineage (P =.01). The trial and WBC count remained significant parameters for EFS in multivariate analysis (P <.0001 and P =.0004). Lineage subgroup analysis showed an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P =.002) and EFS (P =.0002) in B-lineage ALL and for EFS (P =.05) in T-lineage ALL. Age was not a significant prognostic factor in this population of adolescents., Conclusion: This study's findings indicate that adolescents should be included in intensive pediatric protocols and that new trials should be designed, inspired by pediatric protocols, for the treatment of young adults with ALL.

The association between a familial history of autoimmune disease and childhood acute leukemia was investigated in a French case-control study that, overall, was designed to assess the role of perinatal, infectious, environmental, and genetic factors in the etiology of childhood acute leukemia. Familial histories of autoimmune disease in first- and second-degree relatives were compared in 279 incident cases, 240 cases of acute lymphocytic leukemia (ALL) and 39 cases of acute non-lymphoblastic leukemia (ANLL), and 285 controls. Recruitment was frequency matched by age, gender, hospital, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0-2.8) was found. A relationship between thyroid diseases overall and ALL (OR, 2.0; 95% CI, 1.0-3.9) was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave's disease and/or hyperthyroidism and Hashimoto's disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1-10.7 and OR, 5.6; 95% CI, 1.0-31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases (thyroid goiter, thyroid nodule, and unspecified thyroid disorders) (OR, 1.6; 95% CI, 0.7-3.5 and OR, 1.3; 95% CI, 0.2-7.0, respectively, for ALL and ANLL). The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia.

We conducted a case-control study to investigate the role of early infections in the aetiology of childhood acute leukaemias. The study included 280 incident cases (240 acute lymphoblastic leukaemia and 40 acute non-lymphoblastic leukaemia) and 288 hospital controls, frequency matched by age, gender, hospital, catchment area of the hospital and ethnic origin. Data were obtained from standardised face-to-face interviews of the mothers. The interviews included questions on early common infections, day-care attendance, breast-feeding, birth order and infantile diseases. Odds ratios were estimated using an unconditional regression model including the stratification variables, parental socio-economic status and perinatal characteristics. Birth order was not associated with childhood leukaemia (acute lymphoblastic or acute non-lymphoblastic). A statistically-significant inverse association was observed between childhood leukaemia and day-care attendance (odds ratio=0.6, 95% Confidence Interval=(0.4-1.0)), repeated early common infections (> or = 4 per year before age two, odds ratio=0.6 (0.4-1.0)), surgical procedures for ear-nose-throat infections before age two (odds ratio=0.5 (0.2-1.0)) and prolonged breast-feeding (> or = 6 months, odds ratio=0.5 (0.2-1.0)). In the multivariate model including day-care attendance, early common infections and breast-feeding, results concerning breast-feeding remained unchanged. A statistically significant interaction between day-care attendance and repeated early common infections was observed. When the interaction was taken into account, the simple effects of day-care and early common infections disappeared (odds ratio=1.1 (0.5-2.3) and odds ratio=0.8 (0.5-1.3), respectively) while the joint effect of day-care attendance and early common infections was negatively associated with childhood leukaemia (odds ratio=0.3 (0.1-0.8)). All the above associations were observed both for acute lymphoblastic leukaemia and acute non-lymphoblastic leukaemia. Our results support Greaves' hypothesis, even though they are not specific of common leukaemia.

1,120 children were included in protocol FRALLE 93 from june 1993 to september 1998. Disease Free Survival for the all protocol is 78% +/- 3 and overall survival 83% +/- 3. Various clinical and laboratory features at the time of diagnosis have been correlated with prognosis. They provide a potential mean to stratify patients into treatment subgroups according their relative risk of treatment failure. The identification of these prognostic factors has been an essential element in the design of current therapeutic trials. Prognostic characteristics of childhood ALL include: age, white blood cell count, tumor burden, cytogénétics (chromosome count and chromosomal translocation), immunophenotype and early response to treatment. Molecular biology has been the revolution of the last two decades permitting the cloning of the genes involved in the leukemic process. Finally the new molecular techniques allow a sensitive diagnostic approach to minimal residual disease (MRD). The better detection of MRD must allow a more rational basis for therapeutic intensification for a subset of poor responder patients. A decrease in therapy of very good responders can also be envisaged.

Many cutpoints have been proposed to categorize continuous variables in childhood acute lymphoblastic leukaemia (white blood cell count, peripheral blast cell count, haemoglobin level, platelet count and age), and have been used to define therapeutic subgroups. This variation in the choice of cutpoints leads to a bias called the 'Will Rogers phenomenon'. The aim of this study was to analyse variations in the relative risk of relapse or death as a function of continuous prognostic variables in childhood ALL and to discuss the choice of cutpoints. We studied a population of 1545 children with ALL enrolled in three consecutive protocols named FRALLE 83, FRALLE 87 and FRALLE 89. We estimated the risk of relapse or death associated with different values of each continuous prognostic variable by dividing the sample into quintiles of the distribution of the variables. As regards age, a category of children under 1 year of age was distinguished and the rest of the population was divided into quintiles. The floated variance method was used to calculate the confidence interval of each relative risk, including the reference category. The relation between the quantitative prognostic factors and the risk was monotonic for each variable, except for age. For the white blood cell count (WBC), the relation is log linear. The risk associated with WBC values in the upper quintile was 1.9 times higher than that in the lower quintile. The peripheral blast cell count correlated strongly with WBC (correlation coefficient: 0.99). The risk increased with the haemoglobin level, and the risk in the upper quintile was 1.3 times higher than that in the lower quintile. The risk decreased as the platelet count increased: the risk in the lower quintile was 1.2 times higher than that in the upper quintile. The risk increased gradually with increasing age above one year. The small subgroup of patients (2.5% of the population) under 1 year of age at diagnosis had a risk 2.6 times higher than the reference category of patients between 3 and 4.3 years of age. When the risk associated with a quantitative prognostic factor varies monotonously, the selection of a cutpoint is arbitrary and represents a loss of information. Despite this loss of information, such arbitrary categorization may be necessary to define therapeutic stratification. In that case, consensus cutpoints must be defined if one wants to avoid the Will Rogers phenomenon. The cutpoints proposed by the Rome workshop and the NCI are arbitrary, but may represent an acceptable convention., (Copyright 2000 Cancer Research Campaign.)

Purpose: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL)., Patients and Methods: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval)., Results: CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups., Conclusion: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.

We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event-free survival rates at 5 years were 54.8% (SD 1.9), 43.1%) (SD 2.7) and 55.6% (SD 2.2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 x 10(9)/l), circulating blastosis. haemoglobin >12 g/dl, platelet count <100 x 10(9)/l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10+ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1.1% for gender, 2.0% for age, 3.5% for leucocytosis, and 1.6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.

The t(12:21) translocation fuses the TEL and AML1 genes and has been found in up to 28% of paediatric B-cell precursor acute lymphoblastic leukaemias (BCP-ALL). The AML1 gene is a transcription factor which regulates expression of several myeloid differentiation associated genes. A molecular analysis of TEL-AML1, E2A-PBX1, MLL-AF4, BCR-ABL expression and an immunophenotypic study of CD13/CD33 myeloid antigen expression have been performed prospectively on tumour cells from 96 paediatric BCP-ALL patients. Percentages of CD13 or CD33 expressing leukaemic cells were found to be higher in TEL-AML1 positive cases (n = 22) than in TEL-AML1 negative (n = 74) cases (P<0.001). In 22/96 cases (23%) >10% of neoplastic cells were found to express at least one of the two markers. In 14 of these cases (63%), TEL-AML1 expression was detected, whereas t(4;11), t(11;19) and t(9;22) translocations were found by molecular methods in only three cases (14%). In four cases (18%) no molecular marker was found. These data show that TEL-AML1 expression is significantly associated with myeloid antigen expression by leukaemic cells and suggests that the prognostic significance of myeloid antigen expression in paediatric ALLs should be re-evaluated in the light of molecular cytogenetic markers.

About 80% of patients with breast cancer ultimately die of metastatic disease at 20 years. Distant metastases are more important as a cause of death than local or regional relapses. It is for this reason that adjuvant chemotherapy is necessary, especially in young patients and those with extensive disease. Initial chemotherapy preceding any local or regional treatment is justified on the grounds that both surgery and anaesthesia lead to immunodepression. Further, the value of initial chemotherapy has been demonstrated in many experimental and clinical trials by Nissen-Meyer, Bonadonna and Cooper (1-3). In the present study 145 patients, including 67 with inflammatory breast cancer (IBC), were treated with 4-6 weeks of Velbe, thiotepa, methotrexate, fluorouracil and prednisone, with Adriblastin added for patients with IBC, T greater than 7 cm, or N2, N3. Because of tumour regression of greater than 50% observed in 80% of the patients, the majority (123 patients) then received radiotherapy alone (cobalt + iridium), resulting in complete remission in all these cases. Maintenance treatment with the same drugs was prescribed for 6-18 months depending on the initial stage. Tumour regression appears to be an important prognostic factor. Median follow-up is only 17 months, the longest being 42 months. Overall survival at 2 years for IBC is 90%, with a disease-free survival of 80%. Cosmetic results are excellent. While these results are encouraging, longer follow-up is needed to confirm this improvement.

Of 91 acute leukaemia patients treated with m-Amsa, 19 received intermittent doses, 23 received daily doses and 49 underwent courses with combined m-Amsa and cytosine arabinoside (Ara-C). Intermittent doses had minimal therapeutic activity and toxicity. Among the 23 patients given daily doses, complete remission was observed in 5/12 relapses of ALL and in 2/11 relapses of AML. When Ara-C (200 mg/m2 x 5 days) was administered concomitantly with m-Amsa (200 mg/m2 x 5 days or 120 mg/m2 x 7 days), 17 out of 37 patients with advanced relapses of ALL (13/25 children and 4/12 adults) went into complete remission. While high doses of m-Amsa alone were well tolerated, the combined treatment with high doses of both drugs resulted in severe gastro-intestinal toxicity. Cardiac disorders were observed in patients who had previously received high doses of anthracyclins; there were 5 cases of dysrhythmia and 1 case each of sudden death, ECG alterations and heart failure. In view of its indisputable activity, m-Amsa should be used at an earlier stage in the treatment of acute leukaemias.

This is a review of the progress achieved in the treatment of acute lymphoblastic leukaemia, based on a series of 1580 children treated in Prof. Jean Bernard's unit, Paris, from 1956 to 1976. The children are retrospectively divided into three prognostic classes and five therapeutic categories. The benefits obtained from successive additions to the therapeutic armentarium during that period are conspicuous in all classes and categories and particularly striking in children with poor initial prognosis. The role of each component of the therapeutic measures applied is discussed.

Burkitt's-type leukemias have specific cytologic, immunologic, and cytogenetic characteristics. Initial symptomatology frequently includes abdominal tumors and initial CNS involvement. Despite intensive treatment including high-dose cyclophosphamide, prognosis remains poor in most patients because of failures to achieve complete remission (CR) or because of early relapses, especially CNS relapses. Class III acute lymphoblastic leukemia in children is defined by the presence of two or more unfavorable parameters and recent progress has been achieved by intensive therapy. Cox's multifactorial analysis allows improved discrimination. A phase I protocol for increased-risk leukemias, including testis preventive irradiation and monthly reinductions without continuous maintenance for the first 6 months of CR, seems promising.

The anthracycline derivatives are intercalating drugs which are of major importance in the treatment of leukemias and in the management of solid tumors. Structural analogs have been prepared by semisynthetic modifications in an attempt to extend the spectrum of antitumor activity and to reduce toxicity (acute myelosuppression and cardiotoxicity). This report concerns our preliminary clinical experience in 111 patients who received detorubicin. Two dose schedules were used in acute leukemia patients. Sequential doses were active in acute leukemia relapses but the mucous membrane toxicity was excessive; more recently, intermittent doses proved active in acute leukemia relapses (one 6-mg/kg dose) and in a patient with resistant Burkitt's lymphoma. In non-Hodgkin's lymphomas, a complete response rate of 71% was achieved with an intermittent schedule (3 mg/kg/day X 3 weeks). A remarkable shrinkage of skin involvement was also observed. Detorubicin showed a high activity in mycosis fungoides (five regressions among six patients) and some activity in soft tissue sarcomas, osteosarcomas, and various solid tumors.

The complete hematological remission (CHR) rate, duration of remission and survival were studied in relation to age, peripheral blast cell (PBC) count, presence or absence of tumor masses, cytological type, and treatment in 650 patients with acute lymphoblastic leukemia. Prognostic factors were considered separately and divided into prognostic classes. Age and PCB count correlated with both the rate and the duration of CHR. This correlation was still observed for more recent treatment schedules though it appears to be becoming progressively less significant. Meningeal relapses were more common in patients less than 1 year old and in those with a high PCB count. It is suggested that stratification of patients according to such factors as age, PCB count, presence or absence of tumor, and cytological type might be necessary for the design of new treatment protocols and for the evaluation of their results.

Amongst 1,200 leukemie children treated between 1958 and 1971, 60 are in complete remission for more than 10 years and 100 for more than 7 years. There were 96 acute lymphoid and 4 acute myeloid leukemias. Ten patients who have relapsed in the past have not done so lately. The F/M sex ratio is 1.5. Poor prognostic features were initially absent in 2/3 of cases. In 1/3 there was associated hyperleucocytosis and/or tumours. 93 children are in remission, their treatment having been stopped for 1 to 12 years. Five children relapsed and 4 are in a second remission for more than 2 years. Two children died in remission: one from a hepatocarcinoma and one from cardiac failure. These patients have been shown to have the following: 1) normal growth; 2) normal puberty: 8 patients have been able to reproduce, giving 10 children, one with multiple malformations; 3) school achievement and later socioprofessional behaviour has been normal. The patients have often sought a medical or paramedical career. Sequelae are minimal, psychological problems being minimal in the child. With the protocols used, mean remission curve shows a plateau after 9 years and complete definitive care is achieved in 92 per cent of patients surviving at 7 years. The very distant future outlook is not known. No other malignant haematological disease has occurred but one child died from a carcinoma.