Persistent osteoarticular pain in children: early clinical and laboratory findings suggestive of acute lymphoblastic leukemia (a multicenter case-control study of 147 patients).

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 × 109/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3-58]), and platelets < 300 × 109/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 × 109/L or platelets < 300 × 109/L.

Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol.

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.

Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study.

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.

[Towards cure for all children with acute lymphoblastic leukemia?]. / Vers la guérison de tous les enfants atteints de leucémie aiguë lymphoblastique?

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.

Impact of genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE-93: the effect of TLX3/HOX11L2 gene expression on outcome.

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.

Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study.

PURPOSE: To identify prognostic factors and to evaluate the outcome of children with acute lymphoblastic leukemia (ALL) failure after induction therapy. PATIENTS AND METHODS: Between June 1993 and December 1999, 1,395 leukemic children were included in the French Acute Lymphoblastic Leukemia 93 study. RESULTS: Fifty-three patients (3.8%) had a leukemic induction failure (LIF) after three- or four-drug induction therapy. In univariate analysis, high WBC count (P = .001), mediastinal mass (P = .017), T-cell phenotype (T-ALL; P = .001), t(9;22) translocation (P = .001), and a slow early response (at day 8 and/or on day 21, P = .001) were predictive of LIF. The following three prognostic groups for LIF were identified by multivariate analysis: a low-risk group with B-cell progenitor (BCP) ALL without t(9;22) (odds ratio [OR] = 1), an intermediate-risk group with T-ALL and a mediastinal mass (OR = 7.4, P < .0001), and a high-risk group with BCP-ALL and t(9;22) or T-ALL without a mediastinal mass (OR = 28.4, P < .0001). Complete remission (CR) was subsequently obtained in 43 patients (81%). The 5-year overall survival (OS) rate of the 53 patients was 30% +/- 6%. The 5-year OS rate among allogeneic graft recipients, autologous graft recipients, and after chemotherapy were 30.4% +/- 9.6% (50% +/- 26% after genoidentical transplantation), 50% +/- 17.7%, and 41.7% +/- 14.2%, respectively (P = .18). Fourteen patients (26%) were still in first CR after a median of 83 months (range, 53 to 117 months). CONCLUSION: Three risk categories for LIF in children with ALL were identified. Approximately one third of patients with LIF can be successfully treated with salvage therapy overall. Subsequent CR after LIF is mandatory for cure.

Vaccination and the risk of childhood acute leukaemia: the ESCALE study (SFCE).

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.

Economic evaluation of recombinant human granulocyte colony-stimulating factor in very high-risk childhood acute lymphoblastic leukemia.

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.

Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials.

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.

Family history of autoimmune thyroid disease and childhood acute leukemia.

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.