Decreased nonrelapse mortality after unrelated cord blood transplantation for acute myeloid leukemia using reduced-intensity conditioning: a prospective phase II multicenter trial.

A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m(2)). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 10(7)/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (<3.4 × 10(7)/kg; P = .001) were associated with increased NRM, and use of 2 or more induction courses to obtain CR1 was associated with increased relapse incidence (P = .04). Leukemia-free survival (LFS) at 2 years was 35%, and the only factor associated with decreased LFS was secondary AML (P = .04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high-risk AML. (EUDRACT 2006-005901-67).

Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react.

Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention.

Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease-guided protocol.

Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10(-3) and 40·4% of those with MRD ≥10(-3).

Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951.

The European Organisation for Research and Treatment of Cancer 58951 trial for children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) addressed 3 randomized questions, including the evaluation of dexamethasone (DEX) versus prednisolone (PRED) in induction and, for average-risk patients, the evaluation of vincristine and corticosteroid pulses during continuation therapy. The corticosteroid used in the pulses was that assigned at induction. Overall, 411 patients were randomly assigned: 202 initially randomly assigned to PRED (60 mg/m(2)/d), 201 to DEX (6 mg/m(2)/d), and 8 nonrandomly assigned to PRED. At a median follow-up of 6.3 years, there were 19 versus 34 events for pulses versus no pulses; 6-year disease-free survival (DFS) rate was 90.6% (standard error [SE], 2.1%) and 82.8% (SE, 2.8%), respectively (hazard ratio [HR] = 0.54; 95% confidence interval, 0.31-0.94; P = .027). The effect of pulses was similar in the PRED (HR = 0.56) and DEX groups (HR = 0.59) but more pronounced in girls (HR = 0.24) than in boys (HR = 0.71). Grade 3 to 4 hepatic toxicity was 30% versus 40% in pulses versus no pulses group and grade 2 to 3 osteonecrosis was 4.4% versus 2%. For average-risk patients treated according to Berlin-Frankfurt-Muenster-based protocols, pulses should become a standard component of therapy.

Childhood Hodgkin's lymphoma, non-Hodgkin's lymphoma and factors related to the immune system: the Escale Study (SFCE).

The study investigated the role of factors considered related to the early stimulation of the immune system in the aetiology of childhood lymphoma. The national registry-based case-control study, Escale, was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. Data from 128 cases of Hodgkin's lymphoma (HL) aged 5-14 years, 164 cases of non-Hodgkin's lymphoma (NHL) aged 2-14 years and 1,312 controls were analyzed. Negative associations were observed between HL and day care attendance [OR = 0.5 (0.2-1.2)] and between HL and repeated early common infections among non-breastfed children [OR = 0.3 (.2-0.7), p = 0.003] [OR for breastfed children: 1.0 (.5-2.1)], but not for the other factors investigated. Negative associations were observed between NHL and birth order 3 or more [OR = 0.7 (0.4-1.1)], prolonged breastfeeding [OR = 0.5 (0.3-1.0)], regular contact with farm animals [OR = 0.5 (0.3-1.0)], frequent farm visits in early life [OR = 0.6 (0.4-1.1)] and history of asthma [OR = 0.6 (0.3-1.1)]. In conclusion, the results partly support the hypothesis that an abnormal maturation of the immune system may play a role in childhood HL or NHL, and call for further investigations.

Childhood acute leukemia, early common infections, and allergy: The ESCALE Study.

This study investigated the role of factors considered related to early stimulation of the immune system in the etiology of childhood acute leukemia. The national registry-based case-control study ESCALE was carried out in France in 2003-2004. Population controls were frequency matched to cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios were estimated using unconditional regression models adjusted for potential confounders. Included were 634 acute lymphoblastic leukemia cases, 86 acute myeloblastic leukemia cases, and 1,494 controls aged ≥1 year. Negative associations were observed between acute lymphoblastic leukemia and birth order (P for trend < 0.0001), attendance at a day-care center before age 1 year (odds ratio (OR) = 0.8, 95% confidence interval (CI): 0.6, 1.1), prolonged breastfeeding (OR = 0.7, 95% CI: 0.5, 1.0), repeated early common infections (OR = 0.7, 95% CI: 0.6, 0.9), regular contact with farm animals (OR = 0.6, 95% CI: 0.5, 0.8), frequent farm visits in early life (OR = 0.4, 95% CI: 0.3, 0.6), and history of asthma (OR = 0.7, 95% CI: 0.4, 1.0) or eczema (OR = 0.7, 95% CI: 0.6, 0.9). Results support the hypothesis that repeated early infections and asthma may play a role against childhood acute leukemia.

Posaconazole-increased vincristine neurotoxicity in a child: a case report.

A 9-year-old girl was managed according to the COPRALL 04 protocol for treatment of a relapse of acute lymphoblastic leukemia. Owing to a previous case of disseminated fusariosis, posaconazole was started 5 days before initiation of chemotherapy. Six days after the last dose of vincristine, the child reported symptoms of severe peripheral neuropathy, abdominal cramps, and constipation. After this, she developed fluctuations in her level of consciousness and seizures. After cessation of therapy with posaconazole, a complete resolution of the above occurred within 7 days. This case illustrates the possibility of vincristine toxicity exacerbated by coadministration of posaconazole. As posaconazole is an inhibitor of the isoenzyme CYP3A4, interactions with drugs that are metabolized via this pathway, such as vincristine, can be anticipated. Another possibility is that, like itraconazole, posaconazole may also inhibit P-glycoprotein-mediated vincristine efflux. Although case reports of neurotoxicity owing to possible interaction between itraconazole and vincristine exist in the literature, only 1 case report relating to the possible interaction between posaconazole and vincristine exists. Clinicians should be made aware of this possible drug-drug interaction.

Childhood hematopoietic malignancies and parental use of tobacco and alcohol: the ESCALE study (SFCE).

OBJECTIVES: Investigating the role of parental smoking and maternal alcohol consumption in the etiology of childhood hematopoietic malignancies. METHODS: The national registry-based case-control study ESCALE was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and gender. Maternal smoking and alcohol consumption during pregnancy and paternal smoking since before conception were reported by the mothers in a structured telephone questionnaire. Odds ratios (OR) were estimated using unconditional regression models closely adjusted for potential confounders. RESULTS: A total of 765 cases of acute leukemia (AL), 130 of Hodgkin's lymphoma (HL), 165 of non-Hodgkin's lymphoma (NHL) and 1681 controls were included. Paternal smoking was significantly associated with childhood ALL (OR = 1.4 [1.1-1.7]), AML (OR = 1.5 [1.0-2.3]), Burkitt (OR = 2.0 [1.2-3.2]), and anaplastic large cell (OR = 3.2 [1.2-9.1]) NHL. For the four diseases, the ORs significantly increased with the number of cigarettes smoked. No association with HL or with other types of NHL was observed. The associations with maternal alcohol consumption and cigarette smoking during pregnancy were less consistent. CONCLUSION: The results support the hypothesis that only paternal smoking, and not maternal alcohol consumption or cigarette smoking, plays a role in childhood hematopoietic malignancies.

Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE).

OBJECTIVES: We investigated the role of household exposure to pesticides in the etiology of childhood hematopoietic malignancies. METHODS: The national registry-based case-control study ESCALE (Etude sur les cancers de l'enfant) was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and sex. Maternal household use of pesticides during pregnancy and paternal use during pregnancy or childhood were reported by the mothers in a structured telephone questionnaire. Insecticides (used at home, on pets, or for garden crops), herbicides, and fungicides were distinguished. We estimated odds ratios (ORs) using unconditional regression models closely adjusting for age, sex, degree of urbanization, and type of housing (flat or house). RESULTS: We included a total of 764 cases of acute leukemia (AL), 130 of Hodgkin lymphoma (HL), 166 of non-Hodgkin lymphoma (NHL), and 1,681 controls. Insecticide use during pregnancy was significantly associated with childhood AL [OR = 2.1; 95% confidence interval (CI), 1.7-2.5], both lymphoblastic and myeloblastic, NHL (OR = 1.8; 95% CI, 1.3-2.6), mainly for Burkitt lymphoma (OR = 2.7; 95% CI, 1.6-4.5), and mixed-cell HL (OR = 4.1; 95% CI, 1.4-11.8), but not nodular sclerosis HL (OR = 1.1; 95% CI, 0.6-1.9). Paternal household use of pesticides was also related to AL (OR = 1.5; 95% CI, 1.2-1.8) and NHL (OR = 1.7; 95% CI, 1.2-2.6); but for AL the relationships did not remain after adjustment for maternal pesticide use during pregnancy. CONCLUSION: The study findings strengthen the hypothesis that domestic use of pesticides may play a role in the etiology of childhood hematopoietic malignancies. The consistency of the findings with those of previous studies on AL raises the question of the advisability of preventing pesticide use by pregnant women.

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.

Familial history of cancer and childhood acute leukemia: a French population-based case-control study.

A case-control study was conducted to investigate the role of a familial history of cancer in the etiology of childhood acute leukemia. The history of cancer in the relatives of 472 cases was compared with that of 567 population-based controls. Recruitment was frequency matched on age, sex and region. The familial history of cancer in each child's relatives was reported by the mother in response to a standardized self-administered questionnaire. A familial history of solid tumor in first or second-degree relatives was associated with an increased risk of acute lymphoblastic leukemia (odds ratio (OR)=1.6 [95% confidence interval, 1.2-2.1]), while a familial history of hematopoietic malignancies in first or second-degree relatives was associated with an increased risk of acute myeloid leukemia (OR=4.3 [1.4-13]). The ORs for the histories of cancer increased with the number of relatives with cancer (OR=1.5 [1.1-2.0] for one relative and OR=2.3 [1.3-3.8] for two relatives or more; Ptrend<0.0001). Significant associations between childhood acute leukemia and familial history of genital cancers and brain tumor were also observed (OR=2.7 [1.2-5.8] and OR=10.7 [1.3-86], respectively). This study supports the hypothesis that a familial history of cancer may play a role in the etiology of childhood acute leukemia. It also evidences some specific associations that require further investigation.

French "real life" experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia.

BACKGROUND: Clofarabine alone or in combination with cyclophosphamide and etoposide has shown a good efficacy and a tolerable toxicity profile in previous studies of children with relapsed or refractory leukaemia. This report describes a retrospective study of 38 French patients who received clofarabine as a monotherapy or in combination for relapsed or refractory acute lymphoblastic leukaemia (ALL) outside of clinical trials after marketing authorization. METHODS: We retrospectively analysed data for 38 patients, up to 21 years old, attending 17 French centres. Thirty patients received clofarabine alone or in combination for a bone marrow relapse of acute lymphoblastic leukaemia (ALL) or refractory disease and eight patients for a high level of minimal residual disease (MRD). Survival and response durations were estimated by the Kaplan-Meier method. RESULTS: For the 30 patients who received clofarabine for a bone marrow relapse of ALL (number of relapse, 1-3; median, 1), the overall remission rate (ORR) was 37%: eight complete remission (CR) and three complete remission without platelet recovery (CRp). Ten of the 11 responding patients subsequently underwent haematopoietic stem cell transplantation (HSCT).Only four of the eight patients who received clofarabine while in remission for a high level of MRD, showed a moderate improvement of MRD. Seven of these eight patients received HSCT and six of them were alive at the end of the study. One other patient was alive without receiving HSCT.However, clofarabine treatment was associated with a high risk of infection and hepatotoxicity. Febrile neutropenia grade ≥ 3 was reported in 79% of patients and documented infections grade ≥ 3 occurred in nine patients (24%). Hepatotoxicity grade 3 was reported in nine patients (24%). We observed four deaths related to treatment. CONCLUSION: In our experience, the efficacy of clofarabine is poorer than previously reported. Its toxicity is high and can be life threatening. Prospective studies on clofarabine used during earlier phases of the disease may help to define how best this new drug can be exploited for childhood and adolescent ALL.

Road traffic and childhood leukemia: the ESCALE study (SFCE).

BACKGROUND: Traffic is a source of environmental exposures, including benzene, which may be related to childhood leukemia. OBJECTIVES: A national registry-based case-control study [ESCALE (Etude Sur les Cancers et les Leucémies de l'Enfant, Study on Environmental and Genetic Risk Factors of Childhood Cancers and Leukemia)] carried out in France was used to assess the effect of exposure to road traffic exhaust fumes on the risk of childhood leukemia. METHODS: Over the study period, 2003-2004, 763 cases and 1,681 controls < 15 years old were included, and the controls were frequency matched with the cases on age and sex. The ESCALE data were collected by a standardized telephone interview of the mothers. Various indicators of exposure to traffic and pollution were determined using the geocoded addresses at the time of diagnosis for the cases and of interview for the controls. Indicators of the distance from, and density of, main roads and traffic nitrogen dioxide (NO(2)) concentrations derived from traffic emission data were used. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. RESULTS: Acute leukemia (AL) was significantly associated with estimates of traffic NO(2) concentration at the place of residence > 27.7 µg/m(3) compared with NO(2) concentration < 21.9 µg/m(3) [OR=1.2; confidence interval (CI), 1.0-1.5] and with the presence of a heavy-traffic road within 500 m compared with the absence of a heavy-traffic road in the same area (OR=2.0; 95% CI, 1.0-3.6). There was a significant association between AL and a high density of heavy-traffic roads within 500 m compared with the reference category with no heavy-traffic road within 500 m (OR=2.2; 95% CI, 1.1-4.2), with a significant positive linear trend of the association of AL with the total length of heavy-traffic road within 500 m. CONCLUSION: This study supports the hypothesis that living close to heavy-traffic roads may increase the risk of childhood leukemia.

Family history of cancer in children with acute leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma: the ESCALE study (SFCE).

The role of a family history of cancer in the etiology of childhood hematopoietic malignancies was investigated using the data from the ESCALE study. ESCALE, a population-based case-control study, was carried out in France over the period, 2003-2004. A total of 773 cases of acute leukemia (AL), 130 of Hodgkin's lymphoma (HL), 163 of non-Hodgkin's lymphoma (NHL) and 1,681 population-based controls were included. The controls were randomly selected from the French population and were frequency matched with the cases on age and gender. Cancer history in first- and second-degree relatives was reported by the mothers in a structured telephone questionnaire that was the same for the cases and controls. Odds ratios (ORs) were estimated using an unconditional regression model taking into account the stratification variables and potential confounders. A family history of cancer was associated with an increased risk of HL (OR = 1.5 [1.0-2.2]) and NHL (OR = 1.8 [1.3-2.5]), but not AL (OR = 1.0 [0.9-1.2]). The ORs were higher when at least 2 relatives had a history of cancer or when 1 case occurred before age 46 years. Only HL was significantly associated with a family history of hematopoietic malignancies (OR = 2.0 [1.0-3.8]), mainly because of a significant association with a history of HL (OR = 5.4 [1.3-22]). In conclusion, the study findings support the hypothesis of familial susceptibility to childhood lymphoma, but do not suggest familial susceptibility to childhood AL.

Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease.

Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD); nevertheless, its use has been limited by the risk of transplantation-related mortality (TRM). Between November 1988 and December 2004, 87 consecutive patients with severe SCD ranging from 2 to 22 years of age received transplants in France. Cerebral vasculopathy was the principal indication for transplantation (55 patients). All the patients received grafts from a sibling donor after a myeloablative conditioning regimen (CR). The only change in the CR during the study period was the introduction of antithymocyte globulin (ATG) in March 1992. The rejection rate was 22.6% before the use of ATG but 3% thereafter. With a median follow-up of 6 years (range, 2.0 to 17.9 years), the overall and event-free survival (EFS) rates were 93.1% and 86.1%, respectively. Graft versus host disease (GVHD) was the main cause of TRM. Importantly, cord blood transplant recipients did not develop GVHD. No new ischemic lesions were detected after engraftment, and cerebral velocities were significantly reduced. The outcome improved significantly with time: the EFS rate among the 44 patients receiving transplants after January 2000 was 95.3%. These results indicate that HLA-identical sibling HSCT after myeloablative conditioning with ATG should be considered as a standard of care for SCD children who are at high risk for stroke.

Neurotoxicity related to valganciclovir in a child with impaired renal function: usefulness of therapeutic drug monitoring.

OBJECTIVE: To report a case of neurotoxicity related to antiviral drugs, discuss the involvement of concomitant medications, and document the pharmacokinetics of ganciclovir (administered as valganciclovir) in a child with impaired renal function. CASE SUMMARY: A 13-year-old boy with acute lymphoblastic leukemia was treated for cytomegalovirus retinitis with valganciclovir 450 mg every 2 days in the course of hematopoietic stem cell transplantation. Concomitant medication included omeprazole, furosemide, and acetaminophen. During treatment, when creatinine clearance decreased to 20 mL/min, the child presented with acute neurotoxicity, consisting of mental confusion and hallucinations, which resolved when all medications were stopped. Valganciclovir therapeutic monitoring showed high ganciclovir concentrations in the plasma (3.85 microg/mL) and cerebrospinal fluid (2.6 microg/mL) 48 hours after the last valganciclovir dose. After recovery of neurologic function, valganciclovir was resumed at a lower dosage (225 mg twice a week) with therapeutic drug monitoring and was well tolerated. However, the cytomegalovirus infection was not resolved. The leukemia relapsed, and the patient had terminal renal failure and died. The Naranjo probability scale indicated a probable relationship between valganciclovir and neurotoxicity. DISCUSSION: Drugs taken by this child (acyclovir, valganciclovir, omeprazole) have been reported to induce neurotoxicity, with the pharmacokinetics of the first 2 being altered by renal failure. At the time when acyclovir was first administered, symptoms of neurotoxicity were already apparent. Moreover, plasma concentrations of ganciclovir were very high during the course of the neurotoxicity. Thus, the adverse effects seemed related to an overdosage of valganciclovir and were worsened by the addition of acyclovir. CONCLUSIONS: This case is informative because few clinical and pharmacokinetic data are available concerning the use of valganciclovir in children. A study should be performed to determine the proper pediatric dose of valganciclovir with and without renal impairment to prevent the occurrence of adverse effects.

c-Flip protein expression in Burkitt's lymphomas is associated with a poor clinical outcome.

The World Health Organization Classification of Lymphoid Neoplasms identifies Burkitt's lymphoma/leukaemia (BL) as a single entity, characterized by unique clinical and genetic features that require specific high intensity chemotherapy regimens. Although remarkable successes in the treatment of the disease have been observed, when compared with paediatric patients, adults are less likely to reach stable complete remission. We investigated 32 BL cases, composed in equal part by adults and children that were treated with the French LMB regimen, for factors that may be implicated in chemoresistance. Immunohistochemical detection of procaspase-8, caspase-3a, survivin, p53, CD95, c-Flip and Phospho-RelA (Ser536) was investigated on paraffin-embedded tissues. The expression of c-Flip was found highly related to a poor prognosis, mostly characterized by adults with a chemoresistant disease, resulting in a high death rate within the first year of diagnosis. The 2-year overall survival with c-Flip expression was 24% compared with 93% in the absence of this marker (P = 0.04). All c-Flip-positive BL cases presented a nuclear Phospho-RelA (Ser536) localization, suggesting the presence of an active nuclear factor (NF)-kappa B transcription pathway. These findings show that c-Flip could be a reliable prognostic factor in BL, suggesting new therapeutic approaches that target the NF-kappa B pathway.

Optimal management of methotrexate intoxication in a child with osteosarcoma.

OBJECTIVE: To describe the time course and management of methotrexate (MTX) toxicity in a 14-year-old Hispanic boy with osteosarcoma treated with high-dose MTX. CASE SUMMARY: During the sixth cycle of high-dose MTX, severe intoxication was observed with high MTX plasma concentrations, acute renal failure, and hepatitis, followed by mucositis and moderate myelosuppression. Intensification of urine alkalinization and increased leucovorin dosages did not decrease plasma concentrations of MTX or prevent systemic toxicities. Carboxypeptidase G2 and aminophylline were thus administered as a second-intention rescue strategy. Within 2 weeks, a recovery of clinical symptoms and normalization of the biological abnormalities were observed. Limb salvage surgery was performed, which permitted classifying the patient as an MTX high-responder. Thereafter, MTX was successfully resumed, leading to clinical recovery of the patient. Concomitantly, homocysteine plasma levels, a marker of the pharmacodynamic effect of MTX, were measured. During the intoxication, homocysteine plasma levels were significantly increased, parallel to the excessive MTX plasma concentrations observed. DISCUSSION: According to the excessive MTX levels measured in this patient, along with the observed clinical (mucositis) and biological (hepatitis, renal injury) adverse effects, we suggest that MTX may be a cause of these complications. Use of the Naranjo probability scale indicated a probable relationship between the complications and MTX. CONCLUSIONS: This observation shows that severe complications observed during one cycle of high-dose MTX is not predictive of the tolerability of further courses. Optimal management of such complications, using specific therapeutic intervention, may be considered.

Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951.

In a series of 153 children with T-cell malignancies enrolled in 2 consecutive European Organization for Research and Treatment of Cancer (EORTC) trials, we assessed the HOX11L2 expression and/or the presence of a t(5;14)(q35;q32). Additionally, in 138 of these patients, HOX11 expression and SIL-TAL rearrangement were also assessed. These alterations were mutually exclusive, and their frequency was 23% (n = 35), 7% (n = 10), and 12% (n = 17), respectively. HOX11L2/t(5;14) positivity was more frequent in acute lymphoblastic leukemia (ALL) with cortical T immunophenotype and in children aged between 6 and 9 years. In contrast with previously reported data, patients positive and negative for HOX11L2/t(5;14) were comparable with regard to clinical outcome as well as to the response to a 7-day prephase treatment or to residual disease at completion of induction therapy. The 3-year event-free survival (EFS) rate (+/- SE percentage) for patients positive and negative for HOX11L2/t(5;14) was 75.5% (+/- 8.1%) and 68.3% (+/- 5.0%), respectively; the hazard ratio was 0.84 (95% confidence interval, 0.40-1.80). Patients with HOX11-high expression and those with SIL-TAL fusion had low levels of residual disease at the end of induction and a favorable prognosis: the 3-year EFS rate was 83.3% (+/- 8.5%) and 75.3% (+/- 12.6%), respectively. The results obtained in HOX11L2/t(5;14) patients in this study do not confirm the unfavorable prognosis reported in previous studies.