Pierre Wacker

Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences

One of the most relevant concerns in long-term survivors of paediatric acute lymphoblastic leukaemia (ALL) is the development of neuropsychological sequelae. The majority of the published studies report on patients treated with chemotherapy and prophylactic central nervous system (CNS) irradiation, little is known about the outcome of patients treated with chemotherapy-only regimens. Using the standardised clinical and neuropsychological instruments of the SPOG Late Effects Study, the intellectual performance of 132 paediatric ALL patients treated with chemotherapy only was compared to that of 100 control patients surviving from diverse non-CNS solid tumours. As a group, ALL and solid tumour survivors showed normal and comparable intellectual performances (mean global IQ 104.6 in both groups). The percentage of patients in the borderline range (global IQ between 70 and 85) was comparable and not higher as expected (10% cases and 13% controls, expected 16%). Only 2 (2%) of the former ALL and 1 (1%) of the solid tumour patients were in the range of mental retardation (global IQ<70). Former known risk factors described in children treated with prophylactic CNS irradiation, like a younger age at diagnosis of ALL and female gender, remained valid in chemotherapy-only treated patients. The abandonment of prophylactic CNS irradiation and its replacement by a more intensive systemic and intrathecal chemotherapy led to a reduction, but not the disappearance of late neuropsychological sequelae.

ATM gene and lymphoid malignancies.

Inherited biallelic mutations of the ATM (ataxia-telangiectasia mutated) gene cause ataxia-telangiectasia, a rare autosomal recessive disorder associated with a high incidence of childhood leukaemias and lymphomas, suggesting that ATM gene alterations may be involved in lymphomagenesis. Loss of heterozygosity at 11q22–23 (location of the ATM gene) is a frequent event in sporadic lymphoid tumours, and several studies have reported a high prevalence of ATM gene alterations in diverse sporadic lymphoproliferative disorders, adding evidence to the postulated contribution of ATM in the pathogenesis of these tumours. This mini-review will summarize the recently published data concerning the ATM gene in sporadic lymphoid malignancies and will discuss the apparent paradox between the predominance of nonsense mutations observed in patient with ataxia-telangiectasia and the high proportion of missense alterations found in sporadic lymphoid tumours.

Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.

PURPOSE In childhood B-precursor acute lymphoblastic leukemia (ALL), possible interactions among sex, time, and widely used prognostic factors (age, WBC count, and DNA index) were investigated for the first 5 years after diagnosis. PATIENTS AND METHODS All eligible patients aged 1 to less than 22 years, registered between February 1986 and September 1994 in two B-precursor ALL studies from the Pediatric Oncology Group (POG), were included in the analysis. Cutpoints for age (3.0, 5.0, and 10.0 years), WBC count (10, 50, and 100 x 10(9)/L), and DNA index (DI; 1.16) were defined. Four time periods after diagnosis (years 1, 2, 3, and 4 and 5 combined) were selected for the study of prognostic significance over time. The cut-off date for analysis was April 1996. RESULTS A total of 3,717 children (2,010 boys and 1,707 girls) were included in the outcome analysis. No major differences between the sexes were observed in age, duration of symptoms before registration, WBC count, hemoglobin level, platelet count, ploidy, presence of CNS disease at diagnosis, or induction failure rate. Event-free survival (EFS) differences between sexes became significantly different from 2 years following diagnosis. At 5 years, in all subsets analyzed, boys fared worse than girls, although not all differences were statistically significant. Major sex differences in EFS were observed in older children (10 to 22 years), in patients with intermediate WBC counts (10 to 50 x 10(9)/ L), and in children who fit both of these subgroups, in whom the 2-year EFS was almost 20% higher in girls than in boys, reaching a 38% difference at 5 years. CONCLUSION This study shows an outcome interaction among sex, time, and commonly used prognostic variables. The important sex difference observed at 2 and 5 years suggests that more intensive consolidation and/or maintenance therapy in some boys with B-precursor ALL should be investigated.

The prognostic significance of cytogenetic aberrations in childhood acute myeloid leukaemia. A study of the Swiss Paediatric Oncology Group (SPOG)

In childhood‐onset acute myeloid leukaemia (AML) the clinical value of karyotypic aberrations is now acknowledged, although there is still debate concerning the prognostic significance of some events. To add to this knowledge, cytogenetic analysis was performed on a consecutive series of 84 childhood AML patients diagnosed in Switzerland. A result was obtained for all patients, with 69 (82%) showing a clonal karyotypic aberration. In the remaining 15 (18%), no karyotypic aberration was seen by either conventional or fluorescence in situ hybridisation analyses. The most frequent aberrations observed were t(11q23) (19% of all patients), t(8;21) (12%) and +8 (11%). Except for cytogenetics, no clinical parameter was shown to be significantly associated with outcome. The analysis of individual cytogenetic subgroups demonstrated that aberrations involving chromosome 16q were the strongest predictor of a good prognosis, while +8 and complex karyotypes represented the strongest predictors of a poor prognosis. It was also noteworthy that patients with the rare aberrations of del(11q) (n = 4) and t(16;21)(p11;q22) (n = 3) had a poor outcome. The results support the importance of cytogenetic analysis in childhood AML, but show that further work is required in the classification of the poor prognosis aberrations.

Early hospital discharge of children with fever and neutropenia : A prospective study

Purpose: We report a prospective study on brief IV antibiotic therapy in selected children with cancer experiencing fever and neutropenia (FN) after chemotherapy. Patients and methods: All children with FN (T⩽≥38°C; ANC<0.5<l09/L) were hospitalized for treatment with broad spectrum IV antibiotics. They were divided into three groups: group A (no infection), group B (clinically documented infection), and group C (bacteremia). Children in group A (and some children in group B) were discharged before recovery of neutropenia, if afebrile and in good condition. Results: Eighty-eight consecutive episodes of FN occurred in 30 children. Children in group A (44 episodes; 50%) received IV antibiotics for a median of 3 days; on 25 occasions (57%), IV antibiotics were stopped before recovery of neutropenia. In children in group B (30 episodes; 34%), early discharge was allowed in eight cases of minor infections (27%); six received oral antibiotics. Two children (group A) were rehospitalized for recurrent FN but recovered without complications. Conclusion: In chemotherapy-induced neutropenia, children hospitalized for fever but without documented infections and some children with minor infections can cautiously be discharged before evidence of bone marrow recovery if afebrile and in good general condition.

Allergic reactions to E. coli L-asparaginase do not affect outcome in childhood B-precursor acute lymphoblastic leukemia: a Children's Oncology Group Study.

We describe the outcome of children with B-precursor acute lymphoblastic leukemia registered on Pediatric Oncology Group 8602 who switched to Erwinia asparaginase (ASP) due to an allergy to the Escherichia coli product. Between February 1986 and January 1991, children in complete remission after induction that included intramuscular E. coli ASP (6000 U/m2×6) were randomized for consolidation. One regimen included intensive weekly intramuscular E. coli ASP (25,000 U/m2/wk×24). In case of an allergic reaction to E. coli ASP, Erwinia ASP was substituted at the same dose and schedule. Of the 540 eligible patients, 408 switched to Erwinia ASP due to an allergic reaction. Allergic reactions were significantly associated with younger age, white race, and standard-risk acute lymphoblastic leukemia. Multivariate Cox analysis adjusting for these factors demonstrated no correlation between the switch per se or the timing of the switch and event-free survival.

Prognostic value of cerebrospinal fluid cytology in pediatric medulloblastoma

BACKGROUND Although the demonstration of leptomeningeal dissemination is the most important predictor of poor outcome in children with medulloblastoma, there is lack of consensus on the prognostic value of a positive cerebrospinal fluid (CSF) cytology (i.e., stage M1). PATIENTS AND METHODS Eighty-six pediatric medulloblastoma patients treated in Switzerland between 1972-1991 were retrospectively studied regarding the influence of M-stage on prognosis. 39 were M0, 13 M1, 15 Mx, 17 M2, and 2 M3. RESULTS Five- and 10-year overall survival rates were 76% and 54% for M0, 68% and 50% for Mx, 36% and 25% for M1, and 22% and 22% for M2-3 (P < 0.001), respectively. No significant survival differences were observed between M1 and M2-3 patients. Among 26 patients with only postoperative CSF cytologies, seven were positive. Their outcome was similar to that of six preoperatively staged M1 and significantly different from that of M0 patients (P = 0.001). In 14 patients both pre- and postoperative CSF cytology was performed. Total agreement was observed between the pre- and postoperative results (six positive and eight negative). Among the 19 M2-3 patients CSF cytology was positive in eight, negative in five, and unknown in six. CONCLUSIONS A positive CSF cytology either pre- or postoperatively predicts for a poor outcome, similar to that observed in stage M2-3 patients. A postoperative cytology is likely to be concordant with cytologic results obtained preoperatively, and seems to have the same prognostic significance. A negative cytology, however, does not exclude a more advanced stage.

STEPPING UP VERSUS STANDARD DOSES OF ERYTHROPOIETIN IN PRETERM INFANTS: A Randomized Controlled Trial

In this study, it is hypothesized that a planned increase in the dose of recombinant human erythropoietin (rh-EPO) can prevent transfusion in very low birth weight infants. Two different regimens of rh-EPO were administrated, one consisting in increasing dosage up to 5000 U/kg/wk, according to the individual reticulocytes response, and the second in a standard therapy of 1250 U/kg/wk. Fifty-one infants participated. Despite a significant higher reticulocytosis, the study was prematurely terminated due to the results of an interim analysis showing that transfusion was not avoided by increasing the rh-EPO. No significant differences were found between the two regimens concerning transfusion rate, volume transfused, gain in weight, and adverse effects. Progressive titration of rh-EPO to improve the biological response does not leave premature infants free of transfusion.

Comparison of totally implanted and external catheters in paediatric oncology patients

From June 1982 until December 1989, 93 permanent central venous catheters [59 external catheters (ECs) and 34 implanted catheters (ICs)] were placed in 69 patients. The median age of these patients at placement was 5.6 years for ECs and 8.8 years for ICs (P less than 0.05). Follow-up evaluation was possible on 86 catheters (58 ECs and 28 ICs). The median time of insertion was 236 days and 316 days for ECs and ICs, respectively (P less than 0.05). The median number of open days was 58 for ECs and 66 for ICs (not significant). 17 catheters (6 ECs and 11 ICs) were transiently obstructed (P less than 0.005). 30 episodes of bacteraemia were documented in 20 patients. The incidence of catheter sepsis and bacteraemia of unknown source was one in 278 and 283 open days for ECs and ICs, respectively (not significant). In this retrospective study, ECs appeared to be as safe as ICs when infection was correlated with use of the catheter, but this finding should be confirmed in a randomised design.

ALK-positive anaplastic large-cell lymphoma: strong T and B anti-tumour responses may cause hypocellular aspects of lymph nodes mimicking inflammatory lesions

Abstract: The anaplastic large cell lymphoma kinase (ALK)‐positive anaplastic large cell lymphoma (ALCL) is a rare type of non‐Hodgkin lymphoma which occurs in children mostly. The ALK protein is highly immunogenic and elicits both humoral and cellular immune responses. A 15‐yr‐old child presented with fever and adenopathy and did not respond to antibiotics. Biopsy of the enlarged lymph node contained almost no lymphoid element except for a few CD8‐positive T cells, plasma cells and isolated CD30‐positive blasts. The patients condition improved following lymphadenectomy but relapse occurred 3 months later with multiple nodes, high fever and an abdominal mass. This time an ALK‐positive ALCL was diagnosed and the retrospective analysis of the initial biopsy revealed rare, isolated ALK+ cells. Molecular analysis showed T‐cell clones and oligoclonal B cells in both biopsies and peripheral blood of the patient. The tumour cells harbour a t(2;5) translocation, revealing a null phenotype by immunohistochemistry and no evidence for T‐cell clonality by Southern blotting. The patients serum contained anti‐ALK antibodies. Our findings suggest that the T‐cell clones and anti‐ALK antibodies in this patient constitute an anti‐tumour response that caused the hypocellularity of the initial lymph node. Hypocellular and oedematous lymph nodes occurring in a child with evocative symptoms should be tested for the presence of ALK.