Perception of effort at low and moderate intensity exercise in survivors of childhood acute lymphoblastic leukaemia.

OBJECTIVE: The study examined the degree to which male and female survivors of acute lymphoblastic leukaemia (ALL) perceive effort at low and moderate intensity exercise in association with related physiological variables. MATERIALS AND METHODS: Participants were 67 children. Thirty-five (14 boys and 21 girls) were long-time survivors of ALL and 32 (18 boys and 14 girls) were control subjects. The Children's Effort Rating Table (CERT) was used to measure whole-body perceived exertion at low and moderate intensity exercise. Peak oxygen uptake was measured using a motorized treadmill. CERT and physiological data were analysed using 2 x 2 mixed analyses of variance, appropriate t-tests and coefficients of correlation. RESULTS: In absolute terms, boys treated for ALL found perception of effort to be more strenuous at both low (3.9 vs. 3.5 units) and moderate (6.1 vs. 5.3 units) intensity exercise than control subjects, although differences were not significant (p > 0.05); girls treated for ALL found perception of effort to be the same as controls at low intensity exercise (3.1 vs. 3.1 units) but slightly higher than controls at moderate intensity exercise (5.6 vs. 5.2 units); neither of these differences were significant (p > 0.05). When CERT values were adjusted for (.-)VO(2) peak (%) and heart rate (HR) peak (%) differences remained non-significant. There were no significant interactions (Intensity x Group) in males, but the interaction for (.-)VO(2) peak (%) was significant in females (p < 0.05). The main effect for Intensity (low and moderate) was significant for all variables in boys and girls (p < 0.0001). The main effect for Group (ALL and controls) identified significantly greater absolute (b.p.m.) and relative (%) HR values in ALL boys at low and moderate intensity exercise. In female ALL and control subjects the interaction (Intensity x Group) distinguished between (.-)VO(2) peak (%) at moderate intensity exercise and HR peak (%) at low and moderate intensity exercise. Coefficients of correlation between perceived effort and (.-)VO(2) peak (%) in boys and girls were low to high (0.28-0.76), and between absolute and relative HR were also low to high (0.33-0.73). There were low correlations between time 'off therapy' and perceived effort, (.-)VO(2) peak (%) and HR peak (%) (-0.003 to -0.49). CONCLUSION: It was concluded that perception of effort in survivors of ALL at low and moderate intensity exercise was the same as that of control subjects. Correlations between perceived effort and physiological variables at moderate exercise were low to high, while those between perceived effort and time from treatment were generally weak.

MRC trials in childhood acute myeloid leukaemia.

The modern approach to therapy for acute myeloid leukaemia (AML) in children began in the late 80's and in the MRC series led to a 30% improvement in survival, up to levels of about 50%. Since 1995 the most recent trial AML 12 has taken those figures to two thirds event free survival and similar overall survival. Resistant disease rates remain at 4% overall but the death rate in complete remission has fallen from 11% to 6% despite increasing intensity of therapy, and due to advances in supportive care including nutrition and antibiotics/antifungals. However, although relapse rates have continued to fall, the biggest challenge is to reduce the currently one third relapse rate. We are much better at predicting who is likely to relapse, based mainly on primary resistance to therapy and karyotype. Analysis of 629 out of the last 808 cases in whom cytogenetic testing was successful (78%) has shown very clearly that t(8;21), t(15;17), inv(16) are independent good risk features. Additionally, loss of a sex chromosome in the 8;21 group defines a group which does exceptionally well, with 93% EFS at 5 years. Chromosome 7 abnormalities also remain of independent prognostic significance when age, WHO classification and white cell count are taken into account, with monosomy 7 doing even worse than 7q abnormalities. The current trial MRC AML 15 investigates the role of fludarabine--idarubicin combination therapy in the induction courses and the role of high dose cytarabine during consolidation; the aim being to increase efficacy and reduce toxicity, particularly that involving the heart. New approaches such as targeted antibody therapy will be explored when toxicity data for children permits.

Pitfalls in the assessment of body composition in survivors of acute lymphoblastic leukaemia.

BACKGROUND: Body fat mass (FM) and fat free mass (FFM) in childhood are often estimated by conversion of a measured variable into compartmental body composition using constants or regression equations that have been previously derived in healthy individuals. Application of such constants or equations to children with disease states may lead to inappropriate conclusions since the "normal" relationships may become altered. AIMS AND METHODS: To test this hypothesis by taking measurements of body composition using dual energy x ray absorptiometry (DEXA) as a "gold standard" method and calculating hydration and body potassium constants using isotopic water dilution and whole body potassium counting. Measurements of bioelectrical impedance (BIA) by two different analysers (RJL and Holtain) were also performed to allow comparison with body water measurements. RESULTS: Measurements were performed in 35 children treated for acute lymphoblastic leukaemia (ALL) and compared to those in 21 children treated for a variety of other malignancies and 32 healthy sibling controls. The mean hydration and potassium content of FFM was significantly reduced in the ALL group compared to both other malignancies and controls. Application of equations derived from controls for the measurement of FFM derived from bioelectrical impedance led to an underestimation of 1.15 kg when compared to that derived from DEXA in children treated for ALL but not in other malignancies. For all groups combined, BIA was significantly different in the two analysers. CONCLUSION: Care needs to be taken in the application of equations derived from the normal population to body composition measurement in children treated for ALL.

Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party.

The clinical features, cytogenetics and response to treatment have been examined in 180 infants (aged <1 year) with acute leukaemia; 118 with acute lymphoblastic leukaemia (ALL) and 62 with acute myeloid leukaemia (AML). Comparison of clinical features showed no difference in age or sex distribution between infants with ALL and AML but infants with ALL tended to have higher leucocyte counts at presentation. Cytogenetic abnormalities involving 11q23 were found in 66% of ALL and 35% of AML cases, the commonest, t(4;11) being found only in ALL. The other recognised 11q23 translocations were found in both types of leukaemia. Few patients had the common cytogenetic abnormalities associated with ALL in older children and few with AML had good risk abnormalities. Four year event-free survival 60% cf 30% (P = 0.001) and survival 65% cf 41% (P = 0.007) were significantly better in AML than ALL. These results were due to a lower risk of relapse 27% cf 62% at four years. Superior event-free survival was also seen in the subgroup of patients with 11q23 abnormalities and AML (55% cf 23%). The reasons for superior response in AML are unknown but may be related to the intensity of treatment, lineage of the leukaemia or other as yet unidentified factors.

Self-help group meeting attendance among clients with dual diagnoses.

This study explores factors associated with self-help group meeting attendance in the aftercare of 81 clients with dual diagnoses of severe mental illness and chemical dependency following their discharge from an inpatient chemical dependency treatment program. It also explores the association between self-help group meeting attendance and treatment outcomes. Data were collected from patient records and results of the Addiction Severity Index (ASI) administered as part of an earlier experiment that evaluated the effectiveness of the treatment program. Collaterals also provided follow-up information. Of thirteen variables examined, only two were associated with increased self-help group meeting attendance: having more years of education and having a major substance problem that did not include alcohol. No association was found between self-help group meeting attendance and treatment outcome regarding psychiatric problem severity or five other domains of the ASI. A moderate association was found indicating that more self-help group meeting attendance was related to improvements in the legal problems domain of the ASI. Implications are discussed for future research and for improving self-help group meeting attendance and its influence on treatment outcomes for individuals with dual diagnoses.

Fatal graft-versus-host disease following HLA-mismatched donor lymphocyte infusion.

We report the case of a 10-year-old boy with molecular relapse of CML following unrelated donor BMT who developed fatal grade 4 acute GVHD of the gut and liver following one antigen-mismatched donor lymphocyte infusion. Previous experience of donor lymphocyte infusion in the HLA-mismatched setting is reviewed and the role of adoptive immunotherapy in this situation is discussed.

Improved outcome of alternative donor bone marrow transplantation in children with severe aplastic anaemia using a conditioning regimen containing low-dose total body irradiation, cyclophosphamide and Campath.

The increasing success of human leucocyte antigen (HLA)-matched sibling donor (MSD) transplants and combination immunosuppressive treatments have dramatically improved the prognosis of severe aplastic anaemia (SAA) in children and young adults. For patients who lack a MSD there is a significant minority who fail immunosuppressive therapy or suffer from a severe constitutional aplastic anaemia in which immunosuppression would be ineffective. Alternative donor bone marrow transplantation (AD-BMT) has only had limited success in this context. We report the successful outcome of AD-BMT in eight consecutive patients aged 7 months to 15 years, six of whom had acquired aplastic anaemia who had previously failed to respond to immunosuppression, and two of whom had a severe (non-Fanconi) constitutional aplastic anaemia. All eight patients had received multiple red cell and platelet transfusions. We used a new combination of agents for pretransplant conditioning aiming to maximize immunosuppression and minimize toxicity, consisting of Campath-1G or -1H, cyclophosphamide and low-dose total body irradiation (LD TBI) or fludarabine. Toxicity was minimal and all eight children are alive, well and free of disease at a median follow-up of 32 months. We suggest that this approach could facilitate the successful treatment of children with SAA in whom immunosuppressive therapy has failed or is not appropriate.

Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia.

Between May 1988 and June 2000, 698 children were treated in the Medical Research Council acute myeloid leukemia 10 and 12 trials. The presenting features and outcomes of therapy in these children were compared by age. Although there was no single cutoff in age, younger children were more likely to have intermediate risk and less likely to have favorable cytogenetics (P <.001), and they had a higher incidence of translocations involving chromosome 11q23 (P <.001). The distribution of French-American-British (FAB) types also varied with age; FAB types M5 (P <.001) and M7 (P <.001) were more common in early childhood, whereas older children were more likely to have FAB types M0 (P =.03), M1 (P =.04), M2 (P =.005), and M3 (P <.001). Involvement of the central nervous system at diagnosis was also more common in the youngest children (P =.01). Younger children had more severe diarrhea (P =.002), whereas older children had worse nausea and vomiting (P =.01) after chemotherapy. When adjusted for other important factors, complete remission rates were similar (P =.5) and although there was less resistant disease in younger children (P =.003), this was partially balanced by a slight increase in deaths during induction therapy in younger patients (P =.06). On multivariate analysis overall survival (P =.02), event-free survival (P =.02), and disease-free survival were better (P =.06) in younger children due to a lower relapse rate (P =.02) especially in the bone marrow (P =.02).

Outcome for children after failed transplant for primary haemophagocytic lymphohistiocytosis.

Primary haemophagocytic lymphohistiocytosis is a rare disorder of childhood, which is usually fatal without allogeneic stem cell transplantation (SCT). For children who lack a matched family or closely matched unrelated donor, SCT using haploidentical parental stem cells has been used, but is associated with an increased risk of graft failure. The most appropriate subsequent management for those children who survive after graft rejection is currently unclear. We report the outcome for three such children. After a period of disease quiescence lasting 4 months to 8 years, disease recurrence and subsequent death occurred in each case. Accordingly, a second SCT is recommended.

Are glomerular filtration rate estimations necessary before high dose methotrexate?

Glomerular filtration rates (GFR) were estimated in 168 children (227 estimates) before treatment for haematological malignancies with high dose, intravenous methotrexate. Clinical management was altered on the basis of GFR in only two cases, both of whom had tumour lysis syndrome. Routine estimations of GFR do not contribute to management.

Improved prognosis for acquired aplastic anaemia.

This study compared the prognosis of patients treated for aplastic anaemia at Great Ormond Street Hospital for Children from 1973-88 (group A; n = 38) with a more recent cohort from 1989-96 (group B; n = 37). The two groups were similar in terms of clinical history, age, and severity of aplasia. The main treatment differences included the use of androgen treatment in group A (21 of 38 patients) but not in group B, and the addition of cyclosporin A to immunosuppressive treatment for 14 patients in group B. Actuarial survival at eight years' follow up was significantly better for group B (84%; 95% CI, 68% to 93%) than for group A (45%; 95% CI, 30% to 60%), because of improved outcome for both immunosuppressive treatment (86% v 39%) and bone marrow transplantation (93% v 56%). There was no evidence for late clonal disorders or secondary malignancies in survivors in either group. The prognosis for aplastic anaemia has improved greatly in recent years so that over 80% of children are long term survivors.

Granulocyte colony-stimulating factor ameliorates toxicity of intensification chemotherapy for acute lymphoblastic leukemia.

BACKGROUND: Intensification chemotherapy improves the prognosis for children with acute lymphoblastic leukemia (ALL), but results in considerable morbidity, primarily due to myelosuppression with resultant neutropenia. Recombinant granulocyte colony-stimulating factor (G-CSF) shortens neutropenia following intensive chemotherapy, but potential benefits in the therapy of ALL remain inadequately explored. Accordingly, a randomized, crossover study was undertaken to clarify this issue. PROCEDURE: Seventeen children with acute lymphoblastic leukemia or T-cell non-Hodgkin lymphoma and treated on standard protocols were randomized to receive G-CSF following either the first or second intensification blocks of chemotherapy. G-CSF was administered as a single daily subcutaneous injection of 5 mcg/kg from day 9 following the start of intensification therapy, and continued until the neutrophil count exceeded 0.5 x 10(9)/l for 3 days. Study endpoints were days of neutropenia (neutrophils < 1 x 10(9)/l) and severe neutropenia (neutrophils < 0.5 x 10(9)/l), days in hospital, days of fever, and days on antibiotics. RESULTS: There were significant reductions in the duration of neutropenia (95% confidence interval 3.8-8 days, P = 0.0001), severe neutropenia (95% confidence interval 1.8-7.4 days, P = 0.002), and days in hospital (95% confidence interval 0.9-6.3 days, P = 0.01) for children receiving G-CSF. Overall, the duration of neutropenia was longer following the second block (95% confidence interval 2.2-6.4 days, P = 0.0003), but this difference was abolished by G-CSF, and children, receiving G-CSF after the second intensification were more likely to restart maintenance chemotherapy on schedule (P = 0.05). CONCLUSIONS: G-CSF reduces the hematological toxicity of intensification chemotherapy and may allow improved compliance with treatment scheduling.

Relative osteopenia after treatment for acute lymphoblastic leukemia.

Osteoporosis in adult life is associated with a significant morbidity and may be predisposed to by osteopenia and failure to reach peak bone mass in childhood. Children treated for acute lymphoblastic leukemia (ALL) may be at risk of osteopenia as a result of previous therapy or as a consequence of the disease process itself. Dual energy x-ray absorptiometry measurements of bone mineral content (BMC) for the whole body and at the lumbar spine and hip were taken in 35 (14 male) long-term survivors of ALL and compared with results in 20 (10 male) survivors of other malignancies and 31 (17 male) healthy sibling controls. The measured BMC was expressed as a percentage of a predicted value derived from the control group and based on the variables that had influence upon it. BMC (%) was reduced at the spine in the ALL group compared with controls [92.4 (8.0)% versus 100.4 (9.7)%, respectively; p < 0.005] and at the hip compared with both other malignancies and controls [89.0 (11.5)% versus 96.1 (11.7)% and 100.4 (9.2)%, respectively; p < 0.0005]. Increasing length of time off therapy was associated with a significant increase in %BMC at both the spine and the hip. For the spine, this association was significantly different between the ALL group and other malignancies, suggesting that any gain in %BMC after therapy was slower in children treated for ALL. Both exercise capacity and levels of physical activity were correlated with %BMC at the hip (r = 0.44, p < 0.001 and r = 0.29, p < 0.01, respectively). Previous exposure to methotrexate, ifosfamide, and bleomycin was associated with a reduction in %BMC at the spine. Exposure to 6-mercaptopurine and cisplatin was associated with a reduction at the hip. In conclusion, children treated for ALL are osteopenic. The mechanism is probably multifactorial but is partially related to previous chemotherapy, limited exercise capacity, and relative physical inactivity.

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party.

Between May 1988 and March 1995, 359 children with acute myeloid leukaemia (AML) were treated in the MRC AML 10 trial. Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children relapsed--103 in the bone marrow only, 12 in the bone marrow combined with other sites, and six had isolated extramedullary relapses (site was not known in four cases). Eighty-seven children received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied--44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates--children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P < 0.0001).

Daily energy expenditure and physical activity in survivors of childhood malignancy.

Changes in body composition, in particular the onset of obesity, may result from reductions in total daily energy expenditure (TDEE) as a consequence of relative physical inactivity. Children previously treated for acute lymphoblastic leukemia (ALL) become obese, yet the mechanism remains undefined. TDEE and physical activity levels [PAL = TDEE/basal metabolic rate (BMR)] were measured in 34 long-term survivors of ALL and compared with results from 21 survivors of other malignancies and 32 healthy sibling control subjects using the flex-heart rate technique. Body composition was measured by dual energy x-ray absorptiometry. The median TDEE was reduced in the ALL group (150 kJ x kg d(-1)) compared with other malignancies and controls (207 and 185 kJ x kg d(-1), respectively, p < 0.01). This reduction was accounted for mainly by a relative decrease in the PAL of the ALL group (1.24) compared with both other malignancies and controls (1.58 and 1.47, respectively, p < 0.01). TDEE and PAL were correlated with percentage body fat (r = -0.39, p < 0.001 and r = -0.24, p < 0.05, respectively). Obesity in survivors of ALL may, in part, be explained by a reduction in TDEE as a consequence of reduced PAL. The cause of such reduction is uncertain.

Measured and predicted bone mineral content in healthy boys and girls aged 6-18 years: adjustment for body size and puberty.

Dual-energy X-ray absorptiometry (DEXA) is a rapid and precise technique for the assessment of bone mineralization in children. Interpretation of the results in growing children is complex as results are influenced by age, body size (height and weight) and puberty. Conventionally, bone mineral data derived from DEXA have been presented as an areal density [BMD; bone mineral content (BMC, g)/projected bone area (BA, cm2)], yet this fails to account for changes in BMC that result from changes in age, body size or pubertal development. Measurement of BMC and BA of the whole body, lumbar spine and left hip were made in 58 healthy boys and girls using DEXA. The relationship between BMC and BA was curvilinear, with the best fit being that of a power model (BMD = BMC/BAlambda, where lambda is the exponent to which BA is raised in order to remove its influence on BMC). The value of lambda changed when measures of body size and puberty were taken into account (e.g. for lumbar spine from 1.66 to 1.49). Predictive formulae for BMC were produced using regression analysis and based on the variables of age, body size and pubertal development. This provides a method for interpreting the measured BMC which is independent of such variables and a constant reference range for children aged 6-18 y.