How I manage aplastic anaemia in children.

Aplastic anaemia (AA) is a rare heterogeneous condition in children. 15-20% of cases are constitutional and correct diagnosis of these inherited causes of AA is important for appropriate management. For idiopathic severe aplastic anaemia, a matched sibling donor (MSD) haematopoietic stem cell transplant (HSCT) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. IST with horse anti-thymocyte globulin (ATG) is superior to rabbit ATG and has good long-term results. In contrast, IST with rabbit ATG has an overall response of only 30-40%. Due to improvements in outcome over the last two decades in matched unrelated donor (MUD) HSCT, results are now similar to that of MSD HSCT. The decision to proceed with IST with ATG or MUD HSCT will depend on the likelihood of finding a MUD and the differing risks and benefits that each therapy provides.

Results of a randomized trial in children with Acute Myeloid Leukaemia: medical research council AML12 trial.

The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten-year event-free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate [32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00] and disease-free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.

Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom.

BACKGROUND: Anthracycline cardiomyopathy is of concern in children treated for acute myeloid leukaemia (AML), but there are few data on the incidence and natural history of cardiotoxicity after AML treatment in the United Kingdom, where regimens have included high anthracycline exposure. PROCEDURE: Prevalence and predictors of cardiotoxicity were retrospectively reviewed in 124 children treated on the MRC AML 10 and AML 12 trials in a single, large centre from November 1987 to September 2004. Subclinical cardiotoxicity was defined as a shortening fraction of less than 28% and clinical cardiomyopathy as evidence of heart failure, and both were classified as late cardiotoxicity 1 year after completing first line therapy. RESULTS: Cumulative survival was 61% at 10 years. The prevalence of early and late cardiotoxicity was 13.7% (95%-CI: 8.2-22.0%) and 17.4% (95%-CI: 10.9-26.8%), respectively. Early cardiotoxicity was a strong predictor (OR = 9.18; 95%-CI: 2.10-40.11; P < 0.005) and children who received salvage therapy following relapse showed a trend towards increased late cardiotoxicity (OR = 3.53; 95%-CI: 0.86-14.48; P < 0.08). Subclinical cardiotoxicity resolved spontaneously in all but one case, but clinical cardiomyopathy always required continuing therapy. Two children died of cardiomyopathy and six remained on medical therapy. CONCLUSIONS: Anthracycline cardiotoxicity remains a major concern for survivors of childhood AML and correlates with early cardiotoxicity and treatment intensity. Long-term follow-up is required to fully determine the outcome for children with subclinical cardiotoxicity.

Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12.

PURPOSE: Karyotype is an independent indicator of prognosis in acute myeloid leukemia (AML) that is widely applied to risk-adapted therapy. Because AML is rare in children, the true prognostic significance of individual chromosomal abnormalities in this age group remains unclear. PATIENTS AND METHODS: This cytogenetic study of 729 childhood patients classified them into 22 subgroups and evaluated their incidence and risk. RESULTS: Rearrangements of 11q23 were the most frequent abnormality found in approximately 16% of patients, with 50% of these in infants. The outcome for all patients with 11q23 abnormalities was intermediate; no difference was observed for those with t(9;11)(p21-22;q23). The core binding factor leukemias with the translocations t(8;21)(q22;q22) and inv(16)(p13q22) occurred at incidences of 14% and 7%, respectively, predominantly in older children, and their prognosis was favorable. An adverse outcome was observed in patients with monosomy 7, abnormalities of 5q, and t(6;9)(p23;q34). Abnormalities of 3q and complex karyotypes, in the absence of favorable-risk features, have been associated with an adverse outcome in adults, but the results were not significant in this childhood series. However, the presence of 12p abnormalities predicted a poor outcome. CONCLUSION: Because the spectrum of chromosomal changes and their risk association seem to differ between children and adults with AML, biologic differences are emerging, which will contribute to the redefinition of risk stratification for different age groups in the future.

Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials.

Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML-DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials. The unique clinical characteristics of ML-DS were confirmed. Overall survival (OS) of ML-DS at 5 years increased from 47% in UK children diagnosed from 1988 to 1995 to 75% in children diagnosed from 1996 to 2002. OS for DS children registered in AML 10 and AML 12 was 74% in 5 years and improved from AML 10 to AML 12 (56% vs. 83%) There was no significant difference in OS between DS and non-DS children (OS: 74% vs. 62%, P = 0.4) in the trials, but this result masked a significant increase in early death amongst DS children, with a significant reduction in mortality later on. Relapse was significantly reduced (3% vs. 39%, P = 0.0003), leading to the improved disease-free survival (83% vs. 56%, P = 0.02). Given the increased number of early treatment-related deaths, future treatment protocols should aim to reduce chemotherapy dosage or intensity whilst maintaining low rates of resistant and recurrent disease.

Optimizing therapy for myeloid disorders of Down syndrome.

Children with Down syndrome (DS) are at increased risk of leukaemia. Myeloid disorders include transient abnormal myelopoiesis (TAM), myelodysplasia (MDS) and acute myeloid leukaemia (AML). Mutations in the GATA-1 gene, which encodes for a transcription factor central to the normal development of the erythroid and megakaryocytic lineages, are found in cases of TAM, MDS and AML in DS children. DS children with MDS/AML mostly present between the ages of 1 and 4 years, and have a large predominance of megakaryoblastic disease (French-American-British type M7). The MDS and AML are part of a single disease entity (myeloid leukaemia of Down syndrome) that is extremely sensitive to chemotherapy. Resistant disease and relapse are rare, but treatment-related toxicity is high, and deaths in remission have exceeded those due to disease in most series. Accordingly, controlled dosage reduction is the focus of contemporary treatment studies.

Prognostic factors and outcome for children after second central nervous system relapse of acute lymphoblastic leukaemia.

The Medical Research Council acute lymphoblastic leukaemia trials (UKALL X and XI) recruited 3,702 children with ALL between January 1985 and March 1997. Seventy-nine children had central nervous system (CNS) involvement in their first two relapses. Fourteen children survived at a median follow-up of 22 months from second relapse; seven (9%) in third remission, two in later remissions and five with disease. Factors predictive of survival from second relapse were site (isolated CNS was better than combined CNS, P = 0.02) and time from diagnosis to second CNS relapse (longer time was better, P = 0.004). Prognosis after second CNS relapse is extremely poor, and palliative therapy is appropriate.

Results of treatment of children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt) in Great Britain 1990-99.

Between 1990 and 1999, 36 children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt), not associated with Down's syndrome, were diagnosed in Britain. A total of 31 children received intensive chemotherapy, six of whom proceeded to a bone marrow allograft in first remission, whereas two received an autograft. Of the 23 given chemotherapy only, four died of toxicity, 10 relapsed and nine are alive in first remission. Out of the 10 who relapsed, four are alive and disease-free following an allograft. Out of the 6 children given an allograft in first remission, two died of disease and four are alive in first remission. Both children given an autograft died of disease. Two children received an allograft without prior chemotherapy but died of toxicity. Three children received supportive care only, and one child survived. The overall survival was 51% at 5 years, and was superior in children with RAEBt (63%) compared with RAEB (28%, P = 0.03). Cytogenetics were available in 35 cases. Monosomy 7 was the most common abnormality (33% of cases). Survival in children with monosomy 7 was 22% at 5 years compared with 66% for the other patients (P = 0.05). Allowing for cytogenetics, outcomes of therapy appear similar to those for de novo acute myeloid leukaemia (AML), and it is appropriate for children with RAEB/RAEBt to be registered in AML trials.

Body composition of long-term survivors of acute lymphoblastic leukaemia.

BACKGROUND: Long-term quality of life is of growing importance in children previously treated for malignancy. Obesity defined indirectly from indices of height and weight, has been described in long-term survivors of acute lymphoblastic leukaemia (ALL) and hypothesised to be a consequence of previous cranial irradiation. PROCEDURE: In this study, measures of whole and regional body composition using skinfold and dual energy X-ray absorptiometry (DEXA) measurements have been made in 35 long-term survivors of ALL who had received cranial irradiation and chemotherapy. To assess the influence of cranial irradiation, results were compared with those obtained in 21 children treated for other malignancies, who received chemotherapy alone and with 31 healthy sibling controls. RESULTS: Girls treated for ALL were significantly fatter than those treated for other malignancies or healthy control siblings whether measured by skinfold thickness (median (range) 37.4% (17.9-41.3) vs. 24.6% (19.1-35.0) and 28.8% (19.6-43.1), respectively, P<0.01) or DEXA (33.5% (20.5-42.8) vs. 25.5% (16.5-31.0) and 24.5% (18.8-53.6), respectively, P<0.01). Boys treated for ALL were not significantly fatter than boys in the other two groups. Measures of whole body percent fat derived from DEXA were persistently less than those derived from skinfold measurements with a mean (95% CI) difference of 2.4% (1.7-3.1, P<0.001) for all groups combined. In ALL survivors, using regression equations for skinfold thicknesses derived from controls with DEXA as the 'gold standard' method, fat mass was significantly overestimated. CONCLUSION: Female survivors of ALL are significantly fatter than those of other malignancies and healthy sibling controls. Caution should be observed in the application of published equations, derived from the normal population, for the calculation of body composition in children treated for ALL. The mechanism of onset of obesity remains unclear, but is probably multifactorial and related to previous cranial irradiation.