C. C. Bailey

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically‐defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event‐free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph‐positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event‐free survival of 87.5% at 5 years. A number of other non‐random abnormalities were identified with no clear prognostic significance.

Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia : the MRC UKALL X experience

We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event‐free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT).

Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI).

In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment‐related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Downs syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.

Improved survival with early intensification: combined results from the Medical Research Council childhood ALL randomised trials, UKALL X and UKALL XI

The Medical Research Council (MRC) United Kingdom trial for childhood acute lymphoblastic leukaemia (UKALL X) randomised patients aged 0–14 years inclusive with an initial white blood count of less than 100 × 109/l to receive an early intensification block, a late intensification block, both, or neither. The next trial, UKALL XI, for children aged 1–14 years, randomised between different central nervous system (CNS) directed therapies. At the beginning of the trial, all patients were also randomised between late intensification alone and both early plus late blocks. The effects of both the early and the late block in UKALL X alone have been reported previously. This paper examines the effect of the addition of the early intensification block to treatment which included late intensification, combining the data from UKALL X and the first part of UKALL XI. Early intensification was associated with fewer bone marrow relapses and a reduction in the odds of death of 0.63 (95% confidence interval: 0.46–0.87). Survival was significantly improved with an increase at 5 years of 8%, from 79 to 87%. Following this demonstration that early intensification improves survival, the effect of a third intensification block is under investigation.

Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X

The relationship between the prescribed dose of drugs during continuing (maintenance) therapy, the degree of marrow suppression caused, and subsequent event‐free survival was examined in a cohort of 740 children with lymphoblastic leukaemia treated on MRC UKALL X. Girls, younger children, and patients who had received intensification treatment, were prescribed lower doses of mercaptopurine, became neutropenic more readily, and had more interruptions of treatment. Children who had one or more episodes of neutropenia with a count of < 0.5 × 109/l had a better prognosis than those who never became neutropenic.

Cytomorphology of childhood lymphoblastic leukaemia: a prospective study of 2000 patients

Blast cell morphology of children with lymphoblastic leukaemia (ALL) entering two national multicentre trials was prospectively reviewed by three haematologists to define the clinical importance of (a) French–American–British (FAB) classification, (b) the presence of cytoplasmic vacuoles, and (c) the presence of ‘hand‐mirror’cells.

Failure of a new protocol to improve treatment results in paediatric lymphoblastic leukaemia: lessons from the UK Medical Research Council trials UKALL X and UKALL XI

Summary. The impact of various types of intensification therapy was examined in a cohort of 3617 children aged 1–14 years with acute lymphoblastic leukaemia (ALL) enrolled in the Medical Research Council (MRC) UKALL X (1985–90) and UKALL XI (1990–97) trials. UKALL XI was modified in 1992 to incorporate the ‘best arm’ of UKALL X with two 5‐d intensification blocks at 5 and 20 weeks, and an additional randomization in respect of a third intensification at 35 weeks but omission of two consecutive injections of daunorubicin during induction. All children were eligible for randomization irrespective of risk group. The impact of the various types of intensification therapy was examined in a stratified analysis. At a median follow up of 102 months, both trials had an identical event‐free survival of 61% (95% CI 58–63%) at 8 years. Survival at 8 years in UKALL XI was significantly better in than in UKALL X, 81% (79–83%) compared with 74% (72–76%) (P = < 0·001), owing to improved management of relapse. There was a highly significant trend in reduction of the number of relapses and deaths with increased intensity of therapy both for children with initial leucocyte count < 50 × 109/l (P = < 0·001) and ≥ 50 × 109/l (P = 0·002). Introduction of a third late intensification block compensated for omission of anthracyclines during induction but produced little additional benefit. These results show, in a large cohort of patients, that minor modifications of therapy may influence relapse rate and obviate the benefit of previous randomized trials. The failure to adapt treatment for higher risk children contributed to these disappointing results.

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

Summary. The Medical Research Council acute lymphoblastic leukaemia trials (UKALL X and XI) recruited 3702 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.

A comparison of cox regression and neural networks for risk stratification in cases of acute lymphoblastic leukaemia in children

For most diseases there is considerable interest in the problem of classification, both in relation to medical diagnosis and for prognosis. Multivariate statistical methods are conventionally used as an aid to clinical decision making. Neural Networks (NNs) offer an alternative approach to this type of classification problem. Exploiting 1271 cases from the United Kingdom Medical Research Council UKALL X trial for childhood Acute Lymphoblastic Leukaemia (ALL), cases were stratified as ‘high risk’ or ‘standard risk’ using both the survival analysis technique of Cox Regression and trained neural networks. Based on 10 random trials with a further 300 cases, and predicting overall five year survival from age, sex and white cell count only, there was no significant difference between the two approaches in terms of mean Receiver Operating Characteristic area, though the regression model was slightly superior to a single neural network at high sensitivity (Wilcoxon signed rank test; p = 0.033). A composite of two networks, one of which included additional prognostic factors, restored the position of no significant difference. It was concluded that in the UKALL X dataset, factors predictive of outcome are fully described by a Cox regression analysis, and that a neural network-based analysis identified no additional prognostic features. The value of the network analysis lay in suggesting that the maximum amount of prognostic information has been extracted from the database.