Tim O B Eden

Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial

Corticosteroids are an essential component of treatment for acute lymphoblastic leukaemia (ALL). Prednisolone is the most commonly used steroid, particularly in the maintenance phase of therapy. There is increasing evidence that, even in equipotent dosage for glucocorticoid effect, dexamethasone has enhanced lymphoblast cytotoxicity and penetration of the central nervous system (CNS) compared with prednisolone. Substitution of dexamethasone for prednisolone in the treatment of ALL might, therefore, result in improved event‐free and overall survival. Children with newly diagnosed ALL were randomly assigned to receive either dexamethasone or prednisolone in the induction, consolidation (all received dexamethasone in intensification) and continuation phases of treatment. Among 1603 eligible randomized patients, those receiving dexamethasone had half the risk of isolated CNS relapse (Pu2003=u20030·0007). Event‐free survival was significantly improved with dexamethasone (84·2% vs. 75·6% at 5u2003years; Pu2003=u20030·01), with no evidence of differing effects in any subgroup of patients. The use of 6·5u2003mg/m2 dexamethasone throughout treatment for ALL led to a significant decrease in the risk of relapse for all risk‐groups of patients and, despite the increased toxicity, should now be regarded as part of standard therapy for childhood ALL.

Long-term follow-up of the United Kingdom medical research council protocols for childhood acute lymphoblastic leukaemia, 1980-2001.

Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party conducted four clinical trials in acute lymphoblastic leukaemia (ALL), which recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of central nervous system-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL XD template (two intensification phases), examined the role of different steroids in induction and of different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared with other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. In addition, ALL97 and ALL97/99 showed a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials, there has been a major improvement in both event-free and overall survival for children in the United Kingdom with ALL.

Long-term results of large prospective trials in childhood acute lymphoblastic leukemia.

Much progress has been made in the biological characterization of acute lymphoblastic leukemia (ALL). Many biologic features with prognostic significance have been used together with clinical factors to define patient groups for risk-adapted therapy. However, it is well recognized that the prognostic significance of virtually all variables depends on the type and intensity of treatment. The differences in risk classification, eligibility (eg upper or lower age limit) and composition of ethnic or racial population have made it difficult to compare results between study groups. The comparison is further complicated by the inclusion of only subsets of patients in some publications. In October 1985, an international workshop (organized by R Mastrangelo) was held in Rome during which recommendations were made to report study results by common, easily available criteria (age and presenting leukocyte count); to collect prospectively information on organ involvement, immunphenotype, genetics and treatment response; and to use standard statistical methods to analyze data.4 Despite this effort, different risk classifications continue to be used, and a large number of clinical trials had been conducted on subgroups of ALL, especially in the USA. In 1993, the US National Cancer Institute organized a workshop for the US cooperative study groups and major institutions to develop uniform risk criteria. The recommendations published in 19965 were more widely accepted. The major groups defined by age and leukocyte count were identical to that of the Rome workshop (Table 1). While the importance of cytogenetics and molecular genetics were recognized, they were not included in the risk criteria because the tests were not widely available at that time. The

Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial.

BACKGROUNDn6-mercaptopurine has been a standard component of long-term continuing treatment for childhood lymphoblastic leukaemia, whereas 6-thioguanine has been mainly used for intensification courses. Since preliminary data have shown that 6-thioguanine is more effective than 6-mercaptopurine, we compared the efficacy and toxicity of the two drugs for childhood lymphoblastic leukaemia.nnnMETHODSnConsecutive children with lymphoblastic leukaemia diagnosed in the UK and Ireland between April, 1997, and June, 2002, were randomly assigned either 6-thioguanine (750 patients) or 6-mercaptopurine (748 patients) during interim maintenance and continuing therapy. All patients received 6-thioguanine during intensification courses. We analysed event-free and overall survival on an intention-to-treat basis. We obtained toxicity data using an adverse-event reporting system, with follow-up questionnaires to seek detailed information for specific toxicities. This trial is registered with the International Standard Randomised Controlled Number 26727615 with the name ALL97.nnnFINDINGSnAfter a median follow up of 6 years, there was no difference in event-free or overall survival between the two treatment groups. Although 6-thioguanine conferred a significantly lower risk of isolated CNS relapse than did 6-mercaptopurine (odds ratio [OR] 0.53, 95% CI 0.30-0.92, p=0.02), the benefit was offset by an increased risk of death in remission (2.22, 1.20-4.14, p=0.01), mainly due to infections during continuing therapy. Additionally, 95 patients developed veno-occlusive disease of the liver. Of these, 82 were randomly assigned 6-thioguanine, representing 11% of all 6-thioguanine recipients. On long-term follow-up, about 5% of 6-thioguanine recipients have evidence of non-cirrhotic portal hypertension due to periportal liver fibrosis or nodular regenerative hyperplasia.nnnINTERPRETATIONnCompared with 6-mercaptopurine, 6-thioguanine causes excess toxicity without an overall benefit. 6-mercaptopurine should remain the thiopurine of choice for continuing therapy of childhood lymphoblastic leukaemia.

The problem of treatment abandonment in children from developing countries with cancer

There is an inequality gap between the outcome of childhood cancer in resource, rich and limited countries. Abandonment of treatment is one of the reasons for this.Background n nThere is an inequality gap between the outcome of childhood cancer in resource, rich and limited countries. Abandonment of treatment is one of the reasons for this. n n n nProcedure n nWe searched the medical literature for evidence on abandonment, its causes, and any preventative interventions. n n n nResults n nAbandonment is a very real problem all across the developing world. Cancers associated with poorer prognosis seem to have higher abandonment rates. It is also related to the socio-economic and educational status of parents, travel time to treatment centers, and affordable, locally available treatment. n n n nConclusions n nTwinning between institutions, which includes several preventative interventions, has clearly been shown to work. Pediatr Blood Cancer 2007;49:941–946.

p53 germline mutations in Li-Fraumeni syndrome

Germline mutations within a defined region of the p53 gene have recently been found in families with the Li-Fraumeni syndrome (LFS). In the present study this region of p53 was sequenced in affected individuals from 8 families with LFS. In only 2 of them were such mutations detected. Our findings suggest that the p53 mutation could be the primary lesion in some but not all families with LFS, and confirm that there is a hot spot for these mutations at the CpG dinucleotide moiety of codon 248. Assigning risks and counselling families on the basis of presence of p53 mutations should be approached with caution.

Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis

Purpose: The HOX genes comprise a large family of homeodomain-containing transcription factors, present in four separate clusters, which are key regulators of embryonic development, hematopoietic differentiation, and leukemogenesis. We aimed to study the role of DNA methylation as an inducer of HOX gene silencing in leukemia. Experimental Design: Three hundred and seventy-eight samples of myeloid and lymphoid leukemia were quantitatively analyzed (by COBRA analysis and pyrosequencing of bisulfite-modified DNA) for methylation of eight HOXA and HOXB cluster genes. The biological significance of the methylation identified was studied by expression analysis and through re-expression of HOXA5 in a chronic myeloid leukemia (CML) blast crisis cell line model. Results: Here, we identify frequent hypermethylation and gene inactivation of HOXA and HOXB cluster genes in leukemia. In particular, hypermethylation of HOXA4 and HOXA5 was frequently observed (26-79%) in all types of leukemias studied. HOXA6 hypermethylation was predominantly restricted to lymphoid malignancies, whereas hypermethylation of other HOXA and HOXB genes was only observed in childhood leukemia. HOX gene methylation exhibited clear correlations with important clinical variables, most notably in CML, in which hypermethylation of both HOXA5 (P = 0.00002) and HOXA4 (P = 0.006) was strongly correlated with progression to blast crisis. Furthermore, re-expression of HOXA5 in CML blast crisis cells resulted in the induction of markers of granulocytic differentiation. Conclusion: We propose that in addition to the oncogenic role of some HOX family members, other HOX genes are frequent targets for gene inactivation and normally play suppressor roles in leukemia development.

Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study

Abstract Objective To test the hypothesis that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia. Design and setting The United Kingdom childhood cancer study (UKCCS) is a large population based case-control study of childhood cancer across 10 regions of the UK. Participants 6305 children (aged 2-14 years) without cancer; 3140 children with cancer (diagnosed 1991-6), of whom 1286 had acute lymphoblastic leukaemia (ALL). Main outcome measure Day care and social activity during the first year of life were used as proxies for potential exposure to infection in infancy. Results Increasing levels of social activity were associated with consistent reductions in risk of ALL; a dose-response trend was seen. When children whose mothers reported no regular activity outside the family were used as the reference group, odds ratios for increasing levels of activity were 0.73 (95% confidence interval 0.62 to 0.87) for any social activity, 0.62 (0.51 to 0.75) for regular day care outside the home, and 0.48 (0.37 to 0.62) for formal day care (attendance at facility with at least four children at least twice a week) (P value for trend < 0.001). Although not as striking, results for non-ALL malignancies showed a similar pattern (P value for trend < 0.001). When children with non-ALL malignancies were taken as the reference group, a significant protective effect for ALL was seen only for formal day care (odds ratio = 0.69, 0.51 to 0.93; P = 0.02). Similar results were obtained for B cell precursor common ALL and other subgroups, as well as for cases diagnosed above and below age 5 years. Conclusion These results support the hypothesis that reduced exposure to infection in the first few months of life increases the risk of developing acute lymphoblastic leukaemia.

Determinants of symptom interval in childhood cancer.

The duration of symptoms before diagnosis (lag time) was defined for 184 of 236 children diagnosed as having a malignancy at the Royal Hospital for Sick Children, Edinburgh for the time period January 1982 until December 1990. The natural logarithm of the lag time was correlated with age, gender, diagnostic group, white cell count in acute leukaemia, clinical stage of disease in solid tumours, and event free survival. Age was significantly associated with lag time, older children presenting later. In the diagnostic groups, mean lag time ranged from 2.8 weeks in nephroblastoma to 13.3 weeks for brain tumours. Diagnostic group was predictive for lag time after adjustment for age, with for example, a significantly longer lag time for those with brain tumours. However lag time was not predictive of event free survival and it is likely that lag time has other major determinants. When compared with previous studies, there also appears to be a regional variation in lag time for diagnostic groups. It seems likely that this is a reflection of geographical difference in the structure of health systems and is therefore yet another important determinant.

Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial.

A retrospective analysis of children with first relapse of acute lymphoblastic leukaemia (ALL), treated on the UKALL R2 protocol at four different hospitals, between June 1995 and December 2002 was performed. Of the 150 children 139 (93%) achieved a second complete remission. The overall survival (OS) and event‐free survival (EFS) for the whole group was 56% and 47% respectively. The duration of first complete remission and immunophenotype, but not sites of relapse, were predictive for survival. Using the Berlin–Frankfürt–Münster risk stratification for relapsed ALL, the OS and EFS for standard, intermediate (IR) and high risk (HR) groups were 92% and 92%, 64% and 51%, and 14% and 15%, respectively; Pu2003<u20030·0001 for both OS and EFS. In the IR group, those with a very early isolated central nervous system relapse also had a significantly worse outcome (Pu2003=u20030·0001). Given the poor outcome of a second relapse, clear strategies are required to identify those in the IR group who will most benefit from stem cell transplantation (SCT). A higher proportion (16%) of induction failures in the HR group suggest the need for novel agents during this phase of treatment, but SCT was associated with a lower relapse rate and better outcome than those treated with chemotherapy alone.