Analysis of the immunophenotype of children treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia Trial XI (MRC UKALLXI). Medical Research Council Childhood Leukaemia Working Party.

Despite many years of meticulous immunophenotyping of childhood acute lymphoblastic leukaemia (ALL) cases the prognostic significance of some subtypes remains unclear. The Medical Research Council UKALLXI trial (1990-1996) in which uniform treatment has been given to 2090 children with ALL below the age of 18 years and above the age of 1 year, has afforded the opportunity to review these issues. Children with ALL of mature B cell type were not entered into this trial. Immunophenotype analysis was performed in each individual trial centre, but results were centrally reviewed in all cases, and were both available and considered adequate in 1934 (93%) of the first 2090 patients entered. The main diagnostic categories were early pre-B or null reported in 60 cases (3.1%), common ALL in 1242 (64.2%), pre-B in 252 (13.0%), 'common' or pre-B in 172 (8.9%) and T cell in 207 (10.7%) cases. Children with T cell disease were significantly more likely to be over the age of 10 years, with central nervous system disease at diagnosis and to be CD34 negative. They also had a higher incidence of high white cell count and were more likely to be of the French-American-British (FAB) L2 morphological subtype. Patients with 'null' cell disease tended to be less than 2 years or greater than 10 years of age, and CD13 and CD33 positive. CD10 was associated with lower white cell count (WBC) at diagnosis, younger age and FAB L1 morphological subtype. The presence of cytoplasmic immunoglobulin in pre-B cells was not associated with any specific clinical or laboratory features. CD34 positivity was less common in T cell patients and was associated with low WBC. Disease-free survival (DFS) and 95% confidence intervals (CI) at 5 years from diagnosis was 52% (95% CI: 44-59%) for T cell disease, 58% (95% CI: 43-73%) for early pre-B (or null cell) disease and 65% (95% CI: 62-68%) for common or pre-B disease; there being no significant difference between common and pre-B disease with regard to disease outcome. Patients with T cell disease had a worse prognosis than any other immunophenotype group (P < 0.00005). However this worse outcome was no longer significant after allowing for the other principal prognostic factors of age, gender and white cell count at diagnosis except for the very small number with WBC <20 x 10(9)/l and T cell disease. Those with CD10-positive leukaemia did better than those who were CD10 negative (P < 0.00005), with DFS at 5 years 64% (95% CI: 62-67%) for positive vs 56% (95% CI: 49-62%) for CD10 negative. CD10 positivity did not have independent significance when white count, gender and age were taken into account. CD13, CD33, and cytoplasmic mu positivity carried no prognostic significance

Plasma levels of von Willebrand factor antigen in acute bronchitis and in a normal population

von Willebrand factor (vWF) is a large glycoprotein secreted predominantly by endothelial cells in both the systemic and pulmonary circulations and has a central role in the formation of the platelet plug. It has been put forward as a possible marker of endothelial cell injury, but is not ideal in that it is not specific for either the pulmonary or systemic circulation and may be released as part of the acute phase response from otherwise healthy endothelial 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.

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 x 10(9)/l (P = < 0.001) and > or = 50 x 10(9)/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

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics

Combined factor V and factor VIII deficiency in a Thai patient: a case report of genotype and phenotype characteristics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71442/1/j.1365-2516.2005.01092.x.pd