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Twenty-one children who suffered an acute encephalopathic illness during induction chemotherapy for ALL are described. Convulsions and coma were a major feature of this illness. In the absence of other predisposing factors we feel that the encephalopathy was secondary to drug toxicity. Two children died, and 4 of the surviving children have also died. Modifications of antileukemic therapy because of encephalopathic illness may have had a part to play in the outcome for some of these children. The surviving children appear to be neurologically and developmentally normal.

Of 53 children with lymphoblastic leukaemia in their first remission who reached the fourth year after stopping treatment, 4 have subsequently relapsed and their cases are described. All are boys and 3 were over 10 at diagnosis despite there being only 6 such patients in the group overall. This suggests that teenage males are at special risk of late relapse and should not be considered cured on criteria applicable to younger females.

Consecutive children suffering from pre-B lymphoblastic leukaemia (pre-B ALL) were compared with those who had 'common' ALL (C-ALL) to assess any clinical and pathological differences between the two groups. Over 101 months 27 pre-B children were seen-an incidence in the population served of around 0.8/100,000 per year. There was some time-clustering and 12 of the 27 presented in one year (1987). The 51 patients with C-ALL who presented for comparison were distributed more evenly over the study period. Pre-B children had more basophilic blast cells with less periodic acid-Schiff positivity. They had higher presenting white cell counts and serum concentrations of lactic dehydrogenase; two variables which were correlated with each other. There was a trend towards pre-B children being younger and fewer had hyperdiploid blasts, but these differences were not statistically significant. No difference from 'common' ALL in response to therapy was apparent for the pre-B patients at a median follow up time of 17 months--too short a period for any conclusion to be drawn. Other than immunophenotype, pre-B ALL has no pathognomonic features, but there are differences from C-ALL in the distribution of some disease characteristics known to be associated with a worse prognosis.

Enolase isoenzymes were measured in the cerebrospinal fluid of seven consecutive children with lymphoblastic leukemia who developed meningeal (CNS) leukemia. Assays were performed at the time CNS disease was discovered and during the subsequent 4 weeks. Three of the seven were also examined 1-3 months before CNS relapse was confirmed. Fourteen children on similar systemic therapy without CNS infiltration served as controls. Prior to and at the onset of CNS disease alpha enolase was elevated in all patients studied. The gamma form was raised in only one beforehand and only three at the time of relapse. The alpha isoenzyme was related to the blast cell count and fell during therapy in all but one child, whereas the gamma was not and showed no significant change. The three patients with raised gamma enolase were the only children with other than common lymphoblastic leukemia. There was no clear indication whether either enzyme concentration had any importance in terms of disease outcome, although one child developed a further CNS relapse 10 months later. He was the only patient whose alpha enolase rose following intrathecal methotrexate. Neuronal disruption due to common lymphoblastic leukemia in the CNS appears to be minimal. Other types of leukemia may give rise to more neuronal damage. The alpha isoenzyme, from glial tissue and malignant cells, may be elevated even in the absence of detectable blasts in the cerebrospinal fluid and may be a sensitive marker of CNS infiltration in such circumstances.

This improvement in medium disease-free survival is probably a result of sustained early cell kill, and UKALL VIII has enabled us to define risk categories requiring even further continuous intensification, as now introduced in MRC UKALL X. Thanks to the greater availability of blood products, for example, the rational use of antibiotics and the development of expertise amongst nurses and doctors, such sustained therapy can now be delivered on a multi-centre basis, but only in experienced centres. The monitoring and removal of morbidity are essential if the advantages of this more sustained chemotherapy are to be realised. All elements of therapy require controlling and patients, parents and, above all, doctors must comply with protocol requirements in order to build further upon these initial promising results.

A formal evaluation of the Sequoia-Turner Cell Dyn 900, a compact eight-parameter semi-automated blood cell counter, was carried out in a small paediatric haematology laboratory. The instrument's precision, linearity and carry-over were adequate. Comparison with a Coulter ZF6 system plus visual platelet count showed good agreement, and results in the UK National External Quality Assessment Scheme also compared well with 'all methods' values. Throughput was assessed at 54 eight-parameter counts per hour. The machine proved to be reasonably economical, highly reliable and easy to operate. It was popular with staff and can be recommended, particularly for the smaller laboratory.

6-Mercaptopurine is extensively used in the treatment of childhood lymphoblastic leukaemia to prolong the duration of remission achieved with other drugs. The response to remission maintenance therapy varies widely. We investigated the relationship between red blood cell 6-thioguanine nucleotide, a metabolite of 6-mercaptopurine, and myelosuppression in 22 children with acute lymphoblastic leukaemia in remission. The peripheral neutrophil count was used as an index of myelosuppression. 6-Mercaptopurine dose was related to 6-thioguanine nucleotide concentration (r = 0.4; P less than 0.001; n = 90; y = 18.51 + 0.36 x). Large individual variations around the regression line are observed. Neither 6-mercaptopurine dose nor 6-thioguanine nucleotide concentration was related to the neutrophil count at the time of sampling (day 0) or 7 days later. Both 6-mercaptopurine dose and 6-thioguanine nucleotide concentration correlated with the neutrophil count at day 14 (r = -0.33; P less than 0.01; n = 90 and r = -0.3; P less than 0.01; n = 90 respectively). This delay is compatible with a cytotoxic action on bone marrow stem cells. Excluding children with other, uncontrolled, potentially myelosuppressive influences the correlation between 6-thioguanine nucleotide concentration and neutropenia improved (r = -0.6; P less than 0.001; n = 37). A significant degree of neutropenia was observed by day 14 if the 6-thioguanine nucleotide concentration (day 0) was greater than 210 pmol/8 X 10(8) RBCs. The assay of 6-thioguanine nucleotide may highlight those individuals with pharmacokinetic resistance. Two children on continuous high dose 6-mercaptopurine, had low red blood cell 6-thioguanine nucleotide concentrations and neutropenia was not observed.

Six patients with various forms of leukaemia had neurological signs and symptoms associated with an extremely high white blood cell count and increased whole blood (but not plasma) viscosity. All were treated by leucapheresis with an Aminco Celltrifuge. Rapid and complete reversal of all symptoms occurred in three patients and partial recovery in one. One patient died shortly after leucapheresis and another (from cerebral intravascular coagulation) two days later. It is concluded that a cellular hyperviscosity syndrome may cause neurological dysfunction in patients with extremely high white cell counts, and that leucapheresis, in carefully selected patients, can be an effective method of treatment.

19 children in their first remission from "standard risk" lymphoblastic leukaemia had the urinary concentration of 17 oxogenic steroids (OGS) measured after two scheduled 5-day courses of prednisolone, only for the second of which were the parents aware of what the urine would be examined for. Despite a carefully standardised dose of the drug, there was a very wide scatter of OGS excretion which changed from time to time with each patient, but not in a way related to when the parents knew what was being measured. 6 low-excreting patients were reassessed in hospital with controlled compliance but only 1 produced her highest level under such circumstances. These results suggest variable bioavailability of prednisolone, but do not indicate the reason. Non-compliance does not appear to the sole explanation.

AST levels from 11 untreated children with T-ALL were found to be significantly higher than those from 74 children with non-T disease. The enzyme was not related to haemoglobin or bilirubin levels nor to the presence of hepatosplenomegaly in any of the patients. It was correlated with the white cell count, but only in the T-cell group and not the remainder. It was also correlated with a parallel (but lesser) rise in ALT, but again only in the T-cell group. The blast cells themselves contained little or no transaminase activity, so it is probable that T-ALL produces more extramedullary tissue damage than non-T disease.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and azathioprine. Human erythrocyte (RBC) TPMT activity is controlled by a common genetic polymorphism. On a genetic basis approximately one in every 300 subjects lacks TPMT activity, and 11% of subjects have intermediate activities. 6-Thioguanine nucleotides (6-TGN) are major metabolites of 6-MP and azathioprine in humans. RBC 6-TGN concentrations are correlated directly with risk for the development of leukopenia in patients treated with thiopurine drugs. Our studies were performed to determine whether there was a relationship between genetically controlled levels of RBC TPMT activity and RBC concentrations of 6-TGN. We found a significant negative correlation between RBC TPMT activity and 6-TGN concentrations in blood samples from 40 children with acute lymphoblastic leukemia receiving long-term therapy with 6-MP (rs = -0.474; P less than 0.005). In addition, RBC TPMT activities were significantly higher in blood samples from these patients than in blood samples from adult control subjects (P less than 0.0001) or children with acute lymphoblastic leukemia who were in remission but were not receiving drug therapy (P less than 0.0001). Finally, three adult patients were studied who developed very high RBC 6-TGN concentrations and thiopurine-induced leukopenia. Two of the three patients had no detectable RBC TPMT activity--presumably on a genetic basis. These results indicate that low TPMT activity may be a risk factor for the occurrence of elevated 6-TGN concentrations and for the development of severe leukopenia in patients treated with thiopurine drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Of 46 adult patients with active leukaemia whose white cells were examined using a Hemalog D automated differential leucocyte counter, 45 showed abnormalities indicative of their disease, and the odd one out would not have been missed due to associated thrombocytopenia. Sequential studies while on chemotherapy allowed rapid and accurate neutrophil counts to be performed even in the presence of profound leucopenia and the re-emergence of blast cells in some cases was detected 2--3 weeks earlier than by microscopy. These findings indicate that the Hemalog D is reliable in the detection and can be useful in the follow-up of patients with leukaemia.

Endogenous NK activity was measured in ALL patients and compared with child and adult control values. ALL children undergoing maintenance chemotherapy showed significantly lower NK activity than control groups; however, patients off treatment and in remission expressed cytotoxicity within the normal range of the control groups. The expression of the HNK-1 marker in the ALL children was not significantly different from child controls, although ALL patients failed to show the same correlation between cytotoxic activity and HNK-1 expression. The target binding capacity of PBLs from ALL children was significantly greater compared with controls but did not correlate with NK activity. In addition plasma from ALL patients was not inhibitory for NK cytolytic activity, suggesting an innate defect in cytotoxicity mediated by NK cells rather than a plasma inhibitory factor. Patients failing to display NK activity against K562 target cells appeared to mediate killing of measles virus infected (Raji) targets.

A prospective study of the effectiveness of ifosfamide as a single agent in the management of previously untreated patients with Evans stage IV neuroblastoma was undertaken. Eighteen children aged more than 1 year were treated with ifosfamide (IFX) 3 g/m2 daily for 2 days immediately after diagnosis and 3 weeks later. Treatment was continued with combination chemotherapy using vincristine, cyclophosphamide, cisplatinum and etoposide (OPEC) or a variant. Mesna (2-mercaptoethane sulphonate) was given to all patients during IFX treatment to prevent urotoxicity. Eight of the 18 patients (44%) responded to IFX. Nine had greater than 66% reduction in baseline tumor volume. Of 15 evaluable patients with raised pre-treatment urinary catecholamine excretion, six (40%) achieved greater than 50% reduction in pretreatment levels. Two of 10 patients evaluable for bone marrow response had complete clearance. Toxicity was mild in all patients. Upon completing 'first line' therapy, only four patients (22%) achieved a good partial remission (GPR) or complete response (CR). Median survival was 11 months. There was a lower rate of attaining GPR and shortened median survival in patients receiving phase II IFX before OPEC or variant, compared to patients with similar pre-treatment characteristics treated with OPEC from diagnosis in an earlier study.

Modulation of NK activity of PBLs from ALL patients was studied following exposure to IFN-alpha, staphylococcal protein A and interleukin-2. Only 52% of ALL patients responded to IFN-alpha stimulation, where the majority of controls showed positive enhancement of NK activity. Protein A failed to cause a significant stimulation of ALL patient PBLs whereas all controls showed a positive response. The majority of ALL patient and child control PBLs were however able to produce significant levels of IFN-gamma (protein A stimulation) and IFN-alpha (Sendai virus stimulation), although significantly more of both types of interferon could be induced in adult PBL samples. The ability of IL-2 to activate NK activity of ALL PBL samples showed a similar trend to IFN-alpha stimulation; thus, not all ALL patients showed positive augmentation of NK activity upon IL-2 stimulation. It is clear from these results that interferons and IL-2 may not necessarily lead to activated NK cytolytic activity, and in the present study approx. 50% of ALL patients failed to respond to lymphokine stimulation.

The platelet transfusion requirements of 70 unselected children with lymphoblastic leukaemia were studied from the time of diagnosis to the achievement of complete remission, or to death if no remission was obtained. Platelets were not transfused unless clinically significant bleeding occurred in association with a platelet count of less than 20.0 x 10(9)/l, and on this basis only 31 transfusions were given to 11 (15%) patients for 17 episodes of apparent or presumed bleeding. No deaths occurred due to haemorrhage, and 67 (95%) patients achieved complete remission. These findings suggest that such children do not need prophylactic platelet transfusions, which are commonly given despite their inherent risks and sequelae.

A 3-year-old child is described with an ovarian relapse arising 2 years after starting treatment for 'common' lymphoblastic leukaemia. This, considered with previously described cases, suggests that ovarian disease can arise as a late complication in girls without poor prognostic features at diagnosis, and may be associated with meningeal infiltration.

During a three year period, of 62 children and adults seen with lymphoblastic leukaemia 6 developed unilateral facial paralysis during the course of their disease, compared to none of 54 adults and children with acute non-lymphatic leukaemia seen during the same period. In all cases the problem arose in patients with refractory disease and was associated with the development of resistant bone marrow infiltration. The neuropathy showed no obvious response to intrathecal therapy and whilst meningeal infiltration was present at some stage in all but one of the 6, this waxed and waned independently of the facial palsy. Four of the 6 cases described had stigmata of the T-cell variety of lymphoblastic leukaemia, which is a significantly higher proportion than would be expected by chance. This apparent association with T-cell disease has not been previously recognised.