Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases.

Myelodysplastic and myeloproliferative disorders are rare in childhood and there is no widely accepted system for their diagnosis and classification. We propose minimal diagnostic criteria and a simple classification scheme which, while based on accepted morphological features and conforming with the recent suggestions of the WHO, allows for the special problems of myelodysplastic diseases in children. The classification recognizes three major diagnostic groups: (1) juvenile myelomonocytic leukemia (JMML), previously named chronic myelomonocytic leukemia (CMML) or juvenile chronic myeloid leukemia (JCML); (2) myeloid leukemia of Down syndrome, a disease with distinct clinical and biological features, encompassing both MDS and AML occurring in Down syndrome; and (3) MDS occurring both de novo and as a complication of previous therapy or pre-existing bone marrow disorder (secondary MDS). The main subtypes of MDS are refractory cytopenia (RC) and refractory anemia with excess of blasts (RAEB). It is suggested retaining the subtype of RAEB-T with 20-30% blasts in the marrow until more data are available. Cytogenetics and serial assessments of the patients are essential adjuncts to morphology both in diagnosis and classification.

Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party.

The clinical features, cytogenetics and response to treatment have been examined in 180 infants (aged <1 year) with acute leukaemia; 118 with acute lymphoblastic leukaemia (ALL) and 62 with acute myeloid leukaemia (AML). Comparison of clinical features showed no difference in age or sex distribution between infants with ALL and AML but infants with ALL tended to have higher leucocyte counts at presentation. Cytogenetic abnormalities involving 11q23 were found in 66% of ALL and 35% of AML cases, the commonest, t(4;11) being found only in ALL. The other recognised 11q23 translocations were found in both types of leukaemia. Few patients had the common cytogenetic abnormalities associated with ALL in older children and few with AML had good risk abnormalities. Four year event-free survival 60% cf 30% (P = 0.001) and survival 65% cf 41% (P = 0.007) were significantly better in AML than ALL. These results were due to a lower risk of relapse 27% cf 62% at four years. Superior event-free survival was also seen in the subgroup of patients with 11q23 abnormalities and AML (55% cf 23%). The reasons for superior response in AML are unknown but may be related to the intensity of treatment, lineage of the leukaemia or other as yet unidentified factors.

Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987-1999.

One hundred and twenty-six infants with acute lymphoblastic leukaemia (ALL) were treated on two consecutive protocols, Infant 87 (n = 40) and Infant 92 (n = 86), in an attempt to improve the poor prognosis of this disease. Both included intensive induction and consolidation with intrathecal and high-dose systemic therapy for central nervous system (CNS) protection. Intensification therapy was modified and high-dose chemotherapy with bone marrow transplantation in first remission was permitted in Infant 92. Four-year event-free survival was superior in Infant 92 (33%; 95% CI 23-44%) compared with Infant 87 (22.5%; 95% CI 12-37%) (P = 0.04) and survival at 4 years was also superior, 46% (95% CI 35-57%) c.f. 32.5% (95% CI 20-48%) (P = 0.01), largely as a result of a significant reduction in remission deaths. Twelve patients in Infant 92 underwent bone marrow transplantation (BMT) in first remission, but their survival was no better than that of patients receiving chemotherapy. Multivariate analysis of prognostic factors showed the adverse influence of younger age, CNS involvement at diagnosis and a high initial leucocyte count, but not of CD10 expression. Cytogenetic analysis, available in 93% of patients in Infant 92, showed that 67% had chromosomal rearrangements involving 11q23 of which 39% had the translocation t(4;11) (q21;q23). There was no significant difference in event-free survival between cytogenetic subgroups, although no children under 6 months of age with 11q23 abnormalities, other than the t(4;11), survived. In conclusion, infants with lymphoblastic leukaemia remain a high-risk group, but it is unclear whether their adverse prognosis can be attributed to unfavourable cytogenetics alone. The role of high-dose therapy and BMT in first remission remains uncertain.

Down's syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment.

AIMS: To examine the clinical and biological features of acute lymphoblastic leukaemia in children with Down's syndrome (DS), to compare their survival with other children, and to determine if entry to trials and survival has improved. METHODS: Examination of presenting features and response to treatment in patients treated in two consecutive national trials, MRC UKALL X and XI. RESULTS: The proportion of children with DS was significantly higher in UKALL XI (1.9%) than UKALL X (0.9%). Children with DS tended to be under 10 years and to have the common ALL subtype. Cytogenetic analysis showed that favourable features, such as high hyperdiploidy and t(12;21) were less frequent but also that there was a lack of translocations associated with a poor prognosis. Children with DS showed no increase in risk of relapse at any site but their survival and event free survival were inferior to other children. These results were caused by an increased number of infective deaths during remission (11% compared to 2%). At five years overall survival was 73% in DS children compared with 82% in other children; event free survival was 53% compared to 63% in non-DS children. CONCLUSIONS: Entry of children with DS to national trials has increased and survival has improved. However they remain at risk of relapse and also of treatment related mortality. These findings emphasise the need for both intensive chemotherapy and optimal supportive care.

The role of bone marrow transplantation in first remission of paediatric all.

Although intensive chemotherapy has improved event-free survival for most children with lymphoblastic leukaemia there remain up to 10% who have not benefited from this approach. These include infants, children with Ph1 positive leukaemia, with near-haploidy, and slow remitters in most of whom event free survival remains below 40%. Evaluation of the benefits of Bone Marrow Transplantation in high risk ALL is fraught with difficulties and to date has not produced clear evidence of benefit. The way forward lies in prospective evaluation of BMT in tightly defined subsets of highest risk children, a task which will require international collaboration.

Childhood leukaemia: the medical cost of cure.

More than 1 in every 1,500 individuals in the UK between 16 and 44 years of age has survived childhood cancer. This article describes the medical cost of cure in survivors of acute leukaemia, the most common form of childhood cancer.

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 Down's 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.

Outcome for children after failed transplant for primary haemophagocytic lymphohistiocytosis.

Primary haemophagocytic lymphohistiocytosis is a rare disorder of childhood, which is usually fatal without allogeneic stem cell transplantation (SCT). For children who lack a matched family or closely matched unrelated donor, SCT using haploidentical parental stem cells has been used, but is associated with an increased risk of graft failure. The most appropriate subsequent management for those children who survive after graft rejection is currently unclear. We report the outcome for three such children. After a period of disease quiescence lasting 4 months to 8 years, disease recurrence and subsequent death occurred in each case. Accordingly, a second SCT is recommended.

Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI.

The role of bone marrow transplantation (BMT) in first remission of children with high-risk acute lymphoblastic leukemia (ALL) remains unclear. There were 3676 patients (aged 1 to 15 years) entered into the United Kingdom (UK) Medical Research Council (MRC) trials UKALL X and XI from 1985 to 1997. Of these patients, 473 patients (13%) were classified as very high (VH) risk and were eligible for a transplantation from a matched histocompatible sibling donor (MSD). We tissue-typed 286 patients; 99 patients had a matched related donor, and 76 patients received transplantations. Additionally, 25 children received transplantations from a matched unrelated donor (MUD) despite trial guidelines for MSD transplantations only. The median time to transplantation was 5 months (range, 2 to 19 months), and the median follow-up was 8 years. The 10-year event-free survival (EFS) adjusted for the time to transplantation, diagnostic white blood cell (WBC) count, Ph chromosome status, and ploidy was 6. 0% higher (95% confidence interval (CI), -10.5% to 22.5%) for 101 patients who received a first-remission transplantation (MSD and MUD) than for the 351 patients treated with chemotherapy (transplantation, 45.3%, vs chemotherapy, 39.3%). The transplantation group had fewer relapses (31%) compared to relapses in the chemotherapy group (55%); however, the transplantation group had more remission deaths (18%) compared to remission deaths in the chemotherapy group (3%). In contrast the adjusted 10-year EFS was 10. 7% higher (95% CI, -2.6% to 24.0%) for patients without a human leukocyte antigen (HLA)-matched donor than for those patients with a donor (no donor, 50.4%, vs donor, 39.7%). In conclusion, for the majority of children with VH-risk ALL, the first-remission transplantation has not improved EFS.

Recent advances in management of acute leukaemia.

There have been significant improvements in the outlook for children with acute leukaemia but these advances are only available to a minority of the world's children. There is still room for improvements in conventional chemotherapy and these need evaluation in randomised trials. The role of bone marrow transplants in first remission is evolving as chemotherapy becomes more effective. New treatments are needed for relapsed patients. Molecular diagnosis has refined the assessment of prognosis but the extra value afforded by measurement of minimal residual disease is not clear. International collaboration is needed to evaluate treatment for rare subtypes of leukaemia.

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

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.

Are glomerular filtration rate estimations necessary before high dose methotrexate?

Glomerular filtration rates (GFR) were estimated in 168 children (227 estimates) before treatment for haematological malignancies with high dose, intravenous methotrexate. Clinical management was altered on the basis of GFR in only two cases, both of whom had tumour lysis syndrome. Routine estimations of GFR do not contribute to management.

Loss of heterozygosity and microsatellite instability at the MLL locus are common in childhood acute leukemia, but not in infant acute leukemia.

Rearrangements involving the MLL gene at chromosome 11q23 are associated with leukemia and are present in up to 70% of infant leukemias. Loss of heterozygosity (LOH) has been shown for anonymous polymorphic markers at 11q23 in adult leukemias. To study LOH at the MLL locus, we have identified two new polymorphic microsatellite markers: a GAA repeat (mllGAAn) in intron 6 of the MLL gene and a GA (mllGAn) repeat in the 5' flanking region of the gene, approximately 2 kb upstream of the translation initiation codon. The heterozygosity index of mllGAAn is 0.54, which renders it useful for analyzing LOH. We screened two groups of leukemia patients to study LOH at the mllGAAn marker. Group A (n = 18) was selected on the basis of presentation before 18 months. Cytogenetic and reverse transcription-polymerase chain reaction analysis showed that 9 of these 18 children had translocations involving MLL. No LOH was observed. Group B (n = 36) were randomly selected children who had presented with leukemia between 1993 and 1994. Cytogenetic analysis of this group showed a variety of different chromosomal abnormalities. LOH was shown in 9 of 20 individuals (45%) who were informative. Microsatellite instability (MSI) was demonstrated in 1 of 18 individuals in group A and 5 of 36 individuals (13.9%) in group B. MSI and LOH were observed simultaneously in three individuals. Loss of an allele was confirmed in one individual by fluorescence in situ hybridization. Individuals with MSI or LOH at mllGAAn were selected for analysis at anonymous polymorphic markers D11S1364 and D11S1356, which flank the MLL gene. No LOH or MSI was observed at these markers in those individuals who were informative. These results show that LOH at the MLL gene locus is a common event during leukemogenesis. Furthermore, the presence of MSI at this locus suggests that the region is a hotspot for genetic instability.

Improved outcome of acute myeloid leukaemia in Down's syndrome.

OBJECTIVE: To review the clinical features, treatment, and outcome of children in the UK with Down's syndrome and acute myeloid leukaemia (AML). DESIGN: A retrospective study of 59 children with Down's syndrome and AML presenting between 1987 and 1995. Data were obtained from hospital case notes, trial records, and by questionnaire. RESULTS: The patients were unusually young (median age, 23 months) with a predominance of megakaryoblastic AML. Two of the seven infants who presented with abnormal myelopoesis aged 2 months or younger achieved complete spontaneous remission. Most of the older children with AML (32 of 52) were treated on recognised intensive protocols but 13 received individualised treatment and seven symptomatic treatment alone. Only four received a bone marrow transplant (BMT) in first remission. For the 45 older children who received chemotherapy the overall survival was 55% (median follow up 4.5 years). Patients on individualised protocols had a similar overall survival and toxic death rate but marginally higher relapse rate than those on standard (intensive) protocols. Children with Down's syndrome treated on the national AML 10 trial had a similar overall survival (70% v 59%) at five years to children of comparable age without Down's syndrome: their improved relapse risk (12% v 38%) offset the slight increase in deaths as a result of treatment toxicity (19% v 11%). CONCLUSION: Neonates with Down's syndrome and abnormal myelopoesis may achieve spontaneous remission, and older children with Down's syndrome and AML can be treated successfully with intensive chemotherapy, without BMT.

Clonality analysis suggests that early-onset acute lymphoblastic leukaemia is of single-cell origin and implies no major role for germ cell mutations in parents.

Childhood leukaemia presenting at a young age has been suspected of resulting from a leukaemogenic mutation in parental germ cells, either spontaneously or due to the exposure of a parent to leukaemogenic environmental hazards, particularly ionizing radiation. Mathematical modelling of leukaemogenesis suggests that any such patient would be especially prone to multiple independent leukaemogenic events leading to multiclonality in terms of cell of origin (analogous to bilaterality in familial retinoblastoma). To test this hypothesis we have carried out a search for multiclonal leukaemogenesis in infant and childhood acute lymphoblastic leukaemia (ALL). We used a polymerase chain reaction-based analysis of the X-linked monoamine oxidase A (MAOA) gene locus to study the clonality of marrow samples obtained from female paediatric ALL patients at the time of disease presentation. We obtained presentation samples from 102 patients of whom 72 were found to be informative at the MAOA locus. These included 20 infant leukaemias (< 1 year at diagnosis). Sixty-six samples were found to be unequivocally monoclonal while the remaining six could not, with certainty, be assigned a clonal origin. We also obtained bone marrow aspirates at first relapse as well as at presentation from eight patients. In each case the same pattern of X-linked allelic inactivation was observed at both time points of the course of the disease. No evidence was found for leukaemic multiclonality in any age group at presentation or for leukaemic 'clone-switching' in relapse. These findings suggest that both infant and childhood ALL is of single-cell origin and implies that leukaemic predisposition resulting from germ cell mutation is unlikely to have a major role in their pathogenesis.

Improved prognosis for acquired aplastic anaemia.

This study compared the prognosis of patients treated for aplastic anaemia at Great Ormond Street Hospital for Children from 1973-88 (group A; n = 38) with a more recent cohort from 1989-96 (group B; n = 37). The two groups were similar in terms of clinical history, age, and severity of aplasia. The main treatment differences included the use of androgen treatment in group A (21 of 38 patients) but not in group B, and the addition of cyclosporin A to immunosuppressive treatment for 14 patients in group B. Actuarial survival at eight years' follow up was significantly better for group B (84%; 95% CI, 68% to 93%) than for group A (45%; 95% CI, 30% to 60%), because of improved outcome for both immunosuppressive treatment (86% v 39%) and bone marrow transplantation (93% v 56%). There was no evidence for late clonal disorders or secondary malignancies in survivors in either group. The prognosis for aplastic anaemia has improved greatly in recent years so that over 80% of children are long term survivors.