Ian Hann

A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial

BACKGROUND Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course. METHODS Patients aged 0-12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487. FINDINGS In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1-78) months, and EFS at 4 years was 47.0% (SE 2.6, 95% CI 41.9-52.1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1-73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60.9% [SE 5.2] for treatment group vs 57.0% [5.5] for controls; p=0.81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes. INTERPRETATION Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.

The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial

Summary. Patients under 55 years in the United Kingdom Medical Research Council Acute Myeloid Leukaemia 10 trial who entered complete remission were tissue typed (n = 1063). Four hundred and nineteen had a matched sibling donor and 644 had no match. When compared on a donor versus no donor basis the relapse risk was reduced in the donor arm (36%vs 52%; P = 0·001) and the disease‐free survival (DFS) improved (50%vs 42%; P = 0·01), but overall survival (OS) was not different (55%vs 50%; P = 0·1). Sixty‐one per cent of patients with a donor underwent transplantation. When patients were subdivided into risk groups based on cytogenetics alone or with the addition of blast response to course 1, a reduction in relapse risk was seen in all risk groups and in three age cohorts (0–14, 15–34 and 35+ years). Significant benefit in DFS was only seen in the intermediate‐risk cytogenetic group (50%vs 39%; P = 0·004). The OS benefit was only seen in intermediate‐risk patients (55%vs 44%; P = 0·02). The reduction in relapse risk in good‐risk patients was attributable to patients with t(15;17) and not to patients with t(8;21) or inv(16). Allogeneic transplantation given after intensive chemotherapy was able to reduce relapse in all risk and age groups. However, due to the competing effects of procedural mortality and an inferior response to chemotherapy if relapse does occur, there was a survival advantage only in patients of intermediate risk. This trial found no survival advantage in children, patients over 35 years or good‐risk disease.

Deficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study

BACKGROUND Infection is a major cause of morbidity and mortality in children with malignancy. Individuals with serum deficient in mannose-binding lectin (MBL)-an important component of the innate immune system-are more susceptible to infection than those with adequate concentrations. In this study, we investigated the capacity of this protein to influence infectious complications in children undergoing treatment for malignancy. METHODS We enrolled 100 children receiving chemotherapy for malignancy at a childrens hospital in London, UK. The frequency, duration, and causes of febrile neutropenic episodes were recorded, and MBL genotype and phenotype were determined by heteroduplex analysis and ELISAs, respectively. Serial MBL concentrations were also measured in patients during febrile episodes, and the results correlated with the MBL genotype (A/A indicating wild type, O/O indicating homozygous for MBL structural-gene mutations, and A/O indicating heterozygous for such mutations). FINDINGS In the A/A patients, MBL concentrations almost doubled by day 7 of the febrile neutropenic episode before declining by day 14 (p=0.004). By contrast, in patients with MBL mutations, concentrations did not alter significantly during the neutropenic episode. In the 6 months after initial diagnosis, most patients had at least one febrile neutropenic episode, but the median duration in patients with MBL mutations was twice as long as that in children with the wildtype genotype (20.5 days vs 10.0 days; p=0.014). Individuals with the lowest serum MBL concentrations at the time of diagnosis (<1000 microg/L) had a higher median number of days of febrile neutropenia than did individuals with higher concentrations of MBL (p=0.012). INTERPRETATION MBL deficiency seems to have an important influence on the duration of febrile neutropenic episodes in children with malignancy. This finding suggests that MBL infusions could represent a new therapeutic approach which would aid the management of chemotherapy-induced complications in this population of children.

A comparison of outcome from febrile neutropenic episodes in children compared with adults: Results from four EORTC studies

The object of this study was to determine whether there were any differences between the ‘typical’ child with fever and neutropenia and their adult counterpart with regard to infection type and outcome, by analysis of 3080 patients, including 759 children < 18 years of age and 2321 adults. These represented patients randomized in previous trials, between 1986 and 1994, which compared empirical antibiotic regimens for fever in neutropenic patients. There were fewer childhood acute myeloid leukaemia patients than adults but more acute lymphoblastic leukaemia cases and more with solid tumours undergoing intensive myelosuppressive therapy. The children were less likely to be undergoing first induction therapy but the relative incidence of patients receiving relapse schedules or maintenance therapies were not significantly different in the two age groups. Children less frequently had a defined site of infection than adults and where they had a defined site there were more upper respiratory tract but fewer lung infections. There was a similar low incidence of shock at presentation in the two groups but the childrens median neutrophil count was lower, and their median duration of granulocytopenia before the trial was shorter. The incidence of bacteraemia was similar, but clinically documented infection was less frequent and fever of unknown origin consequently more common in children. Children developed more streptococcal bacteraemias and fewer staphylococcal bacteraemias than adults (P = 0.003) but the relative incidence of various gram‐negative species was similar (P = 0.57). In general, the children had a better overall success rate and lower mortality than adults. Death from infection was only 1% in children versus 4% in adults (P = 0.001), and time to defervescence was shorter in children. In the younger age group, univariate logistic regression models showed high temperature, prolonged neutropenia before the trial and shock as prognostic indicators for the presence of bacteraemia. Solid tumour patients were significantly less likely to have a bacteraemia. Multivariate analysis confirmed the independent prognostic value of these indicators. Using the logistic equation of the selected model, the overall discriminant ability was poor. However, it was possible to identify a small subgroup without shock or high fever and with a short prior duration of neutropenia which carries a particularly low risk of bacteraemia, who could be considered for early discharge, monotherapy and shortened courses of antibodies, in prospective trials.

Cytogenetics of childhood Acute Myeloid Leukemia: United Kingdom Medical Research Council treatment trials AML 10 and 12

PURPOSE Karyotype is an independent indicator of prognosis in acute myeloid leukemia (AML) that is widely applied to risk-adapted therapy. Because AML is rare in children, the true prognostic significance of individual chromosomal abnormalities in this age group remains unclear. PATIENTS AND METHODS This cytogenetic study of 729 childhood patients classified them into 22 subgroups and evaluated their incidence and risk. RESULTS Rearrangements of 11q23 were the most frequent abnormality found in approximately 16% of patients, with 50% of these in infants. The outcome for all patients with 11q23 abnormalities was intermediate; no difference was observed for those with t(9;11)(p21-22;q23). The core binding factor leukemias with the translocations t(8;21)(q22;q22) and inv(16)(p13q22) occurred at incidences of 14% and 7%, respectively, predominantly in older children, and their prognosis was favorable. An adverse outcome was observed in patients with monosomy 7, abnormalities of 5q, and t(6;9)(p23;q34). Abnormalities of 3q and complex karyotypes, in the absence of favorable-risk features, have been associated with an adverse outcome in adults, but the results were not significant in this childhood series. However, the presence of 12p abnormalities predicted a poor outcome. CONCLUSION Because the spectrum of chromosomal changes and their risk association seem to differ between children and adults with AML, biologic differences are emerging, which will contribute to the redefinition of risk stratification for different age groups in the future.

Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia

This study of children and adults with acute lymphoblastic leukaemia (ALL) is the largest series of patients with hypodiploidy (<46 chromosomes) yet reported. The incidence of 5% was independent of age. Patients were subdivided by the number of chromosomes; near‐haploidy (23–29 chromosomes), low hypodiploidy (33–39 chromosomes) and high hypodiploidy (42–45 chromosomes). The near‐haploid and low hypodiploid groups were characterized by their chromosomal gains and a doubled hyperdiploid population. Structural abnormalities were more frequent in the low hypodiploid group. Near‐haploidy was restricted to children of median age 7 years (range 2–15) whereas low hypodiploidy occurred in an older group of median age 15 years (range 9–54). Patients with 42–45 chromosomes were characterized by complex karyotypes involving chromosomes 7, 9 and 12. The features shared by the few patients with 42–44 chromosomes and the large number with 45 justified their inclusion in the same group. Survival analysis showed a poor outcome for the near‐haploid and low hypodiploid groups compared to those with 42–45 chromosomes. Thus cytogenetics, or at least a clear definition of the modal chromosome number, is essential at diagnosis in order to stratify patients with hypodiploidy into the appropriate risk group for treatment.

TESTICULAR HISTOLOGY AFTER COMBINATION CHEMOTHERAPY IN CHILDHOOD FOR ACUTE LYMPHOBLASTIC LEUKÆMIA

A study of testicular histology has been made in 44 boys treated with combination chemotherapy for acute lymphoblastic leukaemia. At the time of testicular biopsy 21 boys were still receiving cytotoxic drugs and 23 had completed their chemotherapy some time earlier. Evidence of leukaemic infiltration was seen in 5 (11%), interstitial fibrosis in 24 (55%), and basement-membrane thickening in 6 (14%). The mean tubular fertility index in the 44 biopsies was 50% of that in age-matched controls, and 18 of the biopsies had a severely depressed tubular fertility index (40% or less). Three variables had a highly significant effect on the tubular fertility index: previous therapy with cyclophosphamide or cytosine arabinoside (greater than 1 g/m2) depressed the tubular fertility index, whereas with increasing time after completion of chemotherapy the tubular fertility index improved. The prognosis for fertility in these subjects is not known. Long-term surveilance is necessary.

Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol.

The single most important prognostic determinant in childhood acute lymphoblastic leukaemia (ALL) is effective therapy and changes in therapy may influence the significance of other risk factors. The effect of intensified therapy on the importance of currently recognized phenotypic and genotypic determinants of outcome was assessed in 2090 children enrolled on the Medical Research Council United Kingdom acute lymphoblastic leukaemia XI (MRC UKALL XI) protocol. Treatment allocation was not determined by risk factors. Multivariate analysis confirmed the dominant influence on prognosis of age, sex and presenting white cell count (WCC). After allowing for these features, blast karyotype, d 8 marrow blast percentage and remission status at the end of induction therapy were the only remaining significant predictors of outcome. Organomegaly, haemoglobin concentration, French–American–British type, body mass index, presence of central nervous system disease at diagnosis, immunophenotype and presence of TEL/AML1 fusion gene (examined in a subset of 659 patients) either had no significant effect on outcome or were significant only in univariate analysis. Among karyotype abnormalities with an independent influence on prognosis, high hyperdiploidy (> 50 chromosomes) was shown to be favourable, whereas near haploidy (23–29 chromosomes), presence of the Philadelphia chromosome, t(4;11) and abnormalities affecting the short arm of chromosome 9 [abn (9p)] were adverse risk factors. Early responders to therapy, determined by residual marrow infiltration after 8 d of induction therapy, had a good outcome, while the small proportion of patients who did not achieve a complete remission by the end of induction therapy had a poor outcome. A third block of late intensification was shown to improve event‐free survival by 8% at 5 years. The effect of these risk factors was not significantly different between those randomized to the third intensification block and those not randomized to a third block.

Treatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10)

Between 1988 and 1995, 341 children with acute myeloid leukaemia (AML) were treated on the Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10). The 5‐year overall survival was 57%, much improved on previous trials. However, there were 47 deaths (13.8%), 11 of which were associated with bone marrow transplantation (BMT). The treatment‐related mortality was significant at 13.8%, but decreased in the latter half of the trial from 17.8% in 1998–91 to 9.6% in 1992–95 (P = 0.03%). The main causes of death were infection (65.9%), haemorrhage (19.1%) and cardiac failure (19.1%). Fungal infection was a significant problem, causing 23% of all infective deaths. Haemorrhage occurred early in treatment, in children with initial white cell counts >100 × 109/l (P = 0.001), and was more common in those with M4 and M5 morphology. Cardiac failure only occurred from the third course of chemotherapy onwards, with 78% (7/9) in conjunction with sepsis as a terminal event. Some deaths could be prevented by identifying those most at risk, and with prompt recognition and aggressive management of complications of treatment. Future options include the prophylactic use of antifungal agents, and the use of cardioprotectants or alternatives to conventional anthracyclines to decrease cardiac toxicity.

Lipid-based amphotericin B: a review of the last 10 years of use.

The last decade has been remarkable for the dramatic increase in the prevalence of serious fungal infections in patients with haematological disorders and neutropenic cancer patients. The mortality rate of deep-seated infection has been in excess of 90% and there is no doubt that this is one of the greatest challenges currently facing haematologists and oncologists. The development of the lipid-based drugs - liposomal amphotericin (AmBisome(R)), amphotericin B lipid complex, ABLC (Abelcet(R)), amphotericin B colloidal dispersion, Amphocil (ABCD(R)), has meant that doses of amphotericin B can be safely escalated for the first time whilst the problems of nephrotoxicity, infusion related reactions (including chills, rigors, fevers and hypoxia) can be reduced. These toxicities are variably reduced with AmBisome more than Abelcet and more than Amphocil and there is little information from randomised trials other than for AmBisome. AmBisome used in the setting of persistent fever and neutropenia not responding after 3-4 days of intravenous antibiotics, is associated with less breakthrough systemic fungal infections. There is also much less need for premedication, including steroids, compared with amphotericin B and Abelcet. The use of intermittent doses of Ambisome given prophylactically is now being explored. A new and exciting era of antifungal therapy is opening up with new compounds, such as itraconazole voriconazole, posaconazole and echinocandins, being investigated and for the first time, we also have options for combination therapy and prophylaxis.