Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol.

This corrects the article DOI: 10.1038/leu.2015.246.

HLA-DPß1 Asp84-Lys69 antigen-binding signature predicts event-free survival in childhood B-cell precursor acute lymphoblastic leukaemia: results from the MRC UKALL XI childhood ALL trial.

We previously reported that children in the UKALL XI ALL trial with HLA-DP 1 and -DP 3 supertypes had significantly worse event-free survival (EFS) than children with other DP supertypes. As DP 1 and DP 3 share two of four key antigen-binding amino-acid polymorphisms (aspartic acid84-lysine69), we asked whether Asp84-Lys69 or Asp84 alone were independent prognostic indicators in childhood acute lymphoblastic leukemia (ALL). We analysed EFS in 798 UKALL XI patients, stratified by Asp84-Lys69 vs non-Asp84-Lys69, for a median follow-up of 12.5 years. Asp84-Lys69 was associated with a significantly worse EFS than non-Asp84-Lys69 (5-year EFS: Asp84-Lys69: 58.8% (95% CI (confidence of interval): 52.7-64.9%); non-Asp84-Lys69: 67.3% (63.4-71.2%); 2P=0.007). Post-relapse EFS was 10% less in Asp84-Lys69 than non-Asp84-Lys69 patients. EFS was significantly worse (P=0.03) and post-relapse EFS marginally worse (P=0.06) in patients with Asp84 compared with Gly84. These results suggest that Asp84-Lys69 predicted adverse EFS in the context of UKALL XI because of Asp84, and may have influenced post-relapse EFS. We speculate that this may be due to the recruitment of Asp84-Lys69-restricted regulatory T cells in the context of this regimen, leading to the re-emergence of residual disease. However, functional and molecular studies of the prognostic value of this and other HLA molecular signatures in other childhood ALL trials are needed.

Slide session, British Society for Haematology, 45th Annual Scientific Meeting, Manchester, 2005.

Each year at the Annual Scientific Meeting of the British Society for Haematology, there is a slide session in which microscopic slides of six patients with haematological disorders are discussed by two experts. Further data and the final diagnosis are then provided. The slide session is presented here, as it occurred at the meeting.

Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials.

Between 1988 and 2002, 758 children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone marrow transplantation following four blocks of intensive chemotherapy and found that while both allogeneic bone marrow transplant (allo-BMT) and autologous bone marrow transplant (A-BMT) significantly reduced the relapse risk (RR), this did not translate into a significant improvement in overall survival (OS). A risk group stratification based on cytogenetics and response to the first course of chemotherapy derived from MRC AML 10 was used to deliver risk-directed therapy in MRC AML 12. Allo-BMT was limited to standard and poor risk patients and A-BMT was not employed. Instead, the benefit of an additional block of treatment was tested by randomising children to receive either four or five blocks of treatment in total. While the results of MRC AML 12 remain immature, there appears to be no survival advantage for a fifth course of treatment. The 5 year OS, disease-free survival (DFS), event-free survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. MRC AML trials employ a short course of triple intrathecal chemotherapy alone for CNS-directed treatment and CNS relapse is uncommon. Improvements in supportive care have contributed to improved outcomes and the number of deaths in remission fell between trials. Anthracycline-related cardiotoxicity remains a concern and the current MRC AML 15 trial tests the feasibility of reducing anthracycline dosage without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose ara-C. MRC studies suggest that the role of allo-BMT is limited in 1st CR and that there may be a ceiling of benefit from current or conventional chemotherapy.

Nijmegen breakage syndrome diagnosed as Fanconi anaemia.

BACKGROUND: Fanconi anaemia (FA) and Nijmegen breakage syndrome (NBS) are rare chromosomal instability disorders with overlapping clinical features. It has recently been shown that, like FA, NBS is also associated with increased chromosomal sensitivity to DNA cross-linking agents. PROCEDURE: We report a family that was initially diagnosed with FA on the basis of increased sensitivity to DNA cross-linking agents. They were atypical in that there were associated severe infection problems. In view of these features we performed immune function studies together with molecular analysis of the FA genes and subsequently the NBS1 gene. RESULTS: Two children in the kindred have died, one from sepsis, and the other with a plasma cell malignancy. A third child underwent bone marrow transplantation because of recurrent infections. All affected members had severe immunological abnormalities. The genetic defect was shown to be a novel mutation in the NBS1 gene, so the diagnosis was revised to that of NBS. CONCLUSIONS: This family illustrates the importance of awareness of the lack of specificity of DNA cross-linking agent tests for FA, particularly in situations where the clinical features are atypical. In addition, one of the cases represents the first use of bone marrow transplantation for NBS that we are aware of; this treatment may have a future role for other patients with the syndrome.

MRC trials in childhood acute myeloid leukaemia.

The modern approach to therapy for acute myeloid leukaemia (AML) in children began in the late 80's and in the MRC series led to a 30% improvement in survival, up to levels of about 50%. Since 1995 the most recent trial AML 12 has taken those figures to two thirds event free survival and similar overall survival. Resistant disease rates remain at 4% overall but the death rate in complete remission has fallen from 11% to 6% despite increasing intensity of therapy, and due to advances in supportive care including nutrition and antibiotics/antifungals. However, although relapse rates have continued to fall, the biggest challenge is to reduce the currently one third relapse rate. We are much better at predicting who is likely to relapse, based mainly on primary resistance to therapy and karyotype. Analysis of 629 out of the last 808 cases in whom cytogenetic testing was successful (78%) has shown very clearly that t(8;21), t(15;17), inv(16) are independent good risk features. Additionally, loss of a sex chromosome in the 8;21 group defines a group which does exceptionally well, with 93% EFS at 5 years. Chromosome 7 abnormalities also remain of independent prognostic significance when age, WHO classification and white cell count are taken into account, with monosomy 7 doing even worse than 7q abnormalities. The current trial MRC AML 15 investigates the role of fludarabine--idarubicin combination therapy in the induction courses and the role of high dose cytarabine during consolidation; the aim being to increase efficacy and reduce toxicity, particularly that involving the heart. New approaches such as targeted antibody therapy will be explored when toxicity data for children permits.

CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials.

PURPOSE: A collaborative meta-analysis was performed to clarify the relative effects on relapse and survival of different types of therapies directed at the CNS in childhood acute lymphoblastic leukemia. MATERIALS AND METHODS: Data were sought for each individual patient in all trials started in or before 1993 that included unconfounded randomized comparisons of such treatments. Log-rank survival analyses were performed for each trial, and overall results for groups of trials addressing similar questions were obtained from the totals of the observed minus expected number of events and their variances. RESULTS: Radiotherapy and long-term intrathecal therapy gave similar outcomes, with no significant difference in event-free survival despite random assignment of treatment to 2,848 patients, 1,001 of whom suffered relapse or death. Intravenous methotrexate reduced non-CNS rather than CNS relapses, and hence, the addition of intravenous methotrexate to a treatment regimen including radiotherapy or long-term intrathecal therapy improved event-free survival, with a 17% reduction in the event rate (95% confidence interval, 6% to 27%; P =.003). The event-free survival at 10 years in these trials was 61.9% without intravenous methotrexate and 68.1% with intravenous methotrexate. There was no significant difference in survival (14% death rate reduction; P =.09). There were insufficient randomly assigned patients to adequately address other questions, such as effect of different doses. No evidence was found of differences, between trials or between subgroups of different types of patients, in the relative effects of treatment. CONCLUSION: Radiotherapy can be replaced by long-term intrathecal therapy. Intravenous methotrexate gives some additional benefit by reducing non-CNS relapses.

Immunodeficiency-related lymphoproliferative disorders: prospective data from the United Kingdom Children's Cancer Study Group Registry.

Clinical data and biological samples were prospectively collected in 42 children with lymphoproliferative disease (LPD) secondary to organ/bone marrow transplant-related immunosuppression (30: 11 liver, 10 heart/lung, 8 kidney and 1 bone marrow), other drug-induced immunosuppression (2), congenital immunodeficiency (8) or human immunodeficiency virus (HIV)-related immune dysfunction (2). Ages ranged from 10 months to 17 years and there were 15 girls. Pathology was centrally reviewed and showed polymorphic features in 5 cases, monomorphic in 23, mixed pattern in 5 patients and 9 other types. Using the Revised European-American Classification of Lymphoid Neoplasms, 5 were B lymphoblastoid, 24 were high-grade B and 14 were other subtypes. Using the Pittsburgh classification, 9 were lymphadenopathic, 10 were systemic, 25 were lymphomatous and, with the Murphy grouping for non-Hodgkin's lymphoma (NHL), 10 were localized and 32 non-localized. Twenty-four out of 38 evaluable cases were Epstein-Barr virus positive. Thirty-five patients were evaluable for clonality; 24 were monoclonal and 11 were polyclonal. Reduced immunosuppression in solid organ transplant patients resulted in resolution of disease in 14/24, which was sustained in 11. Nineteen patients received chemotherapy, 14/18 evaluable responded, which was sustained in 8 cases. Seven out of 29 solid organ transplant and 10/13 other immune-deficient patients died. In the largest group of patients, solid organ transplants, no significant clinical or biological characteristics that predicted outcome were identified. In the transplant group close monitoring of response during reduction in immunosuppression is essential and the early use of B NHL chemotherapy may be effective.

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.

T cryptantigen activation is associated with advanced necrotizing enterocolitis.

BACKGROUND/PURPOSE: Thomsen-Friedenreich cryptantigen activation (TCA) exposes neonates with necrotizing enterocolitis NEC to the risk of hemolysis after transfusion of blood products. The authors aimed to determine the prevalence of TCA in neonates with NEC and to correlate TCA with severity of disease and outcome. METHODS: One hundred four neonates with NEC were tested for TCA on admission. Patients with TCA requiring transfusion were given packed red cells, low-titer anti-T fresh frozen plasma, and washed platelets to avoid hemolysis. RESULTS: Twenty-three infants had TCA, and 96% of these had stage III disease. The incidence of TCA was significantly higher in infants with stage III disease compared with those with stage II (30% v 4%; P <.01). A total of 91% of infants with TCA required laparotomy compared with 81% of those with no activation. At laparotomy, widespread disease was more common in the TCA group (71% v 55%). TCA did not significantly increase mortality rate (TCA, 39% v no TCA, 28%); this may reflect the transfusion policy of our unit. CONCLUSIONS: Twenty-two percent of neonates with NEC referred to our unit had TCA. There is an association between TCA and advanced NEC. Screening of neonates with advanced NEC for TCA is advised to identify those at risk of hematologic complications.

Oral ciprofloxacin plus colistin: prophylaxis against bacterial infection in neutropenic patients. A strategy for the prevention of emergence of antimicrobial resistance.

Following a 2-year study, the combination of oral ciprofloxacin and colistin has been used continuously for 10 years without the emergence of resistance. During a 2-year period (1987-1989), we compared ciprofloxacin + colistin (CIP + COL) with neomycin + colistin (NEO + COL) in a randomized trial--combinations chosen because of the potential for prophylaxis of Gram-negative infection by ciprofloxacin, with colistin given to reduce the risk of emergence of resistance. Sixty-four patients with similar demographics in each arm were evaluable for efficacy analysis. Patients on CIP + COL had a significantly lower proportion of neutropenic days with fever (P < 0.001) and neutropenic days on intravenous antibiotics (P < 0.001) than patients on NEO + COL. A total of 54 (15 bacteriologically documented) pyrexial episodes occurred in patients on CIP + COL and 77 (41 bacteriologically documented) in patients on NEO + COL. Only two Gram-negative bacterial infections occurred in the CIP + COL arm compared with 16 in the NEO + COL arm. No Staphylococcus aureus infections occurred in the CIP + COL group compared with 10 in the other patients. Two CIP-resistant Gram-negative bacilli were isolated from patients on CIP + COL compared with 13 NEO-resistant Gram-negative bacilli from patients on NEO + COL. Following a subsequent decade of unchanged use of this prophylactic strategy in neutropenic patients, a 2-year follow-up study between 1 January 1998 and 31 December 1999 showed 66 significant infections during 700 [corrected] neutropenic episodes. Thirty-five of the 111 (31%) isolates were ciprofloxacin-resistant, involving 5% of the neutropenic episodes [corrected].

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 children's 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.

Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia.

Between May 1988 and June 2000, 698 children were treated in the Medical Research Council acute myeloid leukemia 10 and 12 trials. The presenting features and outcomes of therapy in these children were compared by age. Although there was no single cutoff in age, younger children were more likely to have intermediate risk and less likely to have favorable cytogenetics (P <.001), and they had a higher incidence of translocations involving chromosome 11q23 (P <.001). The distribution of French-American-British (FAB) types also varied with age; FAB types M5 (P <.001) and M7 (P <.001) were more common in early childhood, whereas older children were more likely to have FAB types M0 (P =.03), M1 (P =.04), M2 (P =.005), and M3 (P <.001). Involvement of the central nervous system at diagnosis was also more common in the youngest children (P =.01). Younger children had more severe diarrhea (P =.002), whereas older children had worse nausea and vomiting (P =.01) after chemotherapy. When adjusted for other important factors, complete remission rates were similar (P =.5) and although there was less resistant disease in younger children (P =.003), this was partially balanced by a slight increase in deaths during induction therapy in younger patients (P =.06). On multivariate analysis overall survival (P =.02), event-free survival (P =.02), and disease-free survival were better (P =.06) in younger children due to a lower relapse rate (P =.02) especially in the bone marrow (P =.02).

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.

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.

Outcome of relapsed or refractory childhood B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols.

Twenty-six children with B-cell acute lymphoblastic leukaemia (B-ALL) or Murphy Stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) progressed or relapsed after first-line therapy with a short, intensive multiagent chemotherapy regimen [United Kingdom Childhood Cancer Study Group (UKCCSG) 9003] (n = 62) or a slightly less intensive regimen (UKCCSG 9002) (n = 112). Eight patients (4.6%) never achieved complete remission (CR) and 18 (10.3%) relapsed. Second-line therapy resulted in remission for eight patients (30%). All patients initially treated with the 9003 protocol died. Three patients (11.5%) in the 9002 group, including one who never achieved CR in the primary site, are alive after second-line therapy. This study confirms that the prognosis of relapsed or refractory B-ALL/B-NHL is poor and exceptionally so if relapse occurred less than 6 months from diagnosis. High-dose therapy with stem cell rescue was used in only seven patients; its role needs to be studied further.

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.

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.

Management of infection in children with bone marrow failure.

The development of new and often more successful regimens of treatment for childhood blood and malignant diseases has usually been associated with a parallel increase in infectious problems. This is because these successes have often, in the absence of new effective drugs, been achieved by increasing drug dose intensity to new limits. This chapter is not intended to deal with every possible infection, but rather to be a practical guide to the current management of infection. The last few years have seen major improvements in the development of haematopoietic growth factors, new antifungal agents, new antibiotics and new ways to use aminoglycosides. Attempts are being made to identify good and poor risk factors for the outcome of infection in order to facilitate shorter courses and possibly home or day care use of antimicrobial agents. In addition the different needs of children are being recognized in view of the restricted use of quinolones in this group and the different organisms and types of infection that they experience.