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Ian Hann

Publications and source records attributed to Ian Hann.

18 recordsLinked to original sources
PubMed2007

Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials.

BACKGROUND: Adolescents with acute lymphoblastic leukaemia (ALL) have languished in the shadow of success of the outcome of therapy in childhood ALL. Their treatment has always been incorporated into either paediatric or adult clinical trials depending on the mode of referral and hence there is a need to address an age and risk specific strategy for improving the outcome of this neglected group of patients. This article has summarised the recent and updated retrospective comparative analysis of adolescents treated on the Medical Research Council (MRC) trials. This analysis adds further emphasis to the treatment approach and the merits and limitations of treatment of adolescents on paediatric and adult trials. METHODS: A retrospective comparative analysis of adolescents aged 15-17 years, treated on either MRC ALL97/revised 99 (n = 61), a randomised paediatric trial or UKALLXII/E2993 (n = 67), an adult trial, between 1997 and 2002 was undertaken. RESULT: Results suggest a trend towards a superior outcome on paediatric trials. The 5-year EFS on ALL97 was 65% (95% CI = 52-78%) and on UKALLXII/E2993 was 49% (95% CI = 37-61%; P = 0.01). Multivariate analysis allowing for age and Ph status, diminished the EFS difference, but confirmed a reduced rate of death in remission in patients managed on the paediatric protocol. CONCLUSIONS: Despite limitations in the methodology, comparative studies including our MRC study suggest a consistent advantage for adolescents managed intensively on paediatric trials. Redefining age limits with risk-based strategy and multi-centre collaboration should be considered to improve the survival of young adults.

Adolescent↗
PubMed2006

Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

We have previously identified a unique subtype of acute lymphoblastic leukemia (ALL) associated with a poor outcome and characterized by intrachromosomal amplification of chromosome 21 including the RUNX1 gene (iAMP21). In this study, array-based comparative genomic hybridization (aCGH) (n = 10) detected a common region of amplification (CRA) between 33.192 and 39.796 Mb and a common region of deletion (CRD) between 43.7 and 47 Mb in 100% and 70% of iAMP21 patients, respectively. High-resolution genotypic analysis (n = 3) identified allelic imbalances in the CRA. Supervised gene expression analysis showed a distinct signature for eight patients with iAMP21, with 10% of overexpressed genes located within the CRA. The mean expression of these genes was significantly higher in iAMP21 when compared to other ALL samples (n = 45). Although genomic copy number correlated with overall gene expression levels within areas of loss or gain, there was considerable individual variation. A unique subset of differentially expressed genes, outside the CRA and CRD, were identified when gene expression signatures of iAMP21 were compared to ALL samples with ETV6-RUNX1 fusion (n = 21) or high hyperdiploidy with additional chromosomes 21 (n = 23). From this analysis, LGMN was shown to be overexpressed in patients with iAMP21 (P = 0.0012). Genomic and expression data has further characterized this ALL subtype, demonstrating high levels of 21q instability in these patients leading to proposals for mechanisms underlying this clinical phenotype and plausible alternative treatments.

Alleles↗
PubMed2006

Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols.

Adolescents and young adults (AYA) with acute lymphoblastic leukaemia (ALL) constitute a distinct population from children and older adults. Based on patterns of referral, they may be treated by either paediatric or adult oncologists. As a group, AYA with ALL have a worse survival and event-free survival (EFS) compared to that achieved by younger children. A systematic review of all published clinical trials, which provide data on treatment and outcome of adolescents with ALL, has been summarised in an effort to determine whether they should be treated on paediatric or adult type protocols. Adolescents appear to have a consistent survival advantage when treated on paediatric regimens.

Adolescent↗
PubMed2006

Single agent efficacy of rituximab in childhood immunosuppression related lymphoproliferative disease: a United Kingdom Children's Cancer Study Group (UKCCSG) retrospective review.

Survival in childhood lymphoproliferative disease (LPD) remains poor, particularly in non-transplant patients. The anti-CD20 antibody rituximab shows promise but data in children is scant. A retrospective study of 22 (aged 11 months to 18 years) children treated with rituximab is presented. Two had primary immunodeficiency, two had prolonged immunosuppression and 18 had post-transplant LPD (eight bone marrow, five liver, four heart, one kidney). Nine patients had multi-organ involvement and 13 single site disease. Seventeen out of 22 had rituximab alone. In 16, a dose of 375 mg/m2 i.v. weekly was used (less in one patient due to renal dysfunction). Twelve patients received four courses and ten patients received one to three courses. Fever was the main side-effect in four. Eight (47%) had single agent response; four complete and four partial. All had other treatment prior to rituximab. Median follow-up was 35 months (range 22 - 47 months). In childhood LPD unresponsive to standard treatment, rituximab showed single agent response and requires further evaluation.

Adolescent↗
PubMed2005

Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial.

We report on the outcome of children with Philadelphia positive acute lymphoblastic leukaemia (Ph+ ALL) treated on the UK Medical Research Council (MRC) trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Forty-two (2.3%) patients were Ph+. Nineteen (45%) had <25% blasts in bone marrow (BM) within the first 2 weeks of treatment and were defined as a good response group (GRG), the others as a poor response group (PRG). Thirty-six (86%) achieved first complete remission (CR1) at the end of induction, of which 28 underwent BM transplantation (BMT). The median follow-up was 42 months (range, 21-84). The 3-year event-free survival (EFS; 52%, 95% CI, 36-66%) was a considerable improvement on the previous MRC UKALL XI trial (27%). EFS for the GRG and PRG were 68% (43-84%) and 39% (18-59%), respectively (P = 0.03); presenting white cell count <50 x 10(9)/l (P = 0.02) was predictive for overall survival. Changes in the MRC ALL97 trial within the study period resulted in some Ph+ ALL receiving daunorubicin and either prednisolone or dexamethasone during induction. Though the use of daunorubicin during induction was not a prospective study question, EFS was significantly better for those whose induction included this drug (P = 0.02). Steroid randomization was not stratified for Ph+ ALL patients and was not predictive for EFS. BMT in CR1 appeared to reduce the risk of a subsequent BM relapse. These results show significant improvement on previous MRC trials; future therapeutic strategies should include early intensive therapy and BMT in CR1.

Adolescent↗
PubMed2005

Red cell pyruvate kinase deficiency: 17 new mutations of the PK-LR gene.

The PK-LR gene was studied in 23 patients with congenital haemolytic anaemia associated with erythrocyte pyruvate kinase (PK) deficiency. Twenty-seven different mutations were detected among the 42 mutated alleles identified: 19 missense mutations, four splice site mutations and one nonsense, one single base deletion and two large deletions. Seventeen of them (107G, 278T, 403T, 409A, 661A, 859C, 958A, 1094T, 1190T, 1209A, 1232C, 1369G, 507A, IVS9 -1c, IVS9 +43c [corrected] del C224, del 5006bp IVS3--> nt 1431) were new. Although all the exons, the flanking regions and the promoter were sequenced in all cases, we failed to detect the second expected mutation in four subjects. To correlate genotype to phenotype, the molecular results were related to the biochemical properties of the mutant enzymes by an analysis of the three-dimensional structure of erythrocyte PK. The new mutant 409A, found in association with the large deletion of 5006 bp in a newborn baby who died soon after birth, was functionally characterized by mutagenesis and in vitro expression of the protein to investigate its contribution in the severity of the clinical pattern. However, the biochemical data obtained for the mutant enzyme cannot explain the severe anaemia found in the PK-deficient patient hemizygous for this mutation.

Adolescent↗
PubMed2005

Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial.

A retrospective analysis of children with first relapse of acute lymphoblastic leukaemia (ALL), treated on the UKALL R2 protocol at four different hospitals, between June 1995 and December 2002 was performed. Of the 150 children 139 (93%) achieved a second complete remission. The overall survival (OS) and event-free survival (EFS) for the whole group was 56% and 47% respectively. The duration of first complete remission and immunophenotype, but not sites of relapse, were predictive for survival. Using the Berlin-Frankfürt-Münster risk stratification for relapsed ALL, the OS and EFS for standard, intermediate (IR) and high risk (HR) groups were 92% and 92%, 64% and 51%, and 14% and 15%, respectively; P < 0.0001 for both OS and EFS. In the IR group, those with a very early isolated central nervous system relapse also had a significantly worse outcome (P = 0.0001). Given the poor outcome of a second relapse, clear strategies are required to identify those in the IR group who will most benefit from stem cell transplantation (SCT). A higher proportion (16%) of induction failures in the HR group suggest the need for novel agents during this phase of treatment, but SCT was associated with a lower relapse rate and better outcome than those treated with chemotherapy alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172).

Concern about late adverse effects of cranial radiotherapy (XRT) has led to alternative approaches to eliminate leukaemia from the central nervous system (CNS) in childhood acute lymphoblastic leukaemia (ALL). The Medical Research Council UKALL XI trial recruited 2090 children with ALL between 1990 and 1997. Median follow-up is 7 years 9 months; event-free survival (EFS) and overall survival were 63.1% and 84.6%, respectively, at 5 years and 59.8% and 79.4% at 10 years. The isolated CNS relapse rate was 7.0% at 10 years. Patients were randomized for CNS-directed therapy within white blood cell (WBC) groups. For WBC <50 x 10(9)/l, high-dose intravenous methotrexate (HDMTX) (6-8 g/m2) with intrathecal methotrexate (ITMTX) was compared with ITMTX alone, and was significantly better at preventing isolated and combined CNS relapse, but non-CNS relapses were similar. There was no significant difference in EFS at 10 years, 64.1% [95% confidence interval (CI) 60.4-67.8] with HDMTX plus ITMTX, and 63.0% (95% CI 59.5-66.5) with ITMTX alone. For WBC >/=50 x 10(9)/l, HDMTX with ITMTX was compared with XRT and a short course of ITMTX. CNS relapses were significantly fewer with XRT, but there was a non-significant increase in non-CNS relapses. EFS was not significantly different, being 55.2% (95% CI 47.8-62.6) at 10 years with XRT and 52.1% (95% CI 44.8-59.4) with HDMTX plus ITMTX.

Adolescent↗
PubMed2004

Non-accidental injury and the haematologist: the causes and investigation of easy bruising.

In cases of suspected non-accidental injury in children, it is vital that a haematologist confirms the presence or absence of a haemostatic disorder so that the child welfare and legal systems can make accurate judgements regarding the cause of isolated injuries. The present paper will discuss commonly used methods for the diagnosis of coagulation disorders in children, and will describe how the investigation of easy bruising and bleeding can be highly problematic. For instance, some frequently used tests for the assessment of haemostasis in children are insensitive, inappropriate, or based on values derived from adult populations. Furthermore, artefact is a frequent problem, and many cases present with a negative family history of bleeding. Therefore, the role played by the haematologist in potential child abuse cases is an essential yet challenging one.

Blood Coagulation Disorders↗
PubMed2004

Rituximab in the treatment of alloimmune factor VIII and IX antibodies in two children with severe haemophilia.

We report the use of rituximab (Genentech, San Francisco, CA, USA) in two children with severe haemophilia with inhibitors to factors VIII and IX, which failed to respond to conventional immune tolerance therapy. The treatment was well tolerated by both children. The child with haemophilia B had no clinical improvement or fall in CD19 and he is currently being treated with recombinant activated factor VII (NovoSeven, Novo Nordisk, Denmark) for bleeding episodes. The child with haemophilia A had a good clinical response with a negative inhibitor assay at 11 months follow-up.

Antibodies, Monoclonal↗
PubMed2004

Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker.

Transient myeloproliferative disorder (TMD) is a unique, spontaneously regressing neoplasia specific to Down's syndrome (DS), affecting up to 10% of DS neonates. In 20-30% of cases, it reoccurs as progressive acute megakaryoblastic leukaemia (AMKL) at 2-4 years of age. The TMD and AMKL blasts are morphologically and immuno-phenotypically identical, and have the same acquired mutations in GATA1. We performed transcript profiling of nine TMD patients comparing them with seven AMKL patients using Affymetrix HG-U133A microarrays. Similar overall transcript profiles were observed between the two conditions, which were only separable by supervised clustering. Taqman analysis on 10 TMD and 10 AMKL RNA samples verified the expression of selected differing genes, with statistical significance (P < 0.05) by Student's t-test. The Taqman differences were also reproduced on TMD and AMKL blasts sorted by a fluorescence-activated cell sorter. Among the significant differences, CDKN2C, the effector of GATA1-mediated cell cycle arrest, was increased in AMKL but not TMD, despite the similar level of GATA1. In contrast, MYCN (neuroblastoma-derived oncogene) was expressed in TMD at a significantly greater level than in AMKL. MYCN has not previously been described in leukaemogenesis. Finally, the tumour antigen PRAME was identified as a specific marker for AMKL blasts, with no expression in TMD. This study provides markers discriminating TMD from AMKL-M7 in DS. These markers have the potential as predictive, diagnostic and therapeutic targets. In addition, the study provides further clues into the pathomechanisms discerning self-regressive from the progressive phenotype.

Acute Disease↗
PubMed2003

Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7.

Primary myelodysplasia (MDS) without an increased number of blasts is a rare finding in childhood. We performed a retrospective analysis of 67 children with a diagnosis of primary MDS to determine the clinical and hematologic course of the disease. The median age at diagnosis was 8.3 years (range, 0.3-18.1 years). In contrast to refractory anemia in adults, 44% of patients had hemoglobin levels greater than 10 g/100 mL. The median white blood cell count and the absolute neutrophil count were 3.6 x 109/L and 0.9 x 109/L, respectively. Seventy-five percent of patients had thrombocytopenia. Bone marrow was hypocellular in 43% of the patients. Results of cytogenetic analysis showed monosomy 7 in 49%, trisomy 8 in 9%, and other abnormalities in 9% of the patients. The probability of survival 10 years after diagnosis was 0.48 (standard error [SE] = 0.10). Patients with monosomy 7 had significantly higher estimated probabilities of progression to advanced MDS than did patients with other chromosomal anomalies or normal karyotype. Of the 67 children, 41 underwent allogeneic stem cell transplantation (SCT). Patients whose disease did not progress to advanced MDS before SCT had significantly greater probability of survival than patients who experienced progression (0.76 [SE = 0.09] vs 0.36 [SE = 0.16]). SCT improved the outcomes for patients with monosomy 7 and should be offered early in the course of the disease. Recommendations for best treatment options for children with other chromosomal abnormalities or normal karyotype may have to await results of prospective clinical trials.

Adolescent↗
PubMed2003

Prenatal chromosomal diversification of leukemia in monozygotic twins.

Previous studies on concordant acute lymphoblastic leukemia (ALL) in identical twins have identified the leukemia as monoclonal with MLL or ETV6-RUNX1 gene fusion as early or initiating events in utero. In the latter case, postnatal latency is associated with secondary genetic events such as ETV6 deletion. We describe here a pair of infant twins with concordant acute monoblastic leukemia (AML). They are a unique pair in that their leukemia blasts display extensive intraclonal chromosomal diversity. Comparison of the leukemic cells between the two twins by karyotype and fluorescence in situ hybridization identifies a common or shared stem line and extensive subclonal diversity for which the twins' leukemic populations are divergent. This case of leukemia illustrates in utero initiation with early imposition of chromosomal instability, the progressively divergent evolution of which can be mapped in the twins into pre- and postnatal periods.

Chromosome Aberrations↗
PubMed2003

Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy.

Severe congenital neutropenia (SCN) is characterized by profound neutropenia, recurrent severe bacterial infections and maturation arrest in the myeloid lineage. Granulocyte colony-stimulating factor (G-CSF) treatment results in clinical improvement in over 90% of cases. Point mutations of the G-CSF receptor (G-CSFR) have been implicated in the progression of SCN to acute myeloid leukaemia (AML). Data are presented here on the 9-year follow-up of seven patients and the further screening of 18 other cases. One of the two original cases with a G-CSFR mutation has improved clinically; nevertheless, mutant DNA could still be detected at a very low level > 8 years after identification. The second child with a mutation progressed to myelodysplasia/AML 5 years after her mutation was detected. No mutations were found in the 18 new cases. One of three transformed cases had a G-CSFR mutation. This work is in agreement with the suggestion that G-CSFR mutations may provide a survival advantage to haemopoietic stem cells, but argues against the inevitability of leukaemic progression in their presence. Furthermore, the low frequency of G-CSFR mutations in SCN and the importance of regular screening and close clinical and laboratory follow-up if a mutation is found were demonstrated.

Acute Disease↗
PubMed2003

The use of recombinant factor VIIa in children with inherited platelet function disorders.

Inherited deficiencies of platelet surface glycoproteins such as Glanzmann's thrombasthenia (GT) or Bernard-Soulier syndrome (BSS) can lead to a severe bleeding diathesis. In the past, bleeding episodes in these patients have often required platelet transfusion to secure haemostasis but recently a number of patient reports have suggested that recombinant factor VIIa (rVIIa) may also be effective. We have used rVIIa on 33 occasions in seven children with inherited platelet function disorders over a 2-year period: five had GT, one had BSS and one had storage pool disease with a severe phenotype. Bleeding ceased with rVIIa alone in 10 of 28 acute bleeding episodes, but recurred in two of these. The two features that predicted response to rVIIa were the severity of the bleeding and the delay from the onset of bleeding to treatment. Five episodes of planned surgical intervention were treated successfully with rVIIa. Eighteen out of the 28 acute episodes and none of the planned surgical episodes required blood product support. We have found variable efficacy of rVIIa for acute bleeding episodes in this small series of children with inherited platelet function defects but larger studies are warranted, particularly as rVIIa is a relatively low-risk treatment approach for these disorders.

Acute Disease↗
PubMed2002

Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors.

The management of acute and surgical bleeding episodes in children with severe factor VIII or IX deficiency who develop high responding inhibitors presents a major therapeutic challenge to clinicians. Recombinant factor VIIa (rVIIa) is an effective, reliable and safe treatment that can be used to treat acute bleeding episodes prior to commencing an immune tolerance programme and to cover surgical procedures until the immune tolerance programme is successful. In a significant minority of patients, immune tolerance therapy is ineffective and an alternative haemostatic agent such as rVIIa is required for life-long treatment. The present study evaluated the use of rVIIa in a paediatric setting. Twelve children, aged 1-16 years, were treated successfully with rVIIa to prevent surgical bleeding in 20 surgical procedures (19 central venous access device insertion or removal, 1 dental extraction). Minor postoperative haematomata developed in 2 out of 20 cases after regular rVIIa therapy had been discontinued and resolved with a short course of rVIIa in both cases. Three children had six life- or limb-threatening bleeding episodes. All bleeding episodes resolved with regular rVIIa treatment although topical fibrin glue was needed in one child with a frenulum tear. One patient required two red cell transfusions for symptomatic anaemia resulting from two separate bleeding episodes. The rVIIa therapy was well tolerated and there was no evidence of treatment-related complications. We conclude that rVIIa is the treatment of choice for the management of surgery and acute life- or limb-threatening bleeding in children with haemophilia and high responding inhibitors.

Acute Disease↗
PubMed2002

Results and follow-up of a phase III randomized study of recombinant human-granulocyte stimulating factor as support for immunosuppressive therapy in patients with severe aplastic anaemia.

In patients with idiopathic severe aplastic anaemia who are treated with immunosuppressive agents to combat T lymphocyte-mediated destruction of haematopoietic progenitor cells, neutropenia is a major cause of infections and toxicity. Evidence from preliminary studies suggests that recombinant human glycosylated granulocyte colony-stimulating factor (lenograstim) increases the number and functionality of neutrophils in patients with severe aplastic anaemia. This randomized, parallel-group, multicentre study was conducted to evaluate the efficacy and safety of subcutaneous lenograstim during the first 12 weeks of standard immunosuppressive therapy in 102 patients with de novo severe aplastic anaemia. The addition of lenograstim to standard therapy resulted in an increase in the proportion of patients showing complete neutrophil response (83.0%vs 44.9%; P < 0.0001). This was seen even among patients with very severe aplastic anaemia (69.2%vs 31.6%; P = 0.012). In patients receiving lenograstim, median time to complete neutrophil response was shorter (6.3 vs 16.1 weeks; P = 0.0001) and mean duration of first neutrophil response was longer (P = 0.0248) than in the control group. At a median follow-up of 5 years, no difference was observed between the groups in term of survival, haematological response and occurrence of secondary leukaemia (one patient in each group). We conclude that lenograstim support of immunosuppressive therapy might be used for patients with severe aplastic anaemia as it significantly enhances neutrophil recovery but does not modify the overall response and survival.

Adolescent↗