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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2013; · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2012; · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2012; · 8.30 Impact Factor
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S Jenkinson,
K Koo,
M R Mansour,
N Goulden,
A Vora,
C Mitchell,
R Wade,
S Richards,
J Hancock, A V Moorman,
D C Linch,
R E Gale
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ABSTRACT: Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1±FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1±FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1±FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.Leukemia advance online publication, 20 July 2012; doi:10.1038/leu.2012.176.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 8.30 Impact Factor
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ABSTRACT: Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled in four successive Medical Research Council-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics was assessed. The factors affecting outcome after relapse were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (> or =30 months from diagnosis) relapses (P<0.0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white blood cell (WBC) count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced outcomes after relapse. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends whereas in high hyperdiploidy (HH) ALL, these seem to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimization using currently available chemotherapy.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2009; 24(2):450-9. · 8.30 Impact Factor
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C Graux,
M Stevens-Kroef,
M Lafage,
N Dastugue,
C J Harrison,
F Mugneret,
K Bahloula,
S Struski,
M J Grégoire,
N Nadal, [......],
K Barber,
A Bosly,
L Michaux,
P Vandenberghe,
I Lahortiga,
K De Keersmaecker,
I Wlodarska,
J Cools,
A Hagemeijer,
H A Poirel
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ABSTRACT: Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1-5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2008; 23(1):125-33. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 23(3):614-7. · 8.30 Impact Factor
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J C Strefford,
H Worley,
K Barber,
S Wright,
A R M Stewart,
H M Robinson,
G Bettney,
F W van Delft,
M G Atherton,
T Davies,
M Griffiths,
S Hing,
F M Ross,
P Talley,
V Saha, A V Moorman,
C J Harrison
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ABSTRACT: Chromosomal abnormalities are important for the classification and risk stratification of patients with acute lymphoblastic leukemia (ALL). However, approximately 30% of childhood and 50% of adult patients lack abnormalities with clinical relevance. Here, we describe the use of array-based comparative genomic hybridization (aCGH) to identify copy number alterations (CNA) in 58 ALL patients. CNA were identified in 83% of cases, and most frequently involved chromosomes 21 (n=42), 9 (n=21), 6 (n=16), 12 (n=11), 15 (n=11), 8 (n=10) and 17 (n=10). Deletions of 6q (del(6q)) were heterogeneous in size, in agreement with previous data, demonstrating the sensitivity of aCGH to measure CNA. Although 9p deletions showed considerable variability in both the extent and location, all encompassed the CDKN2A locus. Six patients showed del(12p), with a common region encompassing the ETV6 gene. Complex CNA were observed involving chromosomes 6 (n=2), 15 (n=2) and 21 (n=11) with multiple regions of loss and gain along each chromosome. Chromosome 21 CNA shared a common region of gain, with associated subtelomeric deletions. Other recurrent findings included dim(13q), dim(16q) and enh(17q). This is the first report of genome-wide detection of CNA in ALL patients using aCGH, and it has demonstrated a higher level of karyotype complexity than anticipated from conventional cytogenetic analysis.
Oncogene 07/2007; 26(29):4306-18. · 6.37 Impact Factor
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ABSTRACT: Deletions from the derivative chromosome 9, der(9), of the translocation, t(9;22)(q34;q11), at the site of the ABL/BCR fusion gene, have been demonstrated by fluorescence in situ hybridisation (FISH), in both Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL). In CML they occur in 10-15% of cases and appear to indicate a worse prognosis, whereas in ALL, the situation is unclear. This study presents the findings of dual fusion FISH used to detect such deletions in a series of 27 BCR/ ABL-positive childhood ALL patients. Metaphase FISH was essential for the accurate interpretation of interphase FISH signal patterns. Three cases (11%) had a single fusion signal, resulting from deletions of the der(9). Three other patients with variant translocations and one with an insertion, also had a single fusion, but with no evidence of deletions. Gain of a fusion in approximately one-third of patients indicated a second Ph, which appears to be a diagnostic marker of Ph-positive ALL. This study shows that the incidence of deletions from the der(9) in childhood ALL is at least as high as that reported for CML.
Leukemia 05/2005; 19(4):564-71. · 9.56 Impact Factor
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A V Moorman,
S C Raimondi,
C H Pui,
A Baruchel,
A Biondi,
A J Carroll,
E Forestier,
P S Gaynon,
J Harbott,
D O Harms,
N Heerema,
R Pieters,
M Schrappe,
L B Silverman,
E Vilmer,
C J Harrison
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ABSTRACT: This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia (ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4;11)(q21;q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del(11)(q23) had the highest incidence (66/93 (71%)). Del(11)(q23) abnormalities were heterogeneous and occasionally secondary to t(9;22)(q34;q11.2). Thus, patients with del(11)(q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X (n = 38), abnormal 12p (n = 32), abnormal 9p (n = 28) and del(6q) (n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% Cl 46-65%) vs 62% (54-69%)) or infants (22% (15-29%) vs 18% (9-29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.
Leukemia 05/2005; 19(4):557-63. · 9.56 Impact Factor
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K E Barber,
M Martineau,
L Harewood,
M Stewart,
E Cameron,
J C Strefford,
S Rutherford,
T D Allen,
Z J Broadfield,
K L Cheung,
R L Harris,
G R Jalali, A V Moorman,
H M Robinson,
C J Harrison
Leukemia 07/2004; 18(6):1153-6. · 9.56 Impact Factor
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H M Robinson,
Z J Broadfield,
K L Cheung,
L Harewood,
R L Harris,
G R Jalali,
M Martineau, A V Moorman,
K E Taylor,
S Richards,
C Mitchell,
C J Harrison
Leukemia 12/2003; 17(11):2249-50. · 9.56 Impact Factor
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L Harewood,
H Robinson,
R Harris,
M Jabbar Al-Obaidi,
G R Jalali,
M Martineau, A V Moorman,
N Sumption,
S Richards,
C Mitchell,
C J Harrison
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ABSTRACT: This study identifies multiple copies of the AML1 gene on a duplicated chromosome 21, dup(21), as a recurrent abnormality in acute lymphoblastic leukemia (ALL). Clusters of AML1 signals were visible at interphase by fluorescence in situ hybridization (FISH). In metaphase, they appeared tandemly duplicated on marker chromosomes of five distinct morphological types: large or small acrocentrics, metacentrics, submetacentrics or rings. The markers comprised only chromosome 21 material. Karyotypes were near-diploid and, besides dup(21), no other established chromosomal changes were observed. A total of 20 patients, 1.5 and <0.5% among consecutive series of childhood and adult ALL respectively, showed this phenomenon. Their median age was 9 years, white cell counts were low and all had a pre-B/common immunophenotype. Although this series is not the first report of this abnormality, it is the largest, permitting a detailed description of the variety of morphological forms that duplicated chromosome 21 can assume.
Leukemia 03/2003; 17(3):547-53. · 9.56 Impact Factor
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Leukemia 01/2003; 17(2):477-477. · 9.56 Impact Factor
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ABSTRACT: Between 1980 and 1998, in the north-west of England, a significant rise in childhood acute lymphoblastic leukaemia was caused by an increase in the precursor B-cell form of this disease. We analysed data on children who were diagnosed with leukaemia in Yorkshire, UK, between 1974 and 1997. The incidence of acute lymphoblastic leukaemia remained stable, although a non-significant yearly increase of 2.4% was noted for the precursor B-cell form of this disease from 1980 onwards. The precursor B-cell form accounted for 80% of all acute lymphoblastic leukaemia. Our data are not consistent with increasing incidence for precursor B-cell acute lymphoblastic leukaemia, although numbers of children with acute myeloid leukaemia are rising.
The Lancet 09/2001; 358(9279):385-7. · 38.28 Impact Factor
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R Clark,
S A Byatt,
C F Bennett,
M Brama,
M Martineau, A V Moorman,
K Roberts,
L M Secker-Walker,
S Richards,
O B Eden,
A H Goldstone,
C J Harrison
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ABSTRACT: Twenty new cases of acute lymphoblastic leukemia (ALL) with the dicentric chromosome dic(9;20)(p1113;q11) are presented. This chromosomal abnormality is difficult to identify from G-banding alone. It masquerades as monosomy 20 and is only accurately identified by fluorescence in situ hybridization (FISH). Monosomy 20 was found in 59/2790 patients with successful karyotypes entered to the Leukaemia Research Fund/UK Cancer Cytogenetics Group Karyotype Database in ALL (LRF/UKCCG Karyotype Database). FISH revealed dic(9;20) in 20/25 cases with available material. Extra copies of chromosome 21 were found in 8 of the 20 cases. Patients were 14 females and six males, aged 1-32 years (median 4 years), with leukocyte counts of 2-536 (median 23) x 109/l and immunophenotypes of common or pre-B ALL (17 cases), T-ALL (one case) or unknown (two cases). Four patients relapsed at 2, 22, 28 and 47 months and two died at 49 and 63 months (median follow-up 37 months). FISH studies on the remaining five patients showed one with monosomy 20 and four with other rearrangements of the chromosome. This study has increased the number of reported cases of dic(9;20) from 17 to 37. It has identified dic(9;20) in one case of T-ALL and shows an association of this translocation with trisomy 21.
Leukemia 03/2000; 14(2):241-6. · 9.56 Impact Factor
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ABSTRACT: Most hematological neoplasms associated with 11q23 chromosomal rearrangement have been cases of acute lymphoblastic or acute myeloid leukemia. Although cases of myelodysplastic syndrome (MDS) are a minority, these syndromes should also be recognized as part of the spectrum of hematological disorders associated with 11q23 rearrangement. In this series of 550 patients with such rearrangement there were 28 (5.1%) who presented with MDS. A further five patients had a history of MDS but had evolved to AML by the time cytogenetic analysis was first undertaken. There were thus a total of 33 patients (6.0%) with an 11q23 abnormality whose initial presentation was as MDS. Of these 33 patients, a quarter (seven patients) were cases of secondary (therapy-related) MDS. Complex karyotypes and other poor prognosis chromosomal abnormalities such as -7 and 7q- were common and were not confined to secondary cases. The likelihood of presentation as MDS differed between different cytogenetic categories. The 28 patients in whom cytogenetic analysis was performed at presentation as MDS showed a wide age distribution, from 1 to 82 years; there were four children, two of 1 year of age. All FAB types of MDS were represented. Median survival was only 19.1 months. Leukemic transformation occurred in five patients including one case of transformation to a biphenotypic M5a/T-lineage acute leukemia.
Leukemia 06/1998; 12(5):834-9. · 9.56 Impact Factor
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ABSTRACT: This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.
Leukemia 06/1998; 12(5):792-800. · 9.56 Impact Factor
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ABSTRACT: The clinical, haematological and cytogenetic data for 20 patients with an acquired abnormality of 11q23 and 10p have been reviewed at this workshop. Patients predominantly presented with de novo AML M5a and the most common cytogenetic finding was an inversion of part of the long arm of chromosome 11 followed by a translocation between 11q and 10p. Band p12 represented the most common breakpoint on chromosome 10. The t(10;11) subgroup defined a subset of younger 11q23 patients, the majority of whom achieve a first complete remission despite the differing treatment regimens.
Leukemia 06/1998; 12(5):801-4. · 9.56 Impact Factor
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ABSTRACT: Balanced translocations of 11q23 are associated with specific clinical features and a poor outcome, but the relevance of deletions involving 11q23 is not clear. Fifty-seven patients with this deletion were collected by the Workshop, 30 had terminal and 27 had interstitial deletions. Twenty-seven patients had acute lymphoblastic leukemia (ALL), 16 had acute myeloid leukemia (AML), one had acute biphenotypic leukemia, one had acute undifferentiated leukemia and 12 had myelodysplastic syndrome (MDS). ALL patients had a median age of 7 years, median white blood cell count (WBC) of 15 x 10(9)/l, and 10/24 had common ALL. AML patients had a median age of 23 years, a median WBC of 49 x 10(9)/l, and 9/16 had M4 or M5. MDS patients were all adult, median age of 69 years, median WBC of 3 x 10(9)/l, and 7/12 had refractory anemia. The clinical outcome depended on diagnosis: children with ALL had a better prognosis (4/16 relapsed, one died) than AML patients; all adults and children with AML and 5/12 MDS patients died. Fluorescence in situ hybridization (FISH) identified 3 del(11q23) as translocations or insertions. Molecular studies revealed a MLL rearrangement in 8/10 patients. Because the involvement of MLL might be of prognostic relevance, identification of a del(11q23) should be an indication for FISH and molecular studies.
Leukemia 06/1998; 12(5):823-7. · 9.56 Impact Factor
