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1
Sarrou, Evgenia, Laura Richmond, Ruaidhrí J. Carmody, Brenda Gibson, and Karen Keeshan. "CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis." International Journal of Molecular Sciences 21, no. 12 (June 15, 2020): 4266. http://dx.doi.org/10.3390/ijms21124266.
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Chromosomal rearrangements of the mixed lineage leukaemia (MLL, also known as KMT2A) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. MLL rearrangements (MLLr) are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells. By utilizing a dual-single guide RNA (sgRNA) approach targeting the breakpoint cluster region of murine Mll and Af9 equivalent to that in human MA9 rearrangements, we show efficient de novo generation of MA9 fusion product at the DNA and RNA levels in the bulk population. The leukaemic features of MA9-induced disease were observed including increased clonogenicity, enrichment of c-Kit-positive leukaemic stem cells and increased MA9 target gene expression. This approach provided a rapid and reliable means of de novo generation of Mll-Af9 genetic rearrangements in murine haematopoietic stem and progenitor cells (HSPCs), using CRISPR/Cas9 technology to produce a cellular model of MA9 leukaemias which faithfully reproduces many features of the human disease in vitro.
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McCarthy, C. M. T., and S. M. Benson. "Cytogenetic abnormalities in acute myelomonocytic leukaemia." Mutation Research/Environmental Mutagenesis and Related Subjects 164, no. 3 (June 1986): 195–96. http://dx.doi.org/10.1016/0165-1161(86)90021-x.
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Farina, Mirko, Giuseppe Rossi, Daniella Bellotti, Eleonora Marchina, and Robert Peter Gale. "Is Having Clonal Cytogenetic Abnormalities the Same as Having Leukaemia?" Acta Haematologica 135, no. 1 (September 17, 2015): 39–42. http://dx.doi.org/10.1159/000437202.
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A finding of cytogenetic abnormalities, even when these are clonal and even when the abnormalities are typically associated with leukaemia, is not the same as a person having leukaemia. We describe a person who had acute myeloid leukaemia (AML) and achieved a complete haematological remission and who then had persistent and transient clonal cytogenetic abnormalities for 22 years but no recurrence of leukaemia. These data suggest that clones of myeloid cells with mutations and capable of expanding to levels detectable by routine cytogenetic analyses do not all eventuate in leukaemia, even after a prolonged observation interval. The possibility of incorrectly diagnosing a person as having leukaemia becomes even greater when employing more sensitive techniques to detect mutations such as by polymerase chain reaction and whole-exome or whole-genome sequencing. Caution is needed when interpreting clonal abnormalities in AML patients with normal blood and bone marrow parameters.
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Arruda, Walter Oleschko, María Belén Montú, Marcelo de Souza R. de Oliveira, and Ricardo Ramina. "Acute myeloid leukaemia induced by mitoxantrone: case report." Arquivos de Neuro-Psiquiatria 63, no. 2a (June 2005): 327–29. http://dx.doi.org/10.1590/s0004-282x2005000200024.
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Mitoxantrone (MX) is an immunosupressant drug used in secondarily progressive multiple sclerosis (SPMS) and in relapsing-remitting multiple sclerosis (RRMS). It has a leukemogenesis potential induced by cytogenetic abnormalities, though with a low incidence. Promyelocitic leukaemia (type M3) and other forms of acute myeloblastic leukaemias (M4 and M5) have been described in a few MS patients who received MX during their treatment. We describe a white female patient, 47 year-old, with SPMS (EDSS = 4) with 14 years of disease. She received MX during her disease and developed acute promyelocytic leukaemia (M3), with severe thrombocytopenia 30 months later. She ultimately died due to intracerebral hemorrhage. Other cases of treatment related to AML are reviewed and discussed.
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R., Senthilprabhu, Aruna R., and Ravichandran C. "Cytogenetic and molecular aberrations in childhood B lineage acute lymphoblastic leukaemia." International Journal of Contemporary Pediatrics 7, no. 3 (February 25, 2020): 511. http://dx.doi.org/10.18203/2349-3291.ijcp20200485.
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Background: Acute Lymphoblastic Leukemia (ALL) is a common hematological malignancy in children and is characterized by genetic changes such as mutations and chromosomal translocations. These cytogenetic and molecular abnormalities have got diagnostic and prognostic significance. Identification of these abnormalities helps in risk categorization and appropriate therapy. Aim of the study was to assess the cytogenetic/molecular abnormalities associated with B Lineage ALL in children.Methods: It was a hospital based retrospective observational study of 79 children diagnosed with B Lineage ALL by Bone marrow aspirate morphology and flow cytometry. Bone marrow samples or Peripheral blood were sent for cytogenetic/molecular analysis by Fluorescent in situ Hybridization technique. Descriptive data analysis was done using SPSS software.Results: Out of 199 cases 163(82%) were B Lineage ALL. 79(48%) undergone molecular analysis. Out of 79 cases of B lineage ALL, Translocation t(9;22) BCR-ABL1 was positive in 2(2.5%) cases , Translocation t(12;21) TEL/AML1 was positive 9(11%) cases and MLL (KMT2A) Gene Rearrangements was seen in 6(7.6%) children. Out of 79 cases of B lineage ALL, 6(7.6%) were Infantile ALL (Males 1(17%); Females 5(83%)). 4(67%) cases were positive for MLL (KMT2A) Gene Rearrangement, all of them were female children. Over all 17(22%) cases (Males 4(24%); Females 13(76%)) were positive for molecular abnormalities.Conclusions: Many children with ALL have got Cytogenetic and Molecular abnormalities. The highest percentage of cytogenetic and molecular genetic abnormalities was related to t(12;21)TEL/AML1 in B Lineage ALL children, if present confer favourable prognosis. MLL (KMT2A) Gene Rearrangement was the common molecular abnormality in Infantile B ALL, presence of it leads to high risk categorization and confer poor prognosis. The evaluation of cytogenetic and molecular genetic abnormalities in children is essential in estimating the prognosis in B Lineage ALL children, which will be a great contribution to offer appropriate therapeutic approaches.
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Young, Bryan D. "Cytogenetic and molecular analysis of chromosome 11q23 abnormalities in leukaemia." Baillière's Clinical Haematology 5, no. 4 (October 1992): 881–95. http://dx.doi.org/10.1016/s0950-3536(11)80050-8.
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Grimwade, David. "The clinical significance of cytogenetic abnormalities in acute myeloid leukaemia." Best Practice & Research Clinical Haematology 14, no. 3 (September 2001): 497–529. http://dx.doi.org/10.1053/beha.2001.0152.
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Manola, Kalliopi N. "Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview." British Journal of Haematology 163, no. 1 (July 25, 2013): 24–39. http://dx.doi.org/10.1111/bjh.12484.
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Harrison, Christine. "New genetics and diagnosis of childhood B-cell precursor acute lymphoblastic leukemia." Pediatric Reports 3, no. 2s (June 17, 2011): 4. http://dx.doi.org/10.4081/pr.2011.s2.e4.
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Over the last 50 years, while significant advances have been made in the successful treatment of childhood leukaemia, similar progress has been made in understanding the genetics of the disease. In childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), the incidences of individual chromosomal abnormalities are well established and cytogenetics provides a reliable tool for risk stratification for treatment. In spite of this role, a number of patients will relapse. Increasing numbers of additional genetic changes, including deletions and mutations, are being discovered. Their associations with established cytogenetic subgroups and with each other remain unclear. Whether they have a link to outcome is the most important factor in terms of refinement of risk factors in relation to clinical trials. For a number of newly identified abnormalities, appropriately modified therapy has significantly improved outcome. Alternatively, some of these aberrations are providing novel molecular markers for targeted therapy.
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Baqi, Saqi Md Abdul, Umme Kulsum Munmun, Md Rafiquzzaman Khan, Md Salahuddin Shah, Shafiqul Islam, Farzana Rahman, Md Abdul Aziz, and Masuda Begum. "Cytogenetic Pattern in Adult Patients with de novo Acute Myeloid Leukaemia: A Single Centre Study in Bangladesh." Haematology Journal of Bangladesh 4, no. 1 (June 20, 2020): 08–12. http://dx.doi.org/10.37545/haematoljbd202047.
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Background: Cytogenetic analysis performed at diagnosis is considered to be the most important prognostic factor in AML. Objective: The purpose of this study was to observe the pattern of cytogenetic abnormalities in adult patients with de novo AML. Method: Total fifty-two newly diagnosed de novo AML patients were selected for the study. Six cytogenetic abnormalities including t(8;21), t(15;17), inv(16), BCR-ABL1, FLT3-ITD & NPM1 mutations were detected by Real-Time PCR. Results: In this study, 36 (69.2%) patients showed different cytogenetic abnormalities. The t(15;17) was found to be the most common. t(15;17), t(8;21) and inv(16) were found only in M3, M2 and M4 FAB subtypes, respectively. Significant association was found with increasing age and cytogenetic risk groups. BCR-ABL1 mutation showed significant relation with increased age. FLT3-ITD mutation showed significant association with increased WBC count and inv16 was significantly associated with relatively less bone marrow blast percentage. Conclusion: Cytogenetic study should be performed routinely in all cases of AML for proper diagnosis, prediction of prognosis and implementation of effective therapeutic measures.
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Xu, Wei, Jianyong Li, Jinlan Pan, Li Li, Hairong Qiu, Yongquan Xue, and Changgeng Ruan. "Interphase Fluorescence In Situ Hybridization Detection of Cytogenetic Abnormalities in B-Cell Chronic Lymphocytic Leukemia." Blood 106, no. 11 (November 16, 2005): 4992. http://dx.doi.org/10.1182/blood.v106.11.4992.4992.
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Abstract The most frequent chromosomal abnormalities in B-cell chronic lymphocytic leukaemia (B-CLL) are deletions on 13q14 and 17p13, trisomy 12 and 14q32 rearrangement. Conventional metaphase cytogenetic analysis underestimates the frequency of specific chromosome aberrations in B-CLL due to the low rate of spontaneous mitoses and poor response to mitogen stimulation. The aim of this study was to investigate the incidence of chromosomal changes in bone marrow or peripheral blood cells (or both) of B-CLL patients using a molecular cytogenetic method, interphase fluorescence in situ hybridization (I-FISH). Probes for 13q14 (D13S319), 17p13 (P53 gene), the centromere of chromosome 12 (D12Z3) and 14q32 (Ig10 and Y6) were applied to detect chromosomal aberrations on bone marrow and peripheral blood smears from 83 B-CLL patients (60 male, 23 female,). Molecular cytogenetic aberrations were found in 60 (72.3%) cases, and 8 (9.6%) patients showed two kinds of abnormalities. The most frequent abnormalities detected in our patients was deletions of 13q14 in 34 cases (41.0%), followed by trisomy of chromosome 12 in 16 patients (19.3%), deletions of 17p13 in 10 patients (12%) and 14q32 rearrangement in 8 patients (9.6%). Statistical analyses were performed to correlate the molecular cytogenetic findings with Binet stages. No apparent differences in distribution were noted for anomalies del(13q14), del(17p13), +12 or 14q32 rearrangement among patients with various Binet stages. FISH was found to be a more rapid, exact and sensitive technique for the analysis of chromosome aberrations in CLL. FISH could provide accurate information of molecular cytogenetics for CLL.
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de Greef, Georgine E., and Anne Hagemeijer. "1 Molecular and cytogenetic abnormalities in acute myeloid leukaemia and myelodysplastic syndromes." Baillière's Clinical Haematology 9, no. 1 (March 1996): 1–18. http://dx.doi.org/10.1016/s0950-3536(96)80034-5.
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XU, W., J. Li, S. Zhang, Y. Wu, Y. Zhu, and Y. Zhu. "Prognostic factors in Chinese patients with chronic lymphocytic leukemia." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 17518. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.17518.
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17518 Background: Recently, some new factors, such as cytogenetic abnormalities, ZAP-70, proliferative antigen Ki-67, and the expression of CD38 in leukaemic cells, were strong indicator of prognosis in B-cell chronic lymphocytic leukaemia (B-CLL). The aim of this study was to explore the characteristics of molecular cytogenetics in Chinese patients with CLL, evaluate the expression of Ki-67, ZAP-70 and CD38 in leukaemic cells, and analyze the influence of factors on the prognosis of CLL. Methods: Interphase fluorescence in situ hybridization (FISH) was used to detect cytogenetic aberrations, and a panel of FISH probes for 13q14 (D13S319), 17p13 (p53 gene), 11q23 (ATM gene), the centromere of chromosome 12 (D12Z3) and 14q32 (IGHC/IGHV) was applied on bone marrow or peripheral blood smears from 52 Chinese B-CLL patients; Four-color flow cytometry was used to determined the expression of ZAP-70 protein and CD38; Immunohistochemistry was applied to measure the expression of Ki-67 antigen and Bcl-2 protein. Kaplan-Meier was used for survival time. Results: Out of the 52 patients, 42 (80.7%) had at least one kind of molecular cytogenetic aberration and 16 (30.8%) with 2 abnormalities. The most frequent abnormalities detected in our patients was deletions of 13q14 in 26 cases (50.0%), followed by trisomy of chromosome 12 in 11 patients (21.2%), deletions of 17p13 in 10 patients (19.2%), deletions of 11q23 in 6 patients (11.5%), and 14q32 translocation in 5 patients (9.6%). Fourteen patients (26.9%) were positive for ZAP-70 (=20%), and 13 patients (25.0%) were positive for CD38. Positive ZAP-70 and CD38 status was associated with advanced disease stage (Binet C). The expression levels of Ki-67 in Binet C stage was higher than that in early stage (Binet A and B). In univariate analysis for survival, 13q14 deletion was a favorable prognostic factor, and the deletions of 17p13 and 11q23 were poor prognostic factors. The survival time was longer in the group with lower expression of Ki-67 than that in the higher expression group. Both ZAP-70 and CD38 expression were shown to predict the clinical course of the disease. Conclusions: Chromosomal aberrations (deletions of 13q14, 17p13 and 11q23), and expression of Ki-67, ZAP-70 and CD38 have been shown highly predictive prognostic value for Chinese patients with B-CLL. No significant financial relationships to disclose.
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Moorman, Anthony V., Hannah M. Ensor, Lucy Chilton, Sue M. Richards, Sally E. Kinsey, Ajay J. Vora, Christopher D. Mitchell, and Christine J. Harrison. "Prognostic Relevance of Cytogenetics in Childhood Acute Lymphoblastic Leukaemia (ALL): Final Results From MRC ALL97." Blood 114, no. 22 (November 20, 2009): 88. http://dx.doi.org/10.1182/blood.v114.22.88.88.
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Abstract Abstract 88 Chromosomal abnormalities in childhood ALL are important disease markers and predictors of prognosis. Virtually all modern protocols recommend that patients with t(9;22), MLL translocations and haploidy (<30 chromosomes) receive intensive therapy. However, there is less consensus regarding the prognostic relevance of other abnormalities, e.g. t(1;19), intrachromosomal amplification of chromosome 21 (iAMP21), dic(9;20), abnormal 9p, CDKN2A deletions and low hypodiploidy (30–39 chromosomes). Furthermore, the long term prognosis and independent effect of some abnormalities, especially t(12;21)/ETV6-RUNX1, has been questioned. We investigated the prognostic relevance of cytogenetics among 1,934 children treated on MRC ALL97. Patients with t(9;22), haploidy, low hypodiploidy and those aged <2yrs with a MLL translocation were treated as high risk. In order to focus on the intrinsic aggressiveness of the leukemic clone, we used relapse-free survival (RFS) as our primary endpoint. In addition, we constructed a cytogenetic based risk index to assess the utility of cytogenetics as a whole in predicting relapse. The 5yr RFS of the whole cohort was 81% (95% CI 79–82%) with a median follow-up of 8.2yrs. Univariate analysis revealed 5 abnormalities that were significantly associated with relapse: t(12;21) Hazard ratio (HR)=0.50 (95% CI 0.36, 0.68); high hyperdiploidy (51–65 chromosomes): 0.58 (0.45, 0.74); iAMP21: 5.51 (3.57, 8.50); t(9;22): 3.31 (2.06, 5.32); other MLL translocations [not t(4;11)]: 2.70 (1.39, 5.25); and 17p loss [del(17p)]: 2.13 (1.35, 3.34) (all p<0.003). Moreover, all abnormalities, except other MLL translocations, retained their significance in multivariate analysis. The following abnormalities were not predictive of relapse: t(4;11), t(1;19), dic(9;20), CDKN2A deletions, −7 and abnormal 9p. There were too few haploid and low hypodiploid patients to be formally tested but 10/18 (56%) relapsed. Further analysis of high hyperdiploid patients revealed that there was no difference in RFS for those with (n=218) and without (n=200) triple trisomy (+4, +10 and +17) [HR=0.81 (0.49, 1.34), p=0.4]. However, high hyperdiploid patients with a +18 (n=396) had a lower risk of relapse [HR=0.44 (0.26, 0.74) (p=0.002)] than other patients (n=86). Among 369 t(12;21) patients 47 (13%) suffered a relapse. The timing of these relapses was different to the rest of the cohort with fewer early relapses (within 6 months of the end of treatment) in the t(12;21) cohort: 9/47 (19%) versus 170/285 (59%), p<0.001. The 5yr and 7yr cumulative risk of relapse for t(12;21) patients was 11% (95% CI 8–15%) and 13% (9–17%) respectively compared to 24% (22–28%) and 27% (24–30%), respectively for other patients. A total of 54/1596 (3.4%) patients had del(17p) by cytogenetics: i(17q) (n=18), del(17)(p) (n=7), monosomy 17 (n=8) and unbalanced translocations (n=21). It is a secondary abnormality co-existing with high hyperdiploidy (n=21), t(12;21) (n=6), MLL translocations (n=2) and t(9;22) (n=1). Overall, these patients had an inferior RFS (64%, (49%–75%), p=0.004). However, the presence of del(17p) did not abrogate the good outcome of patients with t(12;21) and high hyperdiploidy [HR=1.70 (0.75, 3.87) p=0.206] but did represent a strong marker of relapse among other patients [HR=2.96 (1.68, 5.20) p<0.001]. We classified 1,733 patients into three cytogenetic risk groups: good (GRG) [t(12;21), high hyperdiploidy] n=928 (54%); poor (PRG) [t(9;22), t(4;11), other MLL, t(17;19), haploidy, low hypodiploidy, iAMP21, del(17p)] n=153 (9%); standard (SRG) [all other cases] n=652 (38%). The 5 year RFS were GRG 88% (85–90%), SRG 79% (75–82%) and PRG 49% (40–57%). In multivariate analysis, patients in the GRG or PRG were less or more likely to relapse compared to patients in the SRG: HR=0.65 (0.50–0.83), p=0.001 and HR=2.67 (2.01–3.53), p<0.001, respectively. Moreover, there was a strong correlation between cytogenetic risk group and the BFM risk classification of relapses, based on immunophenotype, timing and site of relapse. Among GRG patients who relapsed, only 11/130 (8.5%) suffered a high risk relapse; whereas 36/76 (47%) PRG patients who relapsed had a high risk relapse. These data clarify the prognostic relevance of several chromosomal abnormalities in the context of a modern childhood ALL therapy and provide further evidence that cytogenetics is a powerful and independent indicator of relapse risk. Disclosures: No relevant conflicts of interest to declare.
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Nahi, Hareth, Bengt Smedmyr, Helene Hallböök, and Hans Hagglund. "Do Deletions in 9p Reflect Prognosis in Adult Precursor B-Cell ALL? a Multi-Centre Study of 381 Patients." Blood 112, no. 11 (November 16, 2008): 4865. http://dx.doi.org/10.1182/blood.v112.11.4865.4865.
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Abstract Despite the fact that the outcome among patients with acute lymphoblastic leukaemia (ALL) has improved, the majority of adult patients relapse and die of their disease. Besides age and white cell count at diagnosis, the cytogenetic abnormalities t(9,22)/BCR-ABL and t(4,11) are important prognostic markers and are often included in the treatment stratification of patients with adult ALL. Deletions in 9p are seen in about 9% of cases of adult ALL, but their prognostic impact has been controversial. Methods: Cytogenetic data from 381 patients diagnosed with B-precursor ALL were reviewed. Chromosomal analysis was successful in 240 cases. Of these cases, 18 (8%) had abnormalities in 9p and they were compared with patients with normal karyotypes and patients with t(9;22)/BCR-ABL. Results: Patients with abnormalities of chromosome 9 showed significantly shorter overall survival compared with patients with normal karyotypes. In fact, overall survival was similar to that in the poor prognosis t(9;22)/BCR-ABL-positive group. Conclusions: The data suggest that chromosomal abnormalities involving 9p may have a significant negative impact on survival in adult B-precursor ALL.
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Wu, H. K., K. Kitamura, Y. R. Xi, Y. T. Wang, S. L. Liu, and D. B. Zhou. "Cytogenetic Analysis of Bone Marrow from Patients with Primary Myelodysplastic Syndrome." Journal of International Medical Research 20, no. 3 (June 1992): 254–66. http://dx.doi.org/10.1177/030006059202000307.
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Of 34 patients with primary myelodysplastic syndrome (MDS), 26 (76.5%) were found to have chromosome defects using an improved bone marrow culture method and high-resolution G-banding technique induced by actinomycin D. The frequency of abnormalities varied among the subtypes: 1/2 in refractory anaemia with ringed sideroblasts; 18/24 in refractory anaemia; 5/6 in refractory anaemia with excess of blasts (RAEB); and 2/2 in refractory anaemia with excess of blasts in transformation. The most frequent abnormalities, either single, double or complex defects, were −5/5q-, −7, +8 and +21; 16q-/16p-, +19 and −X were also common. The percentage of aneuploid cells, in particular hypodiploid cells, was increased. The abnormalities were detected more frequently in complex aberrations associated with RAEB and RAEB in transformation. The presence of −5/5q- as a sole aberration was associated with longer mean survival time (>18 months) but multiple (more than two) chromosomal abnormalities were associated with a poorer prognosis and a mean survival time of only 7.5 months. Chromosome follow-up studies indicated that patients with −7, +8, +21, −X and complex defects, increased hypodiploid cells and karyotpic evolution were likely to have a high risk of transformation to leukaemia or to a more severe subtype of MDS with a short overall mean survival time. These defects, mostly of the deleted type, are assumed to play a specific role in the pathogenesis of myelodysplasia. Repeated chromosomal analyses during the clinical course convey more accurate prognostic criteria for patients.
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Davids, Matthew S., Alexander Vartanov, Lillian Werner, Donna Neuberg, Paola Dal Cin, and Jennifer R. Brown. "Controversial fluorescencein situhybridization cytogenetic abnormalities in chronic lymphocytic leukaemia: new insights from a large cohort." British Journal of Haematology 170, no. 5 (June 1, 2015): 694–703. http://dx.doi.org/10.1111/bjh.13498.
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Chen, Xiangjun, Jine Zheng, Kaiwei Liang, Yanli He, Wen Du, Juan Li, Wei Liu, Yanjie Hu, Shiang Huang, and Junxia Yao. "Characterisation of clonal Philadelphia-negative cytogenetic abnormalities in a large cohort of chronic myeloid leukaemia." Internal Medicine Journal 48, no. 4 (April 2018): 439–44. http://dx.doi.org/10.1111/imj.13527.
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Harrison, Christine J., Kerry Barber, Zoë Broadfield, Adam Stewart, Sarah Wright, Mary Martineau, Jon C. Strefford, and Anthony V. Moorman. "Cytogenetic Classification of T Lineage Acute Lymphoblastic Leukaemia: Multiple Partners of BCL11B and Other Novel Rearrangements." Blood 108, no. 11 (November 1, 2006): 2062. http://dx.doi.org/10.1182/blood.v108.11.2062.2062.
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Abstract Increasing numbers of genetic changes are being described in T lineage acute lymphoblastic leukaemia (T ALL), which may be used to classify patients into subgroups, defining multi-step oncogenic pathways. We have integrated the significant abnormalities into a comprehensive genetic classification of T ALL, using appropriate probes for fluorescence in situ hybridization (FISH). Break-apart probes were designed, which detected rearrangements of the TCR loci. Metaphase FISH, confirmed by informative break-apart probes for the significant oncogenes, were used to identify partner genes, as shown in the table. This approach revealed new recurrent translocation partners, as well as determining the incidence and simultaneous occurrence of the different abnormalities. The series included 295 patients, children 0–14 years (n=206) and adults ≥ 15 years (n=89), with a diagnosis of T ALL, entered to one of the UK MRC/NCRI ALL treatment trials. The incidences of the common cryptic abnormalities, SIL-TAL1 fusion and TLX3 were more prevalent in children (20% and 17%, respectively) compared to adults (9% each). There was no difference in event free survival between the childhood patients with SIL-TAL1 fusion and TLX3 rearrangements. CALM-AF10 fusion and MLL rearrangements accounted for 4% each. A single patient was found with a BCR-ABL fusion, but the same probe identified nine (3%) with NUP214-ABL1 amplification. Deletions involving CDKN2A were present in 49% of patients, in association with all abnormalities. Among the patients with NUP214-ABL1 amplification, associated abnormalities were: CDKN2A deletions (n=9), TRA@-TLX1 (n=2), BCL11B-TLX3 (n=2), TRB@-TLX3 (n=1). Concurrent rearrangements were found between the TCR genes, as well as associations between MYC, IGH and the other oncogenes. For example, (1) complex abnormalities between (a) TRA@, TRG@, BCL11B (n=2) and (b) HOXA@ (n=1); (2) deletions of 3′TRB@ in association with (a) complex ring chromosomes (n=2) and (b) cytogenetically visible deletions (n=2). FISH detected several novel, recurrent rearrangements, in particular a t(6;14) involving BCL11B and the 6q26 region (n=5) and a t(9;14)(p24;q31.1) involving JAK2 (n=2), the partners of which are currently being defined. BCL11B was also involved with (a) LMO2 and (b) the 2q23 region; LMO2 was rearranged with an unidentified partner in a complex translocation with chromosomes 16 and 18; TLX1 was involved in a translocation with 3q; new partners of TRB@ were found at (a) 1q11, (b) on 12p (n=2), (c) on 21q. These findings demonstrate the valuable role of FISH analysis, with a panel of carefully selected probes, to classify T ALL patients into genetic subgroups, including rare variants, and provide information on the relationship between them. A metaphase FISH approach has facilitated the identification of potential new target genes. In particular, multiple partners of TRB@ and BCL11B, other than the known TLX3 and HOXA@ genes, have emerged, highlighting the importance of these genes in the pathogenesis of T ALL. Promotor and Oncogenes in T ALL Promotor Genes Oncogenes BCL11B TRA@ TRB@ TRG@ CDK6 Novel***/Unknown *includes 3 telomeric deletions, **includes 3 centromeric deletions, ***listed in text TLX3 38* 3 1 2 TLX1 12 3 1 HOXA@ 1 5 1 LMO1 1 LMO2 1 14 3 1 4** LYL1 2 TAL2 6 NOTCH1 1 MYC 2 3 1 MYB 1 IGH@ 4
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Moorman, Anthony V., Amy Erhorn, Catriona Parker, Rosemary Sutton, Claire Schwab, Nicola C. Venn, Peter M. Hoogerbrugge, Tamas Revesz, Vaskar Saha, and Christine J. Harrison. "The Clinical Relevance Of Genetics In Predicting Outcome After a First Relapse In Children With B-Cell Precursor Acute Lymphoblastic Leukaemia." Blood 122, no. 21 (November 15, 2013): 2566. http://dx.doi.org/10.1182/blood.v122.21.2566.2566.
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Abstract Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease at the genetic level. Chromosomal abnormalities, gene deletions, mutations and amplifications relevant for diagnosis, prognosis or treatment allocation have been identified. This knowledge is mostly derived from presentation samples and focussed on predicting for relapse after frontline therapy. Studies genetically characterising a large cohort of relapsed patients treated uniformly on a single protocol have rarely been reported. In this study, we assessed the outcome of B-cell precursor (BCP) ALL patients treated on the international relapse trial, ALLR3, according to the presence of established chromosomal abnormalities and the most prevalent gene deletions. Among 416 childhood BCP-ALL patients, a representative cohort of 372 (89%) patients were classified into three risk groups based on cytogenetic analysis at presentation and/or relapse: (1) good risk (GR, n=181, 49%) - ETV6-RUNX1, high hyperdiploidy; (2) poor risk (PR, n=69, 19%) - BCR-ABL1, MLL translocation, near haploidy, low hypodiploidy, intrachromosomal amplification of chromosome 21 (iAMP21), t(17;19)(q23;p13) and, in the absence of GR abnormalities, deletions of 13q and abnormalities of 17p; and (3) intermediate risk (IR, n=122, 33%) – all other cases with abnormal or normal cytogenetics. Relapses were categorised as very early (<18 months from initial diagnosis), early (within 6 months of stopping frontline treatment) or late (6 months after the end of frontline treatment). There was a significant correlation between cytogenetic risk group and duration of first remission: GR patients comprised 2% very early, 27% early and 71% late relapses, whereas the distribution among IR and PR patients was 15%/36%/49% and 26%/38%/36% respectively (p<0.001). There was no significant difference in the site of relapse (isolated marrow, isolated CNS, other) according to cytogenetic risk group. Overall survival at 5 years post first relapse differed significantly across the three cytogenetic risk groups: GR – 66% (95% CI 57-73%); IR – 49% (39-59%); PR – 29% (17-42%), p<0.0001. This difference remained significant among patients treated as standard risk (p=0.004) but was borderline among those treated as high risk (p=0.057). Similar results were observed for event (EFS) and relapse (RFS) free survival. Patients at first relapse with bone marrow involvement (minimum 50% blasts in the marrow) were screened by multiplex ligation-dependent probe amplification (P335 kit, MRC Holland) for the most prevalent micro-deletions seen in paediatric ALL. Among 285 eligible patients, a representative cohort of 187 (66%) patients was analysed. Over two-thirds (126, 67%) of patients harboured at least one micro-deletion at relapse: CDKN2A/B (77, 41%), IKZF1 (44, 24%), PAX5 (37, 20%), ETV6 (31, 17%), PAR1 (P2RY8-CRLF2) (18, 10%), EBF1 (7, 4%), BTG1 (6, 3%) and RB1 (6, 3%). IKZF1 and PAX5 deletions were significantly less prevalent among GR patients compared to IR and PR patients: IKZF1 8/81 (10%) v 22/53 (42%) v 12/38 (32%) (p<0.001) and 8/81 (10%) v 16/53 (30%) v 9/38 (24%) (p=0.01), respectively. None of these micro-deletions correlated with relapse stage or outcome whether we examined second complete remission rate, EFS, RFS or OS in the whole cohort or within the aforementioned treatment or cytogenetic risk groups. A subset of 87 patients with a marrow relapse was screened successfully by MLPA at both presentation and relapse to estimate the degree of clonal evolution. The majority of patients (47/87, 54%) displayed evidence of evolution defined as the gain or loss of at least one micro-deletion. The acquisition of a micro-deletion was more common than loss (54 v 22). There was a trend towards late relapses being more likely to show evidence of clonal evolution compared to very early and early relapses: 34/54 (63%) v 12/28 (43%) v 1/5 (20%), p=0.065, respectively. However, there was no evidence of an association between clonal evolution and cytogenetic risk group or outcome. In conclusion, cytogenetic risk groups strongly correlated with both the duration of first remission and outcome after first relapse. However, the most prevalent eight micro-deletions, which were frequently gained or lost between presentation and relapse, did not influence outcome after first relapse. Disclosures: No relevant conflicts of interest to declare.
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Cox, Charlotte Victoria, Paraskevi Diamanti, Matthew Hazell, and Allison Blair. "CD200 May be a Potential Target for Therapy in Standard Risk Childhood ALL." Blood 124, no. 21 (December 6, 2014): 4787. http://dx.doi.org/10.1182/blood.v124.21.4787.4787.
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Abstract Multiagent therapies for children with acute lymphoblastic leukaemia (ALL) have resulted in impressive remission rates of around 90%. Unfortunately, relapse rates remain high and most children who relapse will not survive. Innovative antibody and chimeric antigen receptor (CAR) modified T-cell therapies have shown promising results in ALL. However, this is a heterogeneous disease and several groups have shown ALL evolves in a branching fashion. Moreover, some leukaemia stem cell (LSC) populations do not express antigens that are the targets of developing therapies such as CD19, CD20, and CD22. Consequently, these cells may be largely unaffected and could provide a reservoir of resistant cells, from which relapse may develop. The diversity of reported LSC populations may be a reason for treatment failure and improvements in therapy will require targeting of all cells that have the potential to initiate and maintain this disease. In an attempt to identify more appropriate therapeutic targets we conducted an extensive microarray screen of several LSC subpopulations and bulk leukaemia cells from a group of paediatric patients with favourable cytogenetic abnormalities. This screen identified a number of genes that were up-regulated in all LSC subpopulations compared to levels in normal haemopoietic cells. The up-regulated genes encode for cell surface antigens, including the type-1 membrane protein, CD200 and signalling pathways. Expression of CD200 was 12-fold higher in bulk ALL cells compared to normal BM cells (p=0.001). CD200 is a key immunosuppressive molecule that has been implicated as a poor prognostic factor in multiple myeloma and acute myeloid leukaemia. To validate the microarray results, we assessed expression of CD200 in 20 BCP-ALL cases (11 pre B, 9 c-ALL) by flow cytometry and in functional assays. Fifteen of these cases were classified as MRD low risk and had favourable cytogenetic abnormalities and 5 were classified as high risk by MRD and cytogenetic abnormalities. ALL cells were stained with antibodies against CD34, CD19 and CD200 and cells were sorted on the basis of expression/lack of expression of CD34/CD200. The functional ability of the sorted populations was assessed in NSG mice and serial transplantation experiments were performed to assess self-renewal capacity. Overall, the flow cytometric analyses confirmed the microarray data in that expression of CD200 was high in this patient cohort (60±6.6%) compared to normal BM (0.1%±0.04, p ≤ 0.001), regardless of cytogenetic abnormality or MRD risk status. In standard risk cases, BM engraftment was achieved with the CD34+/CD200+ (2-66% human leukaemia) and CD34-/CD200+ (10-26%) subpopulations only, using inocula of 4x104-107 cells. No engraftment was attained using similar numbers of CD200- cells, regardless of expression of CD34 or CD19 in this group. Interestingly, when cells from the 5 patients defined as high risk were inoculated, engraftment was achieved using all four sorted subpopulations. The levels of leukaemia engraftment in these cases ranged from 2-95% using 1x103-5x106 cells and levels were similar across all subpopulations in individual patient samples. Results from serial transplantation studies to date demonstrate the sorted subpopulations were capable of self-renewal. As with the primary transplants, all four subpopulations from high risk samples engrafted while this ability was restricted to CD200+ subpopulations in standard risk cases. FISH analyses have confirmed all the engrafting cells had an abnormal karyotype. These data provide further evidence that surface antigen immunophenotype is not a good predictor of function in paediatric ALL, particularly in high risk cases. However, in standard risk cases it may be possible to eliminate LSC by targeting CD200. Treating human chronic lymphocytic leukaemia cells with anti-CD200 antibodies has been shown to prevent engraftment in NSG mice. Our data suggests that investigation of the effects of anti-CD200 in standard risk childhood ALL are warranted. Disclosures No relevant conflicts of interest to declare.
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Wetzler, Meir, Richard K. Dodge, Krzysztof Mrózek, Carleton C. Stewart, Andrew J. Carroll, Ramana Tantravahi, James W. Vardiman, Richard A. Larson, and Clara D. Bloomfield. "Additional cytogenetic abnormalities in adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a study of the Cancer and Leukaemia Group B." British Journal of Haematology 124, no. 3 (January 12, 2004): 275–88. http://dx.doi.org/10.1046/j.1365-2141.2003.04736.x.
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Schwab, Claire, Deniz Bakkalci, Brenda Gibson, and Christine Harrison. "Fluorescence in Situ Hybridisation (FISH) Detection of Prognostically Relevant Chromosomal Abnormalities in Childhood Acute Myeloid Leukaemia (AML)." Blood 128, no. 22 (December 2, 2016): 2897. http://dx.doi.org/10.1182/blood.v128.22.2897.2897.
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Abstract Cytogenetics is important in diagnosis of acute myeloid leukaemia (AML) and a number of chromosomal abnormalities have prognostic significance. AML clinical trials use three prognostic cytogenetic groups: good, intermediate and poor risk, for risk stratification of newly diagnosed patients to the most appropriate treatment arm. Many AML studies have combined data from children and adults, although the biology of their disease and treatment responses differ. For example, chromosomal abnormalities are observed in 80% of childhood AML, compared to only 50% of adults. The recent opening of the International Randomised Phase III Clinical Trial in Children with Acute Myeloid Leukaemia, MyeChild01, required extensive review of existing and novel genetic risk factors for stratification of patients in this study. The final consensus was to include the following abnormalities: Good risk; t(8;21)(q22;q22)/RUNX1-RUNX1T1 (approximate expected incidence in childhood AML, 12%), inv(16)(p13q22)/CBFB-MYH11 (6%); Poor Risk: inv(3)(q21q26)/t(3;3)(q21;q26)/abnormalities of 3q/MECOM rearrangements (~1%), monosomy 5/deletion of the long arm of chromosome 5 (5q) (~1%), monosomy 7 (4%), t(6;9)(p23;q34)/DEK-NUP214 (~1%), t(9;22)(q34;q11)/BCR-ABL1 (~1%), t(6;11)(q27;q23)/MLL-MLLT4/t(4;11)(q21;q23)/MLL-AFF1/t(10;11)(p11-p14;q23)/MLL-MLLT10 (5%), t(5;11)(q35;p15.5)/NUP98-NSD1(<5%),abnormalities of the short arm of chromosome 12 (12p) (~4%), inv(16)(p13.3q24.3)/CBFA2T3-GLIS2 (<2%); Intermediate risk; t(9;11)(p21;q23)/MLL-MLLT3/t(11;19)(q23;p13.3)/MLL-MLLT1/other MLL rearrangements (11%) and all other cases (25%). A pilot study was performed to evaluate the role of FISH in accurate detection of these abnormalities using a retrospective cohort of 158 paediatric AML patients. Patients were initially classified according to available karyotype, as t(8;21)(q22;q22) (n=15, 9%), inv(16)(p13q22) (n=12, 8%), t(15;17)(q24;q21) (n=8, 5%, although these patients are excluded from MyeChild01), monosomy 7/abnormalities of long arm of chromosome 7 (7q) (n=13, 8%), chromosome 5 abnormalities (n=3, 2%), t(9;22)(q34:q11) (n=1, 0.6%) and MLL rearrangements (n=49, 31%). Those patients with normal karyotype and other abnormalities were grouped together as other (n=57, 36%). They were analysed using a range of specific FISH probes, either commercially available from CytoCell or Kreatech or home grown, for the abnormalities listed above. No additional patients were identified with RUNX1-RUNX1T1, PML-RARα, CBFβ-MYH11 or BCR-ABL1, although copy number changes involving the chromosomal regions covered by these probes were indicated. No patients were found with the poor risk abnormality, inv(16)(p13.3q24.3)/CBFA2T3-GLIS2, likely due to its rarity.However, a number of previously undetected abnormalities were identified: MLL rearrangement, with poor risk translocations excluded (n=2), MLL-MLLT3 (n=1), 12p abnormalities (n=6), NUP98-NSD1 (n=3), DEK-NUP214 (n=1) and MECOM rearrangement (n=1). These latter 11 patients, accounting for 19 % of the other group, originally classified as intermediate risk became re-classified as poor risk following FISH screening. Cytogenetics is important to identify those significant chromosomal abnormalities involved in paediatric AML, which are used to stratify patients for treatment. FISH enables accurate detection of rare cryptic abnormalities associated with poor risk, meaning that more patients can benefit from appropriate risk stratification. Thus we are confident that FISH provides a reliable detection method to be implemented in MyeChild01, alongside screening for those mutations of prognostic relevance: NPM1, CEBPA and FLT3-ITD. Disclosures No relevant conflicts of interest to declare.
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Harrison, Christine J., Anthony V. Moorman, Kerry E. Barber, Zoë J. Broadfield, Kan L. Cheung, Rachel L. Harris, G. Reza Jalali, et al. "Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study." British Journal of Haematology 129, no. 4 (May 2005): 520–30. http://dx.doi.org/10.1111/j.1365-2141.2005.05497.x.
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Schoch, Claudia, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach, and Frank Dicker. "Immunostimulatory CpG-Oligonucleotide Activated Metaphase Cytogenetics Is Feasible in Routine Diagnostics of Chronic Lymphocytic Leukaemia and Reveals More Abnormalities Than Interphase FISH." Blood 106, no. 11 (November 16, 2005): 3252. http://dx.doi.org/10.1182/blood.v106.11.3252.3252.
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Abstract Genetic characterization of chronic lymphocytic leukemia (CLL) cells by fluorescence in situ hybridization (FISH) has identified genetic aberrations in 80% of CLL patients. In contrast, conventional metaphase cytogenetics detected chromosomal aberrations in only 40–50% of all cases. Immunostimulatory CpG-oligonucleotides (CpG-ODN) in combination with interleukin 2 (IL-2) have recently been reported to induce proliferation in CLL B cells. Therefore, we evaluated this stimulus for its efficacy in metaphase generation for the detection of chromosomal aberrations by cytogenetic banding techniques. In addition these results were compared with data obtained by interphase FISH. For metaphase induction 107 cells were cultured in growth medium with the CpG-ODN DSP30 and IL-2. After 2 days colchicine was added for another 24h before preparation. Of the 133 samples that were included in this study, all cases could be successfully analyzed by interphase FISH with a rate of 79% aberrations like deletions of chromosomes 13q (57%, in 38% as sole abnormality), 11q (17%), trisomy 12 (13%), 6q (7%), 17p (6%) and translocations involving 14q32 (4%). By FISH 55% of all samples showed a single aberration, 22% two aberrations and 2% 3 aberrations. In comparison, 126 cases (95%) could be successfully analyzed by cytogenetic banding techniques. 102 (81%) of the 126 samples showed chromosomal aberrations, which involved all different chromosomes. 9 cases with a normal karyotype in conventional cytogenetics revealed genetic aberrations by FISH. In all but 1 of these cases the aberrant clone represented < 30% of the cell population. In addition to the aberrations that were detected by the FISH probes, a substantial amount of other aberrations was revealed by chromosome banding analysis. Interestingly, 10 cases of a total of 27 cases without abnormalities detected by FISH displayed aberrations in chromosome analysis indicating that the true amount of CLL patients with aberrations exceeds 79%. Overall, 47 samples (37%) showed chromosomal aberrations in chromosome banding analysis in addition to FISH analysis. Compared to FISH analysis, which detected 2 cases with 3 aberrations, metaphase cytogenetics detected 22 cases with 3 or more unbalanced aberrations, which can be considered as a complex aberrant karyotype. Loss of p53 referred to as del(17p13) in FISH has attracted considerable attention, because of the poor clinical outcome of affected patients. In our study, all del(17p13) cases (n=7) displayed either a loss of the short arm of chromosome 17 (n=6) or a complete loss of chromosome 17 (n=1) indicating that chromosomal regions in addition to the p53 locus might be relevant for this phenotype. Furthermore, numerous recurrent aberrations have been identified in this study beyond the aberrations that are detected by FISH. Of note are gains of 2p and 3q, losses in 11q13 and gains in 11q23–25, gains in 13q31–34, gains of 17q21–25 and cases with trisomy 18 and 19, which occurred in parallel to trisomy 12. The results of the present study show that immunostimulatory CpG-oligonucleotides plus interleukin 2 are a simple and cheap stimulus for efficient metaphase induction in CLL. The rate of aberrations detected by conventional banding techniques was even slighty increased compared to FISH analysis, however, the complexity of cytogenetic aberrations is underestimated by FISH analysis in a large portion of CLL cases (37%).
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Moorman, Anthony V., Amir Enshaie, Lucy Chilton, Claire Schwab, Thelma Tembo, Sue Richards, Sally Kinsey, Ajay J. Vora, Chris Mitchell, and Christine J. Harrison. "Delineation of Risk Factors in Paediatric Acute Lymphoblastic Leukaemia with Favourable Cytogenetics." Blood 120, no. 21 (November 16, 2012): 292. http://dx.doi.org/10.1182/blood.v120.21.292.292.
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Abstract Abstract 292 Children with ETV6-RUNX1 or high hyperdiploid (HeH, 51–65 chromosomes) acute lymphoblastic leukaemia (ALL) have an excellent prognosis when treated on modern protocols and achieve survival rates in excess of 90% at 5 years. They are prevalent aberrations and together account for nearly 60% cases at diagnosis. Approximately 10–15% patients with these aberrations will suffer a relapse; usually off-treatment. Despite their good outcome their high prevalence means that they account for roughly 40% childhood ALL relapse. Therefore predicting those that will suffer a relapse remains a significant clinical issue. Numerous studies have postulated that certain secondary genetic abnormalities or cytogenetic characteristics correlate with outcome. However, the results have been inconsistent and few abnormalities or characteristics have been studied or confirmed in independent cohorts. In this study, we have investigated the prognostic impact of the major secondary abnormalities and characteristics among ETV6-RUNX1 and HeH patients treated on MRC ALL97/99 between 1997 and 2002. The cohort had a median follow-up time of 8.5 years and survival rates are quoted at 7 years. Additional genetic abnormalities were detected either by fluorescence in situ hybridization (FISH) using probes for ETV6 and RUNX1 or Multiplex Ligation-Dependent Probe Amplification (MLPA) using the SALSA P335 ALL IKZF1 kit. Patients were also analysed by National Cancer Institute (NCI) risk status: standard risk (SR) patient were less than 10 years old with a white cell count (WCC) lower than 50×109/L; high risk (HR) included all other patients. Among 368 ETV6-RUNX1 patients, 47 (13%) relapsed and 20 died (5%) resulting in event free (EFS) and overall survival (OS) rates of 88% and 96%, respectively. The majority of patients were SR (n=283, 77%) and although they did not have a significantly lower relapse rate (32/283 (11%) v 15/85 (18%), p=0.14) they did have a lower death rate (8/283 (3%) v 12/85 (14%), p<0.001). Accordingly, HR patients had significantly inferior EFS and OS rates compared to SR patients: 76% v 90% (p=0.001) and 87% v 99% (p<0.001). A total of 247 (67%) patients were screened using FISH probes designed to detect deletions of the non-rearranged ETV6 allele (n=165, 67%), gain of chromosome 21 (n=57, 23%) and gain of der(21)t(12;21) (n=38, 16%). Analysis of these secondary abnormalities within NCI risk groups did not reveal any association with outcome. The incidence of micro-deletions detected by MLPA among 114 patients was: ETV6 (65%), PAX5 (27%), CDKN2A/B (23%), BTG1 (21%), RB1 (8%), IKZF1 (5%), EBF1 (4%). There was no difference in the distribution of micro-deletions between SR and HR patients and none of the deletions were associated with outcome in the two risk groups. Among 553 HeH patients, 81 (15%) relapsed and 48 (9%) died resulting in EFS and OS rates of 83% and 91%, respectively. The majority of patients were SR (79%) with a significantly lower relapse and death rate: 57/439 (13%) v 24/114 (21%), p=0.033 and 30/439 (7%) v 18/114 (16%), p=0.002). HR patients had significantly inferior EFS and OS rates compared to SR patients: 76% v 85% (p=0.03) and 85% v 94% (p=0.002). HeH karyotypes were classified according to the presence of triple trisomy (+4,+10,+17) (47%), double trisomy (+4,+10) (60%), trisomy 18 (78%) and modal chromosome number (51–53, 21%; 54–57, 56%; 58–65, 23%). Only the incidence of trisomy 18 varied by NCI risk status: SR 80% v HR 69%, p=0.016. The incidence of micro-deletions detected among 144 patients was similar for SR and HR patients: CDKN2A/B (16%), IKZF1 (9%), ETV6 (8%), PAX5 (3%), RB1 (3%), BTG1 (1%) and EBF1 (0%). Among SR patients only trisomy 18 was significantly associated with a good outcome: EFS 88% v 73% (p=0.0013); OS 96% v 90% (p=0.016). There were no significant risk factors among the HR group; although all 4 patients with an IKZF1 deletion relapsed. In contrast to previous studies most secondary genetic abnormalities or cytogenetic characteristics were not associated with outcome in this study. Although NCI HR patients did have a significantly inferior outcome compared to their SR counterparts with the same chromosomal abnormality, the EFS and OS rates at 7 years were in excess of 75%, highlighting the excellent prognosis for patients with these abnormalities. These findings support the risk stratification of ETV6-RUNX1 and HeH patients by NCI risk status on current protocols. Disclosures: No relevant conflicts of interest to declare.
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Tomlins, Jo, Nick Telford, Mike Dennis, Tim Somervaille, Adrian Bloor, Jim Cavet, Mike Green, Sven Armin Sommerfeld, John Murray, and Samar Kulkarni. "Population Based Study of Cytogenetic Abnormalities in Addition to Philadelphia (Ph) Chromosome in Patients with Chronic Myeloid Leukaemia (CML) and Impact on Survival." Blood 124, no. 21 (December 6, 2014): 4567. http://dx.doi.org/10.1182/blood.v124.21.4567.4567.
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Abstract Ph chromosome is the hallmark of CML. However there are few reports of additional chromosomal abnormalities at the time of diagnosis and the impact this has on overall survival (OS). [NT1] The Cytogenetic laboratory at this hospital provides a regional service as a single facility. The data from this laboratory was combined with survival information to evaluate the impact of additional chromosomal changes on outcomes in patients with CML. Methods: This is a retrospective population based study, it was not possible to obtain consent from individual patients and details about haematological parameters or treatments delivered were not available. The aim was to evaluate if cytogenetic changes should be considered in addition to established risk scoring systems. Patients were classified as complex-Philadelphia (Ph) if they had t(9;22)(q31;q34) with additional chromosomal abnormalities. Impact of individual additional abnormalities was analysed and then the effect was stratified according to presence of chromosomal gains, deletions or translocations. Few cases who had normal cytogenetics on their first sample as they were initially treated elsewhere. Results: 1129 patients were diagnosed with CML between 1985 and 2013, with 4760 samples analysed. The median age of the patient was 52.4 years (4.3-103, 602 male; 511 female; 16 unknown). Median follow up was 6.4 years [0-26.8 years, 725/1129 (64.2%) had follow-up more than 10 years]. End point for analysis was probability of survival at 10yr. 194/1129 (17.2%) had complex-Ph at diagnosis, 759/1129 (67.2%) had standard Ph, 77/1129 (6.8%) had negative cytogenetics and in 34/1129 (3%) cytogenetic analysis failed at diagnosis. Patients with standard Ph translocation had significantly better chance of achieving cytogenetic CR than those with complex-Ph (23.4% vs. 13.4%, p<0.001). OS was significantly better in patients below the age of 45 (65% vs 25% p <0.0001). OS was also better in patients diagnosed after 2000 (67 % vs 40 %, p<0.0001). In univariate analysis OS was significantly lower with trisomy 8 (10% vs 50%, p<0.0001), del(5q) [NT2] (20% vs 50%, p=0.001), other deletions (12% vs 48%, p=0.0005), del 17( 48% vs. 0%, p<0.0001), add 21 (50% vs. 0%, p<0.0001), any translocations (50% vs. 22%, p<0.0001), der 22 or iso 17 (48% vs. 10%, p<0.0001), any deletions (50% vs. 20%, p<0.0001) and variant Ph translocations (50% vs 22%, p=0.004). In multivariate analysis, excluding year of diagnosis, age group (HR 1.93, 95% CI:1.6-2.4 P=<0.0001), complex t(9;22;v) (HR 1.8, 95% CI:1.0-3.1, P=0.035), del(17q) (HR 3.8, 95% CI:1.1-12.6, P=0.033), translocations (HR:1.6, 95% CI: 1.1-2.25, p=0.013), trisomy 8 (HR: 1.76, 95% CI: 1.19-2.65, p=0.005), add 21 (HR: 3.21, 95% CI: 1.65-6.25, p=0.001) and der 22 or iso17 (HR: 1.57, 95% CI: 1.1-2.25, p=0.013) were independently associated with inferior OS. Number of risk factors in individual patients was used to design a scoring system. Patients with 0 risk factor (70% OS at 10 yr.), 1 risk factor (40% OS at 10 years), 2 risk factors (22% OS at 10 years) or more than 3 risk factors (12% OS at 10 years) had incrementally reduced OS. This was true of patients diagnosed before and after 2000. This analysis suggests that incorporating nature of karyotype at diagnosis can refine established scoring systems. However this data needs to be analysed with larger patient population to include all established risk factors and the effect of therapeutic measures. Disclosures Cavet: Novartis: Research Funding; BMS: Research Funding.
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Fazio, Grazia, Valentina Massa, Andrea Grioni, Vojtech Bystry, Silvia Rigamonti, Claudia Saitta, Marta Galbiati, et al. "First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia." Journal of Clinical Pathology 72, no. 8 (April 4, 2019): 558–61. http://dx.doi.org/10.1136/jclinpath-2019-205707.
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Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.
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Lebailly, Pierre, Eleanor V. Willett, Anthony V. Moorman, Eve Roman, Ray Cartwright, Gareth J. Morgan, and Christopher P. Wild. "Genetic polymorphisms in microsomal epoxide hydrolase and susceptibility to adult acute myeloid leukaemia with defined cytogenetic abnormalities." British Journal of Haematology 116, no. 3 (March 2002): 587–94. http://dx.doi.org/10.1046/j.0007-1048.2001.03320.x.
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Kuchenbauer, F., S. Schnittger, T. Look, G. Gilliland, D. Tenen, T. Haferlach, W. Hiddemann, C. Buske, and C. Schoch. "Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO." British Journal of Haematology 134, no. 6 (September 2006): 616–19. http://dx.doi.org/10.1111/j.1365-2141.2006.06229.x.
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Holmes, P. J., S. C. Peiper, G. K. Uppal, J. Z. Gong, Z. X. Wang, and R. Bajaj. "Efficacy of DSP30-IL2/TPA for detection of cytogenetic abnormalities in chronic lymphocytic leukaemia/small lymphocytic lymphoma." International Journal of Laboratory Hematology 38, no. 5 (August 27, 2016): 483–89. http://dx.doi.org/10.1111/ijlh.12513.
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Kottaridis, Panagiotis, Diana Brazma, Julie Howard-Reeves, Helen Mazzullo, and Elisabeth P. Nacheva. "A Cell Line SYRMO Derived From AML with EVI 1 Rearrangements Following Imatinib Mesylate Therapy for Chronic Myeloid Leukaemia." Blood 116, no. 21 (November 19, 2010): 4470. http://dx.doi.org/10.1182/blood.v116.21.4470.4470.
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Abstract Abstract 4470 Chronic Myeloid Leukaemia (CML) is a malignant disorder of the haematopoeitic stem cell, usually characterised by the t(9;22) giving rise to the Philadelphia chromosome (Ph), and by the BCR-ABL gene rearrangement at the molecular level. Imatinib mesylate (IM), which targets the tyrosine kinase (TK) activity of BCR-ABL, has become the first line therapy for CML patients. Dasatinib or Nilotinib is now indicated as a second line therapy for patients who develop resistance or intolerance to IM. Here we report the case of a 51 year old woman who was diagnosed in Cyprus (2007) with BCR/ABL1 positive CML. After failing to respond to IM therapy, she was treated with Dasatinib achieving complete cytogenetic remission (CCR), and subsequent complete molecular remission. In July 2009 the patient presented with 88% blasts in the bone marrow. Immunophenotyping showed the presence of CD34+, CD117+ myeloblasts, and a diagnosis of AML was confirmed. Analysis of G banded metaphases from cultured peripheral blood revealed a complex karyotype: 46,XX, t(2;3)(p21;q26),t(4;8)(q12;q22), del(6)(q13;q23)[1]/45,idem,der(6)ins(6;6)(q23;),-7[9]. FISH revealed EVI 1 rearrangement resulting from the t(2;3) in the absence of BCR/ABL1 fusion and confirmed the secondary monosomy 7. The patients failed to respond to treatment and passed away shortly afterwards. Whole genome screening by aCGH using a 244K platform (Agilent) confirmed the loss of chromosome 7 and the 6q22/23 region. Clonal cytogenetic abnormalities (CCA) in Ph-negative metaphases are known to develop in some patients during IM therapy. The most frequent of these abnormalities are trisomy 8, -7, del(7q), and del(20q), which are also associated with MDS and AML. These abnormalities are usually transient and disappear after a short time, or have no clinical consequence (Deininger et al., Cancer 2007). However, reports of development of high risk MDS or AML in association with CCA in Ph-negative cells are rare, but patients with chromosome 7 abnormalities appear to be at greater risk. The t(2;3) is a non random abnormality in MDS and AML, including therapy-related leukaemias, frequently associated with -7 and a complex karyotype with a poor prognosis (Stevens-Kroef et al Leukemia 2004). This is the first report of a CML patient on TKI treatment with t(2;3) and EVI1 gene rearrangements in Ph(-) cells. This cryptic translocation could easily be overlooked in the presence of a monosomy 7 with a dramatic effect on patient management. Disclosures: No relevant conflicts of interest to declare.
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Hall, Andrew G., Lisa C. Bloodworth, Linda A. Hogarth, Nick P. Bown, and Julie A. Irving. "Loss of Heterozygosity in Childhood Acute Lymphoblastic Leukaemia Detected by Genome-Wide Microarray Single Nucleotide Polymorphism Analysis." Blood 104, no. 11 (November 16, 2004): 1088. http://dx.doi.org/10.1182/blood.v104.11.1088.1088.
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Abstract Loss of heterozygosity (LOH) is detectable in many forms of malignancy, including leukaemia, using techniques such as microsatellite analysis and comparative genomic hybridisation. However, these techniques are laborious and require the use of relatively large amounts of DNA if the whole genome is to be examined. Here we describe the use of oligonucleotide microarrays to characterise single nucleotide polymorphisms (SNPs) in lymphoblasts isolated from children with acute lymphoblastic leukaemia for the pan-genomic mapping of LOH with a resolution of 100–200kb. Results were compared with DNA obtained during remission and on relapse. Abnormalities were seen in 8 of 10 cases. The two cases with no abnormalities and one case which showed identical changes affecting whole chromosomes at relapse and presentation remain in remission 1–9 years following retreatment. The 7 cases which showed LOH not affecting entire chromosomes died following relapse, suggesting that partial LOH may be associated with a poor prognosis. In 4 cases LOH was only detectable at relapse suggesting that progressive LOH may be a cause of disease progression and/or drug resistance. This was supported by detailed analysis of one case in which LOH involving the glucocorticoid receptor (GR) was associated with mutation of the remaining allele. In cell line models the loss of a functional GR is associated with profound resistance to steroids. The most frequent abnormality detected in this series involved chromosome 9p. In each of the four cases where this was observed LOH included the INK4 locus. In three of the four cases INK4 loss was only observed at relapse (see figure), suggesting that this abnormality may be commonly associated with treatment failure, supporting previous reports that 9p abnormailities are associated with a poor prognosis. One case was reported as showing monosomy 20 as the sole cytogenetic aberration but LOH analysis identified 9p LOH and loss of 20q, with retention of heterozygocity for 20p. These findings strongly implicate unbalanced translocation der(9)t(9;20),-20 as described by Clark et al (Leukaemia, 2000, 14:241). Our observations demonstrate that SNP array analysis is a powerful new tool for the analysis of allelic imbalance and unbalanced translocations in leukaemic blasts.
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Jianyong, LI, Wei Xu, Yujie Wu, Lei Fan, Hongxia Qiu, and Changgeng Ruan. "CD38 as a Prognostic Factor in Chinese Patients with Chronic Lymphocytic Leukaemia." Blood 110, no. 11 (November 16, 2007): 4691. http://dx.doi.org/10.1182/blood.v110.11.4691.4691.
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Abstract B-cell chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world, however, infrequent in the Eastern. Although the median survival is around 10 years, CLL patients have a highly variable clinical course and prognosis. While some patients show an indolent disease and never require treatment, others suffer from a much more aggressive course requiring intensive treatment shortly or immediately after diagnosis. Identification of these subgroups and insight into the prognosis for each individual patient will be important to determine individualized treatment strategies. To explore the prognostic significance of CD38 expression in Chinese patients with CLL, multi-parameter flow cytometry was used to detect the expression of CD38 on CD5+CD19+ cells of 147 patients with CLL. CD38 expression and its association with some other prognostic factors such as Binet stage, lymphocyte count in peripheral blood, serum lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), ZAP-70 expression and cytogenetic abnormalities were analyzed. The Kaplan-Meier method was used to construct survival curves, and results were compared using the log-rank test. Univariate and multivariate Cox regression analyses were used to assess associations between survival time and potential risk factors. Out of the 147 CLL patients, positive expression of CD38 was found in 45 (30.6%) cases. CD38-positivity identified a subgroup of CLL patients with aggressive disease of Binet stage at the time of the test (P=0.036). Furthermore, the presence of higher serum LDH and β2-MG levels at diagnosis was strongly correlated with CD38-positive (P=0.016 and P=0.025, respectively). Prognostically unfavorable cytogenetic abnormalities, including 17p13 deletions and 11q22 deletions were significantly more frequent in CD38-positive patients than in CD38-negative ones (P=0.047 and P=0.001, respectively). There was no significant difference between CD38-positive and CD38-negative subgroups in terms of age, sex, or lymphocyte count. In addition, in CD38-positive patients, the percentage of leukemic cells expressing ZAP-70 protein was not significantly higher than in CD38-negative ones (P=0.120). There was no significant difference between CD38-positive and CD38-negative groups in molecular cytogenetic aberrations of del(6q23), del(13q14), 14q32 translocation, or trisomy 12. CD38 expression was associated with poor outcome. Patients with positive expression of CD38 had significantly shorter overall survival (mean, 81 months) than patients without CD38 expression (mean, 179 months) (P=0.015). Univariate and multivariate analysis showed that serum levels of LDH and β2-MG, del(17p13) and CD38 expression were strongly associated with survival. It was showed that the patients with high level of CD38 expression had poorer outcome; CD38 was a good predictor of survival time in Chinese patients with CLL.
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McDonald, Laura, Brian Hennessy, Senthil Kumar, Mutaz Nur, Christine Schilling, and Ezzat El Hassadi. "Impact of p53 and BCL2 Expression on Prognosis in Patients with Acute Myeloid Leukaemia." Blood 136, Supplement 1 (November 5, 2020): 29–30. http://dx.doi.org/10.1182/blood-2020-140920.
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Introduction Acute myeloid leukaemia (AML) is a heterogenous disorder that arises from clonal expansion of malignant hematopoietic precursor cells. The tumor suppressor p53 gene plays an important role in regulation of the cell cycle and apoptosis. Somatic mutations of the p53 gene have been reported in 5-10% of all patients with AML, although the rate is higher in therapy-related disease and elderly patients. Alteration or loss of p53 is one of the most powerful independent indicators of poor outcome. BCL2 positivity in AML and its impact on prognosis is less well described. Methods This is a single-centre, retrospective analysis of AML patients treated over a ten year period (2006-2016). Patients were identified through our pathology database. P53 expression (as a surrogate marker for tp53 mutation) and BCL2 expression were analysed by immunohistochemical (IHC) analysis of marrow biopsies (greater than 30% was considered positive). We analyzed AML presentation, management and overall survival (OS), and correlated these with presence of p53 mutation and BCL2 expression. Results We identified 48 patients; the majority were elderly (median age 68.5 years). Thirty-four patients (71%) haddenovopresentation of AML, 6 had underlying Myelodysplastic Syndrome (13%), 4(8%) progressed to AML from underlying Myelofibrosis, and 8% had therapy-associated AML. Patient and disease characteristics are outlined inTable 1. Median blast count by IHC of bone marrow biopsies was 70%. The results of cytogenetic analysis were available for 38 patients (79%). Fourteen patients (37%) had normal cytogenetics, but a wide range of genetic abnormalities were identified(Table 1). NPM1 (for 22 patients) and FLT3 mutation analysis (for 33 patients) were available, and reported as positive in 4(18%) and 5(15%) respectively. p53 overexpression was identified in 6 patients (12.5%). 50% of these had secondary AML, and the remainder weredenovopresentations. Four of these patients (66%) had complex cytogenetics, one had deletion 5q and cytogenetic analysis was not available for the remaining patient. Median age of patients who were p53 positive was 60 years, compared to 70 years in those without p53 overexpression. BCL2 expression analysis showed a median value of 60% (range 5-100%). BCL2 positivity was seen in 39 patients (81.2%); half of this cohort (15 patients) had normal cytogenetics and only five patients (16%) had abnormalities that indicated poor risk cytogenetics (complex, deletion 7q, etc.). Thirty-nine patients (83%) received active treatment and nine received supportive care only due either to frailty or patient choice. Twenty-two patients (60%) had induction chemotherapy, 7(19%) received Azacitadine, and a further 7 patients had low-dose cytarabine. Nineteen patients (51%) had relapsed/refractory disease. Five patients (13.5%) with BCL2 positive disease received Venetoclax as a single agent for relapsed or refractory disease. Median OS was 11.5 months (range 0-72); 39 patients (81%) had died at the time of analysis. 26 died from disease progression (79%), and 7(19%) of sepsis. One patient was lost to follow up. OS in those with wild-type p53 was 11.5 months, which compared favorably to 7.5 months in those with p53 mutation. BCL2 overexpression also conferred a poorer prognosis; median OS was 10 months compared to 17 months in BCL2 negative disease. Conclusion This study reflects the potential use of p53 and BCL2 in real-life practice in assessing prognosis in AML patients outside of a clinical trial setting. We confirmed the previously reported poor prognosis of p53 alterations in AML (OS 7.5 months), and the study also indicates a poorer prognosis in patients with BCL2 positivity. The widespread availability of IHC techniques for trephine biopsies and the potential for rapid turn-around times in routine clinical laboratories suggests that further studies of the prognostic impact of such gene alterations are warranted. Disclosures No relevant conflicts of interest to declare.
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Villafuerte-Gutiérrez, Paola, Montserrat López Rubio, Pilar Herrera, and Eva Arranz. "A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation." Case Reports in Hematology 2018 (December 6, 2018): 1–4. http://dx.doi.org/10.1155/2018/5724960.
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Hematopoietic myeloproliferative neoplasms with FGFR1 rearrangement result in the 8p11 myeloproliferative syndrome that in the current Word Health Organization classification is designated as “myeloid and lymphoid neoplasm with FGFR1 abnormalities.” We report the case of a 66-year-old man who had clinical features that resembled chronic myeloid leukaemia (CML), but bone marrow cytogenetic and fluorescent in situ hybridization (FISH) studies showed t(8;22)(p11;q11) and BCR-FGFR1 fusion gene. He was initially managed with hydroxyurea, and given the aggressive nature of this disease, four months later, the patient underwent an allogeneic hematopoietic stem-cell transplantation (HSCT) from an HLA-haploidentical relative. Currently, HSCT may be the only therapeutic option for long-term survival at least until more efficacious tyrosine kinase inhibitors (TKIs) become available.
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Bendari, Mounia, Nisrine Khoubila, Siham Cherkaoui, Nezha Hada, Mouna Lamchahab, Bouchra Oukache, Abdellah Madani, Mohamed Rachid, Meryem Qachouh, and Asmaa Quessar. "Acute Myeloid Leukemia (AML) In Elderly: Cytogenetic Characteristics of Patients Treated At Hematology and Pediatric Oncology Center in Casablanca." Open Access Macedonian Journal of Medical Sciences 6, no. 12 (December 14, 2018): 2328–32. http://dx.doi.org/10.3889/oamjms.2018.484.
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We conducted a retrospective analysis of 283 patients with acute myeloid leukemia (AML) treated in our unit, we will report the incidence of AML in elderly, describe cytogenetic characteristics of this population, observe rare and novel cytogenetic abnormalities and compare our finding with that previously reported in literature. Among the 283 patients, 157 (54,4%) patients performed the karyotype, cytogenetic analysis failed in 17 cases (11%). Prognostic group distribution was found to be favorable in 8 patients (6%) with 6 cases of t (8; 21) and 2 cases of inv (16), intermediate group in 94 patients (67%), including 58 cases (41,5%) with a normal karyotype, and an unfavorable group in 38 patients (27%) including complex karyotype (15%), -5 or del 5q (3%), -7 or del 7q (3.5%), t(9,22) (2%). Some rare anomalies were observed. However, occurrence of a complex karyotype was more frequent than younger patients. In our unit, elderly benefit from supportive care, our study shows that it is heterogeneous group and our treatment approach have to change especially for patient from favorable risk group who can benefit from intensive chemotherapy. We have to improve our diagnosis with including molecular genetics that provide a documented substrate for a thoughtfully considered treatment plan.
AIM: The goals of this paper are: to report the incidence of AML in elderly, to describe cytogenetic characteristics of this population, to observe rare and novel cytogenetic abnormalities and lastly, to compare our finding with that previously reported in the literature.
METHODS: We conducted a retrospective analysis of 283 patients with acute myeloid leukaemia (AML) treated in our unit, we will report the incidence of AML in elderly, describe cytogenetic characteristics of this population, observe rare and novel cytogenetic abnormalities and compare our finding with that previously reported in the literature.
RESULTS: Among the 283 patients, 157 (54.4%) patients performed the karyotype, the cytogenetic analysis failed in 17 cases (11%). Prognostic group distribution was found to be favorable in 8 patients (6%) with 6 cases of t (8; 21) and 2 cases of inv (16), intermediate group in 94 patients (67%), including 58 cases (41,5%) with a normal karyotype, and an unfavorable group in 38 patients (27%) including complex karyotype (15%), -5 or del 5q (3%), -7 or del 7q (3.5%), t (9; 22) (2%). Some rare anomalies were observed.
CONCLUSION: However, the occurrence of a complex karyotype was more frequent than younger patients. In our unit, elderly benefit from supportive care, our study shows that it is a heterogeneous group and our treatment approach have to change especially for the patient from favourable risk group who can benefit from intensive chemotherapy. We have to improve our diagnosis with including molecular genetics that provides a documented substrate for a thoughtfully considered treatment plan.
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Moorman, Anthony V., Amir Enshaei, Claire Schwab, Lucy Chilton, Rachel Wade, Nicholas Goulden, Ajay J. Vora, and Christine J. Harrison. "Integration Of Cytogenetic and Copy Number Alteration (CNA) Data Into a Single Risk Profile For Paediatric Acute Lymphoblastic Leukaemia (ALL)." Blood 122, no. 21 (November 15, 2013): 1308. http://dx.doi.org/10.1182/blood.v122.21.1308.1308.
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Abstract Chromosomal abnormalities are established indicators of outcome in paediatric ALL. Recently numerous CNA have been reported which target genes involved in leukaemogenesis. The prognostic impact of these CNA has yet to be fully elucidated. We have used a novel approach to simultaneously assess the prognostic impact of the most prevalent CNA and integrate the results with cytogenetic risk groups. The CNA status of 8 genes/loci (CDKN2A/B, IKZF1, PAX5, ETV6, PAR1 (P2RY8-CRLF2), EBF1, BTG1 & RB1) was determined by multiplex ligation-dependent probe amplification (P335 kit, MRC Holland) in a representative cohort of 864 B-cell precursor (BCP) ALL patients treated on MRC ALL97/99. The presence or absence of each CNA was determined and each individual 8-gene combination was assessed and classified into risk categories on the basis of patient numbers, hazard ratio (HZR) for an event and p value. Using these risk categories patients were assigned to 3 groups: good (CNA-GR, 64% cases); intermediate (CNA-IR, 25%); poor (CNA-PR, 11%). The 5 year event free survival (EFS) rates were: CNA-GR 83%; IR 70%; PR 55%. The HZR comparing CNA-GR/IR and CNA-PR/IR were 0.54 (99% CI 0.40-0.73) p<0.001 & 1.76 (1.23-2.53) p=0.002. Next, we validated these groups using an independent and representative cohort of 781 BCP-ALL patients treated on UKALL2003. The distribution of patients across the three groups was similar: 64%/28%/9%. The EFS rates were: CNA-GR 93%; IR 82%; PR 90%. The HZR comparing CNA-GR/IR and CNA-PR/IR were 0.35 (0.22-0.56), p<0.001 and 0.60 (0.27-1.35), p=0.221. This validation confirmed the utility of CNA risk grouping to identify robust good and intermediate, but not poor, risk groups. We previously defined 3 cytogenetic risk groups: CYTO-GR - ETV6-RUNX1, high hyperdiploidy; CYTO-PR - BCR-ABL1, MLLtranslocation, near haploidy, low hypodiploidy, intrachromosomal amplification of chromosome 21 (iAMP21), t(17;19)(q23;p13) and, in the absence of GR abnormalities, 13q deletions and 17p abnormalities; CYTO-IR - other cytogenetically normal or abnormal cases. There was a significant correlation between the CNA and cytogenetics risk groups (p<0.001). Using the ALL97/99 cohort, we cross-tabulated the CNA and cytogenetic risk groups, examined the outcome of all 9 combinations and then derived 3 genetic risk groups: GEN-GR (72%); IR (16%); and PR (13%) which had differential EFS rates: 85%, 65% and 47%. The GEN-GR/IR and GEN-IR/PR HZR were 0.34 (0.24-0.47) p<0.001, 1.69 (1.17-2.43) p=0.005. These 3 genetic risk groups were then validated on the UKALL2003 cohort where they identified patient groups with differential EFS: GEN-GR 93%, IR 82%; PR 71%. The HZR for GEN-GR/IR and GEN-PR/IR were 0.33 (0.20-0.56) p<0.001 and 1.89 (1.01-3.57), p=0.048. The GEN-PR and CYTO-PR groups were equivalent indicating that the integration of CNA data did not identify any new high risk (HR) patient groups. In addition, all the CYTO-GR patients were classified in the GEN-GR group confirming their good prognosis. However, the integration of CNA data allowed the CYTO-IR group to be split; identifying a novel group of patients which accounted for 18% of BCP-ALL and was associated with inferior outcome. UKALL2003 patients in this group (n=141) had a mean age of 9.4 years, 60% were NCI-HR and 54% were MRD-HR. Compared with other UKALL2003 CYTO-IR patients those in this novel subgroup had a 3-fold increased risk of a relapse (14% v 5% at 5years, HZR 3.14 (1.25-7.93) p=0.015), an inferior EFS (82% v 94%, HZR 3.52 (1.52-8.17), p=0.003) and lower survival (86% v 98%, HZR 9.32 (2.17-40.03), p=0.003) (all at 5 years). In conclusion, the genetic heterogeneity in paediatric ALL can be used to classify patients into clinically relevant groups. The integration of CNA data into our previously identified cytogenetic risk system enabled refinement of the CYTO-IR risk group to identify a subgroup of patients with inferior outcome. Disclosures: No relevant conflicts of interest to declare.
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Stark, Batia, Marta Jeison, Leticia Glazer Gabay, Jacques Mardoukh, Drorit Luria, Irit Bar-Am, Gali Avrahami, et al. "Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report from a referral centre in Israel." British Journal of Haematology 126, no. 3 (June 30, 2004): 320–37. http://dx.doi.org/10.1111/j.1365-2141.2004.05038.x.
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Hockley, Sarah L., Monica Else, Paola E. Leone, Brian A. Walker, Alison Morilla, Daniel Catovsky, Gareth J. Morgan, Estella Matutes, and David Gonzalez. "High Resolution Genomic Profiling Using Single Nucleotide Polymorphism Microarrays Reveals Novel Genomic Lesions in Hairy Cell Leukaemia and Hairy-Cell Leukaemia Variant." Blood 112, no. 11 (November 16, 2008): 3136. http://dx.doi.org/10.1182/blood.v112.11.3136.3136.
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Abstract Hairy-cell leukaemia (HCL) is a rare B-cell disorder, with a variant form (HCL-v), which differs from the former in morphology, immunophenotype, clinical behaviour and response to treatment. Whilst HCL is highly sensitive to purine analogues, HCL-v patients do not respond to these treatments and have a median survival of only 7 years compared to over 20 years in HCL. The relationship between these two disorders is yet to be determined and the molecular mechanisms underlying them are still largely unknown. Genomic studies are limited due to the rarity of the disease and have mainly been performed at the cytogenetic level. We have used single nucleotide polymorphism (SNP) arrays to examine DNA copy number changes and loss of heterozygosity (LOH) in 14 HCL and 15 HCL-v cases with the aim of finding genetic markers that may distinguish both disease types and can explain their different clinical outcome. DNA extracted from PBMC samples enriched for tumour cells (HC >84%) was interrogated using the Affymetrix Human Mapping 500K Array Set. Data were analysed using CNAG 2.0 and dCHIP 2006 to identify regions of genomic imbalance and LOH by comparison to a set of 25 normal controls. DNA copy number abnormalities (excluding the IGH and IGL heterogeneic loci) were identified in 11/14 (78%) HCL and 13/15 (87%) HCL-v cases. The median number of lesions per patient in HCL (2.5, range=0–14) was half that observed for HCL-v (5, range=0–34) (p=0.1, not significant) with 3/15 cases of HCL-v exhibiting more than 20 aberrations. The most significant difference between HCL and HCL-v was the occurrence of deletions on 17p, involving monoallelic loss of TP53. Such losses were evident in 33% (5/15) of HCL-v cases compared to 0% of HCL cases (p=0.02). Sequencing analysis detected mutations in the non-deleted allele in 3/5 of these cases, suggesting biallelic loss of TP53 function. Other frequent events were present in both HCL and HCL-v and included gains on chromosome 5 (1/14 HCL and 5/15 HCL-v) and deletions on 7q (3/14 HCL and 3/15 HCL-v) and 14q (2/14 HCL and 1/15 HCL-v). Similar aberrations have been detected in previous cytogenetic studies of typical HCL but the high resolution of the SNP arrays has allowed us to further define these regions of imbalance in both disorders. Chromosome 5 abnormalities included trisomy 5 in two cases and a minimal region of gain, 18.9 Mb in size (5q34–q35.3), was present in 4/6 cases. The cases exhibiting 7q deletions allowed the minimal region to be further defined to 4.1 Mb (7q31.31–q31.33), a region containing approximately 25 known genes. Deletion of 14q24.1–q32.13 was seen in two HCL cases, therefore further minimising the 14q22–q32 region identified previously. One HCL-v case exhibited an interesting region of deletion at 14q32.32, consisting of a focal homozygous deletion flanked by hemizygous loss, containing candidate tumour suppressor genes that may be involved in HCL-v pathogenesis. In addition to these larger lesions, focal gains, harbouring only a single gene, were identified in both disorders at 19p13.2 (3/14 HCL, 3/15 HCL-v), 20p13 (4/14 HCL, 3/15 HCL-v) and 17q21.2 (4/16 HCL and 5/15 HCL-v). High-resolution copy number analyses allow the identification of novel genetic lesions in HCL and HCL-v and further define known cytogenetic aberrations. Our data show that HCL and HCL-v are generally similar at the genomic level but can be distinguished based on 17p deletions, suggesting that biallelic loss of TP53 may contribute to the greater genomic instability and to the aggressiveness of HCL-v. Other HCL-v cases may carry aberrations of other genes involved in DNA damage/repair pathways aside from TP53 and will be investigated.
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Howard, Julie, Diana Brazma, Beverly Vaughan, and Elisabeth P. Nacheva. "Bi-Allelic Involvement in AML: Examples of 16q Aberrations in Two Cases." Blood 108, no. 11 (November 16, 2006): 4459. http://dx.doi.org/10.1182/blood.v108.11.4459.4459.
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Abstract Acute Myeloid Leukaemia is a heterogeneous clonal disorder of the bone marrow, which has characteristic acquired chromosomal abnormalities. Cytogenetic rearrangements of chromosome 16 have a well-established association with AML subtype M4Eo although they have also been described in other AML FAB types. Patients with rearrangements involving CBFb (16p13) and MYH11 (16q22) are associated with a more favourable prognosis. We describe two cases of AML where both homologues of chromosome 16 are involved in separate rearrangements; this to our knowledge has not been reported previously. Further more both patients have had previous treatment and thus the abnormality of the second homologue of chromosome 16 is thought to be treatment related, in-spite of which they have responded well and are both currently in remission. In case 1 (male, AML M5a) it is chromosome16 at band q22 that is involved, inv(16)(p13q22) and t(16;17)(q22;q11), while in case 2 (female, t-AML) chromosome 16 band q24 appears rearranged in der(16)t(8;16)(q1?3;q24) and t(16;21)(q24;q22). Extensive molecular cytogenetic investigations including mapping are presented and candidate gene aberrations discussed.
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Rand, Vikki, Stephen Johnstone, Rachel E. Crossland, Sarah Wilkinson, and Andrew G. Hall. "The Genomic Landscape of Relapsed B-Cell Acute Lymphoblastic Leukaemia (B-ALL) in Adolescents and Adults." Blood 124, no. 21 (December 6, 2014): 3769. http://dx.doi.org/10.1182/blood.v124.21.3769.3769.
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Abstract Despite significant advancements in the treatment of paediatric B-cell acute lymphoblastic leukaemia (B-ALL), ALL remains one of the most challenging adult malignancies. Outcome of adult B-ALL is poor with only 40% 5-year event-free survival compared to >80% in children. B-ALL is characterised by the acquisition of chromosomal abnormalities and many are strong predictors of outcome. The difference in the prevalence of cytogenetic subtypes and specific genomic abnormalities observed between adult and childhood ALL suggests a difference in tumour biology that may contribute to the differences in patient outcome. Detailed analysis of the paediatric B-ALL genome have revealed a plethora of abnormalities targeting key pathways. Although specific alterations have been investigated in adult and adolescent B-ALL, studies of the genomic landscape remain scarce. In this study we set-out to define the genomic landscape of adolescent and adult relapsed B-ALL. Genomic backtracking analysis of sequential diagnostic and relapse samples revealed known and novel abnormalities that may play a role in chemoresistance and disease progression in these tumours. DNA was isolated from the diagnostic and relapse samples from 12 adolescents/adult patients (5 female and 7 male) diagnosed with B-ALL. Eight of the 12 patients had remission samples available. Known cytogenetic abnormalities were detected in 7 patients: high hyperdiploid, t(1;19), t(8;14) and t(4;11) rearrangements. Two cases were positive for the BCR-ABLfusion gene. The mean age at diagnosis was 36.8 years (range 16-59 years) of which 10 relapsed early, within 2 years of initial diagnosis. DNA for the 12 diagnostic, 12 relapse and 8 remission sample were hybridised to the Affymetrix SNP6.0 array to determine copy number abnormalities (CNAs). The mutational landscape was captured for 4 cases using the Agilent SureSelect Human All Exon V4+UTR kit and sequenced to depths of 200X. The incidences of the most prevalent abnormalities in paediatric B-ALL were determined in each adult/adolescent sample: CDKN2A/B 88% (21/24), IKZF1 20% (5/24), PAX5 8% (2/24), ETV6 0% (0/24), RB1 8% (2/24), BTG1 8% (2/24) and EBF1 17% (4/24). Deletions of CDKN2A/B were detected in all but one patient. In 9 cases the abnormality was seen at both diagnosis and relapse and one case had a de novo deletion at relapse. A further case had a sub-clone harbouring CDKN2A/B deletion at diagnosis that emerged as the dominant clone at relapse. Deletion of CDKN2A/Bhas been associated with poor overall survival and has been reported at high incidence in relapsed adult BCR-ABL1-ALL, but the association with prognosis and relapse in other subtypes has not been confirmed. Genomic backtracking analysis of the matched diagnostic and relapse samples identified, on average, 36 somatic mutations at relapse that were either not detected or were only detectable in a sub-clone at diagnosis. An average of 0.05 mutations per Mb were computationally predicted to be damaging to the function of the protein. Novel de novo mutations seen at relapse were identified in cancer-related genes: FAT4, CDCA7 and PVRL4. Sequencing at depth of >200X demonstrates the ability to detect mutations in the resistant clone which could be involved in disease progression. Mutations in the ATP-binding cassette transporter gene, ABCC9, were identified in a sub-clone at diagnosis at a variant frequency of 5% (13/268 reads) and at 43% (113/260) in the relapse sample. ABCC9is involved in drug resistance suggesting a potential role in chremoresistance in this patient. In conclusion, in-depth genomic analysis and whole-exome sequencing of matched diagnostic and relapse samples in adult/adolescent B-ALL has identified known and novel genomic abnormalities. Deletion of CDKN2A/B was prevalent in 11 of the 12 cases confirming the importance of this region in relapsed B-ALL. We have identified novel mutations in genes associated with chemoresistance and tumorigenesis: ABCC9, FAT4, CDCA7 and PVRL4. Our study provides the most comprehensive genetic portrait of adult relapsed B-ALL to date and is a significant step to defining the genetic causes of disease progression and chemoresistance. Disclosures No relevant conflicts of interest to declare.
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Schmitt-Graeff, Annette, Juergen Thiele, Hans M. Kvasnicka, and Michael Lübbert. "Acute Panmyelosis with Myelofibrosis: An Evaluation of Distinctive Clinicopathological Features Including Bone Marrow Stroma." Blood 106, no. 11 (November 16, 2005): 4568. http://dx.doi.org/10.1182/blood.v106.11.4568.4568.
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Abstract Acute panmyelosis with myelofibrosis (APMF) is a rare AML category of the current WHO-classification. The main clinical characteristics are an acute onset of disease, no splenomegaly, few blasts in the blood and an aggressive clinical course. Differentiation of APMF from hyperfibrotic high-grade myelodysplastic syndromes with excess blasts or acute megakaryoblastic leukaemia may be difficult because of the actual lack of molecular markers. As a consequence of myelofibrosis and dry tap, bone marrow cytology and cytogenetic analyses are only available in a minority of cases. Therefore, histopathology and immunohistochemistry of trephine bone marrow biopsies may offer further clues to the biology of APMF. Our study focused on the clinicopathological features of 52 patients meeting the criteria of APMF. Cases with any other category of MDS or AML, a history of preceding chronic myeloproliferative disorder, especially idiopathic myelofibrosis, autoimmune disorders, and cytotoxic or radiation therapy were excluded. All patients presented with anemia, granulocytopenia, low to normal platelets and low peripheral blast counts (≤5%). Cytogenetic abnormalities included monosomy 7, del (7p), del (17p) and trisomy 8 or complex karyotypic abnomalities. The median survival was <12 months. The lethal outcome was due to severe pancytopenia or overt leukaemia. Multilineage maturation defects associated with a strikingly increased atypical megakaryopoiesis and slight to marked degrees of fibrosis were the characteristic features common to all bone marrow trephines. Abnormalities of megakaryocytes included loose grouping or prominent clusters of medium sized to small cells with nuclear hypolobulation and dwarf cells and occasionally scattered bizarre forms. By confocal laser scanning microscopy (CLSM) we observed heterogeneous megakaryocyte c-Mpl signals using a polyclonal rabbit antibody kindly provided by Dr. J. Spivak, Baltimore, MG, USA. Cytoplasmic immunolabeling ranged from weak in larger polymorphous forms to moderate or strong in smaller megakaryocytes. The predominantly membraneous c-Mpl localization of normal megakaryocytes was generally downregulated. In contrast to acute megakaryoblastic leukaemia, blasts rarely expressed CD61 or CD41, but predominantly myeloid or myelomonocytic antigens. In accordance with the data recently published by Orazi et al. (Mod Pathol2005; 18: 603–14) blasts were less numerous than in acute megakaryoblastic leukaemia. Bone marrow stroma contained increased microvessels, CD4 and CD8+ T-cell subsets, B-cell rich lymphoid nodules and CD68+ macrophages. By CLSM, myofibroblastic cells coexpressing alpha-smooth muscle actin and cellular retinol-binding protein 1, a key molecule of retinoid metabolism, could be visualized ín the stromal compartment. In conclusion, refined in situ imaging techniques of bone marrow trephines improve the diagnostic impact of the WHO criteria for the diagnosis of APMF. Our study provides further evidence that both hematopoietic and stromal components of the bone marrow are conspicuously modulated in this uncommon disorder in keeping with the designation as a panmyelosis.
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Geisler, C. H., P. Philip, B. Egelund Christensen, K. Hou-Jensen, N. Tinggaard Pedersen, O. Myhre Jensen, K. Thorling, et al. "In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: A cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients." Leukemia Research 21, no. 11-12 (November 1997): 1011–23. http://dx.doi.org/10.1016/s0145-2126(97)00095-7.
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Raghavan, Manoj, Manu Gupta, Tracy Chaplin, Sabah Khalid, T. Andrew Lister, and Bryan D. Young. "Genome-Wide Micro-Deletions and Amplifications Acquired at Relapse in Acute Myeloid Leukemia." Blood 114, no. 22 (November 20, 2009): 166. http://dx.doi.org/10.1182/blood.v114.22.166.166.
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Abstract Abstract 166 Recurrence of acute myeloid leukemia AML has a poor prognosis with only 20% of adults surviving to 5 years. Therefore it is of importance to identify molecular changes that explain the pathogenesis of relapsed AML. Previous studies had not identified consistently acquired cytogenetic changes at relapse. Recently, acquired uniparental disomy due to mitotic recombination was described in 40% of relapsed AML (Raghavan et al 2008). Most of the events lead to homozygosity for FLT3 mutations. This study aimed to discover if there are further genetic abnormalities acquired at disease recurrence that cannot be identified by conventional cytogenetics, i.e. microdeletions or gains. Twenty-one presentation and relapse paired AML patient blood and marrow samples were stored with consent at St Bartholomew's Hospital, London. Eleven patient samples had a normal karyotype at diagnosis, two had favourable prognosis cytogenetics (inv(16) and t(8;21)) and others had varying numerical cytogenetic abnormalities and rearrangements associated with an intermediate prognosis. DNA from the samples was analysed by array based high-resolution single nucleotide polymorphism (SNP) genotyping (Affymetrix Human SNP array 6.0). Data was analysed using Partek Genome Browser (Partek, MO). In all cases, the leukemia infiltrate of the marrow or blood was greater than 60% and most cases were greater than 90% allowing accurate identification of DNA copy number changes. Abnormalities of a size that would be identified by cytogenetics were disregarded. Using segmentation analysis using a p-value less than 0.001, over 400 microdeletions and gains were detected that were acquired at relapse in the 21 pairs. Each of the copy number changes was less than 2 megabases in size. One AML sample with a normal karyotype at diagnosis and trisomy 8 and add(9)(q34) at relapse had not acquired any microdeletions or gains. In contrast, in other samples as many as 69 microdeletions/gains were detected. There was no correlation between increased complexity of the karyotype of the leukemia and the number of microdeletions/gains. Several of the acquired microdeletions/gains were in regions containing genes known to be involved in AML, including a deletion of 234Kb at 13q12.2 involving FLT3 and CDX2, and an acquired deletion at 21p11.2 of 150Kb involving exons encoding the runt domain of RUNX1. Another copy number gain was detected at the MLL locus, suggestive of partial tandem duplication. Other detected locations are in Table 1.Table 1Location by cytobandCopy number changeSize / KbP valueGene13q12.2Deletion23410−33FLT3, CDX221q22.12Deletion15010−13RUNX111q23.3Gain5.10.0099MLL11p15.4Gain830.00001NUP9817q21.31Deletion8.00.0007BRCA1The results indicate that recurrent AML may be associated with the deletion or gain of several genes involved in leukaemogenesis. Many other locations are involved throughout the genome, suggesting at least some of these are also involved in the clonal evolution of the leukaemia at recurrence. Further studies should identify novel genes from these regions involved in the pathogenesis of AML. Disclosures: No relevant conflicts of interest to declare.
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Moorman, Anthony V., Sue M. Richards, Jerry P. Hancock, Chris D. Mitchell, Ajay J. Vora, Christine J. Harrison, and Nick J. Goulden. "Cytogenetic-Specific Heterogeneity in the Kinetics of Minimal Residual Disease (MRD) Clearance in Childhood Acute Lymphoblastic Leukaemia (ALL)." Blood 110, no. 11 (November 16, 2007): 1426. http://dx.doi.org/10.1182/blood.v110.11.1426.1426.
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Abstract Although both MRD and karyotype are powerful determinants of outcome in childhood ALL, few studies have examined the kinetics of MRD clearance by cytogenetic subgroup. ALL2003 is an ongoing UK trial open to all patients aged 1–19 years with ALL, except those with mature-B ALL. At diagnosis, patients are stratified by NCI criteria to receive a three drug (Regimen A - age 1–9 years and white cell count (WCC) <50×109/L) or four drug (Regimen B - age 10–18 years or WCC >50×109/L) induction. MRD is assessed at day 29 and week 11 of therapy using a standardised and quality controlled RQ-PCR of at least two patient specific immunoglobulin or T cell receptor rearrangements. MRD risk groups were defined as: MRD high risk (HR) MRD >10−4 at day 29; MRD low risk (LR) MRD negative or <10−4 at day 29 and negative at week 11; MRD indeterminate risk - all other patients. Cytogenetic analysis was performed on pre-treatment samples and six abnormalities were defined as high risk: t(9;22)(q34;q11), near-haploidy (23–29 chromosomes), low hypodiploidy (30–39 chromosomes), 11q23/MLL translocations, t(17;19)(q22;p13) and intrachromosomal amplification of chromosome 21 (iAMP21). Among the first 1000 patients entered into the trial, 979 (98%) patients were eligible for these analyses. A total of 920 (94%) had a successful cytogenetic result and 555 (57%) were assigned to MRD high or low risk groups. Of these 555 patients, 298 (54%) were classified as MRD-HR whereas 257 (45%) were classified as MRD-LR. Collectively, patients with high risk cytogenetics were more likely to be classified as MRD-HR [20/24 (83%) v 261/501 (52%), p=0.003]. Patients with ETV6-RUNX1 (TEL-AML1) fusion were less likely to be classified as MRD-HR [40/145 (28%) v 241/380 (63%), p<0.001]. In contrast, high hyperdiploid patients were more likely to be MRD-HR compared to all other patients [99/155 (64%) v 182/370 (49%), p=0.002]. However, this effect was driven by the low rate of MRD-HR among the ETV6-RUNX1 positive patients and excluding these patients from the analysis revealed that high hyperdiploid patients were as likely to be MRD-HR as other ETV6-RUNX1 negative patients [99/155 (64%) v 142/225 (63%), p=0.880]. There was no difference between high hyperdiploid patients with and without the triple trisomy of +4, +10 and +17 with respect to MRD status. T-ALL patients were also more likely to be classified as MRD-HR compared to B-cell precursor ALL patients [32/46 (70%) v 249/479 (52%), p=0.022]. In particular, 9/10 patients with t(5;14)/TLX3-BCL11B fusion and 6/6 patients with SIL-TAL1 fusion were classified as MRD-HR. In conclusion, we have clearly demonstrated that MRD status varies by cytogenetic subgroup with ETV6-RUNX1 patients having the fastest MRD clearance rate. Despite the good prognosis associated with high hyperdiploidy, these patients were as likely to be MRD-HR as other standard risk patients. Longer follow-up is required to determine the clinical significance of this finding.
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Laurenti, Luca, Dimitar Efremov, Michela Tarnani, Laura de Padua, Nicola Piccirillo, Patrizia Chiusolo, Federica Sora’, et al. "Germline IgVH, del(17p13.1) and del(11q22.3) Predict Duration of Response in Patients Affected by Chronic Lymphocytic Leukaemia Treated with Oral Fludarabine and Cyclophosphamide as First-Line Therapy." Blood 110, no. 11 (November 16, 2007): 4717. http://dx.doi.org/10.1182/blood.v110.11.4717.4717.
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Abstract We test the efficacy and safety of the oral formulation of fludarabine combined with cyclophosphamide as front-line therapy of CLL. We studied the influence of IgVH gene mutation status, interphase cytogenetic abnormalities, and expression of ZAP-70 and CD38 on the overall response rate (OR), progression free survival (PFS), time to re-treatment (TTR) and overall survival (OS). Twenty seven patients were male and 10 were female, with a median age of 68 years (range, 52 to 75 years). Thirty patients were in stage B/II, 1 in stage C/III, and 6 in stage C/IV. The treatment schedule consisted of oral fludarabine (30 mg/m2) and oral cyclophosphamide (250 mg/m2) for 3 consecutive days every 4 weeks, for a maximum of 6 cycles. Eighteen patients had unmutated and 15 had mutated IgVH genes; in 4 patients the mutation status was not determined. Nine patients (24%) had the ‘high risk’ cytogenetic abnormality del(11q22.3) or del(17p13.1). Fifteen patients had more than 20% ZAP-70-positive and 8 patients had more than 30% CD38-positive CLL B-cells, respectively. Thirty-five patients were evaluable for response to treatment. Two patients discontinued the treatment protocol because of the development of immune thrombocytopenia after 2 and 4 cycles, respectively. Both of them belonged to the ‘high risk’ cytogenetic category. Fourteen patients (40%) obtained a complete response and 13 (37%) a partial response with an ORR of 77%. Four patients showed stable disease and four patients experienced progressive disease after 2, 3, 4 and 6 cycles, respectively. The median PFS was 23 months (range 2–42) and the median TTR was 38 months (range 2–42). The ‘high risk’ cytogenetic abnormalities del (17p13.1) and del (11q22.3) were predictive of a lower OR rate (43% vs 85%, p=0.011) as well as a shorter PFS (22 vs 27 months, p= 0.015) and shorter TTR (22 vs 40 months, p=0.031). In addition, unmutated IgVH genes were significantly associated with a reduced TTR (26 vs 41 months, p=0.035), whereas no significant impact was noticed in terms of OR, PFS and OS, even though all four deaths occurred in patients with unmutated IgVH genes. Expression of CD38 and ZAP-70 had no significant impact on clinical outcome. At present, median follow-up is 30 months, with an OS rate of 89%. The median time of OS has not been reached for any of the prognostic categories. In terms of haematological toxicity, ten patients developed grade IV neutropenia during treatment and received G-CSF. Three patients developed grade III and IV anemia that required red blood cell transfusions. Extra-hematological toxicity consisting of nausea was detected in 14 patients (40%) of whom 12 with grade I–II and 2 (6%) with grade III; half of these patients also experienced vomiting (6 patients grade I–II and one patient grade III). One patient developed fever of unknown origin after the first cycle of chemotherapy, which spontaneously resolved without hospitalization. The oral combination of fludarabine and cyclophosphamide is an effective, safe and well tolerated regimen that appears especially appropriate for a subset of previously untreated CLL patients characterized by mutated IgVH genes and the absence of “high risk” cytogenetic abnormalities.
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Mroczek, Anna, Joanna Zawitkowska, Jerzy Kowalczyk, and Monika Lejman. "Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia." International Journal of Molecular Sciences 22, no. 2 (January 15, 2021): 808. http://dx.doi.org/10.3390/ijms22020808.
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Acute lymphoblastic leukaemia (ALL) is a relevant form of childhood neoplasm, as it accounts for over 80% of all leukaemia cases. T-cell ALL constitutes a genetically heterogeneous cancer derived from T-lymphoid progenitors. The diagnosis of T-ALL is based on morphologic, immunophenotypic, cytogenetic, and molecular features, thus the results are used for patient stratification. Due to the expression of surface and intracellular antigens, several subtypes of T-ALL can be distinguished. Although the aetiology of T-ALL remains unclear, a wide spectrum of rearrangements and mutations affecting crucial signalling pathways has been described so far. Due to intensive chemotherapy regimens and supportive care, overall cure rates of more than 80% in paediatric T-ALL patients have been accomplished. However, improved knowledge of the mechanisms of relapse, drug resistance, and determination of risk factors are crucial for patients in the high-risk group. Even though some residual disease studies have allowed the optimization of therapy, the identification of novel diagnostic and prognostic markers is required to individualize therapy. The following review summarizes our current knowledge about genetic abnormalities in paediatric patients with T-ALL. As molecular biology techniques provide insights into the biology of cancer, our study focuses on new potential therapeutic targets and predictive factors which may improve the outcome of young patients with T-ALL.
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Ahmed, Ali, Ch Altaf Hussain, Hamid Saeed Malik, M. Abdul Naeem, Rafia Mehmood, and Khadija . "CORRELATION OF TRISOMY 12 WITH CLINICAL FEATURES AND OTHER LABORTARY PARAMETERS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA." PAFMJ 71, no. 2 (April 28, 2021): 473–77. http://dx.doi.org/10.51253/pafmj.v71i2.2679.
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Objective: To determine the frequency of trisomy 12 in B-Cell chronic lymphocytic leukaemia (CLL), to correlate its association with clinico-pathologic features and to determine the role of this cytogenetic defect to the prognosis.
Study Design: Cross sectional study.
Place and Duration of Study: Haematology department, Armed Forces Institute of Pathology, Rawalpindi, from May 2017 to Aug 2018.
Methodology: A total of 56 newly diagnosed patients of Chronic Lymphocytic Leukaemia were included in the study. Patients were diagnosed on the basis of National Cancer Institute Working Group guidelines. A detailed history and thorough clinical examination were performed and complete blood counts, biochemical profile, bone marrow examination, immunophenotyping on bone marrow/peripheral blood samples were done for the diagnosis of Chronic lymphocytic leukaemia. Interphase FISH studies were performed on blood/bone marrow aspiration for detection of Trisomy 12 were performed.
Results: Out of 56 patients, trisomy was detected in 12 (10.7%) patients. Out of 7 patients with trisomy 12, five patients presented in late stages (Binet stage B and C), however this association of Trisomy 12 with Binet stage was also statistically insignificant (p=0.474). About six with trisomy 12 were positive for CD 38, however this association was also not statistically significant (p=0.124). Results revealed that patients having trisomy 12 underwent chemotherapy at diagnosis and during follow ups as compared to patients having other cytogenic abnormalities. Moreover, patient with trisomy 12 develop progression in disease during course of illness, however association was statistically insignificant (p>0.05)............
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Murthy, Vidhya, Nilupulee Kapuge, Charalampos Kartsios, Joanne Ewing, Evgenia Xenou, Maria Kaparou, Elmoamly Shereef, and Emmanouil Nikolousis. "Azacitidine Improves Outcome in Patients with MDS and AML with High Risk Cytogenetics - a Single Center Experience." Blood 132, Supplement 1 (November 29, 2018): 5529. http://dx.doi.org/10.1182/blood-2018-99-109774.
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Abstract Azacitidine is a novel hypomethylating agent shown to improve leukaemia free survival and overall survival in comparison with other modalities of treatment in MDS and AML patients. There is proven reduction in transfusion requirements by improvement in haematological parameters with continuous azacitidine use. However azacitidine benefit in high risk cytogenetics group is unclear. Recent retrospective study from GESMD and GFM registries showed that Azacitidine improves outcome in higher‐risk MDS patients with chromosome 7 abnormalities. Here we report our experience in high risk cytogenetics group including complex karyotype. Methodology:- We retrospectively reviewed patients with MDS and AML who received Azacitidine at the Heart of England NHS Foundation Trust from April 2012- January 2018. Patient's demographic data, disease characteristics, treatment, outcome and follow up data were obtained and all patients were included irrespective of the number of the cycles. Results 57 patients were included in the analysis. Median age of treatment was 73.9 years. Median number of cycles was 6 (range from 1 to 43). There were 68% of MDS patients, 22.8% of AML and 8.8% of CMML2 patients in the cohort .Varying degree of performance stage was noted including ECOG 0,1 and 2 at 40.4%,43.9% and 7.7% respectively. 9 patients had monosomy 7 and 11 patients had complex karyotype (3/>3). 42.1% had high risk cytogenetics. At presentation, median Hb was 9g/dl, Neutrophil count was 0.7x109/l and platelet count was 41x109/l. Median bone marrow blast percentage was10% and median RIPSS score was 6.5. Causes of death were mainly disease progression and sepsis. 42.2% died due to disease progression and 35.1% died due to sepsis. Overall survival was not affected by age, Bone marrow median blast percentage and median neutrophil count, however, survival was affected by presenting peripheral blast percentage, cytogenetic risk group and was statistically significant (P<0.05) Overall, median progression free survival (PFS) was 19monts while median overall survival (OS) was 12 months. There was no statistically significant PFS or OS difference for patients who had varying performance stage. High risk cytogenetics group: Among high risk cytogenetics group, 21% Patients had red cell transfusion independence at 6 months, 28% had an improvement in the neutrophil count to >1x10^9/L at 6 months. 25% patients had doubling of platelet count at 3 months leading to platelet independence and 17.8% maintained platelet transfusion independence. A significant difference was noted in the group of who had high risk cytogenetic versus other cytogenetic risks with PFS of 15 and 29 months respectively, OS of 8 months and 15 months respectively. with high risk cytogenetics still had a PFS advantage with treatment. Conclusion Azacidine therapy has benefited for the patients who had advanced age AML CMML and MDS who has non high risk cytogenetic based on IPSS-R risk categorization. However, the group of patients with high risk cytogenetic considered historically very poor survival had considerable PFS and OS benefitting treatment rather than best supportive care. Figure. Figure. Disclosures Murthy: celgene: Consultancy, Other: Travel grant for educational meeting; Abbview: Other: Travel grant for Educational meeting. Kartsios:Bayer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Boehringer Inglelheim: Consultancy, Honoraria, Speakers Bureau. Nikolousis:Celgene: Consultancy, Other: Travel grant for educational meetings.