Background: Analysis of Philadelphia (Ph) chromosome, a hallmark of chronic myeloid leukemia (CML) plays an important role in disease monitoring of the targeted drug Imatinib. Apart from Ph, genomic imbalances such as...Background: Analysis of Philadelphia (Ph) chromosome, a hallmark of chronic myeloid leukemia (CML) plays an important role in disease monitoring of the targeted drug Imatinib. Apart from Ph, genomic imbalances such as additional chromosomal abnormalities (ACAs) of major route occur during transformation of the disease and show negative impact on prognosis. Objective: The present study was carried out to investigate frequencies of ACAs, genomic deletions, complex Ph variants and their prognostic influences in a large cohort of newly diagnosed CML-CP (chronic phase) and CML-AP/BP (accelerated/blast phase). Material & Methods: Retrospective, single institutional study on 1367 cases of CML-CP and 82 cases of CML-AP/BP between 2009 and 2015, using conventional cytogenetics along with fluorescence in situ hybridization. Results: Of the 1367 patients in CML-CP, 1041 patients who completed 12 - 18 months of Imatinib therapy showed complete cytogenetic remission (CCyR) rates of 76% and 82% at 12 and 18 months respectively. Imatinib induced 81% and 33% CCyR in CML-AP and CML-BP respectively. Frequencies of ACAs in CML-CP, AP and BP were 2%, 27% and 67% respectively. Patients in chronic and AP/BP phase with ACAs showed resistance to Imatinib (p < 0.0005). The incidence of genomic deletions and complex Ph variants was 21% and 6.3% respectively with no comparable difference of cytogenetic response to Imatinib (p p < 0.210 respectively). In a cohort of 112 patients in CCyR, development of new clonal abnormalities, more frequently trisomy 8 was detected in Ph negative clone. Conclusion: Our data demonstrated that Imatinib as a frontline therapy had significantly improved management of CML. However, ACAs play an important role in resistance to Imatinib, both in chronic and acute phase, which may limit sole ABL targeted therapy.展开更多
Background: Various genetic technologies have been employed in the identification of genomic complexity and refinement of prognostic classification of clinically heterogeneous disease of chronic lymphocytic leukemia (...Background: Various genetic technologies have been employed in the identification of genomic complexity and refinement of prognostic classification of clinically heterogeneous disease of chronic lymphocytic leukemia (CLL). Objective: The present study of interphase cytogenetics and conventional karyotyping was undertaken to perform comprehensive analysis of CLL genetics with an approach to refine early prognostication of disease. Material & Methods: Retrospective analysis by fluorescence in situ hybridization (FISH) was carried out on total 671 patients of CLL at diagnosis between 2008 and 2015. Conventional cytogenetics studies were performed in 50 of 671 patients using CPG Oligonucleotide + IL-2 and TPA (12-O-Tetradecanyl Phorbol 13-acetate) for stimulation of lymphocytes cultures. Results: Interphase cytogenetics could detect recurrent abnormalities such as del(13q14), +12, del(17p13), del(11q22), del(6q23) in 71% of cases. The incidence of del(13q) was higher in Rai stage 0, I, II (p = 0.0005);whereas patients with ≥2 aberrations were more common in advance stage III, IV (p = 0.001). Frequency of IgH translocation was 7%. Morphology and immunophenotypic analysis revealed atypical CLL with higher frequency of t(14;19) than t(14;18). Conventional karyotype could detect abnormal karyotype in 97% of cases which displayed targeted FISH abnormalities along with additional non-targeted chromosomal abnormalities. Patients with negative FISH markers showed clonal non-recurrent numerical and structural changes. The complex karyotype was identified in 24% cases which included targeted FISH aberrations as well as non-targeted numerical and structural abnormalities like deletions, and unbalanced translocations. A significant association was observed between complex karyotype and coexistence of ≥2 FISH markers (p = 0.009) and del(11q22) &/or del(17p) (p = 0.03). Conclusion: Our data of interphase FISH with integration of conventional karyotyping revealed genomic complexity that helped identification of biological subclasses with clinical impact at diagnosis. Further, these cytogenetic subclasses along with molecular markers are likely to evolve more refined prognostic groups, which will help design risk-adapted therapies in B-CLL.展开更多
Background: Cytogenetics is one of the most important diagnostic parameters in the classification of acute leukemia. Recurrent chromosomal aberrations in acute leukemia have provided insights into the molecular mechan...Background: Cytogenetics is one of the most important diagnostic parameters in the classification of acute leukemia. Recurrent chromosomal aberrations in acute leukemia have provided insights into the molecular mechanism of leukemogenesis. The variable frequencies of recurrent cytogenetic markers due to ethical/racial differences have been reported from Western and some Asian countries. Objective: We report cytogenetic data of largest cohort of 7209 adult and pediatric patients with de novo acute leukemia (AL) to determine the prevalence of various cytogenetic sub groups and compare with the Western and Asian population. Material & Methods: The AL patients included 2609 AML (adult: 2042, pediatric: 567), 3708 B-cell-precursor (BCP)-ALL (adult: 1300, pediatric: 2408) and 892 cases of T-ALL (adult: 480, pediatric: 412). Cytogenetic studies included conventional karyotyping and FISH using panel of probes. Results: The incidence of t(8;21) was high, comparable to other Asian countries. In comparison to our series and Western population, t(15;17) was more prevalent in Chinese population. Cytogenetic profiling of BCP-ALL revealed low prevalence of ETV6/RUNX1 in ours as well as other Asian population. The MLL aberrations in BCP-ALL and TLX1 & TLX3 aberrations in T-ALL occurred less frequently in our series as compared with Western population. Conclusion: The present study with a large cohort showed the heterogeneity of AL that involved various factors, such as age, gender and prevalence of distinct cytogenetic subgroups. Our data in comparison with other population based studies revealed differential distribution of some cytogenetic sub-groups indicating geographic heterogeneity due to differential environmental exposure which probably influenced underlying genetic susceptibility.展开更多
文摘Background: Analysis of Philadelphia (Ph) chromosome, a hallmark of chronic myeloid leukemia (CML) plays an important role in disease monitoring of the targeted drug Imatinib. Apart from Ph, genomic imbalances such as additional chromosomal abnormalities (ACAs) of major route occur during transformation of the disease and show negative impact on prognosis. Objective: The present study was carried out to investigate frequencies of ACAs, genomic deletions, complex Ph variants and their prognostic influences in a large cohort of newly diagnosed CML-CP (chronic phase) and CML-AP/BP (accelerated/blast phase). Material & Methods: Retrospective, single institutional study on 1367 cases of CML-CP and 82 cases of CML-AP/BP between 2009 and 2015, using conventional cytogenetics along with fluorescence in situ hybridization. Results: Of the 1367 patients in CML-CP, 1041 patients who completed 12 - 18 months of Imatinib therapy showed complete cytogenetic remission (CCyR) rates of 76% and 82% at 12 and 18 months respectively. Imatinib induced 81% and 33% CCyR in CML-AP and CML-BP respectively. Frequencies of ACAs in CML-CP, AP and BP were 2%, 27% and 67% respectively. Patients in chronic and AP/BP phase with ACAs showed resistance to Imatinib (p < 0.0005). The incidence of genomic deletions and complex Ph variants was 21% and 6.3% respectively with no comparable difference of cytogenetic response to Imatinib (p p < 0.210 respectively). In a cohort of 112 patients in CCyR, development of new clonal abnormalities, more frequently trisomy 8 was detected in Ph negative clone. Conclusion: Our data demonstrated that Imatinib as a frontline therapy had significantly improved management of CML. However, ACAs play an important role in resistance to Imatinib, both in chronic and acute phase, which may limit sole ABL targeted therapy.
文摘Background: Various genetic technologies have been employed in the identification of genomic complexity and refinement of prognostic classification of clinically heterogeneous disease of chronic lymphocytic leukemia (CLL). Objective: The present study of interphase cytogenetics and conventional karyotyping was undertaken to perform comprehensive analysis of CLL genetics with an approach to refine early prognostication of disease. Material & Methods: Retrospective analysis by fluorescence in situ hybridization (FISH) was carried out on total 671 patients of CLL at diagnosis between 2008 and 2015. Conventional cytogenetics studies were performed in 50 of 671 patients using CPG Oligonucleotide + IL-2 and TPA (12-O-Tetradecanyl Phorbol 13-acetate) for stimulation of lymphocytes cultures. Results: Interphase cytogenetics could detect recurrent abnormalities such as del(13q14), +12, del(17p13), del(11q22), del(6q23) in 71% of cases. The incidence of del(13q) was higher in Rai stage 0, I, II (p = 0.0005);whereas patients with ≥2 aberrations were more common in advance stage III, IV (p = 0.001). Frequency of IgH translocation was 7%. Morphology and immunophenotypic analysis revealed atypical CLL with higher frequency of t(14;19) than t(14;18). Conventional karyotype could detect abnormal karyotype in 97% of cases which displayed targeted FISH abnormalities along with additional non-targeted chromosomal abnormalities. Patients with negative FISH markers showed clonal non-recurrent numerical and structural changes. The complex karyotype was identified in 24% cases which included targeted FISH aberrations as well as non-targeted numerical and structural abnormalities like deletions, and unbalanced translocations. A significant association was observed between complex karyotype and coexistence of ≥2 FISH markers (p = 0.009) and del(11q22) &/or del(17p) (p = 0.03). Conclusion: Our data of interphase FISH with integration of conventional karyotyping revealed genomic complexity that helped identification of biological subclasses with clinical impact at diagnosis. Further, these cytogenetic subclasses along with molecular markers are likely to evolve more refined prognostic groups, which will help design risk-adapted therapies in B-CLL.
文摘Background: Cytogenetics is one of the most important diagnostic parameters in the classification of acute leukemia. Recurrent chromosomal aberrations in acute leukemia have provided insights into the molecular mechanism of leukemogenesis. The variable frequencies of recurrent cytogenetic markers due to ethical/racial differences have been reported from Western and some Asian countries. Objective: We report cytogenetic data of largest cohort of 7209 adult and pediatric patients with de novo acute leukemia (AL) to determine the prevalence of various cytogenetic sub groups and compare with the Western and Asian population. Material & Methods: The AL patients included 2609 AML (adult: 2042, pediatric: 567), 3708 B-cell-precursor (BCP)-ALL (adult: 1300, pediatric: 2408) and 892 cases of T-ALL (adult: 480, pediatric: 412). Cytogenetic studies included conventional karyotyping and FISH using panel of probes. Results: The incidence of t(8;21) was high, comparable to other Asian countries. In comparison to our series and Western population, t(15;17) was more prevalent in Chinese population. Cytogenetic profiling of BCP-ALL revealed low prevalence of ETV6/RUNX1 in ours as well as other Asian population. The MLL aberrations in BCP-ALL and TLX1 & TLX3 aberrations in T-ALL occurred less frequently in our series as compared with Western population. Conclusion: The present study with a large cohort showed the heterogeneity of AL that involved various factors, such as age, gender and prevalence of distinct cytogenetic subgroups. Our data in comparison with other population based studies revealed differential distribution of some cytogenetic sub-groups indicating geographic heterogeneity due to differential environmental exposure which probably influenced underlying genetic susceptibility.
