Study of the Influence of Additional Chromosomal Abnormalities in Young Chronic Myeloid Leukemic Patients and its Impact on Disease ProgressionRana Gamal Ahmed
AbstractRecent interest in additional chromosomal abnormalities (ACAs) in chronic myeloid leukemic patients is now gaining more importance particularly in progressive disease. Current evidence indicates that acquired genetic instability as a consequence of the Philadelphia (Ph) translocation t(9;22)(q34;q11) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACAs) and mutations, and thereby progression to the accelerated phase (AP) and blast crisis (BC) of CML. The appearance of ACAs during treatment is commonly known as clonal evolution (CE) and seems to play an important role in imatinib mesylate resistance. The World Health Organization classification suggests that those patients showing ACAs emerging during treatment should be considered in accelerated phase (AP). The European Leukemia Net recommendation suggest that the presence of ACAs at diagnosis may represent a “warning” feature, requiring careful monitoring of the chromosomal changes were thought to unequally influence disease progression depending on the type of ACA and its time of appearance. Major-route ACAs were thought to be more correlated with worse prognoses than minor-route ACAs. The most frequent aberrations detected in advanced CML were trisomy 8,(+8) a second Ph chromosome, and a partial trisomy of the long arm with partial monosomy of the short arm of chromosome 17 [isochromosome (17)(q10)], vanishing Y chromosome(−Y), monosomy 7(−7), +19, +21, +17, which were designated “major-route of karyotypic evolution” , While ACAs that were rarely observed in AP or BC, such as t(3;12), t(4;6), t(2;16), and t(1;21), were designated minor-route ACAs hematologic malignancies and has been described both as a primary and a secondary aberration. An i(17q), usually observed in a complex karyotype, has been reported in solid tumors and in various types of hematological diseases. It is found in 1.4% to 2.4% of: acute myeloid leukemias and chronic myeloid leukemias, myelodysplastic syndromes and myeloproliferative neoplasms, acute lymphoid leukemias and chronic lymphoid leukemias, and Hodgkin and non-Hodgkin lymphomas. I(17q) is a frequent secondary chromosomal aberration in the accelerated phase or blast crisis of chronic myeloid leukemia (CML), indicating that this abnormality plays an important role in the disease progression. Isochromosome 17q usually occurs at time of blast transformation and heralds an aggressive clinical course.It is either presents solely in 10% of cases, or with other additional anomalies, in at least another 10% of cases, in particular with +8. It is believed that i(17q) as a sole abnormality is a distinctive clinicopathological entity with a high risk to a leukemic progression. The most relevant finding is our study is the highly significant negative impact of major-route ACAs on the prognosis and response to treatment with imatinib in young chronic myeloid patients ,As found that the clone ACA occurred in 15 patients out of the studied CML patients (30%) in the form of abnormalities involving chromosome 17 i(17q) with 14 patients of them showed failure to treatment (93%) and only one was responding (7%) with (P=0.001) which shows highly statistically significant difference between the presence of ACA and the response or failure to imatinib. Despite the relatively small sample size and small number of CML cases included in the study, yet a different statistically positive correlation was found between the acquisition of Additional chromosomal anomalies namely isochromosome 17 i(17q) and the response to imatinib. In conclusion, ACA were frequently detected and were significantly associated with failure of response to imatinib in young patients with Ph-positive CML according to ELN and NCCN new guidelines which makes shifting to the second line of TKI a must. This indicates that conventional cytogenetics on metaphases remains mandatory at diagnosis and during follow-up. Our study concludes that the presence of ACAs has a negative impact in young CML patients treated with imatinib as frontline therapy. Our data confirm that patients with ACAs constitute a “warning” category, in terms of responses, and they suggest that these cases could require a close monitoring and treatment with second generation TKIs as frontline therapy. Perhaps the major-route, rather than the minor-route ACAs, had the observed prognostic impact, and therefore, the evaluation of these groups together may obscure the impact to TKI and thus the impact prognosis. We found also that ACA in young CML Egyptian patients are secondary rather than primary clonal evolution occurred after exposure to the treatment which is one of the mechanisms by which a mutant CML cells may escape or evade the response to TKI therapy.
|Other Titles||دراسة عن تأثير شذوذ الصبغيات الإضافية في مرضى اللوكيميا المزمنة صغار السن وأثره على تطور المرض||Issue Date||2015||URI||http://research.asu.edu.eg/handle/12345678/8088|
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