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The first ALN report1 demonstrated that age-specific rates for CML in Egypt and Arab nations are lower by at least two decades compared to western populations1. Geographic and ethnic variations contribute to the variability of incidences among CML registries2. ACAs were reported in 5% of CML patients in chronic phase (CP). At diagnosis considered by ELN as a “warning” requiring careful patient monitoring, while ACAs emerging during treatment are considered by WHO classification as accelerated phase (AP) CML .ACAs influence response to Imatinib and outcome of TKI therapy. The occurrence of ACAs and additional mutations besides Ph‏ chromosome(Ch) indicates that the leukemia has become at least partially BCR-ABL independent by secondary genetic acquisitions 2.Although the underlying mechanisms of resistance /disease progression are not fully understood for all ACAs, some are well identified as poor prognostic factors. such as the acquisition of additional Ph‏ chromosome which might confer resistance via increasing the kinase activity of BCR-ABL3, the isochromosome 17q i(17q) which leads to inactivation of the tumor suppressor gene p53 and impedes the response to Imatinib via allowing the damaged cells to escape the DNA repair machinery of p53 and thus escape cell growth arrest or apoptosis, the extra 8 which is known to lead to      c-Myc over expression that enhances the transformation of BCR-ABL positive cells or allows rapid growth of leukemic cells, and the extra 19 which might hinder Imatinib activity via hypermethylation / inactivation of neoplastic transformation silencing gene promoters such as ATG16L2 gene promoter4.

1) To Release data of second ALN report concerning epidemiology of CML in Egypt, after enrolling 6 new centres ,228 patients and adding ACAs to evaluate disease and clonal evolution. 2) Investigate the low mean age of CML in Egypt and the role of ACAs..

We analyzed data of 578 CML Egyptian patients (302 male and 276 female) followed-up for 5 years. Data were collected from 10 centers according to ELN2 and EUTOS recommendations2-3 by using a multicenter web based data registery portal, the ALN. (www.aln-afme.com). Chromosome banding analysis and FISH were performed according to the International System for Human Cytogenetic Nomenclature. we tested for ACAs defined as “major route” namely trisomy 8, duplication of Ph chromosome, i(17q), and trisomy 19.21.FISH was performed on at least 200 cells on bone marrow cells prepared according to cytogenetic techniques and by using DNA probes that hybridize at the BCR and ABL regions. RT-PCR, and real-time quantitative PCR were performed

Patients Median age was 43y, (40y for males, 41y for females), The age specific rates were highest for the age group of 30-35 years.  Female patients presented with lower hemoglobin, higher platelet counts and smaller spleen size (P<0.0001). 98%of patients achieved CH respone,89% CYR,87% CYR,and 83% MMR. At diagnosis 87% patients were in CP-CML, 8.1% in AP and 4.9% in blastic phase. Sokal score: Low risk 57.8% Intermediate24.5% and High in 17.7% . EURO (Hasford) score ( 59% Low risk, 28.4% Intermediate risk and12.6% High risk). 42% of patients received first generation TKI, 54 % second  generation TKI, and 4% needed therapies plus TKI). Transplantation rate was 19%, PFS and OS were equal in female and male patients. ACAs were found in 62(11%) patients, they had lower cytogenetic and molecular response rates and longer response time to TKI and inferior outcome. ACAs were more frequent in younger, Imatinib resistant patients, and in blast phase. We identified loss of Y Ch in 18 patients (29%), trisomy 8 in 7 (11%), trisomy 19 in 12 (19%), i (17q) in 12(19%), other different single abnormalities in 8 patients (13%), complex karyotype with double ACAs in only 5 patient (8%).Four patient showed variant Ph Ch: t(9;22;22)(q34;q11;q11). Deletion of der(9) Ch in 17 cases (27%): (10 cases with loss of Y Ch,  case with del(20)(q11q13), and 3 case with t(X;13)(q13;q32)). The cytogenetic and molecular response rates were uniformly lower in patients with ACAs, CCgR and MMR rates were significantly lower in patients with ACAs (68% vs 89% and 55% vs 86% respectively), responses were significantly slower in patients with ACAs, 54 patients presented with ACAs at diagnosis while 8 patients developed or acquired ACAs while on treatment.

The importance of ethnicity and gender differences in relation to disease incidence, and prognosis are major health policy focus2.To investigate the low mean age of CML in Egypt and evaluate role of ACAs on disease and clonal evolution, we analyzed CML data of 10 Medical Centers in Egypt. We identified 62(11%) cases with clonal ACAs. ACAs are more frequent in younger patients and adversely affected time and response rates to Imatinib treatment they were related to lower cytogenetic and molecular response rates and longer response time toTKI and inferior outcome and lower overall survival.