Incidence of BCR-ABL transcript variants in patients with chronic myeloid leukemia: Their correlation with presenting features, risk scores and response to treatment with imatinib mesylate

Abstract

Context: The exact role of the different transcript variants of BCR-ABL in the pathogenesis of chronic myeloid leukemia (CML) and their impact on prognosis is yet to be definitely enumerated. Aims: In this study, we have tried to correlate the presenting features, risk scores and treatment response with the BCR-ABL variants detected in our patients. Settings and Design: A cross-sectional unicentric hospital-based study on 80 patients diagnosed to have CML by bone marrow cytogenetics and confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). Materials and Methods: RT-PCR for BCR-ABL was performed on consecutive patients with CML attending the CML clinic from January 2010 to December 2010.The medical charts of these patients were analyzed after a follow-up of 18 months in a retrospective manner. Statistical Analysis: Box plot and histogram was used to see the distribution of variables. t-test was performed to enumerate the difference between risk scores in two populations of patients carrying two different BCR-ABL transcript variants. Results: Nearly 56.25% of patients had b3a2 (e14a2) while 41.25% of patients showed b2a2 (e13a2) transcripts. The rest 2.5% (two patients) expressed the rare e19b2 variant. Patients with b2a2 presented with higher Sokal, Hasford and European Treatment and Outcomes Study score than their b3a2 counterpart. Different parameters such as the platelet count, leukocyte count, hemoglobin and splenomegaly showed a minor difference between the groups. More patients in the b2a2 group achieved complete hematologic response at 3 months, but it was not significant. Conclusions: Patients with b2a2 variant CML tend to present with higher risk score, but do not behave in a vastly different manner than their b3a2 counterparts.

Keywords

BCR-ABL transcript variants - chronic myeloid leukemia - chronic myeloid leukemia risk scores - imatinib mesylate

Publication History

Article published online:
19 July 2021

• References

• 1 Nowell PC. The minute chromosome (Phl) in chronic granulocytic leukemia. Blut 1962;8:65-6.
• 2 Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005;5:172-83.
• 3 Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 1986;233:212-4.
• 4 Lucas CM, Harris RJ, Giannoudis A, Davies A, Knight K, Watmough SJ, et al. Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript. Haematologica 2009;94:1362-7.
• 5 Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 1985;315:550-4.
• 6 Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984;63:789-99.
• 7 Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon Alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90:850-8.
• 8 Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: The EUTOS score. Blood 2011;118:686-92.
• 9 van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: Investigation of minimal residual disease in acute leukemia. Leukemia 1999;13:1901-28.
• 10 Perego RA, Costantini M, Cornacchini G, Gargantini L, Bianchi C, Pungolino E, et al. The possible influences of B2A2 and B3A2 BCR/ABL protein structure on thrombopoiesis in chronic myeloid leukaemia. Eur J Cancer 2000;36:1395-401.
• 11 Verschraegen CF, Kantarjian HM, Hirsch-Ginsberg C, Lee MS, O′Brien S, Rios MB, et al. The breakpoint cluster region site in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Clinical, laboratory, and prognostic correlations. Cancer 1995;76:992-7.
• 12 Inokuchi K, Inoue T, Tojo A, Futaki M, Miyake K, Yamada T, et al. A possible correlation between the type of bcr-abl hybrid messenger RNA and platelet count in Philadelphia-positive chronic myelogenous leukemia. Blood 1991;78:3125-7.
• 13 Balatzenko G, Vundinti BR, Margarita G. Correlation between the type of bcr-abl transcripts and blood cell counts in chronic myeloid leukemia-A possible influence of mdr1 gene expression. Hematol Rep 2011;3:e3.
• 14 Goh HG, Hwang JY, Kim SH, Lee YH, Kim YL, Kim DW. Comprehensive analysis of BCR-ABL transcript types in Korean CML patients using a newly developed multiplex RT-PCR. Transl Res 2006;148:249-56.
• 15 Iqbal Z, Manzoor F, Iqbal M, Ali S, Sheikh N, Khan M. Frequency of BCR-ABL Fusion Oncogene Splice Variants Associated with Chronic Myeloid Leukemia (CML). J Cancer Ther 2011;2:176-80.
• 16 de Lemos JA, de Oliveira CM, Scerni AC, Bentes AQ, Beltrão AC, Bentes IR, et al. Differential molecular response of the transcripts B2A2 and B3A2 to imatinib mesylate in chronic myeloid leukemia. Genet Mol Res 2005;4:803-11.
• 17 Rosas-Cabral A, Martínez-Mancilla M, Ayala-Sánchez M, Vela-Ojeda J, Bahena-Reséndiz P, Vadillo-Buenfil M, et al. Analysis of Bcr-abl type transcript and its relationship with platelet count in Mexican patients with chronic myeloid leukemia. Gac Med Mex 2003;139:553-9.
• 18 Udomsakdi-Auewarakul C, U-Pratya Y, Boonmoh S, Vatanavicharn S. Detection of molecular variants of BCR-ABL gene in bone marrow and blood of patients with chronic myeloid leukemia by reverse-transcriptase polymerase chain reaction (RT-PCR). J Med Assoc Thai 2000;83:928-35.
• 19 Martínez-Mancilla M, Gutiérrez M, de la Rosa GZ, García-Carrancá A, Gariglio P, Miranda E. Younger age and shorter chronic phase in b2a2-positive chronic myeloid leukemia adults with high white blood cell count at diagnosis. Haematologica 2002;87:666-8.
• 20 Shepherd P, Suffolk R, Halsey J, Allan N. Analysis of molecular breakpoint and m-RNA transcripts in a prospective randomized trial of interferon in chronic myeloid leukaemia: No correlation with clinical features, cytogenetic response, duration of chronic phase, or survival. Br J Haematol 1995;89:546-54.
• 21 Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-51.
• 22 Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809-20.