The incidence of atypical patterns of BCR-ABL1 rearrangement and molecular-cytogenetic response to tyrosine kinase inhibitor therapy in newly diagnosed cases with chronic myeloid leukemia (CML)

Željka Tkalčić Švabek; Marina Josipović; Ivana Horvat; Renata Zadro; Sanja Davidović-Mrsić

doi:10.5045/br.2018.53.2.152

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Original Article

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Blood Res 2018; 53(2):

Published online June 25, 2018

https://doi.org/10.5045/br.2018.53.2.152

The incidence of atypical patterns of BCR-ABL1 rearrangement and molecular-cytogenetic response to tyrosine kinase inhibitor therapy in newly diagnosed cases with chronic myeloid leukemia (CML)

Željka Tkalčić Švabek^1*, Marina Josipović², Ivana Horvat³, Renata Zadro⁴, and Sanja Davidović-Mrsić¹

Author Info. +

¹Clinical Department of Laboratory Diagnostics, Division for Cytogenetics, University Hospital Centre Zagreb, Zagreb, Croatia.

²Department of Laboratory Diagnostics, General Hospital “Dr. Josip Benčević”, Slavonski Brod, Croatia.

³Clinical Department of Laboratory Diagnostics, Division of Laboratory Hematology and Coagulation, University Hospital Centre Zagreb, Zagreb, Croatia.

⁴Department of Medical Biochemistry and Hematology, University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia.

Correspondence to : Željka Tkalčić Švabek, M.Ed. Clinical Department of Laboratory Diagnostics, Division for Cytogenetics, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia. zeljka.tkalcic@gmail.com

Received: October 5, 2017; Revised: December 23, 2017; Accepted: February 22, 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Background

To analyze the frequency of atypical fluorescence in situ hybridization signal patterns and estimate the complete cytogenetic response (CCyR) and major molecular response (MMR) during 12 months of tyrosine kinase inhibitor therapy in patients with newly diagnosed chronic myeloid leukemia.

Methods

The study included bone marrow and peripheral blood samples from 122 patients with newly diagnosed chronic myeloid leukemia. Detection of the breakpoint cluster region—Abelson fusion gene (BCR-ABL1) was performed using fluorescence in situ hybridization with a dual-color dual-fusion translocation probe, and MMR analysis was performed using the real-time quantitative polymerase chain reaction method.

Results

Variant translocation was determined in 10 samples and a deletion on the derivative chromosome 9 (del/der(9)) was found in 20 samples. The rates of CCyR and MMR were similar between patients with reciprocal translocation, variant translocation, deletion of derivative BCR, or ABL1-BCR fusion gene. The Kaplan-Meier test did not show any significant differences in the rates of CCyR and MMR among those groups of patients.

Conclusion

The frequencies of variant translocation and del/der(9) in the present study agree with the results of other studies performed worldwide. No differences were observed in the rates of CCyR and MMR between patients with atypical patterns and reciprocal translocation.

Keywords Bone marrow, Chromosomes, Myeloid leukemia, Chronic, Tyrosine kinase

Article

Original Article

Blood Res 2018; 53(2): 152-159

Published online June 25, 2018 https://doi.org/10.5045/br.2018.53.2.152

The incidence of atypical patterns of BCR-ABL1 rearrangement and molecular-cytogenetic response to tyrosine kinase inhibitor therapy in newly diagnosed cases with chronic myeloid leukemia (CML)

Željka Tkalčić Švabek^1*, Marina Josipović², Ivana Horvat³, Renata Zadro⁴, and Sanja Davidović-Mrsić¹

¹Clinical Department of Laboratory Diagnostics, Division for Cytogenetics, University Hospital Centre Zagreb, Zagreb, Croatia.

²Department of Laboratory Diagnostics, General Hospital “Dr. Josip Benčević”, Slavonski Brod, Croatia.

³Clinical Department of Laboratory Diagnostics, Division of Laboratory Hematology and Coagulation, University Hospital Centre Zagreb, Zagreb, Croatia.

⁴Department of Medical Biochemistry and Hematology, University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia.

Correspondence to:Željka Tkalčić Švabek, M.Ed. Clinical Department of Laboratory Diagnostics, Division for Cytogenetics, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia. zeljka.tkalcic@gmail.com

Received: October 5, 2017; Revised: December 23, 2017; Accepted: February 22, 2018

Abstract

Background

Methods

Results

Conclusion

Keywords: Bone marrow, Chromosomes, Myeloid leukemia, Chronic, Tyrosine kinase

Abstract

Fig 1.

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Figure 1.The karyotype of case number 10; 46, XX, t(9;9;22) (q34;q34;q11.2).

Blood Research 2018; 53: 152-159https://doi.org/10.5045/br.2018.53.2.152

Fig 2.

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Figure 2.Representative FISH signal patterns using LSI BCR/ABL dual color dual fusion probe. (A) Metaphase cell, negative, 2R2G, (B) interphase nuclei carrying positive reciprocal t (9;22), 2F1R1G, (C) variant t (9;22), 1F2R2G, (D) ABL1 deletion, 1F1R2G, (E) BCR deletion, 1F2R1G, (F) ABL1-BCR deletion, 1F1R1G.

Blood Research 2018; 53: 152-159https://doi.org/10.5045/br.2018.53.2.152

Fig 3.

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Figure 3.Cumulative incidence curves for complete cytogenetic response in the 12-month period.

Blood Research 2018; 53: 152-159https://doi.org/10.5045/br.2018.53.2.152

Fig 4.

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Figure 4.Cumulative incidence curves for major molecular response in the 12-month period.

Blood Research 2018; 53: 152-159https://doi.org/10.5045/br.2018.53.2.152

Fig 5.

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Figure 5.Mechanisms of variant translocations. (A) 1-step mechanism in which chromosome breakage occurs simultaneously on 3 or 4 different chromosomes in 3-way or 4-way translocation and (B) 2-step mechanism involving 2 sequential translocations in which a reciprocal t(9;22) is followed by a second translocation involving additional chromosomes.

Blood Research 2018; 53: 152-159https://doi.org/10.5045/br.2018.53.2.152

Table 1 . Details of ten cases with variant t(9;22)..

Abbreviations: F, fusion; G, green signal; NCD, no cell in division; Ph, Philadelphia chromosome; R, red signal..

Table 2 . Details of twenty cases with t(9;22) and with del/der(9) including <italic>ABL1</italic>, <italic>BCR</italic>, and <italic>ABL1-BCR</italic> deletions..

Abbreviations: 1A, Deletion of ABL1; 2A, Deletion of BCR; 3A, Deletion of ABL1-BCR; F, female; M, male; NCD, No cell in division..

Table 3 . The rates of cytogenetic and molecular response according to cumulative incidence..