Retrospective analysis of own long-term experience in studying the BCR::ABL kinase domain mutational status in patients with chronic myeloid leukemia

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Abstract

Background. Most patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors achieve durable optimal responses. Loss of the achieved molecular response is observed in 15–30 % of patients. Mutations in the BCR::ABL kinase domain are one of the most common mechanisms for the development of resistance to tyrosine kinase inhibitors.

Aim. To conduct a retrospective analysis of the BCR::ABL kinase domain mutational profile in patients with CML observed at the Russian Research Institute of Hematology and Transfusiology from 2012 to 2023. To assess the impact of mutations type and number on the rate of achieving a major molecular response (MMR). To study the risk of MMR loss depending on the therapy line and existing mutational status.

Materials and methods. 1831 patients with CML were examined at different times. The mutational status of the BCR::ABL kinase domain was analyzed by direct Sanger sequencing. A standard cytogenetic study was carried out using GTG banding technology with the analysis of at least 20 metaphase plates.

Results. Mutations in the BCR::ABL kinase domain were identified in 27.6 % of the total studied patients. The most common mutation, 6.3 % in the overall group or 22.7 % among patients with mutations, was the T315I mutation. Additional chromosomal aberrations (ACAs) were detected in Ph-positive cells in 20.5 % of patients, in Ph-negative clones in 3.9 % of cases (p = 0.0001). The frequency of ACAs detection did not statistically significantly differ (p = 0.25) between patients with BCR::ABL mutations (23.5 %) and with a negative mutation status (17.7 %), and the presence of mutations in the kinase domain did not correlate with ACAs in Ph-positive clones (p = 0.73). However, the frequency of T315I mutation detection in Ph-positive cells had significant differences: 40.9 % in combination with ACAs and 21 % without ACAs (p = 0.032). Patients with the T315I mutation had significantly worse MMR than patients with mutations in other BCR::ABL regions (p = 0.04) and patients without mutations (p = 0.02). The probability of MMR achieving did not differ significantly between patients with different numbers of BCR::ABL mutations (p = 0.14). Loss of MMR occurred more often in patients with mutations (p = 0.04) and not depend on the line of therapy (p = 0.03).

Conclusion. For complete monitoring and optimal choice of therapy, CML patients require not only monitoring of BCR::ABL relative expression level, but also standard cytogenetic and analysis of the mutational status.

About the authors

D. V. Kustova

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

ORCID iD: 0000-0003-4546-5808

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

E. V. Motyko

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

ORCID iD: 0000-0002-6052-6472

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

A. N. Kirienko

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

ORCID iD: 0000-0002-2519-306X

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

T. N. Gert

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

ORCID iD: 0000-0002-2793-452X

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

I. V. Leppyanen

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

ORCID iD: 0000-0002-2158-0855

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

M. P. Bakay

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

ORCID iD: 0000-0001-7780-1736

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

E. V. Efremova

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

E. V. Morozova

I.P. Pavlov First Saint Petersburg State Medical University, Ministry of Health of Russia

ORCID iD: 0000-0003-0752-0757

6–8 L’va Tolstogo St., Saint Petersburg 197022,

Russian Federation

E. G. Lomaia

V.A. Almazov National Medical Research Centre, Ministry of Health of Russia

ORCID iD: 0000-0003-3290-7961

2 Akkuratova St., Saint Petersburg 197341

Russian Federation

V. A. Shuvaev

A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center, Ministry of Health of Russia;
Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia

ORCID iD: 0000-0003-3536-0770

4 Koroleva St., Obninsk 249031,

Build. 1, 2 / 1 Barrikadnaya St., Moscow 125993

Russian Federation

S. V. Sidorkevich

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

ORCID iD: 0000-0001-9931-9406

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

I. S. Martynkevich

Russian Research Institute of Hematology and Transfusiology, Federal Medical and Biological Agency

Author for correspondence.
Email: mis2907@mail.ru
ORCID iD: 0000-0001-5958-0490

Irina S. Martynkevich

16 2nd Sovetskaya St., Saint Petersburg 191024

Russian Federation

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