Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016)

VV Tikhonova1,2, MA Isakov3, VA Misyurin1, YuP Finashutina1,2, LA Kesaeva1,2, NA Lyzhko 1, IN Soldatova2, NN Kasatkina1, EN Misyurina4, AV Misyurin1,2

1 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 GenoTekhnologiya, 104 Profsoyuznaya str., Moscow, Russian Federation, 117485

3 Aston Consulting, 31g Shabolovka str., Moscow, Russian Federation, 115162

4 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

For correspondence: Vera Vyacheslavovna Tikhonova, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(967)008-02-84; e-mail: brilfor@mail.ru

For citation: Tikhonova VV, Isakov MA, Misyurin VA, et al. Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016). Clinical oncohematology. 2018;11(3):227–33.

DOI: 10.21320/2500-2139-2018-11-3-227-233


Background. Kinase domain mutations of BCR-ABL gene is the most common cause of tyrosine kinase inhibitor resistance.

Aim. To present the data on prognostic value of BCR-ABL mutation burden in Russian patients over the last 10 years.

Materials & Methods. The study included 1885 chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitor resistance who were followed up from 2006 to 2016. BCR-ABL point mutations in mRNA samples were analyzed by means of polymerase chain reaction and subsequent Sanger sequencing.

Results. In 1257 CML patients with signs of tyrosine kinase inhibitor resistance BCR-ABL expression level was > 1 %. BCRABL mutations were detected in 31.8 % of patients. Total mutation count was 467 (70 mutation types). Total count of patients with mutation-associated tyrosine kinase inhibitor resistance decreased from 36.6 % (2006–2008) to 24.95 % (2013–2016) and to marked decrease of 23.12 % in 2014. Detection rate of imatinib-resistant mutations and F359V mutation was shown to decrease within the period from 2010–2011 to 2014–2015. F317L level, which is responsible for dasatinib resistance, considerably increased in 2015. T315I frequency was the highest in 2014, afterwards it was gradually decreasing. Mutation-associated resistance rates varied by region of the Russian Federation.

Conclusion. The analysis of trends of mutation incidence in patients with CML can be of extreme significance in long-term prognosis of resistance development and in improvement of treatment planning.

Keywords: chronic myeloid leukemia, kinase domain mutations of BCR-ABL gene, targeted therapy, resistance.

Received: January 22, 2018

Accepted: April 16, 2018

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PD-1 Blockade with Nivolumab as a New Immunotherapy for Classical Hodgkin’s Lymphoma

EA Demina

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Prof. Elena Andreevna Demina, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: drdemina@yandex.ru

For citation: Demina EA. PD-1 Blockade with Nivolumab as a New Immunotherapy for Classical Hodgkin’s Lymphoma. Clinical oncohematology. 2018;11(3):213–19.

DOI: 10.21320/2500-2139-2018-11-3-213-219


During the last two decades individualization of programmed treatment combined with intensified chemotherapy has proven to be effective treatment for the majority of classical Hodgkin’s lymphoma (cHL) patients. However, in 10–30 % of cases relapses and resistance to therapy still occur. Further intensification of therapy induces toxicity that leads to decrease in overall survival and quality of life. The standard second-line treatment with high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (auto-HSCT) allows for the achievement of long-term 5-year progression-free survival only in 50–60 % of patients with relapsed disease and not more than 40–45 % of patients with refractory disease. Approximately 50 % of patients relapse after HDCT and auto-HSCT. The median overall survival of relapsed patients does not exceed 2 years. Allogeneic HSCT improves treatment results to some extent, but is not an optimal strategy in all patients. A search for new treatment options has been made to improve effectiveness of relapsed and refractory cHL treatment and to reduce toxicity of highly effective programs. А new CD30-targeted conjugate brentuximab vedotin was developed to use anti-CD30 monoclonal antibodies against a specific marker of tumor Reed-Sternberg cells allowing for the transfer of the highly effective antitumor compound of monomethyl auristatin E directly to tumor cells. This drug showed high effectiveness, although failed to provide a complete solution to the problem. The development of anti-PD1 antibody nivolumab opened up new opportunities for cHL treatment. This paper reviews literature information on pharmacological data and antitumor mechanisms of the drug as well as the results of significant international randomised studies.

Keywords: nivolumab, Hodgkin’s lymphoma, relapse, resistance, treatment.

Received: February 5, 2018

Accepted: April 30, 2018

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