Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Practical Recommendations)

EYu Chelysheva1, AG Turkina1, ES Polushkina2, MA Vinogradova2, RG Shmakov2

1 National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 VI Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 4 Akademika Oparina str., Moscow, Russian Federation, 117997

For correspondence: Ekaterina Yur’evna Chelysheva, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-48-60; e-mail: denve@bk.ru

For citation: Chelysheva EYu, Turkina AG, Polushkina ES, et al. Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Clinical Experience). Clinical oncohematology. 2019;12(2):202–10.

DOI: 10.21320/2500-2139-2019-12-2-202-210


ABSTRACT

Background. The tyrosine kinase inhibitors (TKI) era is marked by a long-term favorable prognosis of chronic myeloid leukemia (CML). In this context CML patients of reproductive age are faced with major issues of family planning with due regard to the risk of TKI treatment interruption during pregnancy. Additionally, TKI impact is another potential risk to the fetus.

Aim. To develop differentiated approach to CML treatment during pregnancy.

Materials & Methods. Analysis includes literature data and clinical experience based on 166 pregnancies of 120 CML patients from CML Pregnancy Registry.

Results. Pregnancy planning is recommended after achieving stable and deep molecular response (with BCR-ABL > 0.01 %, IS) within the period of at least 2 years. At conception TKI therapy does not have to be interrupted. However, early pregnancy detection and TKI treatment interruption after pregnancy confirmation are of vital importance due to teratogenic risks. Furthermore, no TKI may be administered during organogenetic period, i.e. up to the 15th week of gestation. In the absence or loss of complete hematologic response and growth of BCR-ABL > 1 % after the 15th week of gestation imatinib or nilotinib administration is justified in the interest of pregnant patients taking into account limited transfer of these drugs through placenta. In the absence of complete hematologic response before the 15th week of gestation interferon-α can be administered. With BCR-ABL < 1 % patients can be either followed-up without therapy or they can receive interferon-α throughout pregnancy. Dasatinib, bosutinib, and other TKI are contraindicated at any stage of pregnancy. There are no special recommendations for childbirth, delivery is to be adapted to obstetric conditions. Breast feeding is not recommended because of the lack of practical evidence for its safety.

Conclusion. A regular molecular monitoring of BCR-ABL and hematologic status is indispensable, health condition of fetus should be continuously monitored as well. CML patient management should be conducted by cooperating hematologists and gynecologists.

Keywords: chronic myeloid leukemia, pregnancy, tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib, bosutinib.

Received: January 9, 2019

Accepted: March 20, 2019

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Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ)

OA Shukhov, AG Turkina, EYu Chelysheva, AV Bykova, AN Petrova, GA Gusarova, IS Nemchenko, AO Abdullaev, TN Obukhova, AB Sudarikov

National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Oleg Aleksandrovich Shukhov, MD, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: shuhov@list.ru

For citation: Shukhov OA, Turkina AG, Chelysheva EYu, et al. Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ). Clinical oncohematology 2019;12(2):194–201.

DOI: 10.21320/2500-2139-2019-12-2-194-201


ABSTRACT

Background. Current clinical guidelines on diagnosis and treatment of chronic myeloid leukemia (CML) define indications for substitution of first-line tyrosine kinase inhibitor (TKI) at therapy failure during different phases of disease progression.

Aim. To assess the efficacy of CML treatment with implementing the protocol of timely monitoring and switching to another TKI.

Materials & Methods. Patients were included into pilot prospective study РИТМ during 5 years. Data on 100 CML patients were analyzed. Therapy and monitoring were conducted according to the Federal clinical guidelines on CML diagnosis and therapy, 2013.

Results. Median follow-up after initiation of treatment was 46 months (range 12–74). Imatinib mesylate was administered as first-line therapy to 91 (91 %) patients, 9 (9 %) patients received 2nd generation TKI (TKI2). Therapy failure was registered in 31 (31 %) patients; 26 (84 %) of them were switched to TKI2. At the time of analysis 95 (95 %) patients were followed-up. Cumulative incidence of CML-associated mortality was 2 %. By the fifth year of follow-up cumulative probability of complete cytogenetic, major and deep molecular responses was 93 %, 88 % and 66 %, respectively.

Conclusion. CML treatment according to current guidelines yields the results comparable with those achieved by first-line TKI2 therapy. This approach reduces CML treatment costs and lowers the risk of TKI2-associated adverse events. Due to a high rate of deep molecular response the proportion of CML patients in remission without treatment can be increased in the future.

Keywords: chronic myeloid leukemia, monitoring, tyrosine kinase inhibitors, TKI switch.

Received: October 21, 2018

Accepted: February 4, 2019

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Cardiovascular Toxicity of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia

IL Davydkin1,2, KV Naumova1, AM Osadchuk1, IA Zolotovskaya1, OE Danilova1, TYu Stepanova1, OV Tereshina1, LV Limareva3, AS Shpigel’1, TP Kuz’mina1

1 Samara State Medical University, 89 Chapaevskaya str., Samara, Russian Federation, 443099

2 SamGMU Research Institute of Hematology, Transfusiology and Intensive Care, 89 Chapaevskaya str., Samara, Russian Federation, 443099

3 SamGMU Institute of Experimental Medicine and Biotechnology, 89 Chapaevskaya str., Samara, Russian Federation, 443099

For correspondence: Kseniya Viktorovna Naumova, 89 Chapaevskaya str., Samara, Russian Federation, 443099; Tel.: +7(905)303-12-08; e-mail: senechka.naumova@rambler.ru

For citation: Davydkin IL, Naumova KV, Osadchuk AM, et al. Cardiovascular Toxicity of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia. Clinical oncohematology. 2018;11(4):378–87.

DOI: 10.21320/2500-2139-2018-11-4-378-387


ABSTRACT

In the present review the cardiovascular complications in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKI) are discussed. It covers current views on pathogenesis of TKI cardiovascular toxicity. The pathophysiology of cardiovascular diseases (CVD) is considered as a part of the so-called pathophysiological continuum, i.e. a complex of processes developing at the molecular and cellular levels before clinical symptoms of the above diseases occur. Cardiovascular toxicity of certain TKIs can contribute to progression of pathophysiological processes in CML patients. The study of mechanisms underlying cardiovascular complications of TKI-based therapy is essential for evaluating the risks of their development in each patient. Identification of CVD predictors during TKI-based therapy can allow to elaborate a scheme for cardiovascular monitoring and safe patient management under consideration of individual risks and to avoid severe life-threatening complications.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, adverse effects, cardiotoxicity, cardiovascular events.

Received: May 14, 2018

Accepted: August 29, 2018

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Expression of the BCR-ABL1 Gene in Patients with Chronic Myeloproliferative Diseases with Signs of Progression

LA Kesaeva1, EN Misyurina2, DS Mar’in2, EI Zhelnova2, AYu Bulanov2, AE Misyurina3, AA Krutov4, IN Soldatova4, SS Zborovskii4, VA Misyurin1,4, VV Tikhonova1, YuP Finashutina1, ON Solopova1, NA Lyzhko1, AE Bespalova1, NN Kasatkina1, AV Ponomarev1, MA Lysenko2, AV Misyurin1,4

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

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

3 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

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

For correspondence: Andrei Vital’evich Misyurin, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)612-80-38; e-mail: and@genetechnology.ru

For citation: Kesaeva LA, Misyurina EN, Mar’in DS, et al. Expression of the BCR-ABL1 Gene in Patients with Chronic Myeloproliferative Diseases with Signs of Progression. Clinical oncohematology. 2018;11(4):354–9.

DOI: 10.21320/2500-2139-2018-11-4-354-359


ABSTRACT

Background. The V617F mutation of JAK2 is known to manifest in Ph-negative chronic myeloproliferative diseases (cMPD), such as polycythemia vera, thrombocythemia, and myelofibrosis. These diseases not infrequently advance into more aggressive forms up to acute leukemia. As the progression mechanism is still unknown, its study retains a high priority. JAK2 carrying the V617F mutation is believed to cause constant activation of V(D)J recombinase in myeloid tumor cells in cMPD patients. Aberrant activation of V(D)J recombinase in tumor cells in cMPD patients can lead to t(9;22)(q34;q11) chromosomal rearrangement.

Aim. To study the expression of BCR-ABL1 resulting from translocation t(9;22)(q34;q11) in cMPD patients at the progression stage in order to test the suggested hypothesis.

Materials & Methods. The BCRABL1 expression was assessed in peripheral blood granulocytes in cMPD patients by real-time PCR. The JAK2 V617F mutation was identified by quantitative allele-specific PCR. The JAK2 exon 12 mutations were determined using Sanger direct sequencing of PCR products.

Results. The BCR-ABL1 expression was discovered in 29 % of patients with cMPD progression. The BCR-ABL1 expression in these patients correlated with hepatosplenomegaly and hyperleukocytosis.

Conclusion. In a significant proportion of cMPD patients the disease progression can be associated with activation of the BCR-ABL expression.

Keywords: JAK2 V617F, BCR-ABL1, V(D)J recombinase, t(9;22)(q34;q11), polycythemia vera, essential thrombocythemia, myelofibrosis, chronic myeloid leukemia.

Received: April 2, 2018

Accepted: August 5, 2018

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Epidemiology of Chronic Myeloid Leukemia in the Republic of Bashkortostan

NR Ryabchikova, GSh Safuanova, VI Nikulicheva

Bashkir State Medical University, 3 Lenina str., Ufa, Russian Federation, 450008

For correspondence: Prof. Guzyal’ Shagbanovna Safuanova, MD, PhD, 3 Lenina str., Ufa, Russian Federation, 450008; Tel.: +7(927)639-03-73; e-mail: safuanova@bk.ru

For citation: Ryabchikova NR, Safuanova GSh, Nikulicheva VI. Epidemiology of Chronic Myeloid Leukemia in the Republic of Bashkortostan. Clinical oncohematology. 2018;11(4):349–53.

DOI: 10.21320/2500-2139-2018-11-4-349-353


ABSTRACT

Background. The planning of therapeutic, diagnostic, and preventive medical care for chronic myeloid leukemia (CML) patients implies the need of not only maintaining patient registries, but also conducting epidemiologic studies in each geographical area.

Aim. To study and analyze CML epidemiological indicators over the last 15 years in the Republic of Bashkortostan for the purposes of evaluation and rational planning of specialized medical care for CML patient population.

Materials & Methods. The incidence, prevalence, and mortality of CML patients of all age groups in the period of 2000–2016 was analyzed in the Republic of Bashkortostan.

Results. The analysis of epidemiological indicators over the period of 2000–2016 showed that the incidence of the disease in the Republic of Bashkortostan was increasing. Within the last 8 years the prevalence rate even quadrupled which is clearly connected with improved detectability of Ph-chromosome and/or BCR-ABL gene, creation and maintenance of CML patient registry since 2008, introduction of treatment using tyrosine kinase inhibitors resulting also in increase in life expectancy. Mortality rates are reported to have a tendency of decrease over the period under study.

Conclusion. Key epidemiological indicators of CML in the Republic of Bashkortostan are comparable with the data of international and Russian researchers. The results obtained can be used for comparative studies and improvement of specialized medical care for CML patients.

Keywords: chronic myeloid leukemia, epidemiology, incidence, prevalence, mortality.

Received: April 9, 2018

Accepted: August 3, 2018

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REFERENCES

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Clinical Experience and Perspectives of Bosutinib Use in Patients with Chronic Myeloid Leukemia

VA Shuvaev1, OYu Vinogradova2,3,4, IS Martynkevich1, NV Novitskaya2, MS Fominykh1, SN Tsareva2, DI Shikhbabaeva2, MM Pankrashkina2,3, MV Chernikov2, NN Sharkunov2, II Zotova1, VYu Udal’eva1, EV Motyko1, SV Voloshin1,5,6

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

3 Dmitrii Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117198

4 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

5 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

6 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

For correspondence: Ol’ga Yur’evna Vinogradova, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(495)945-97-61; e-mail: olgavinz@mail.ru.

For citation: Shuvaev VA, Vinogradova OYu, Martynkevich IS, et al. Clinical Experience and Perspectives of Bosutinib Use in Patients with Chronic Myeloid Leukemia. Clinical oncohematology. 2018;11(4):288–94.

DOI: 10.21320/2500-2139-2018-11-4-288-294


ABSTRACT

Aim. To evaluate the clinical experience of bosutinib use for treatment of chronic myeloid leukemia (CML) patients with intolerance and resistance to other tyrosine kinase inhibitors (TKI), as well as to compare the obtained results with the data of clinical trials.

Materials & Methods. The analysis was conducted on case history records of 51 CML patients (25 men and 26 women; median age was 56 years, range 28–86). By the beginning of bosutinib therapy 37 chronic phase, 8 acceleration phase, and 6 blast crisis patients were included in the study. Bosutinib was administered as secondline TKI treatment in 10 patients, as thirdline treatment in 18 patients, and as fourthline treatment in 23 patients. The causes for switching to bosutinib were poor tolerance of previous TKI therapy in 21 patients and resistance to previous TKI therapy in 30 patients.

Results. The median duration of bosutinib treatment was 6 months (range 1–50). Bosutinib toxicity profile and its tolerance in common clinical practice corresponded to the data of clinical trials. Because of adverse events the therapy was discontinued only in 5 (10 %) patients. Complete hematological response was 88 % (persistent response was maintained in 76 % of patients); complete cytogenetic response (CCyR) was 39 %, (persistent response in 37 % of cases); major molecular response (MMR) was 31 % (it was confirmed in 25 % of patients during the last follow-up visit). The efficacy of bosutinib in the real clinical setting was slightly higher compared to the results of clinical trials. This difference was associated with a disease phase, a reason for withdrawal of the previous TKI, line of treatment, BCRABL mutations, and the form of them. The therapy was continued in 22 (43 %) patients, most of them reached stable optimal response, both CCyR and MMR.

Conclusion. Bosutinib appears to be an acceptable alternative to other TKIs having its specific mechanisms of action and adverse events. The efficacy and safety of bosutinib proved in routine clinical practice are sufficient to recommend it for use in national hematology.

Keywords: chronic myeloid leukemia, bosutinib, target therapy, tyrosine kinase inhibitors, clinical practice.

Received: May 9, 2018

Accepted: August 10, 2018

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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


ABSTRACT

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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REFERENCES

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Chronic Myeloid Leukemia Patient Registry in the Russian Federation: From Observational Studies to the Efficacy Evaluation in Clinical Practice

AG Turkina1, NV Novitskaya2, AK Golenkov3, VA Shuvaev4, LI Napso5, IV Krylova6, AM Savrilova7, GSh Safuanova8, AV Korobkin9, TYu Klitochenko10, EV Burnasheva11, EV Vasil’ev12, OM Senderova13, EYu Fedorova14, LM Yalunina15, EK Nekhai16, GB Kuchma17, AS Lyamkina18, NG Shchedrova19

1 Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

3 NF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina str., Moscow, Russian Federation, 129110

4 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

5 Clinical Oncology Dispensary No. 1, 146 Dimitrova str., Krasnodar, Russian Federation, 350040

6 Sverdlovsk Regional Clinical Hospital No. 1, 185 Volgogradskaya str., Ekaterinburg, Russian Federation, 620102

7 Republican Clinical Hospital, 138 Orenburgskii trakt, Kazan’, Russian Federation, 420064

8 GG Kuvatov Republican Clinical Hospital, 132 Dostoevskogo str., Ufa, Russian Federation, 450005

9 Chelyabinsk Regional Clinical Hospital, 70 Vorovskogo str., Chelyabinsk, Russian Federation, 454076

10 Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

11 Rostov State Medical University, 29 Nakhichevanskii per., Rostov-na-Donu, Russian Federation, 344022

12 Regional Clinical Hospital, 3A Partizana Zheleznyaka str., Krasnoyarsk, Russian Federation, 660022

13 Irkutsk Order of the Badge of Honor District Clinical Hospital, 100 Yubileinyi microdistrict, Irkutsk, Russian Federation, 664049

14 VD Seredavin Samara Regional Clinical Hospital, 159 Tashkentskaya str., Samara, Russian Federation, 443095

15 SV Belyaev Kemerovo Regional Clinical Hospital, 22 Oktyabr’skii pr-t, Kemerovo, Russian Federation, 650066

16 Regional Clinical Hospital No. 2, 55 Russkaya str., Vladivostok, Russian Federation, 690105

17 Orenburg Regional Clinical Hospital No. 1, 5/3 Tsvillinga str., Orenburg, Russian Federation, 460006

18 Novosibirsk State Medical University, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091

19 Novartis Pharma, 72 bld. 3, Leningradskii pr-t, Moscow, Russian Federation, 125315

For correspondence: Anna Grigor’evna Turkina, DSci, Professor, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: turkianna@yandex.ru

For citation: Turkina AG, Novitskaya NV, Golenkov AK, et al. Chronic Myeloid Leukemia Patient Registry in the Russian Federation: From Observational Studies to the Efficacy Evaluation in Clinical Practice. Clinical oncohematology. 2017;10(3):390–401 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-390-401


ABSTRACT

Background. Due to the significant increase in life expectancy and the quality of life in patients with chronic myeloid leukemia (CML) as well as the growing need for expensive tyrosine kinase inhibitors (TKI), the analysis of cost-effectiveness and lifelong monitoring of patients is especially important.

Aim. We present the results of a multicenter observational study “The Russian Registry of Chronic Myeloid Leukemia in routine clinical practice (2011–2016)”.

Materials & Methods. The study included Russian patients with CML, confirmed by the detection of a Ph-chromosome or a BCR-ABL transcript. The statistical analysis (July 1, 2016) included 7609 patients from 80 regions of the Russian Federation (covering 95 % of the population). The annual increase in the number of patients with newly diagnosed CML was 600–650 patients. At the time of the statistical analysis, 6995 (92 %) patients remained under observation, 473 (6 %) died and 141 (2 %) were withdrawn. The registry included 44 % of men and 56 % of women, the median age was 49 years (range 2–94 years). The peak incidence (46.3 %) occurred at the age of 40–60 years. The median disease duration by the time of the analysis was 6 years (range 0.1–30 years).

Results. The disease was diagnosed in the chronic phase (CP), acceleration phase, and blast crisis in 6560 (93.8 %), 380 (5.5 %) and 47 (0.7 %) patients, respectively. The proportion of risk groups according to Sokal for low, intermediate and high risk in CP was 49 %, 30 %, and 21 %, respectively. TKI were administered to 6473 (92.5 %) patients. Imatinib and the second generation TKI (TKI2) were administered to 5570 (86 %) and 903 (14 %) patients, respectively. The total of 30.4 % of patients received the increased imatinib dose of 600–800 mg. In the TKI2 group, 558 (61.7 %) patients received nilotinib and 345 (38.2 %) patients received dasatinib. The proportion of patients with completed molecular genetic studies (MGS) in 2014, 2015 and the first 6 months of 2016 amounted to 61 %, 58 % and 23 %, respectively. The proportion of patients with cytogenetic studies (CS) for the same period was 28 %, 26 % and 7 %, respectively. No CS or MGS data were presented for 34 %, 35 % and 63 % of patients during this period. Optimal molecular response and major molecular response (MMR) for TKI therapy were observed in 23 % and 58 % of patients treated < 12 months and > 12 months, respectively. When nilotinib was used in the second line, MMR was obtained in 42 % of patients, and a deep molecular response was obtained in 25 % of patients (BCR-ABL < 0.01 %).

Conclusion. The high efficacy of TKI therapy was observed in the majority of patients with the possibility of achieving a minimal residual disease. The problems concerning untimely monitoring and suboptimal administration of second line treatment were identified. In general, the CML patient registry allowed the data integration of data and information management of population with CML in Russia.

Keywords: chronic myeloid leukemia, registry, tyrosine kinase inhibitors, imatinib, nilotinib, quality of medical care.

Received: January 17, 2017

Accepted: April 27, 2017

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Clinical Recommendations for the Diagnosis and Treatment of Chronic Myeloid Leukemia

GROUP OF AUTHORS UNDER THE SUPERVISION OF ACADEMICIAN VG SAVCHENKO

AG Turkina1, AYu Zaritskii2, VA Shuvaev3, EYu Chelysheva1, EG Lomaia2, EV Morozova4, AK Golenkov5, TI Pospelova6, OA Shukhov1, MS Fominykh3, GA Gusarova1, LA Kuz’mina1, AO Abdullaev1, IS Martynkevich3

1 Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

3 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

4 RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

5 NF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina str., Moscow, Russian Federation, 129110

6 Novosibirsk State Medical University, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091

For correspondence: Anna Grigor’evna Turkina, DSci, Professor, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: turkianna@yandex.ru

For citation: Turkina AG, Zaritskii AYu, Shuvaev VA, et al. Clinical Recommendations for the Diagnosis and Treatment of Chronic Myeloid Leukemia. Clinical oncohematology. 2017;10(3):294–316 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-294-316


ABSTRACT

This article is the 4th edition of the recommendations for the diagnosis and treatment of chronic myeloid leukemia. The group of authors reviewed and discussed relevant new publications, and included the significant remarks and comments of experts. Particular attention was paid to the control of risk factors for the development of arterial vascular events and their prevention, and adverse effects of the long-term therapy with tyrosine kinase inhibitors, which were being increasingly reported in recent years.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, molecular response, vascular complications, therapy algorithm.

Received: November 15, 2016

Accepted: February 19, 2017

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Dasatinib in First- and Second-Line Therapy of Chronic Myeloid Leukemia: Efficacy, Safety and Quality of Life

TI Ionova1,2, NB Bulieva3, OYu Vinogradova4,5,6, TA Gritsenko7, LK Kozlova8, GB Kuchma8, EG Lomaia9, ER Machyulaitene10, TP Nikitina1,2, NV Novitskaya4, AYu Rodionova2, EI Usacheva11, TV Shneider12

1 Saint Petersburg Multifield Medical Center under the Ministry of Health of Russia, 154 Nabereznaya Reki Fontanki, Saint Petersburg, Russian Federation, 198103

2 Multinational Center for Quality of Life Research, 1 Artilleriiskaya str., office 152, Saint Petersburg, Russian Federation, 191014

3 I Kant Baltic Federal University, 14 A Nevskogo str., Kaliningrad, Russian Federation, 236041

4 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-zd, Moscow, Russian Federation, 125284

5 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology under the Ministry of Health of the Russian Federation, 1 Samory Mashela str., Moscow, Russian Federation, 117198

6 NI Pirogov Russian National Research Medical University under the Ministry of Health of the Russian Federation, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

7 Samara State Medical University under the Ministry of Health of the Russian Federation, 89 Chapaevskaya str., Samara, Russian Federation, 443099

8 Orenburg State Medical University, 6 Sovetskaya str., Orenburg, Russian Federation, 460000

9 Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

10 Outpatient Department, Academician IP Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

11 RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

12 Leningrad District Clinical Hospital, 43/49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Tat’yana Ivanovna Ionova, DSci, 1 office 152 Artilleriiskaya str., Saint Petersburg, Russian Federation, 191014; Tel: +7(812)579-61-38; e-mail: qlife@rambler.ru

For citation: Ionova TI, Bulieva NB, Vinogradova OYu, et al. Dasatinib in First- and Second-Line Therapy of Chronic Myeloid Leukemia: Efficacy, Safety and Quality of Life. Clinical oncohematology. 2017;10(2):206–17 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-206-217


ABSTRACT

Background & Aims. The article presents results of two observational, prospective, multicenter studies “Quality of Life, Symptom Profile, and Adherence to Treatment in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Receiving Dasatinib” (2012–2015) and “Quality of Life and Symptom Profile in Imatinib-Resistant or Intolerant Patients with Chronic Myeloid Leukemia” (2011–2014).

Methods. Data of 107 patients with chronic myeloid leukemia in chronic phase were involved in the real-world analysis — 32 newly diagnosed patients on first-line treatment with dasatinib or after yearly switch to dasatinib after imatinib treatment failure and 75 imatinib-resistant or intolerant patients on second-line treatment with dasatinib. Treatment effectiveness and safety of dasatinib were assessed during first and second-line dasatinib treatment using clinical outcomes as well as quality of life and symptom profile assessment.

Results. The real-world data obtained during observational study in limited population of CML patients conform the results of clinical trials devoted to evaluation of treatment efficacy and safety of dasatinib treatment in first and second-line treatment and demonstrate the importance of patient-reported outcomes. Patient’s quality of life improved within 12 months of the first-line dasatinib therapy according to the following scales: role physical functioning, pain, vitality, social functioning and role emotional functioning. The most pronounced and clinically significant improvement was observed for the role emotional functioning (51.1 vs. 68.9). During the second-line dasatinib treatment, stabilization of quality of life parameters was registered for the following scales: vitality, social functioning, mental health, and pain. Significant improvement of the Integral Quality of Life Index was observed (p < 0.05). Positive dynamics of relevant symptoms was registered. The symptom severity decreased during both the first and second-line therapy.

Conclusion. Quality of life and symptom assessment in CML patients contribute to a better disease control in accordance with the principles of risk-adaptive therapy.

Keywords: quality of life, chronic myeloid leukemia, dasatinib, therapy effectiveness, therapy safety, routine clinical practice.

Received: November 10, 2016

Accepted: February 10, 2017

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