essential thrombocythemia

Current Quality-of-Life Aspects in Patients with Classical Ph-Negative Myeloproliferative Neoplasms in the Russian Federation: Results and Discussion of the National Observational Program MPN-QoL-2020

AUTOIMMUNE THROMBOCYTOPENIA , , ,

TI Ionova1,2,3,*, EA Andreevskaya4,*, EN Babich5,*, NB Bulieva6,7,*, OYu Vinogradova8,9,10,*, EM Volodicheva11,*, SV Voloshin12,13,14,*, NN Glonina15,*, SK Dubov16,*, NB Esef’eva17,*, AYu Zaritskey18,*, EE Zinina19,*, MO Ivanova20,*, TYu Klitochenko21,*, AV Kopylova22,*, AD Kulagin23,*, GB Kuchma24,25,*, OYu Li26,*, EG Lomaia18,*, AL Melikyan27,*, VYa Melnichenko3,*, SN Menshakova28,*, NV Minaeva29,*, TA Mitina30,*, EV Morozova23,*,TP Nikitina1,2,*, OE Ochirova31,*, AS Polyakov13,*, TI Pospelova32,*, AV Proidakov33,*, OA Rukavitsyn34,*, GSh Safuanova35,36,*, IN Subortseva27,*, MS Fominykh37,*, MV Frolova38,*, TV Shelekhova39,*, DG Sherstnev39,*, TV Shneider40,*, VA Shuvaev12,41,*, ZK Abdulkhalikova23,†, LV Anchukova38,†, IA Apanaskevich15,†, AN Arnautova22,†, MV Barabanshchikova23,†, NV Berlina34,†, AP Bityukov34,†, EA Gilyazitdinova27,†, VI Gilmanshina36,†, EK Egorova27,†, EV Efremova12,†, EB Zhalsanova31,†, EN Kabanova19,†, OB Kalashnikova20,†, AE Kersilova41,†, TI Kolosheinova27,†, PM Kondratovskii16,†, EV Koroleva28,†, AN Kotelnikova34,†, NA Lazareva16,†, NS Lazorko18,†, EV Lyyurova33,†, AS Lyamkina32,†, YuN Maslova20,†, ES Mileeva12,†, NE Mochkin3,†, EK Nekhai16,†, YaA Noskov13,†, ES Osipova29,†, MM Pankrashkina8,†, EV Potanina16,†, OD Rudenko25,†, TYu Rozhenkova36,†, EI Sbityakova18,†, NT Siordiya18,†, AV Talko16,†, EI Usacheva42,†, YuB Chernykh30,†, TV Chitanava18,†, KS Shashkina27,†, DI Shikhbabaeva8,†, KS Yurovskaya23,†

1 Saint Petersburg State University Hospital, 154 Fontanki nab., Saint Petersburg, Russian Federation, 198103

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

3 NI Pirogov National Medical and Surgical Center, 70 Nizhnyaya Pervomaiskaya ul., Moscow, Russian Federation, 105203

4 Krai Clinical Hospital No. 1, 7 Kokhanskogo ul., Chita, Russian Federation, 672038

5 Yugry District Clinical Hospital, 40 Kalinina ul., Khanty-Mansiisk, Russian Federation, 628011

6 I Kant Baltic Federal University, 14 Aleksandra Nevskogo ul., Kaliningrad, Russian Federation, 236041

7 Clinical Hospital of Kaliningrad Region, 74 Klinicheskaya ul., Kaliningrad, Russian Federation, 236016

8 Moscow Municipal Center for Hematology, SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

9 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova ul., Moscow, Russian Federation, 117997

10 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela ul., Moscow, Russian Federation, 117997

11 Tula Regional Clinical Hospital, 1A korp. 1 Yablochkova ul., Tula, Russian Federation, 300053

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

13 SM Kirov Military Medical Academy, 6 Akademika Lebedeva ul., Saint Petersburg, Russian Federation, 194044

14 II Mechnikov North-Western State Medical University, 47 Piskarevskii pr-t, Saint Petersburg, Russian Federation, 195067

15 SI Sergeev Krai Clinical Hospital No. 1, 9 Krasnodarskaya ul., Khabarovsk, Russian Federation, 680009

16 Krai Center of Hematology, Krai Clinical Hospital No. 2, 55 Russkaya ul., Vladivostok, Russian Federation, 690105

17 Ulyanovsk Regional Clinical Hospital, 7 III Internatsionala ul., Ulyanovsk, Russian Federation, 432017

18 VA Almazov National Medical Research Center, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341

19 Surgut District Clinical Hospital, 14 Energetikov ul., Surgut, Russian Federation, 628408

20 Clinical and Diagnostic Center, IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022

21 Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki ul., Volgograd, Russian Federation, 400138

22 Lipetsk Municipal Hospital No. 3 “Svobodnyi sokol”, 10 Ushinskogo ul., Lipetsk, Russian Federation, 398007

23 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Rentgena ul., Saint Petersburg, Russian Federation, 197022

24 Orenburg State Medical University, 6 Sovetskaya ul., Orenburg, Russian Federation, 460000

25 Orenburg Regional Clinical Hospital, 23 Aksakova ul., Orenburg, Russian Federation, 460018

26 Sakhalin Regional Clinical Hospital, 430 Mira pr-t, Yuzhno-Sakhalinsk, Russian Federation, 693004

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

28 Regional Clinical Hospital, 105 Peterburgskoe sh., Tver, Russian Federation, 170036

29 Kirov Research Institute of Hematology and Transfusiology, 72 Krasnoarmeiskaya ul., Kirov, Russian Federation, 610027

30 MF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina ul., Moscow, Russian Federation, 129110

31 NA Semashko Republican Clinical Hospital, 12 Pavlova ul., Ulan-Ude, Russian Federation, 670031

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

33 Komi Republican Oncology Dispensary, 46 Nyuvchimskoe sh., Syktyvkar, Republic of Komi, Russian Federation, 167904

34 NN Burdenko Main Military Clinical Hospital, 3 Gospital’naya pl., Moscow, Russian Federation, 105229

35 Bashkir State Medical University, 3 Lenina ul., Ufa, Republic of Bashkortostan, Russian Federation, 450008

36 GG Kuvatov Republican Clinical Hospital, 132 Dostoevskogo ul., Ufa, Republic of Bashkortostan, Russian Federation, 450005

37 Multispecialty Clinic “Skandinaviya”, AVA-PETER, 55A Liteinyi pr-t, Saint Petersburg, Russian Federation, 191014

38 Vologda Regional Clinical Hospital, 17 Lechebnaya ul., Vologda, Russian Federation, 160002

39 VI Razumovskii Saratov State Medical University, 6/9 53rd Strelkovoi Divizii ul., Saratov, Russian Federation, 410028

40 Leningrad Regional Clinical Hospital, 45 korp. 2A Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

41 VV Veresaev Municipal Clinical Hospital, 10 Lobnenskaya ul., Moscow, Russian Federation, 127644

42 SM Clinic, 19 korp. 1 Udarnikov pr-t, Saint Petersburg, Russian Federation, 195279

* Coordinators and members of Expert Panel.

† Program participants.

For correspondence: Tatyana Pavlovna Nikitina, MD, PhD, 1 Artilleriiskaya ul., Saint Petersburg, Russian Federation, 191014; e-mail: qolife@mail.ru

For citation: Ionova TI, Andreevskaya EA, Babich EN, et al. Current Quality-of-Life Aspects in Patients with Classical Ph-Negative Myeloproliferative Neoplasms in the Russian Federation: Results and Discussion of the National Observational Program MPN-QoL-2020. Clinical oncohematology. 2022;15(2):176–97. (In Russ).

DOI: 10.21320/2500-2139-2022-15-2-176-197

ABSTRACT

Background. The National Observational Program MPN-QoL-2020 was aimed at collecting the data on QoL (quality of life) characteristics and symptoms as well as patient- and physician-related disease and treatment perceptions in classical Ph-negative myeloproliferative neoplasms (MPN) in the Russian Federation.

Aim. Using new standardized forms, to analyze the quality of life among patients with various MPNs, to characterize ubiquitous symptoms and their effect on quality of life among the myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) patients as well as to describe the perceptions of disease- and therapy-associated problems as reported by patients and hematologists treating them.

Materials & Methods. The study enrolled 1100 patients with Ph-negative MPNs (355 MF, 408 PV, and 337 ET patients at the mean age of 58 ± 14 years, 61 % women). The study also involved 100 hematologists (mean age of 42 ± 12 years, 85 % women) from 37 health and preventive facilities in 8 Federal districts of the Russian Federation. The patients contributed to the study by one-time completing a special MPN10 form for MPN symptom assessment, a special QoL questionnaire HM-PRO for hematological malignancy patients, as well as a patient checklist. The task of hematologists consisted in one-time filling out of a physician checklist and completing the medical records of all the enrolled MPN patients.

Results. For the first time in the Russian Federation, the real clinical practice yielded the data on the quality of life in Ph-negative MPN patients, symptom profiles in different MPNs, and the extent of their effect on everyday life. QoL impairments mostly relate to physical and emotional functioning of MPN patients and to feeding and drinking regime, but rarely to social functioning. More than 1/3 of patients with Ph-negative MPNs reported on considerable QoL impairments. Absolute majority of patients complain of weakness: 92.6 % in MF, 83.7 % in PV, and 82 % in ET. The profiles of relevant symptoms and their intensity differ in various MPNs. The study identified the symptoms which need most to be corrected, both in the view of patients and physicians. There were established differences between patient- and doctor-reported evaluations of the attitude to the disease and treatment as well as the aspects for improvement in physician-patient relationship.

Conclusion. The National Observational Program MPN-QoL-2020 has resulted in characterization of QoL impairments in MPN patients in Russia. It determined the spectrum of particular disease and treatment challenges specific to these patients. Moreover, their unmet needs were updated. The outcomes of MPN-QoL-2020 can serve as a basis for the guidelines for QoL improvement/maintenance in Ph-negative MPNs and for activities aimed at raising MPN patients’ awareness about the disease and its treatment.

Keywords: classical Ph-negative myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, quality of life, MPN10 form.

Received: October 12, 2021

Accepted: February 10, 2022

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Correlation of the Number of TGFβF1-Expressing Atypical Megakaryocytes with the Degree of Bone Marrow Stroma Fibrosis and Osteosclerosis in Patients with Essential Thrombocythemia and Different Stages of Primary Myelofibrosis

AUTOIMMUNE THROMBOCYTOPENIA , ,

DI Chebotarev, AM Kovrigina, AL Melikyan

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

For correspondence: Dmitrii Ilich Chebotarev, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(916)091-27-09; e-mail: chebadmitry@gmail.com

For citation: Chebotarev DI, Kovrigina AM, Melikyan AL. Correlation of the Number of TGFβF1-Expressing Atypical Megakaryocytes with the Degree of Bone Marrow Stroma Fibrosis and Osteosclerosis in Patients with Essential Thrombocythemia and Different Stages of Primary Myelofibrosis. Clinical oncohematology. 2022;15(1):76–84. (In Russ).

DOI: 10.21320/2500-2139-2022-15-1-76-84

ABSTRACT

Background. As morphological pattern of bone marrow (BM) biopsy samples at advanced stages of clonal evolution in essential thrombocythemia (ET) appears similar to that in the development of post-thrombocythemic myelofibrosis and primary myelofibrosis (PMF), the expression of fibrogenesis factors by atypical megakaryocytes (MKC) acquires increased interest.

Aim. To study the expression of the transforming growth factor TGFβF1 by atypical MKC; to relate the number of TGFβF1-positive MKCs with the degree of BM stroma fibrosis and trabecular bone changes in patients with ET and different PMF stages.

Materials & Methods. BM biopsy samples of ET and PMF patients, obtained before cytoreductive therapy, were subjected to histochemical study with Gomori stain and Masson trichrome as well as to CD42b and TGFβF1 antibody immunohistochemical assays. The degree of myelofibrosis and osteosclerosis was estimated by semi-quantitative method in accordance with the European Consensus guidelines. The morphological characteristics of atypical MKC included the comparative evaluation of nuclear-cytoplasmic ratio.

Results. The number of MKCs with high nuclear-cytoplasmic ratio was significantly higher in BM biopsy samples of patients with pre-fibrosis/early PMF (pre-PMF) stage and fibrosis stage of PMF (f-PMF) compared with BM biopsy samples of ET patients. The analysis of TGFβF1 expression showed different numbers of positive MKCs in the study groups. The matching of the number of TGFβF1-positive MKCs with the degree of myelofibrosis and osteosclerosis, with no regard to nosologic entities, revealed significant moderate correlation between these features (r = 0.431, p = 0.001 и r = 0.499, p = 0.001, respectively). In 55 % of pre-PMF patients’ BM biopsy samples, histochemical study with Masson trichrome stain visualized minimal immature osteoid deposits on bone trabeculae. Similar changes were also identified in f-PMF patients’ BM biopsy samples, whereas the ET patients’ samples featured none of them.

Conclusion. The results of the study prove that the pathological clone of MKC with TGFβF1 expression affects myelofibrosis and osteosclerosis processes whose manifestation in BM biopsy samples is associated with the number of TGFβF1-expressing atypical MKCs.

Keywords: primary myelofibrosis, pre-fibrosis and fibrosis stages, essential thrombocythemia, osteosclerosis, TGFβF1, pathomorphology, immunohistochemistry.

Received: August 12, 2021

Accepted: November 30, 2021

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National Clinical Guidelines on Diagnosis and Treatment of Ph-Negative Myeloproliferative Neoplasms (Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis) (Edition 2020)

AUTOIMMUNE THROMBOCYTOPENIA , , , , , ,

AL Melikyan1, AM Kovrigina1, IN Subortseva1, VA Shuvaev2, EV Morozova3, EG Lomaia4, BV Afanasyev3, TA Ageeva5, VV Baikov3, OYu Vinogradova6, SV Gritsaev2, AYu Zaritskey4, TI Ionova7, KD Kaplanov6, IS Martynkevich2, TA Mitina8, ES Polushkina9, TI Pospelova5, MA Sokolova1, AB Sudarikov1, AG Turkina1, YuV Shatokhin10, RG Shmakov9, VG Savchenko1

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

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

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

4 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

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

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

7 NI Pirogov Clinic for High Medical Technology, Saint Petersburg State University, 7/9 Universitetskaya emb., Saint Petersburg, Russian Federation, 199034

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

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

10 ФГБОУ ВО «Ростовский государственный медицинский университет» Минздрава России, Нахичеванский пер., д. 29, Ростов-на-Дону, Российская Федерация, 344022

For correspondence: Anait Levonovna Melikyan, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: anoblood@ mail.ru

For citation: Melikyan AL, Kovrigina AM, Subortseva IN, et al. National Clinical Guidelines on Diagnosis and Treatment of Ph-Negative Myeloproliferative Neoplasms (Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis) (Edition 2020). Clinical oncohematology. 2021;14(2):262–98. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-262-298

ABSTRACT

The development of National clinical guidelines on diagnosis and treatment of Ph-negative myeloproliferative neoplasms comes in response to the need to standardize the approach to diagnosis and treatment. The availability of clinical guidelines can facilitate the choice of adequate treatment strategy, provides practicing physicians with exhaustive and up-to-date information on advantages and shortcomings of different treatment methods as well as lets health professionals better assess expected extents of treatment required by patients. In 2013 a working group was formed to develop and formulate clinical guidelines on the treatment of myeloproliferative neoplasms. These guidelines were first published in 2014, afterwards they were revised and republished. The dynamic development of current hematology presupposes constant updating of knowledge and implementation of new diagnosis and treatment methods in clinical practice. In this context clinical guidelines present a dynamic document to be continuously amended, expanded, and updated in accordance with scientific findings and new requirements of specialists who deal directly with this category of patients. The present edition is an upgraded version of clinical guidelines with updated information on the unification of constitutional symptoms assessment using MPN-SAF TSS questionnaire (MPN10), on applying prognostic scales in primary myelofibrosis, assessing therapy efficacy in myeloproliferative neoplasms, revising indications for prescription, on dose correction, and discontinuation of targeted drugs (ruxolitinib). The guidelines are intended for oncologists, hematologists, healthcare executives, and medical students.

Keywords: myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, JAK2V617F, CALR, MPL, prognosis, hydroxyurea, interferon-α, ruxolitinib, anagrelide.

Received: November 12, 2020

Accepted: February 23, 2021

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Current View on Diagnosis and Treatment of Classical Ph-Negative Myeloproliferative Neoplasms

AUTOIMMUNE THROMBOCYTOPENIA , , , , ,

AL Melikyan1, IN Subortseva1, VA Shuvaev2,3, EG Lomaia4, EV Morozova5, LA Kuzmina1, OYu Vinogradova6,7,8, AYu Zaritskey4

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

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

3 VV Veresaev Municipal Clinical Hospital, 10 Lobnenskaya str., Moscow, Russian Federation, 127644

4 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

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

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

7 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

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

For correspondence: Anait Levonovna Melikyan, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: anoblood@mail.ru

For citation: Melikyan AL, Subortseva IN, Shuvaev VA, et al. Current View on Diagnosis and Treatment of Classical Ph-Negative Myeloproliferative Neoplasms. Clinical oncohematology. 2021;14(1):129–37. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-129-137

ABSTRACT

Classical Ph-negative myeloproliferative neoplasms (MPN) constitute a group of diseases including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Over the past decade, the approaches to understanding of MPN pathogenesis and therapy have considerably changed. At the same time, etiological factors and pathophysiological mechanisms of disease progress are being thoroughly studied. The improvement of diagnosis methods and new approaches to therapy can reduce complications and mortality risks. The review outlines the current diagnosis methods, such as the molecular genetic one, and provides prognostic scores. Different methods of conservative therapy are assessed. Special attention is paid to quality of life measurement and targeted treatment of patients.

Keywords: myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, JAK2V617F, CALR, MPL, prognosis, constitutional symptoms, MPN10, ruxolitinib.

Received: September 1, 2020

Accepted: December 10, 2020

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REFERENCES

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Ph-Negative Myeloproliferative Neoplasms: Diagnosis and Treatment Challenges in Russia (the Case of Saint Petersburg)

AUTOIMMUNE THROMBOCYTOPENIA , ,

MO Ivanova, EV Morozova, MV Barabanshchikova, BV Afanasyev

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

For correspondence: Mariya Olegovna Ivanova, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: marilexo@yandex.ru

For citation: Ivanova MO, Morozova EV, Barabanshchikova MV, Afanasyev BV. Ph-Negative Myeloproliferative Neoplasms: Diagnosis and Treatment Challenges in Russia (the Case of Saint Petersburg). Clinical oncohematology. 2021;14(1):45–52. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-45-52

ABSTRACT

Ph-negative myeloproliferative neoplasms (MPN) are rare oncohematological diseases characterized by long duration and indolence. World epidemiological data on these diseases considerably vary depending on geographical area and time frame of the study. The breakthrough in the understanding of MPN pathogenesis, observed in the early 2000s, enabled to elaborate approaches to differential diagnosis and treatment of Ph-negative MPNs as well as to improve their prognosis. Although these approaches are specified in the Russian clinical guidelines, physicians still face challenges in their implementation in practice. The present review provides a detailed description and analysis of literature data on epidemiology, pathogenesis, and principles of Ph-negative MPN diagnosis and treatment. It also describes the situation in Saint Petersburg as an example of existing challenges in management of patients with Ph-negative MPNs in Russia and offers potential solutions.

Keywords: myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis.

Received: August 13, 2020

Accepted: November 29, 2020

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Pharmacokinetics, Safety, and Tolerance of Anagrelide, the First Domestic Generic, Compared with Reference Drug

AUTOIMMUNE THROMBOCYTOPENIA ,

SK Zyryanov1,2, VV Chistyakov1, OI Butranova1, ES Stepanova1, OG Potanina1, RA Abramovich1

1 RUDN University, 6 Miklukho-Maklaya str., Moscow, Russian Federation, 117198

2 Municipal Clinical Hospital No. 24, 10 Pistsovaya str., Moscow, Russian Federation, 127015

For correspondence: Olga Igorevna Butranova, MD PhD, 6 Miklukho-Maklaya str., Moscow, Russian Federation, 117198; Tel.: +7(903)376-71-40; e-mail: butranova-oi@rudn.ru, butranovaolga@mail.ru

For citation: Zyryanov SK, Chistyakov VV, Butranova OI, et al. Pharmacokinetics, Safety, and Tolerance of Anagrelide, the First Domestic Generic, Compared with Reference Drug. Clinical oncohematology. 2020;13(3):346–53. (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-346-353

ABSTRACT

Background. Anagrelide is used for the treatment of essential thrombocythemia. This drug selectively affects thrombocytes without inducing pronounced myelosuppression, which provides a satisfactory safety profile.

Aim. To compare pharmacokinetics and to assess bioequivalence of two anagrelide drugs for oral administration in healthy volunteers.

Materials & Methods. Open, randomized, two-period, two-sequence, crossover study comparing pharmacokinetics and bioequivalence of anagrelide included 30 volunteers. The participants received a single dose of either test or reference drug, depending on the study period. Serial blood samples for pharmacokinetic analysis were collected within 12 hours after drug administration. Plasma anagrelide concentration was measured by high-performance liquid chromatography/mass spectrometry. Pharmacokinetic parameters were analyzed by non-compartmental method. ANOVA analysis of variance was used for assessing the difference between the mean values of the AUC0-t, AUC0-∞ and Cmax pharmacokinetic parameters at 5 % significance level.

Results. The mean values of maximum concentration (Сmax) after a single dose of anagrelide were 12.68 ± 2.99 ng/mL and 12.46 ± 3.15 ng/mL for test and reference drugs, respectively. Relative bioavailability was 1.16 ± 0.18. The AUC0-12 mean values calculated by anagrelide concentrations after a single dose of test and reference drugs were 30.38 ± 7.0 ng • h/mL and 28.78 ± 7.50 ng • h/mL, respectively, and the AUC0-∞ mean values were 31.13 ± 7.15 ng • h/mL and 29.55 ± 7.61 ng • h/mL, respectively. The assessment of main vital functions and laboratory parameters did not reveal any effect of the drugs on the health status of trial participants.

Conclusion. Pharmacokinetic profile of the test drug (generic anagrelide) did not considerably differ from that of reference drug, which indicates in vivo bioequivalence of it. The assessment of drug safety yielded satisfactory tolerance; no serious adverse events have been reported.

Keywords: anagrelide, generic, bioequivalence, essential thrombocythemia, safety, tolerance.

Received: February 19, 2020

Accepted: May 25, 2020

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REFERENCES

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WT1 Gene Overexpression in Differential Diagnosis of Ph-negative Myeloproliferative Disorders

MYELOID TUMORS , , , ,

EG Lomaia1, NT Siordiya1, EG Lisina2, OM Senderova3, AA Silyutina1, AYu Zaritskey1

1 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

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

3 Irkutsk Regional Clinical Hospital, 100 Yubileinyi microdistrict, Irkutsk, Russian Federation, 664049

For correspondence: Nadiya Tamazovna Siordiya, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(921)358-31-32; e-mail: siordian@list.ru

For citation: Lomaia EG, Siordiya NT, Lisina EG, et al. WT1 Gene Overexpression in Differential Diagnosis of Ph-Negative Myeloproliferative Disorders. Clinical oncohematology. 2019;12(3):297–302 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-297-302

ABSTRACT

Aim. To assess the rate of WT1 gene overexpression and its clinical value in Ph-negative myeloproliferative disorders (MPD).

Materials & Methods. The trial included 72 patents with Ph-negative MPD. Among them there were patients with primary myelofibrosis (MF; n = 32), post-polycythemia vera MF (n = 7), polycythemia vera (PV; n = 17), and essential thrombocythemia (ET; n = 16) with median age of 57 years (range 19–78 years). Median (range) time from diagnosis to the date of evaluating WT1 expression in PV, ET, and MF was 9.4 (0–309), 14.4 (0–55), and 21.4 months (0–271 months), respectively. WT1 expression in terms of WT1 copies/104 ABL copies was measured by quantitative PCR.

Results. WT1 gene overexpression is revealed solely in patients with MF (in 34/39; 87 %). In PV/ET no WT1 gene overexpression was observed. Median WT1 expression in MF was 230/104 ABL copies (range 42.2–9,316.45/104 ABL copies). Sensitivity and specificity of WT1 gene overexpression in MF with respect to PV/ET were 87 % and 100 %, respectively. A distinct correlation was identified between WT1 gene expression level and spleen size, duration of the disease, blast cell count, and DIPSS risk group. WT1 gene expression level could be correlated neither with age and sex, nor with MF mutation status and leucocyte, thrombocyte, and haemoglobin levels.

Conclusion It appears that due to a high specificity and sensitivity of WT1 gene expression in MF it can be used as a marker for differential diagnosis of Ph-negative MPD. A correlation between WT1 gene expression and tumor mass in MF cannot be excluded. It is advisable to analyze the dynamics of WT1 expression level to predict the efficacy of current targeted therapy.

Keywords: WT1 gene, Ph-negative myeloproliferative disorders, myelofibrosis, polycythemia vera, essential thrombocythemia.

Received: December 27, 2018

Accepted: June 2, 2019

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

MYELOID TUMORS , , , , ,

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 BCR–ABL1 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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Molecular Genetic Markers and Clinical Characteristics of Essential Thrombocythemia

MYELOID TUMORS ,

AA Zhernyakova, IS Martynkevich, VA Shuvaev, LB Polushkina, MS Fominykh, VYu Udal’eva, II Zotova, DI Shikhbabaeva, MN Zenina, NA Potikhonova, SV Voloshin, SS Bessmel’tsev, AV Chechetkin, KM Abdulkadyrov

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

For correspondence: Anastasiya Andreevna Zhernyakova, MD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(921)343-01-05; e-mail: zhernyakova.a@mail.ru

For citation: Zhernyakova AA, Martynkevich IS, Shuvaev VA, et al. Molecular Genetic Markers and Clinical Characteristics of Essential Thrombocythemia. Clinical oncohematology. 2017;10(3):402–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-402-408

ABSTRACT

Background & Aims. The presence of different molecular genetic markers of clonality (mutations in JAK2, MPL, CALR) or their absence (triple negative status, TN) in essential thrombocythemia (ET) indicates a biological heterogeneity of the disease and can determine its clinical forms. The aim was to evaluate the association of molecular genetic markers with the clinical form and the prognosis of ET.

Materials & Methods. We analyzed the data of 240 patients with ET at the age of 20–91 years (median age 58.7 years), who were observed in the Russian Research Institute of Hematology and Transfusiology from 1999 to 2016 (median observation period 37.2 months).

Results. The JAK2V617F (JAK2+) mutation was found in 182 (75.9 %) of 240 patients. CALR (CALR+) mutations were found in 30 (12.5 %): type 1 (CALR1+) mutations in 13/30 (43.3 %) and type 2 (CALR2+) in 17/30 (56.7 %). MPL (MPL+) mutations were found in only 2 (0.8 %) of 240 patients. None of the mutations were detected in 26 (10.8 %) of 240 patients (TN status). Significantly higher platelet counts were observed in CALR1+ and CALR2+ subgroups during the primary diagnosis of ET compared with JAK2+ and TN groups. The mean platelet counts were 1252 × 109/L for CALR2+ and 1079 × 109/L for CALR1+ vs 841 × 109/L (p < 0.001; p = 0.06) and 775 × 109/L (p < 0.001; p = 0.04) for JAK2+ and TN, respectively. Thrombosis was diagnosed in 50 (27.4 %) of 182 patients of the JAK2+ subgroup, in 8 (30.7 %) of the 26 patients of the TN subgroup, and in 2 (18.2 %) of 11 patients of the CALR1+ subgroup. No thrombosis was found in the CALR2+ and MPL+ subgroups (p < 0.001). In general, the CALR1+ status was characterized as the most favorable in terms of prognosis (5-year overall survival rate of 100 %), compared to the least favorable TN status (5-year overall survival rate of 85 %).

Conclusion. Mutations in the CALR gene were characterized by a more favorable prognosis in comparison with JAK2+ and TN, as well as a decrease in the risk and frequency of thrombosis, despite higher platelet counts. TN-status of ET was associated with unfavorable prognosis.

Keywords: essential thrombocythemia, CALR, JAK2V617F, MPL.

Received: December 26, 2016

Accepted: March 6, 2017

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Biology of Myeloproliferative Malignancies

MYELOID TUMORS , , , , , , ,

AL Melikyan, IN Subortseva

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

For correspondence: Irina Nikolaevna Subortseva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-71; e-mail: soubortseva@yandex.ru

For citation: Melikyan AL, Subortseva IN. Biology of Myeloproliferative Malignancies. Clinical oncohematology. 2016;9(3):326-35 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-314-325

ABSTRACT

Chronic myeloproliferative diseases (WHO, 2001), or myeloproliferative neoplasms/malignancies (MPN) (WHO, 2008), are clonal diseases characterized by proliferation of one or more myelopoietic cell line in the bone marrow with signs of unimpaired terminal differentiation and is normally associated with changes in peripheral blood characteristics. The group of classical Ph-negative MPNs consists of polycythemia vera, essential thrombocythemia, primary myelofibrosis and unclassified MPNs. Acquired somatic mutations contributing to the pathogenesis of Ph-negative MPNs include JAK2 (V617F, exon 12), MPL, CALR gene mutations found in about 90 % of patients. However, these molecular events are not unique in the pathogenesis of the diseases. Mutations of other genes (ТЕТ2, ASXL1, CBL, IDH1/IDH2, IKZF1, DNMT3A, SOCS, EZH2, TP53, RUNX1, and HMGA2) are involved in formation of the disease phenotype. This review describes current concepts concerning the molecular biology of MPNs.

Keywords: chronic myeloproliferative diseases, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, genes JAK2, CALR, and MPL.

Received: April 11, 2016

Accepted: April 11, 2016

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