The Use of Checkpoint Inhibitors in Classical Hodgkin’s Lymphoma during the COVID-19 Pandemic (Pirogov Medical Center’s Experience)

VO Sarzhevskii, EA Demina, NE Mochkin, AA Spornik, AA Mamedova, EG Smirnova, AE Bannikova, AA Samoilova, VS Bogatyrev, OYu Bronov, YuA Abovich, VYa Melnichenko

NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Vladislav Olegovich Sarzhevskii, MD, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel.: +7(495)603-72-17; e-mail: vladsar100@gmail.com

For citation: Sarzhevskii VO, Demina EA, Mochkin NE, et al. The Use of Checkpoint Inhibitors in Classical Hodgkin’s Lymphoma during the COVID-19 Pandemic (Pirogov Medical Center’s Experience). Clinical oncohematology. 2020;13(3):307–15 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-307-315


ABSTRACT

Background. Currently, there are neither systematic data nor clinical guidelines for checkpoint inhibitor immunotherapy in cancer patients in the context of the COVID-19 pandemic. In this respect classical Hodgkin’s lymphoma (cHL) is no exception. The article deals with the experience of Pirogov Medical Center (NI Pirogov Russian National Medical Center of Surgery) in PD-1-inhibitor immunotherapy in relapsed/refractory cHL in the context of the COVID-19 pandemic. The authors endeavour to cover matters of current interest concerning immunotherapy and differential diagnosis of pulmonary adverse events emerging in the context of new realities in providing medical care to cancer patients.

Aim. To assess feasibility and safety of checkpoint inhibitor immunotherapy in relapsed/refractory cHL in the context of the COVID-19 pandemic.

Materials & Methods. This is a retrospective analysis of adverse events of therapy and COVID-19 mortality, and incidence in 50 cHL patients who received immunotherapy at the Pirogov Medical Center in the period of spring COVID-19 pandemic in 2020.

Results. During the reported period (from March 11, 2020, when the COVID-19 pandemic was declared, to May 25, 2020) the group of 50 cHL patients showed relatively low overall incidence rate of newly diagnosed immune-mediated adverse events (14 %; n = 7). Severe adverse events were identified in 2 (4 %) patients. Bacterial infection incidence was 6 % (n = 3). Clinical signs of corona virus confirmed by subsequent laboratory COVID-19 tests were observed in 2 (4 %) patients. One patient died due to the non-COVID-19-associated reason. The main issue the center’s staff was faced with was the need for differential diagnosis between drug-induced (as well as immune-mediated) pulmonitis and COVID-19-associated pneumonia.

Conclusion. The retrospective analysis reveals that PD-1-inhibitor immunotherapy in cHL patients during the COVID-19 pandemic is a feasible method of therapy, but it requires high awareness. Special focus should be given to clinical and radiological similarities of COVID-19-associated pneumonia and pulmonitis as a complication of immunotherapy.

Keywords: classical Hodgkin’s lymphoma, immunotherapy, PD-1-inhibitors, COVID-19 pandemic.

Received: May 29, 2020

Accepted: June 28, 2020

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Breakthrough Hemolysis as a Challenging Issue in Targeted Therapy of Paroxysmal Nocturnal Hemoglobinuria (Resolution of Expert Panel)

ЭКСПЕРТЫ:

Ирина Александровна Вилюм — ассистент кафедры клинической фармакологии и доказательной медицины, ПСПбГМУ им. акад. И.П. Павлова, член отделения ISPOR, член Ассоциации специалистов в области оценки технологии здравоохранения, г. Санкт-Петербург.

Мария Алексеевна Виноградова — канд. мед. наук, руководитель отделения репродуктивной гематологии и клинической гемостазиологии, НМИЦ акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова, г. Москва.

Татьяна Семеновна Капорская — канд. мед. наук, руководитель отделения гематологии, Областная клиническая больница, г. Иркутск.

Татьяна Семеновна Константинова — канд. мед. наук, руководитель отделения гематологии, Областная клиническая больница № 1, г. Екатеринбург.

Александр Дмитриевич Кулагин — д-р мед. наук, профессор кафедры гематологии, трансфузиологии и трансплантологии, ПСПбГМУ им. акад. И.П. Павлова, г. Санкт-Петербург.

Галина Борисовна Кучма — канд. мед. наук, доцент кафедры факультетской терапии и эндокринологии, Оренбургский государственный медицинский университет, г. Оренбург.

Елена Алексеевна Лукина — д-р мед. наук, профессор, руководитель отделения орфанных заболеваний, НМИЦ гематологии, г. Москва.

Елена Алексеевна Михайлова — д-р мед. наук, профессор, ведущий научный сотрудник отделения химиотерапии гемобластозов и депрессий кроветворения, НМИЦ гематологии, г. Москва.

Валентина Захаровна Молоствова — заместитель главного врача по терапии, клинический руководитель отделения гематологии и химиотерапии, Краевая клиническая больница № 1 им. проф. С.И. Сергеева, г. Хабаровск.

Вадим Вадимович Птушкин — д-р мед. наук, профессор, заместитель главного врача по гематологии, Городская клиническая больница им. С.П. Боткина, г. Москва.

Ольга Дмитриевна Сердюк — руководитель отделения гематологии, Краевой клинический онкологический диспансер № 1, г. Краснодар.


20 декабря 2019 г. в Москве состоялся совет экспертов, в ходе которого ведущие специалисты обсудили актуальную проблему прорывного внутрисосудистого гемолиза на фоне современной таргетной терапии пароксизмальной ночной гемоглобинурии (ПНГ) с целью дальнейшего улучшения результатов лечения в России. Собранию совета экспертов предшествовало дистанционное анкетирование специалистов по реальной клинической практике длительной антикомплементарной терапии ПНГ.

В совещании приняли участие гематологи федеральных и региональных центров: Мария Алексеевна Виноградова, Татьяна Семеновна Капорская, Татьяна Семеновна Константинова, Александр Дмитриевич Кулагин, Галина Борисовна Кучма, Елена Алексеевна Лукина, Елена Алексеевна Михайлова, Валентина Захаровна Молоствова, Вадим Вадимович Птушкин, Ольга Дмитриевна Сердюк, а также специалист в области оценки технологий здравоохранения Ирина Александровна Вилюм.

Советом экспертов были рассмотрены следующие аспекты патогенетической терапии ПНГ:

  • причины недостаточной эффективности таргетной терапии ПНГ;
  • проблема прорывного внутрисосудистого гемолиза на фоне современной терапии ПНГ;
  • клинико-экономические последствия прорывного гемолиза у пациентов с ПНГ, получающих терапию экулизумабом;
  • клиническая тактика в случае прорывного гемолиза и возможные пути улучшения таргетного контроля гемолиза при ПНГ.

Пароксизмальная ночная гемоглобинурия (ПНГ) является редким клональным заболеванием крови, характеризуется хроническим внутрисосудистым гемолизом, костномозговой недостаточностью, угрожающими жизни тромбозами и другими тяжелыми осложнениями.

С 2012 г. в России современным методом терапии внутрисосудистого гемолиза при ПНГ является использование экулизумаба, представляющего собой гуманизированное моноклональное антитело против С5-компонента системы комплемента. Длительность лечения экулизумабом у ряда больных ПНГ в России превышает 7 лет.

По данным отечественных и зарубежных публикаций, около 1/3 пациентов с ПНГ имеет лишь субоптимальный ответ на терапию экулизумабом. Основной вклад в недостаточную эффективность экулизумаба при ПНГ вносят следующие причины и механизмы: прорывной внутрисосудистый гемолиз, экстраваскулярный гемолиз (опсонизация эритроцитов с фенотипом ПНГ за счет активного связывания фрагментов C3 и последующее повышенное разрушение эритроцитов в селезенке и печени) и нарушения кроветворения (недостаточность костного мозга, клональная эволюция).

Накопленный опыт антикомплементарной терапии позволил включить в новую редакцию «Клинических рекомендаций по диагностике и лечению ПНГ» следующие термины.

Прорывной гемолиз — это утрата контроля внутрисосудистого гемолиза, в т. ч. с развитием гемолитического криза, на фоне регулярной патогенетической терапии ПНГ.

Фармакокинетический прорывной гемолиз (ФК) развивается у пациентов с индивидуальными параметрами снижения концентрации экулизумаба за 1–4 дня до очередного введения препарата в поддерживающей фазе.

Фармакодинамический прорывной гемолиз (ФД) связан с комплемент-активирующими состояниями (инфекции, операции, беременность и др.) и может развиваться у любого пациента.

Эксперты, представляющие федеральные центры и крупные регионы России, обсудив результаты проведенного анкетирования, а также опираясь на современные данные НИИ ДОГиТ им. Р.М. Горбачевой ПСПбГМУ им. И.П. Павлова о долгосрочной эффективности терапии экулизумабом, сделали следующие выводы.

  • В реальной клинической практике до 30 % пациентов с ПНГ имеют субоптимальный контроль гемолиза и нуждаются в коррекции терапевтической тактики.
  • ФК прорывной гемолиз является частой причиной недостаточной эффективности экулизумаба при ПНГ.
  • До 15 % пациентов с ПНГ демонстрируют ФК прорывной гемолиз. Коррекция лечения в этом случае предполагает сокращение интервала между введениями стандартной дозы 900 мг экулизумаба до 10–12 дней или увеличение дозы до 1200 мг каждые 14 дней. Уменьшение интервала между введениями до 12–10 дней остается более доступной опцией в реальной клинической практике (у каждого второго пациента возникает необходимость сокращения интервала), но создает ряд неудобств в связи с графиком инфузий препарата. Данная тактика позволяет добиться контроля прорывного гемолиза не у всех пациентов, у около 30 % больных требуется увеличение дозы до 1200 мг. У небольшой группы пациентов с ФК/ФД прорывным гемолизом (~10 %) приходится одновременно сокращать интервал и повышать дозу экулизумаба до 1200–1500 мг.

Эксперты наблюдали развитие симптомов и осложнений при возникновении прорывного гемолиза (утомляемость, слабость, боль в животе, эпизоды острого повреждения почек, тромбозы). До 50 % пациентов, по мнению экспертов, нуждаются в гемотрансфузиях в связи с прорывным гемолизом. В ряде регионов из-за ограниченного доступа к экулизумабу нет возможности ни увеличить дозу, ни сократить интервал. В таких случаях потребность в гемотрансфузиях повышается. Прорывной гемолиз зачастую требует госпитализации пациентов в стационар и назначения дополнительной терапии для стабилизации состояния.

Эксперты приняли во внимание результаты фармакоэкономического анализа последствий прорывного гемолиза у пациентов с ПНГ, получающих терапию экулизумабом, подготовленного на кафедре клинической фармакологии и доказательной медицины ПСПбГМУ им. И.П. Павлова. При моделировании распространенности ПНГ и учете текущих показаний патогенетическая терапия экулизумабом в России, в т. ч. с использованием биоаналога, требует значительных средств бюджета — до 13,5 млрд рублей в год. Показано, что коррекция терапии при развитии прорывного гемолиза (увеличение дозы, сокращение интервалов между введениями или одновременное использование подобных приемов) закономерно влечет за собой рост затрат на патогенетическую терапию в 1,8 раза в расчете на 1 пациента. Для снижения издержек предложено начинать коррекцию терапии с увеличения дозировки экулизумаба как более экономичного подхода и только при сохранении случаев прорывных гемолизов использовать тактику сокращения интервалов. Дополнительно отмечено, что использование пролонгированного ингибитора С5-компонента комплемента, отличного по фармакокинетическим характеристикам, может быть способом решения проблем, связанных с экономическими последствиями развития эпизодов прорывного гемолиза при терапии экулизумабом. Эксперты рекомендовали продолжить изучение этого вопроса и провести дополнительный анализ.

Принимая во внимание актуальность проблемы прорывного гемолиза и развитие таргетного контроля гемолиза при ПНГ, эксперты обсудили результаты ключевых клинических исследований нового пролонгированного ингибитора С5-компонента комплемента равулизумаба по сравнению с экулизумабом у взрослых пациентов с ПНГ и пришли к следующим выводам.

  1. В случае ФК прорывного гемолиза может быть рекомендовано использование пролонгированного ингибитора комплемента для улучшения таргетного контроля внутрисосудистого гемолиза и профилактики развития угрожающих жизни осложнений ПНГ.
  2. Равулизумаб может быть рекомендован для лечения ПНГ у 10–15 % пациентов, испытывающих ФК прорывной гемолиз. Равулизумаб сохраняет эффективность, равную экулизумабу, при более редком режиме введения (1 раз в 2 мес.). Он быстро (к концу первой инфузии) и стойко (С5 < 0,5 мкг/мл) ингибирует свободный С5 на протяжении 52-недельного периода. В исследованиях равулизумаба не зарегистрированы случаи ФК прорывного гемолиза, связанные с уровнем свободного C5 ≥ 0,5 мкг/мл, а перевод пациентов с экулизумаба на равулизумаб приводил к существенному уменьшению частоты ФК прорывного гемолиза, что, вероятно, обусловлено улучшением контроля свободного С5. Редкие события ФД прорывного гемолиза на фоне лечения равулизумабом связаны с развитием инфекции. Эффективное лечение инфекции купирует эпизод и не приводит к отказу от лечения.
  3. Равулизумаб может быть рекомендован к включению в «Клинические рекомендации по диагностике и лечению ПНГ» с момента регистрации в России.
  4. Терапия равулизумабом может служить индивидуальным показанием к назначению в следующих клинических группах пациентов: работающие пациенты, профессиональная деятельность которых не позволяет регулярные пропуски работы (каждые 14 дней); пациенты, проживающие на отдаленных территориях, что резко затрудняет проведение внутривенных инфузий каждые 14 дней; пациенты с отсутствием или резко затрудненным венозным доступом.

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

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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  6. Ianotto JC, Curto-Garcia N, Lauermanova M, et al. Characteristics and outcomes of patients with essential thrombocythemia or polycythemia vera diagnosed before 20 years of age: a systematic review. Haematologica. 2019;104(8):1580–8. doi: 10.3324/haematol.2018.200832.

  7. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk‐stratification and management. Am J Hematol. 2019;94(1):133–43. doi: 10.1002/ajh.25303.

  8. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057–69. doi: 10.1038/s41375-018-0077-1.

  9. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood. 2013;121(10):1720–8. doi: 10.1182/blood-2012-07-443770.

  10. Samuelson B, Chai-Adisaksopha C, Garcia D. Anagrelide compared with hydroxyurea in essential thrombocythemia: a meta-analysis. J Thromb Thrombolysis. 2015;40(4):474–9. doi: 10.1007/s11239-015-1218-2.

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  15. Okamoto S, Miyakawa Y, Smith J, et al. Open-label, dose-titration and continuation study to assess efficacy, safety, and pharmacokinetics of anagrelide in treatment-naive Japanese patients with essential thrombocythemia. Int J Hematol. 2013;97(3):360–8. doi: 10.1007/s12185-013-1265-4.

Early Response and Long-Term Outcomes of Ruxolitinib Therapy in Myelofibrosis: Multicenter Retrospective Study in 10 Centers of the Russian Federation

EG Lomaia1, NT Siordiya1, OM Senderova2, OE Ochirova3, EB Zhalsanova3, AYu Furtovskaya1, GP Dimov4, MG Pozina4, OYu Li5, KB Trizna6, MA Mikhalev7, EV Sokurova8, AA Otmorskaya9, AS Khazieva10, VV Ust’yantseva11, YuD Rogovaya1, AYu Zaritskey1

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

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

3 NA Semashko Republican Clinical Hospital, 12 Pavlova str., Ulan-Ude, Russian Federation, 670031

4 Municipal Clinical Hospital No. 1, 16 Vorovskogo str., Chelyabinsk, Russian Federation, 454048

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

6 Tomsk Regional Clinical Hospital, 96 Ivana Chernykh str., Tomsk, Russian Federation, 634063

7 Krasnoyarsk Interdistrict Clinical Hospital No. 7, 4 Akademika Pavlova str., Krasnoyarsk, Russian Federation, 660003

8 Vladivostok Polyclinic No. 4, 5 Voropaeva str., Vladivostok, Russian Federation, 690000

9 Regional Clinical Hospital, 1 Lyapidevskogo str., Barnaul, Russian Federation, 656024

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

11 Railway Clinical Hospital, the Chelyabinsk Railway Station, 41 Tsvillinga str., Chelyabinsk, Russian Federation, 454000

For correspondence: Nadiya Tamazovna Siordiya, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: siordian@list.ru

For citation: Lomaia EG, Siordiya NT, Senderova OM, et al. Early Response and Long-Term Outcomes of Ruxolitinib Therapy in Myelofibrosis: Multicenter Retrospective Study in 10 Centers of the Russian Federation. Clinical oncohematology. 2020;13(3):335–45 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-335-345


ABSTRACT

Aim. To assess the efficacy of targeted therapy with ruxolitinib in patients with myelofibrosis in real clinical practice in Russia. To determine the prognostic value of spleen reduction in the early stages of ruxolitinib treatment and its effect on overall survival.

Materials & Methods. The present retrospective study was based on the data of 10 centers of Russia. It included 56 myelofibrosis (primary or post-polycythemic and post-thrombocythemic) patients who received ruxolitinib. The median age of patients was 56 years (range 26–76 years). Most of them (59 %) were considered intermediate-1 risk according to DIPSS and had massive splenomegaly (80 %), and constitutional symptoms (86 %). The initial drug dose was 30 mg per day in 64 % of cases, and the level of thrombocytes was ≥ 200 × 109/L in 61 % of patients. The spleen size was evaluated by palpation.

Results. By the start of data collection most of patients (79 %) had been treated with ruxolitinib. In no case therapy was withdrawn for the reason of drug toxicity. On ruxolitinib constitutional symptoms were reversed in 70 %, 87 %, and 98 % of patients by months 1, 3 and 6, respectively. In 36 % and 46 % of patients by months 3 and 6, respectively, ≥ 50 % decrease in spleen size was observed. Overall, in 31 % and 27 % of cases the size of the spleen decreased by less than 25 % by months 3 and 6, respectively. The factors affecting the changes in spleen size have not been identified. The probability of overall survival by years 2 and 5 of follow-up was 97 % and almost 70 %, respectively. This parameter was significantly affected by the extent of spleen size reduction by month 3 of follow-up as well as by its initial size.

Conclusion. Ruxolitinib shows high efficacy for both decrease of general myelofibrosis symptoms and reduction in spleen size. The extent of spleen reduction is an important prognostic factor. In patients with insufficient spleen reduction an increase in drug dose is advisable. If it is not possible, alternative methods of treatment should be sought.

Keywords: myelofibrosis, ruxolitinib, spleen size changes, constitutional symptoms, overall survival.

Received: January 31, 2020

Accepted: May 15, 2020

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REFERENCES

  1. Tefferi A, Lasho TL, Jimma T, et al. One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience. Mayo Clin Proc. 2012;87(1):25–33. doi: 10.1016/j.mayocp.2011.11.001.

  2. Patriarca F, Bacigalupo A, Sperotto A, et al. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica. 2008;93(10):1514–22. doi: 10.3324/haematol.12828.

  3. Harrison CN, Mesa RA, Kiladjian JJ, et al. Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol. 2013;162(2):229–39. doi: 10.1111/bjh.12375.

  4. Verstovsek S, Mesa RA, Gotlib I, et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. N Engl J Med. 2012;366(9):799–807. doi: 10.1056/NEJMoa1110557.

  5. Verstovsek S, Mesa RA, Gotlib I, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. doi: 10.1186/s13045-017-0417-z.

  6. Miller CB, Komrokji RS, Mesa RA, et al. Practical Measures of Clinical Benefit With Ruxolitinib Therapy: An Exploratory Analysis of COMFORT-I. Clin Lymphoma Myel Leuk. 2017;17(8):479–87. doi: 10.1016/j.clml.2017.05.015.

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  9. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. 2013;122(8):1395–8. doi: 10.1182/blood-2013-03-488098.

  10. Джакави® (инструкция по медицинскому применению). Novartis Pharma, AG (Швейцария). Доступно по: https://www.vidal.ru/drugs/jakavi Ссылка активна на 15.05.2020.[Jakavi® (package insert). Novartis Pharma, AG, Switzerland. Available from: https://www.vidal.ru/drugs/jakavi__38878. (accessed 15.05.2020) (In Russ)]

  11. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120(6):1202–9. doi: 10.1182/blood-2012-02-414631.

  12. Vannucchi AM, Kantajian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9):1139–45. doi: 10.3324/haematol.2014.119545.

  13. Mesa RA, Verstovsek S, Gupta V, et al. Effects of ruxolitinib treatment on metabolic and nutritional parameters in patients with myelofibrosis from COMFORT-I. Clin Lymphoma Myel Leuk. 2015;15(4):214–21.e1. doi: 10.1016/j.clml.2014.12.008.

  14. Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8(45):79073–86. doi: 10.18632/oncotarget.18674.

  15. Palandri F, Tiribelli M, Benevolo G, et al. Efficacy and safety of ruxolitinib in intermediate-1 IPSS risk myelofibrosis patients: Results from an independent study. Hematol Oncol. 2018;36(1):285–90. doi: 10.1002/hon.2429.

  16. Palandri F, Catani L, Bonifacio M, et al. Ruxolitinib in elderly patients with myelofibrosis: impact of age and genotype. A multicentre study on 291 elderly patients. Br J Haematol. 2018;183(1):35–46. doi: 10.1111/bjh.15497.

  17. Harrison CN, Schaap N, Vannucchi A, et al. Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study. HemaSphere. 2019;3:671–72. doi: 10.1097/01.hs9.0000564100.83392.c9.

  18. Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. 2016;101(9):1065–73. doi: 10.3324/haematol.2016.143677.

Comorbidity and Personalized Treatment of Multiple Myeloma in Real Clinical Practice

NV Skvortsova1, IB Kovynev1, KV Khalzov1, TI Pospelova1, IN Nechunaeva2

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

2 Municipal Clinical Hospital No. 2, 21 Polzunova str., Novosibirsk, Russian Federation, 630051

For correspondence: Nataliya Valer’evna Skvortsova, MD, PhD, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091; Tel.: 8(905)955-59-91; Fax: 8(383)279-94-06; e-mail: nata_sk78@mail.ru

For citation: Skvortsova NV, Kovynev IB, Khalzov KV, et al. Comorbidity and Personalized Treatment of Multiple Myeloma in Real Clinical Practice. Clinical oncohematology. 2020;13(3):322–34 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-322-334


ABSTRACT

Aim. To study incidence and structure of comorbidity in multiple myeloma (MM) patients depending on their age; to determine its effect on overall survival, efficacy, and safety of the first-line therapy in real clinical practice.

Materials & Methods. Overall, 369 patients with newly diagnosed MM were enrolled in the trial from January 2012 to December 2017. Among them there were 134 men and 235 women hospitalized at the Unit of Hematology in the Novosibirsk Municipal Clinical Hospital No. 2. Median age of patients was 67 years (range 32–82 years).

Results. The analyzed patients were divided into three age groups: the first group of young/middle age (32–59 years) (n = 105), the second group of elderly patients (60–74 years) (n = 186), and the third group of old age (≥ 75 years) (n = 78). In each patient prior to chemotherapy the comorbidity spectrum was identified and CIRS-G, CCI, and MCI comorbidity scores were calculated. Patients with newly diagnosed MM in real clinical practice prove to have high and increasing with age comorbidity incidence (91 % in patients of young/middle age, 97,7 % and 100 % in patients of elderly and old age, respectively). Comorbidity significantly reduces overall survival (OS) of MM patients. Important OS predictors are rhythm and conduction disorder (odds ratio, OR, 2.762; < 0.002), chronic pancreatitis (OR 1.864; < 0.001), exogenous constitutive obesity (OR 1.948; < 0.002), chronic obstructive pulmonary disease (OR 2.105; < 0.021), chronic kidney disease, stage С4–С5 (OR 2.255; < 0.003), and chronic heart failure, functional class II (OR 1.915; < 0.002). Highest importance in predicting OS, efficacy, and tolerance to chemotherapy in MM patients is attached to MCI score (OR 3.771; < 0.001). MM patients with high risk by MCI are characterized by lower rate and depth of response to the first-line therapy, shorter time before the first relapse, higher incidence of non-hematologic toxicity of grade ≥ 3, and therapy withdrawal or drug dose reduction.

Conclusion. Comorbidity assessment in MM patients is important for outcome prediction and treatment planning.

Keywords: multiple myeloma, comorbidity, comorbidity scores, overall survival, personalized treatment.

Received: April 2, 2020

Accepted: June 18, 2020

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Treatment of Aggressive Non-Hodgkin’s Lymphomas in Pregnancy

YaK Mangasarova1, AU Magomedova1, ES Nesterova1, LG Gorenkova1, FE Babaeva1, RG Shmakov2, SK Kravchenko1

1 National Research Center for Hematology, 4 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: Yana Konstantinovna Mangasarova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(926)395-82-52; e-mail: v.k.jana@mail.ru

For citation: Mangasarova YaK, Magomedova AU, Nesterova ES, et al. Treatment of Aggressive Non-Hodgkin’s Lymphomas in Pregnancy. Clinical oncohematology. 2020;13(3):316–21 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-316-321


ABSTRACT

Background. The management of aggressive lymphomas in pregnancy depends on the time of diagnosis and immunomorphological variant of tumor. The rarity of aggressive lymphomas in pregnant women, the absence of consistent approaches to the treatment of such patients, the lack of data on physical growth of children as well as the incidence of newborns’ congenital and acquired pathology make this subject of vital importance.

Aim. To analyze the treatment results in patients with newly diagnosed aggressive lymphoma at different stages of pregnancy.

Materials & Methods. From 1993 to 2020 at the National Research Center for Hematology 74 pregnant women with lymphomas were treated. Aggressive tumors were detected in 17 (23 %) of them: primary mediastinal (thymic) large B-cell lymphoma (n = 14), anaplastic large-cell lymphoma ALK+ (n = 1), high-grade B-cell lymphoma, unspecified (n = 1), and diffuse large B-cell lymphoma (n = 1). The median age of patients was 30 years (range 21–37 years). The median pregnancy stage on the diagnosis of aggressive lymphoma was 21 weeks (range 11–32 weeks).

Results. In 1 case on the diagnosis of aggressive lymphoma at 11 weeks gestation dexamethasone 8 mg daily was administered up to the second trimester of pregnancy, afterwards the patient received polychemotherapy. On the diagnosis of aggressive lymphoma in the second (n = 13) and third (n = 2) trimesters of pregnancy the patients received polychemotherapy followed by delivery. In the third trimester of pregnancy delivery was performed with subsequent polychemotherapy in 1 patient. There were born 18 babies (1 pregnancy was multifetal): 8 girls and 10 boys.

Conclusion. As a result of the chosen tactics and the work of interdisciplinary team of doctors all patients, who completed the treatment, are followed-up in complete remission. All born babies, despite chemotherapy and perinatal complications, are alive and develop without abnormalities.

Keywords: malignant lymphoproliferative disorders, chemotherapy, primary mediastinal (thymic) large B-cell lymphoma, pregnancy.

Received: April 1, 2020

Accepted: June 22, 2020

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REFERENCES

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Efficient Transduction of T-Lymphocytes by Lentiviral Particles in Oncoimmunological Studies

EK Zaikova1,2, KA Levchuk1, DYu Pozdnyakov1, AA Daks2, AYu Zaritskey1, AV Petukhov1,2,3

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

2 Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

3 Sirius University of Science and Technology, 1 Olimpiiskii pr-t, Sochi, Russian Federation, 354340

For correspondence: Ekaterina Konstantinovna Zaikova, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: Catherine3452@yandex.ru

For citation: Zaikova EK, Levchuk KA, Pozdnyakov DYu, et al. Efficient Transduction of T-Lymphocytes by Lentiviral Particles in Oncoimmunological Studies. Clinical oncohematology. 2020;13(3):295–306 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-295-306


ABSTRACT

Aim. To compare different methods of lentivirus concentration in order to select the best way of providing high-level transduction for generating laboratory CAR-T cells.

Materials & Methods. Concentration of lentiviral supernatant was carried out by 4 methods: ultrafiltration, ultracentrifugation, polyethylene glycol (PEG), water-soluble non-ionic polymer, precipitation method, and ion-exchange chromatography. Functional viral titer was determined by mCherry reporter protein expression in the transduced HeLa cell line as well as by rapid immunochromatographic (IC) tests. Physical titer was determined by ELISA. Transduction efficiency of healthy donor’s T-lymphocytes was assessed by flow cytometry with respect to signal intensity of reporter protein FusionRed. Functional activity of generated anti-CD19 CAR-T was evaluated by microscopy after co-cultivation with CD19-HeLa+ cell line as well as subsequent cytokine testing.

Results. Lentivirus purification and concentration by ultrafiltration provided the greatest number of transduced cells, i.e. 84.7 %. Methods of ultracentrifugation, PEG precipitation, and ion-exchange chromatography yielded 56.08 %, 74.22 %, and 21.05 % of T-cell transduction, respectively. Results of rapid IC tests were comparable (r = 0.91) with cell line titer data. The mean T-cell transduction efficiency was 59.55 % ± 2.94 %, and its maximum reached 76.26 %.

Conclusion. The focus was laid on optimization of CAR-T cell production during the generation of lentiviral vectors and their purification. Ultrafiltration was selected as the best method of lentiviral supernatant concentration to efficiently transduce T-lymphocytes and to generate functional CAR-T cell population.

Keywords: CAR-T lymphocytes, CD19, recombinant lentivirus, lentivirus concentration.

Received: April 29, 2020

Accepted: June 25, 2020

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Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Treatment with and without the Use of Granulocyte Colony-Stimulating Factor in Post-Transplantation Period

SV Gritsaev, II Kostroma, AA Zhernyakova, IM Zapreeva, VN Chebotkevich, SS Bessmeltsev, AV Chechetkin

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

For correspondence: Ivan Ivanovich Kostroma, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: 8(812)717-54-68; e-mail: obex@rambler.ru

For citation: Gritsaev SV, Kostroma II, Zhernyakova AA, et al. Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Treatment with and without the Use of Granulocyte Colony-Stimulating Factor in Post-Transplantation Period. Clinical oncohematology. 2020;13(3):289–94 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-289-294


ABSTRACT

Background. There exist different data on how the administration of granulocyte colony-stimulating factor (G-CSF) after autologous hematopoietic stem cell transplantation (auto-HSCT) affects the duration of post-transplantation agranulocytosis in multiple myeloma (MM) patients.

Aim. To study the effect of G-CSF, administered after auto-HSCT to MM patients, on the duration of neutrophil engraftment, febrile neutropenia rate, and hospitalization duration.

Materials & Methods. The trial included 36 MM patients aged 42–69 years (median 59 years), 16 of which were not treated with G-CSF (1st group), and 20 patients received a single injection of 6 mg pegylated G-CSF on Day +4 or Day +5 (2nd group).

Results. Patients of the 1st group were significantly younger than patients of the 2nd group: median 55.5 and 61 years, respectively (= 0.006). There were no differences with respect to the number of patients who previously received lenalidomide, the overall and very good partial response rate, the number of the first and repeated auto-HSCTs, and the number of melphalan conditioning regimens. The patients who received G-CSF engrafted neutrophils on day 11 (median) after auto-HSCT, i.e. earlier than patients without G-CSF administration who engrafted neutrophils on day 13 (= 0.006). In the 1st group intravenous antibiotics were administered for a longer time than in the group with G-CSF: median 13 and 11 days, respectively (= 0.04). In 2 patients from the group without G-CSF sepsis was diagnosed. G-CSF administration led to a shorter hospital stay: median 16 and 18 days in the 1st and 2nd groups, respectively (= 0.08). There were no differences in the number of patients with febrile neutropenia.

Conclusion. G-CSF administration improves the course of the post-transplantation period in MM patients. The final decision on the feasibility of G-CSF administration after auto-HSCT can be made after more clinical observations are available.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, granulocyte colony-stimulating factor.

Received: January 14, 2020

Accepted: April 30, 2020

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Long-Term Outcomes of Nivolumab Therapy in Patients with Relapsed/Refractory Classic Hodgkin’s Lymphoma after High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Real Clinical Practice

KV Lepik1, NP Volkov1, NB Mikhailova1, EV Kondakova1, LA Tsvetkova1, YuR Zalyalov1, EE Lepik1, LV Fedorova1, AV Beinarovich1, MV Demchenkova2, OG Smykova1, PV Kotselyabina1, IS Moiseev1, VV Baikov1, BV Afanasyev1

1 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

2 Regional Oncologic Dispensary, 32 Frunze str., Irkutsk, Russian Federation, 664035

For correspondence: Kirill Viktorovich Lepik, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; е-mail: lepikkv@gmail.com

For citation: Lepik KV, Volkov NP, Mikhailova NB, et al. Long-Term Outcomes of Nivolumab Therapy in Patients with Relapsed/Refractory Classic Hodgkin’s Lymphoma after High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Real Clinical Practice. Clinical oncohematology. 2020;13(3):280–8 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-280-288


ABSTRACT

Aim. To assess prognostic factors and to analyze the outcomes of nivolumab therapy in patients with relapsed/refractory classic Hodgkin’s lymphoma (cHL) after autologous hematopoietic stem cell transplantation (auto-HSCT).

Materials & Methods. The retrospective analysis included 42 patients treated with nivolumab 3 mg/kg after auto-HSCT in the period from 2016 to 2020. The response to nivolumab therapy was assessed every three months by whole-body PET/CT based on LYRIC criteria. Toxicity profile was assessed by establishing adverse events (AE) based on NCI CTCAE 4.03 criteria.

Results. The study included 42 patients with relapsed/refractory cHL: 21 (50 %) men and 21 (50 %) women. The median age was 32.5 years (range 22–43 years). At diagnosis the following cHL stages were identified: stage II in 14 pts (33.3 %), stage III in 12 pts (28.6 %), and stage IV in 16 pts (38.1 %). Primary chemoresistance after the first-line therapy was observed in 26 pts (61.9 %) and early relapse in 4 pts (9.52 %). The median follow-up was 38 months, 3-year overall survival was 97 % (95% confidence interval, 95% CI, 83.2–99.6 %), 3-year progression-free survival (PFS) was 34.8 % (95% CI 20.3–49.9 %; median 12.9 months). Objective response was reported in 69 % of patients, complete response (CR) in 33.3 %, partial response in 35.7 %, stable disease in 7.1 %, indeterminate response in 14.3 %, and progression in 9.5 % of patients. The analysis of factors affecting PFS revealed significant differences in patients who reached CR after 6 nivolumab cycles: 3-year PFS 56.2 % (95% CI 24.4–79.1 %) vs. 25.2 % (95% CI 10.46–43.1 %) in patients who did not reach CR (= 0.054). If extranodal lesions were identified at nivolumab therapy onset, PFS was 29 % (95% CI 7.8–37.5 %) vs. 68 % (95% CI 35.9–86.8 %) in their absence (= 0.0079). The overall rate of AEs on nivolumab therapy was 92.9 %, severe AEs of grade 3–4 were observed in 19.1 % of patients.

Conclusion. Nivolumab shows high efficacy in the treatment of patients with relapsed/refractory cHL after the failure of auto-HSCT and considerably improves prognosis compared with historical control. The efficacy of nivolumab is independent of brentuximab vedotin use and duration of prior therapy. Throughout the follow-up period the toxicity level of nivolumab was acceptable and controlled. Clinical factors that affect prognosis for patients on immunotherapy were identified.

Keywords: Hodgkin’s lymphoma, nivolumab, brentuximab vedotin, auto-HSCT, immunotherapy.

Received: March 24, 2020

Accepted: June 15, 2020

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