danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1561-8323-2023-67-2-126-133dan-1120Research ArticleМЕДИЦИНАMEDICINEНепосредственные и отдаленные результаты применения схем R-CHOP И R-CHOP + интерлейкин-2 в первой линии терапии у пациентов, страдающих диффузной В-крупноклеточной лимфомойResults of R-CHOP and R-CHOP + interleukin-2 regimens in first-line therapy in patients with diffuse B-cell lymphomaКрасныйС. А.KrasnyS. A.

Красный Сергей Анатольевич ‒ академик, д-р мед.наук, профессор, заместитель директора

223040, агр. Лесной, Минский р-н

Krasny Sergei A. ‒ Academician, D. Sc. (Medicine), Professor, Deputy Director

223040, Lesnoy, Minsk region

sergeykrasny@tut.byhttps://orcid.org/0000-0003-0592-7182КонопляН. Е.KonoplyaN. E.

Конопля Наталья Евгеньевна – д-р мед. наук, профессор, гл. науч. сотрудник

223040, агр. Лесной, Минский р-н

Konoplya Natalya E. – D. Sc. (Medicine), Professor,Chief Researcher

223040, Lesnoy, Minsk region

nkonoplya@mail.ruhttps://orcid.org/0000-0001-8629-2830КаленикО. А.KalenikV. A.

Каленик Ольга Александровна – канд. мед. наук, вед. науч. сотрудник

223040, агр. Лесной, Минский р-н

Kalenik Volha A. – Ph. D. (Medicine), Leading Researcher

223040, Lesnoy, Minsk region

olga.a.kalenik@mail.ruhttps://orcid.org/0000-0002-1324-3656ДемешкоП. Д.DziameshkaP. D.

Демешко Павел Дмитриевич ‒ д-р мед. наук, доцент,гл. науч. сотрудник

223040, агр. Лесной, Минский р-н

Dziameshka Pavel D. ‒ D. Sc. (Medicine), AssociateProfessor, Chief Researcher

223040, Lesnoy, Minsk region

pdemeshko@icloud.comРеспубликанский научно-практический центр онкологии и медицинской радиологии имени Н. Н. АлександроваN. N. Alexandrov National Cancer Centre202307052023672126133Copyright © Красный С.А., Конопля Н.Е., Каленик О.А., Демешко П.Д., 20232023Красный С.А., Конопля Н.Е., Каленик О.А., Демешко П.Д.Krasny S.A., Konoplya N.E., Kalenik V.A., Dziameshka P.D.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://doklady.belnauka.by/jour/article/view/1120

Исследование проведено с целью оценки влияния применения интерлейкина-2 (ИЛ-2) в составе схемы R-CHOP на частоту достижения полного метаболического ответа (ПМО) по данным ранней позитронно-эмиссионной томографии (ПЭТ/КТ) и выживаемость без прогрессирования в сравнении со стандартной схемой у пациентов с диффузной В-крупноклеточной лимфомой (ДВКЛ). В исследование включены данные 152 пациентов с ДВКЛ, проходивших обследование и лечение в РНПЦ ОМР им. Н. Н. Александрова в период 2015–2020 гг. Из их числа 59 пациентов включены в проспективную группу (R-CHOP + ИЛ-2 в суммарной курсовой дозе 5 000 000 МЕ), группу исторического контроля составили 93 человека, получавших стандартную терапию R-CHOP. ПЭТ/КТ выполнялось после 4 курсов терапии, метаболический ответ оценивали по шкале Довиль, к ПМО относили Довиль 1-2. В группе R-CHOP + ИЛ-2 частота ПМО составила 67,8 %, в контрольной – 50,5 % (рχ² = 0,044). 5-летняя выживаемость без прогрессирования (ВБП) в группах R-CHOP + ИЛ-2 и R-CHOP составила соответственно 80,7 и 64,5 % (р = 0,04). В группах благоприятного и промежуточного прогноза (МПИ 0–3) ВБП статистически значимо не отличалась в зависимости от проведенного лечения. При высоком риске (МПИ 4–5) 5-летняя ВБП в группах R-CHOP + ИЛ-2 и R-CHOP составила 71,4 и 25,0 % соответственно (р = 0,02). Дополнительное включение ИЛ-2 в схему R-CHOP в первой линии лечения пациентов с ДВКЛ повышает частоту ПМО по данным 18-ФДГ ПЭТ/КТ после 4 курсов химиоиммунотерапии и ВБП в группе высокого риска. 

The study was made to evaluate the effect of interleukin-2 (IL-2) as part of the R-CHOP regimen on the rate of a complete metabolic response (CMR) using the data of interim positron emission tomography (PET/CT) and progression-free survival compared to the standard regimen in patients with diffuse B-cell lymphoma (DCLC). The data of 152 patients with biopsy-proven DCLC who were treated in the period 2015–2020 were included. Among them, 59 patients were included in the prospective group (R-CHOP + IL-2 in a total course dose of 5,000,000 IU). The control group consisting of 93 patients received standard R-CHOP therapy. PET/CT was performed after 4 courses of therapy, metabolic response was assessed using the Deauville scale, and Deauville 1-2 was classified as CMR. The rate of CMR in the R-CHOP+IL-2 group was 67.8 %, while in the control group it was 50.5 % (pχ² = 0.044). The 5-year progression-free survival (PFS) in the R-CHOP+IL-2 and R-CHOP groups was 80.7 and 64.5 %, respectively (p = 0.04). In the favorable and intermediate prognosis groups (IPI 0–3), PFS was not statistically significantly different depending on treatment. At high risk (IPI 4–5), the 5-year PFS in the R-CHOP + IL-2 and R-CHOP groups was 71.4 and 25.0 %, respectively (p = 0.02). Including IL-2 in the R-CHOP regimen in the first-line treatment of patients with DCLC increases the incidence of CMR according to 18-FDG PET/CT after 4 courses of chemoimmunotherapy and PFS in the high-risk group.

диффузная В-крупноклеточная лимфомаR-CHOPинтерлейкин-2позитронно-эмиссионная томографияdiffuse B-cell lymphomaR-CHOPinterleukin-2interim positron emission tomographyReferencesSehn, L. H. Diffuse Large B-Cell Lymphoma / L. H. Sehn, G. N. Salles // Engl. J. Med. – 2021. – Vol. 384, N 9. – P. 842–858. https://doi.org/10.1056/NEJMra2027612Sehn L. H., Salles G. N. Diffuse Large B-Cell Lymphoma. New England Journal of Medicine, 2021, vol. 384, no. 9, pp. 842–858. https://doi.org/10.1056/NEJMra2027612A guide to Hodgkin and non-Hodgkin lymphomas: similarities and differences / F. Holdsworth [et al.] // Br. J. Nurs. – 2021. – Vol. 23, N 30. – P. 16–22. https://doi.org/10.12968/bjon.2021.30.17.S16Holdsworth F., Worku D., Bretton A. L., Vella C., Walker E. A guide to Hodgkin and non-Hodgkin lymphomas: similarities and differences. British Journal of Nursing, 2021, vol. 30, no. 17, pp. 16–22. https://doi.org/10.12968/bjon.2021.30.17.S16Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma / Н. Tilly [et al.] // Blood. – 2003. – Vol. 102, N 13. – Р. 4284–4289. https://doi.org/10.1182/ blood-2003-02-0542Tilly H., Lepage E., Coiffier B. [et al.]. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood, 2003, vol. 102, no. 13, pp. 4284–4289. https://doi. org/10.1182/blood-2003-02-0542CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group / M. Pfreundschuh [et al.] // Lancet. Oncol. – 2011. – Vol. 12, N 11. – P. 1013–1022. https://doi.org/10.1016/S1470-2045(11)70235-2Pfreundschuh M., Kuhnt E., Trümper L. [et al.]. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncology, 2011, vol. 12, no. 11, pp. 1013–1022. https://doi.org/10.1016/S1470-2045(11)70235-2Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60) / M. Pfreundschuh [et al.] // Lancet. Oncol. – 2008. – Vol. 9, N 2. – P. 105–116. https://doi.org/10.1016/s1470-2045(08)70002-0Pfreundschuh M., Schubert J, Ziepert M. [et al.]. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncology, 2008, vol. 9, no. 2, pp. 105–116. https://doi.org/10.1016/s1470-2045(08)70002-0Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study / M. Crump [et al.] // Blood. – 2017. – Vol. 130, N 16. – P. 1800–1808. https://doi.org/10.1182/blood-2017-03-769620Crump M., Neelapu S. S., Farooq U. [et al.]. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood, 2017, vol. 130, no. 16, pp. 1800–1808. https://doi.org/10.1182/blood-2017-03-769620Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients / J. J. Eertink [et al.] // Blood. Adv. – 2021. – Vol. 5, N 9. – P. 2375–2384. https://doi.org/10.1182/bloodadvances.2021004467Eertink J. J., Burggraaff C. N., Heymans M. W. [et al.]. Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients. Blood Advances, 2021, vol. 5, no. 9, pp. 2375–2384. https://doi.org/10.1182/bloodadvances.2021004467A Predictive model for aggressive non-Hodgkin’s lymphoma. The International non-Hodgkin’s lymphoma prognostic factors project / M. A. Shipp [et al.] // N. Engl. J. Med. – 1993. – Vol. 329. – P. 987–994. https://doi.org/10.1056/NEJM199309303291402Shipp M. A., Harrington D. P., Anderson J. R. [et al.]. A Predictive model for aggressive non-Hodgkin’s lymphoma. The International non-Hodgkin’s lymphoma prognostic factors project. New England Journal of Medicine, 1993, vol. 329, pp. 987–994. https://doi.org/10.1056/NEJM199309303291402Cragg, M. S. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents / M. S. Cragg, M. J. Glennie // Blood. – 2004. – Vol. 103, N 7. – P. 2738–2743. https://doi.org/10.1182/blood-2003-06-2031Cragg M. S., Glennie M. J. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood, 2004, vol. 103, pp. 2738–2743. https://doi.org/10.1182/blood-2003-06-2031Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy / M. J. Maurer [et al.] // J. Clin. Oncol. – 2014. – Vol. 32, N 10. – P. 1066–1073. https://doi. org/10.1200/JCO.2013.51.5866Maurer M. J., Ghesquières H, Jais J.-P. [et al.]. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. Journal of Clinical Oncology, 2014, vol. 32, no. 10, pp. 1066–1073. https://doi.org/10.1200/JCO.2013.51.5866Phase I studies of interleukin (IL-2) and rituximab in B-cell non-Hodgkin’s lymphoma: IL-2 mediated natural killer cell expansion correlates with clinical response / W. L. Gluck [et al.] // Clin. Cancer. Res. – 2004. – Vol. 10, N 7. – P. 2253– 2264. https://doi.org/10.1158/1078-0432.ccr-1087-3Gluck W. L., Hurst D., Yuen A. [et al.]. Phase I studies of interleukin (IL-2) and rituximab in B-cell non-Hodgkin’s lymphoma: IL-2 mediated natural killer cell expansion correlates with clinical response. Clinical Cancer Research, 2004, vol. 10, no. 7, pp. 2253–2264. https://doi.org/10.1158/1078-0432.ccr-1087-3Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration – effect relationship / S. Dall’Ozzo [et al.] // Cancer. Res. – 2004. – Vol. 64, N 13. – P. 4664–4669. https://doi.org/10.1158/0008- 5472.CAN-03-2862Dall’Ozzo S., Tartas S., Paintaund G., Cartron G., Colombat P., Bardos P., Watier H., Thibault G. Rituximabdependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration – effect relationship. Cancer Research, 2004, vol. 64, no. 13, pp. 4664–4669. https://doi.org/10.1158/0008-5472.CAN-03-2862Combination immunotherapy of B-cell non-Hodgkin’s Lymphoma with rituximab and interleukin-2: a preclinical and phase I study / C. F. Eisenbeis [et al.] // Clin. Cancer Res. – 2004. – Vol. 10, N 18. – P. 6101–6110. https://doi.org/10.1158/1078- 0432.CCR-04-0525Eisenbeis C. F., Grainger A., Fisher B. [et al.]. Combination immunotherapy of B-cell non-Hodgkin’s Lymphoma with rituximab and interleukin-2: a preclinical and phase I study. Clinical Cancer Research, 2004, vol. 10, no. 18, pp. 6101–6110. https://doi.org/10.1158/1078-0432.CCR-04-0525Combination immunotherapy with rituximab and interleukin-2 in patients with relapsed or refractory follicular non-Hodgkin’s lymphoma / J. W. Friedberg [et al.] // Brit. J. Haemathol. – 2002. – Vol. 117, N 4. – P. 828–834. https://doi. org/10.1046/j.1365-2141.2002.03535.xFriedberg J. W., Neuberg D., Gribben J. G. [et al.]. Combination immunotherapy with rituximab and interleukin-2 in patients with relapsed or refractory follicular non-Hodgkin’s lymphoma. British Journal of Haematology, 2002, vol. 117, no. 4, pp. 828–834. https://doi.org/10.1046/j.1365-2141.2002.03535.x

The authors declare that there are no conflicts of interest present.