В журнале «Клиническая онкогематология. Фундаментальные исследования и клиническая практика» опубликована статья Ю.О. Давыдовой и соавт. «Субпопуляционный состав T-хелперов у больных острыми лейкозами после трансплантации аллогенных гемопоэтических стволовых клеток» (2023;16(2):137–45). В разд. «Вклад авторов» (с. 144) напечатано: «Концепция и дизайн: Л.А. Кузьмина, Т.В. Гапонова, И.В. Гальцева, Е.Н. Паровичникова». Следует читать: «Концепция и дизайн: М.Ю. Дроков, Л.А. Кузьмина, Т.В. Гапонова, И.В. Гальцева, Е.Н. Паровичникова». Напечатано: «Предоставление материалов исследования: Д.В. Камельских, М.Ю. Дроков». Следует читать: «Предоставление материалов исследования: Д.В. Камельских».

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OE Danilova, GR Gimatdinova, IL Davydkin, OV Tereshina, VD Sabanova, GI Davydkin

Samara State Medical University, 89 Chapaevskaya ul., Samara, Russian Federation, 443099

For correspondence: Geliya Rifkatovna Gimatdinova, 89 Chapaevskaya ul., Samara, Russian Federation, 443099; Tel.: +7(919)809-68-56; e-mail: gimatdinova1995@icloud.com

For citation: Danilova OE, Gimatdinova GR, Davydkin IL, et al. New Approaches to Cardiovascular Toxicity Assessment in Patients with Hematological Malignancies: A Literature Review. Clinical oncohematology. 2023;16(3):331–6. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-331-336

ABSTRACT

Since 2016, the management of cardiovascular complications has been guided by a few documents that are based on the recommendations of the European Society of Cardiology and are regularly updated. The present literature review deals with algorithms of diagnosis and correction of cardiovascular adverse events occurring on or after drug chemotherapy in patients with hematological malignancies. The aim of this paper is to analyze the literature data on optimizing the management of chemotherapy recipients, improving their quality of life as well as reducing mortality due to drug therapy-related cardiovascular complications.

Keywords: cardiotoxicity, cardio-oncology, oncology, cardiovascular complications, chemotherapy.

Received: January 14, 2023

Accepted: June 3, 2023

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ER Shilova, NA Romanenko, DA Chebykina, TV Glazanova, MN Zenina, IE Pavlova, SS Bessmeltsev

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

For correspondence: Elena Romanovna Shilova, MD, PhD, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024; Tel.: +7(981)129-09-77; e-mail: rniiht@mail.ru

For citation: Shilova ER, Romanenko NA, Chebykina DA, et al. Long-Term Outcomes of Immunosuppressive Therapy for Aplastic Anemia: A Single-Center Experience. Clinical oncohematology. 2023;16(3):321–30. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-321-330

ABSTRACT

Background. Bone marrow transplantation-ineligible aplastic anemia (AA) is most effectively treated with combined immunosuppressive therapy (IST). It yields remissions in most patients. However, it has such disadvantages as frequent relapses, incomplete hematologic recovery, and clonal evolution risk. Besides, АА is not always treated according to standard regimens. For different reasons, some AA patients receive delayed therapy or IST mono-treatment predominantly with cyclosporine A (CsA).

Aim. To assess long-term IST outcomes in AA patients followed-up at the Russian Research Institute of Hematology and Transfusiology for 5 years after therapy onset.

Materials & Methods. The study enrolled 30 AA patients who received IST for more than 5 years (continuous follow-up of 5.5–33 years) with monitoring of the main hemogram parameters and PNH clone size. Patients were aged 19–73 years (median 29 years). There were 8 women and 12 men. Based on international criteria, severe AA (SAA) was initially diagnosed in 18 patients, and non-severe АА (NAA) was diagnosed in 12 patients. Combined IST was administered to 22 patients (18 SAA patients and 4 NAA patients), the remaining 8 patients received ATG (n = 1) and CsA (n = 7).

Results. A response to IST was achieved in 28 (93.3 %) out of 30 patients, 16 (53.3 %) of them showed complete remission. This paper documents the characteristics of hematologic recovery depending on the compliance with standard therapy regimens, as well as on the disease variant, development of late complications and clonal evolution, characteristics of pregnancy and childbirth in 4 female patients in remission. PNH clone increased in more than a half (10 out of 16) patients whose clone was initially > 2.6 %. Long-term clonal evolution to myeloid neoplasia (13 years after IST onset) was registered in 2 (6.7 %) patients with complete AA remission. Aseptic (avascular) osteonecrosis as complication was reported in 6 (20 %) followed-up patients.

Conclusion. The results of the study highlight the importance of and the need for early start and adherence to standard combined IST regimens aimed at optimum therapeutic effect in both SAA and NAA patients, as well as for long-term follow-up of patients after completing IST.

Keywords: aplastic anemia, immunosuppressive therapy, remission, complications, clonal evolution, PNH clone, pregnancy.

Received: March 7, 2023

Accepted: June 2, 2023

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EA Mamaeva, MV Solov’eva, LP Mendeleeva

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

For correspondence: Elizaveta Andreevna Mamaeva, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(982)480-51-44; e-mail: mamaeva.e@blood.ru

For citation: Mamaeva EA, Solov’eva MV, Mendeleeva LP. Multiple Myeloma Complicated by Bone Plasmacytomas: Pathogenesis, Clinical Features, Treatment Approaches (A Literature Review). Clinical oncohematology. 2023;16(3):303–10. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-303-310

ABSTRACT

Bone plasmacytoma is a malignant neoplasm consisting of plasma cells. It develops in the medullary cavities of the skeletal bones. The tumor can destroy bone cortex and proliferate into the surrounding tissues. In contrast to bone plasmacytomas, extramedullary plasmacytomas occur as a result of hematogenous dissemination in various tissues and organs. Based on literature data, the incidence of bone plasmacytomas at multiple myeloma (MM) onset is 7.0 % to 32.5 %, and at relapsed/progression ММ stages it is 9.0 % to 27.4 %. During bone plasmacytoma development, tumor cells acquire a number of new features: expression of adhesion molecules is decreased, new cytogenetic aberrations occur, autocrine secretion and neoangiogenesis are increased. The clinical course of MM complicated by bone plasmacytomas is characterized by minimal bone marrow damage, hemoglobin concentration within reference range, and decreased values of β2-microglobulin, paraprotein, calcium, and lactate dehydrogenase. Acute renal failure and immunoparesis are rare, early MM stages predominate. In literature, the MM form with multiple bone plasmacytomas is referred to as ‘macrofocal MM’. Survival rates of MM patients with bone plasmacytomas are at the intermediate level in terms of prognosis. The MM patients without plasmacytomas have the most favorable prognosis, whereas the MM patients with extramedullary plasmacytomas have the poorest prognosis. There is no unified approach to the treatment of MM complicated by bone plasmacytomas. There are no randomized prospective clinical studies on the efficacy of treating it. A successful use of proteasome inhibitors and immunomodulatory drugs was reported based on a small number of MM cases with plasmacytomas. Some studies proved the efficacy of auto-HSCT in this MM form. Bone plasmacytomas are treated with radiotherapy mainly after systemic chemotherapy.

Keywords: multiple myeloma, bone plasmacytoma, auto-HSCT.

Received: November 18, 2022

Accepted: May 22, 2023

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NI Enukashvili^1,2,3, LA Belik^1,2,3, II Kostroma¹, NYu Semenova¹, VA Balashova¹, DV Baram¹, SV Gritsaev¹, SS Bessmeltsev¹, SV Sidorkevich¹, IS Martynkevich¹

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

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

³ Pokrovskii Cell Technology Center, 85 Bolshoi pr-t V.O., Saint Petersburg, Russian Federation, 1949106

For correspondence: Natella Iosifovna Enukashvili, PhD in Biology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024; Tel.: +7(965)085-93-25; e-mail: natellae@gmail.com

For citation: Enukashvili NI, Belik LA, Kostroma II, et al. Expression of the WNT Family Genes in Multiple Myeloma Patients with Different Chemotherapy Response. Clinical oncohematology. 2023;16(3):294–302. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-294-302

ABSTRACT

Aim. To compare the expression levels of the WNT family genes in mesenchymal stromal cells (MSC) of the bone marrow (BM) hematopoietic niche in multiple myeloma (MM) patients vs. healthy donors.

Materials & Methods. The study enrolled 12 MM patients aged 49–71 years (the median age 61 years) after standard induction bortezomib therapy. The treatment efficacy was assessed in accordance with the criteria of International Myeloma Working Group (IMWG). Patients were stratified in groups with complete and partial response (CPR; group 1, n = 9) and no response (group 2, n = 3). Besides, a group of primary untreated patients was formed (n = 2). The control group included healthy donors of BM (n = 3). The levels of the WNT and CTNNB1 gene expression were assessed by real-time PCR on cDNA isolated from MSC.

Results. In the group of 2 primary patients, two genes (WNT2B and WNT9B) considerably differed in the degree of expression. In non-responders (n = 3), the WNT2B expression could not be determined, whereas the WNT15 expression appeared to be increased. In group CPR (n = 9), mRNA level of the WNT5A gene increased after therapy, whereas the WNT3A gene expression returned to the normal level. The WNT7B gene transcription level did not differ in the control and comparison groups. In group CPR, a significant expression increase in the β-catenin-coding CTNNB1 gene was detected.

Conclusion. The differences identified in the expression of the WNT2B, WNT9B, and CTNNB1 genes suggest the possibility of their use as prognostic molecular markers in MM.

Keywords: multiple myeloma, WNT signaling pathway, hematopoietic niche, mesenchymal stromal cells, prognostic markers.

Received: January 5, 2023

Accepted: May 27, 2023

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II Kostroma¹, VA Yudina^1,2, RR Sabitova¹, ES Stepchenkova^3,4, ZhV Chubukina¹, SS Bessmeltsev¹, SV Sidorkevich¹, SV Gritsaev¹

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

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

³ Saint Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

⁴ NI Vavilov Institute of General Genetics, Saint Petersburg branch, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

For correspondence: Ivan Ivanovich Kostroma, MD, PhD, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-54-68; e-mail: obex@rambler.ru

For citation: Kostroma II, Yudina VA, Sabitova RR, et al. Efficacy of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients Aged over 60 Years. Clinical oncohematology. 2023;16(3):287–93. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-287-293

ABSTRACT

Aim. To compare toxicity and efficacy of high-dose melphalan chemotherapy with subsequent autologous hematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients aged under and over 60 years.

Materials & Methods. The retrospective analysis was conducted on the data of 107 MM patients, 78 of them were aged under 60 years (median 54 years), and 29 of them were aged 61 years and older (median 63 years). All patients received auto-HSCT in the period of 2017–2022. Single and tandem auto-HSCT were performed in 92 and 15 patients, respectively. Patients with tandem auto-HSCT (n = 15), lost to follow-up patients (n = 8), and patients who died during early post-transplant period (n = 4) were excluded from survival analysis. Survival rates were calculated based on the date of auto-HSCT.

Results. A comparative evaluation of the results in two age groups showed a significant difference in the number of patients treated with ixazomib during the induction period (р = 0.019) and cyclophosphamide 3 g/m² as part of auto-HSC mobilization (р = 0.014), as well as 200 or 140 mg/m² melphalan as part of conditioning regimen (р = 0.039 and р = 0.009, respectively). With a follow-up median of 13 months (range 1–57 months), the median progression-free survival in the groups ≤ 60 years vs. > 60 years was 32 and 47 months, respectively (hazard ratio [HR] 0.688; 95% confidence interval [95% CI] 0.270–1.754; p = 0.704). The median overall survival in patients aged under 60 years appeared to be 57 months, it was not reached in patients aged 61 years and older (HR 0.689; 95% CI 0.169–2.803; р = 0.577).

Conclusion. The results of the study suggest that all newly diagnosed MM patients aged under 70 years should be regarded as being eligible for auto-HSCT.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, elderly patients.

Received: March 7, 2023

Accepted: June 8, 2023

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YaK Mangasarova¹, TN Moiseeva¹, OV Margolin¹, LG Gorenkova¹, ES Nesterova¹, FE Babaeva¹, MO Bagova¹, EA Fastova¹, RR Abdurashidova¹, LS Al-Radi¹, EI Dorokhina¹, EM Volodicheva², VA Lapin³, OS Samoilova⁴, SK Kravchenko¹, AU Magomedova¹, EE Zvonkov¹

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

² Tula Regional Clinical Hospital, 1A korp. 1 Yablochkova ul., Tula, Russian Federation, 300053

³ Regional Clinical Hospital, 7 Yakovlevskaya ul., Yaroslavl, Russian Federation, 150062

⁴ NA Semashko Nizhny Novgorod Regional Clinical Hospital, 190 Rodionova ul., Nizhny Novgorod, Russian Federation, 603126

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, Moiseeva TN, Margolin OV, et al. Nivo-BeGEV as Preparation for Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Classical Hodgkin Lymphoma: Results of a Multi-Center Prospective Clinical Study. Clinical oncohematology. 2023;16(3):280–6. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-280-286

ABSTRACT

Aim. To assess efficacy and safety of the Nivo-BeGEV (nivolumab combined with bendamustine, gemcitabine, and vinorelbine) immunochemotherapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) selected as candidates for autologous hematopoietic stem cell transplantation (auto-HSCT).

Materials & Methods. During 2018–2022, the study enrolled 51 r/r cHL patients treated with the Nivo-BeGEV immunochemotherapy. The median age was 38 years (range 19–57 years). There were 30 men and 21 women. PET-CT was performed to assess the response according to the LYRIC criteria. Safety and tolerability were analyzed by registering adverse events in line with the NCI CTCAE criteria, version 5.

Results. The median follow-up was 12 months (range 3–54 months). Complete remissions were reported in 100 % of cases. An early relapse was observed in 1 (2 %) patient. The 2-year overall and progression-free survivals were 100 % and 93 %, respectively. During Nivo-BeGEV administration, severe adverse events of grade 3/4 developed in 6 (13 %) out of 51 patients.

Conclusion. The results of this multi-center prospective clinical study of the Nivo-BeGEV immunochemotherapy used as preparation for auto-HSCT in r/r cHL patients showed high efficacy irrespective of prior drug chemotherapy and its duration with an acceptable toxicity profile.

Keywords: classical Hodgkin lymphoma, Nivo-BeGEV immunochemotherapy, autologous hematopoietic stem cell transplantation, immune checkpoint inhibitors, relapse, refractory course.

Received: March 13, 2023

Accepted: June 9, 2023

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KA Levchuk¹, AA Goldaeva², EA Stolyarova³, PA Mateikovich⁴, AKh Valiullina⁵, ER Bulatov⁵, AV Petukhov¹, AA Daks⁶, NA Barlev⁶, EV Baidyuk⁶, YaG Toropova¹

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

² Saint Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

³ Dr. Sergey Berezin Medical Institute (MIBS), 1 korp. 3 Esenina ul., Saint Petersburg, Russian Federation, 194354

⁴ HEMA, 3 korp. 3 4th 8 Marta ul., Moscow, Russian Federation, 125319

⁵ Kazan (Privolzhsky) Federal University, 18 Kremlevskaya ul., Kazan, Russian Federation, 420008

⁶ Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

For correspondence: Kseniya Aleksandrovna Levchuk, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341; Tel.: +7(951)680-79-60; e-mail: ksenialevchuk2@gmail.com

For citation: Levchuk KA, Goldaeva AA, Stolyarova EA, et al. Classic and Activating Chimeric Antigen Receptors PD-1 as an Element of Multi-Target Approach to the Treatment of Hematological and Solid Neoplasms. Clinical oncohematology. 2023;16(3):268–79. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-268-279

ABSTRACT

Aim. To generate anti-PD-L1 CAR-T effectors carrying extracellular domain PD-1 as antigen-recognizing site and to study their cytolytic activity as well as to functionally assess the anti-PD-L1 CAR-T effectors in vitro with a view to apply them in multi-targeted tumor therapy.

Materials & Methods. Chimeric antigen receptor PD-1 was constructed using molecular cloning of PD-1 antigen-recognizing region (12–170 amino acids) into mammalian expression plasmid vector adding activation and co-stimulatory domains. Primary Т-lymphocytes of healthy donor peripheral blood mononuclear fraction were derived by expanding monoclonal antibody combination on surface markers CD3/CD28. Anti-PD-L1 CAR-T effectors were obtained by lentiviral transduction of primary T-lymphocyte genome of a healthy donor. Chimeric antigen receptor PD-1 expression and transduction efficiency were assessed by flow cytofluorometry. Specific cytotoxicity of the anti-PD-L1 CAR-T effectors was analyzed in vitro by means of real-time cytotoxicity assay (RTCA) with HeLa_PD-L1 target cell line co-cultivation. The level of cytokines IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A was assessed by flow cytofluorometry using Human Th1/Th2/Th17 CBA Kit (BD, USA).

Results. The efficiency of lentiviral transduction and the proportion of the anti-PD-L1 CAR-T effectors were 42 %. The specificity of cytotoxic response of the anti-PD-L1 CAR-T effectors with a low effector/tumor ratio (1:20) was verified during HeLa_PD-L1 co-cultivation by a 1.5-fold decrease in the cell index (CI = 0.738) versus control (CI = 1.0645). The increase in synthesis of cytokines IL-2 (1000 pg/mL), IL-6 (438.5 pg/mL), TNF-α (44 pg/mL), and IFN-γ (1034 pg/mL) during HeLa_PD-L1 target cell line co-cultivation confirms the functionality of the analyzed effector cells.

Conclusion. Anti-PD-L1 chimeric antigen receptor was constructed and tested in vitro. Anti-PD-L1 CAR-T lymphocytes specifically recognize and promote the cytolysis of tumor target cells by increased secretion of pro-inflammatory cytokines IFN-γ, TNF-α, IL-6, and IL-2. Chimeric antigen receptor PD-1 can be modified into chimeric switch receptor (CSR) by deleting CD3ζ-domain and can be used together with other CARs without predicted non-specific toxicity.

Keywords: CAR-T cell therapy, PD-1, anti-PD-L1 CAR-T effectors, tumor microenvironment, multi-targeted immunotherapy.

Received: February 8, 2023

Accepted: June 3, 2023

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BT Dzhumabaeva

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

For correspondence: Boldukyz Tolgonbaevna Dzhumabaeva, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-64-63, +7(926)271-92-82; e-mail: bola.blood@yandex.ru

For citation: Dzhumabaeva BT. The Role of Leukocytes in the Formation of Neutrophil Extracellular Traps and Thrombosis in Ph-Negative Myeloproliferative Neoplasms: A Literature Review. Clinical oncohematology. 2023;16(3):263–7. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-263-267

ABSTRACT

Thrombotic complications often cause death in patients with chronic Ph-negative myeloproliferative neoplasms (MPNs). In spite of numerous studies, the pathogenesis of thrombus formation in MPN patients remains unclear. Its mechanism is complex and is determined by many factors. One of the essential phases in thrombogenesis is characterized by the activation of cell mechanisms and formation of neutrophil extracellular traps (NETs). NETs consist of DNA strands, histones, granular proteins and along with pathogen destruction provide an ideal matrix for platelet and clotting mechanism activation.

Keywords: myeloproliferative neoplasms, neutrophils, thrombosis, neutrophil extracellular traps (NETs).

Received: December 14, 2022

Accepted: May 29, 2023

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