AA Shatilova¹, IG Budaeva², IE Prokop’ev², YuV Mirolyubova¹, DV Ryzhkova², KV Bogdanov¹, TS Nikulina², AV Petrov², TV Chitanava¹, DV Motorin¹, EN Tochenaya², AI Reshetova¹, SV Efremova², EK Antonov¹, VV Ivanov¹, AV Petukhov¹, YuA Alekseeva¹, EG Lomaia¹, LL Girshova¹

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

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

For correspondence: Aleksina Alekseevna Shatilova, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341; Tel.: +7(911)476-35-58; e-mail: alexina-96@list.ru

For citation: Shatilova AA, Budaeva IG, Prokop’ev IE, et al. Gilteritinib as a New Option for the Treatment of Relapsed/Refractory Acute Myeloid Leukemias with FLT3 Gene Mutation: A Literature Review and Three Case Reports. Clinical oncohematology. 2023;16(1):69–79. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-69-79

ABSTRACT

Acute myeloid leukemias (AML) are the most ubiquitous of all adult leukemias. The prognosis of the disease depends on its genetic profile. The mutation in FLT3 gene, which codes FMS-like tyrosine kinase 3, is observed in 1/3 of patients and is responsible for a high rate of relapses. The prognosis of relapsed/refractory FLT3-positive AML is extremely poor. The standard intensive therapy rarely yields long-term responses. The new first- and second-generation FLT3 tyrosine kinase inhibitors enriched treatment opportunities for patients with this mutation. Gilteritinib, a potent second-generation FLT3-ITD/TKD inhibitor, is a new effective and well tolerated drug for the treatment of relapsed/refractory FLT3-positive AML. Due to its efficacy, low toxicity, and good manageability, this drug can be administered to all patients, including the elderly or those with severe comorbidities and complications of previous therapy. Besides, this drug can be used in outpatient units. The present paper contains three case reports dealing with different clinical situations in patients with FLT3-positive AML treated with gilteritinib in real-world clinical practice.

Keywords: acute myeloid leukemias, FLT3, gilteritinib.

Received: September 16, 2022

Accepted: December 12, 2022

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AG Turkina¹, EA Kuzmina¹, EG Lomaia², EV Morozova³, EYu Chelysheva¹, OA Shukhov¹, AN Petrova¹, TV Chitanava², YuYu Vlasova³, IS Nemchenko¹, AV Bykova¹, EI Sbityakova², MA Gurianova¹, NN Tsyba¹, AV Kokhno¹, EN Parovichnikova¹

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

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

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 ul., Saint Petersburg, Russian Federation, 197022

For correspondence: Elena Andreevna Kuzmina, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(918)167-35-69; e-mail: 1110ekuzmina@gmail.com

For citation: Turkina AG, Kuzmina EA, Lomaia EG, et al. Asciminib in Chronic Myeloid Leukemia Patients Without Therapeutic Alternatives Alternatives: Results of the MAP (Managed Access Program, NCT04360005) Trial in Russia. Clinical oncohematology. 2023;16(1):54–68. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-54-68

ABSTRACT

Aim. To assess the efficacy and tolerability of asciminib in chronic myeloid leukemia (CML) patients after failure of ≥ 2 lines of tyrosine kinase inhibitors (TKIs) therapy under the МАР (Managed Access Program, NCT04360005) in Russia.

Materials & Methods. The study enrolled 68 patients with Ph-positive CML chronic phase (CF), over 18 years of age, after failure of ≥ 2 lines of TKI therapy. The analysis was conducted on data from 50 patients who were followed-up for at least 3 months and did not undergo allo-HSCT. Dosing regimens were prescribed depending on T315I mutation. Asciminib 200 mg per os was administered twice a day to 20 patients with this mutation, and asciminib 40 mg per os was administered twice a day to 30 patients without this mutation. By the time of admission into the MAP, there were 42 (82 %) CF CML patients as well as 8 patients with second CF after accelerated phase (AF, n = 7) and myeloid blast crisis (BC, n = 1). None of them could be treated with any therapeutic alternative. 92 % of patients had received ≥ 3 lines of prior TKI therapy. Overall survival (OS) and discontinuation-free survival were estimated by the Kaplan-Meier method. A cumulative incidence function (CIF) was used to calculate the probability of achieving response. Multivariate analysis was based on Cox regression model.

Results. The median asciminib treatment duration was 11 months (range 4–30 months). The probable 2-year OS was 96 %. After 12 and 24 months, discontinuation-free survival was 92 % and 70 %, respectively. On asciminib therapy, complete cytogenetic (CCyR/МR2), major molecular (MMR), and deep molecular (MR4) responses were achieved in 17 (42 %), 14 (30 %), and 9 (19 %) patients who had not responded to prior treatment at the point of enrollment. After completing the 12- and 24-month therapy, the probability of CCyR/МR2 achievement was 44 % and 62 %, that of MMR achievement was 32 % and 40 %, and that of MR4 achievement was 26 % and 37 %, respectively. The patients treated with different doses did not significantly differ in achieving either CCyR/МR2 or MMR. By multivariate analysis, the independently significant factor impacting the probability of achieving MMR on asciminib treatment was the best MR (BCR::ABL1 < 1 % vs. 1–10 % vs. ≥ 10 %) after prior TKI therapy (hazard ratio 7.5873; p = 0.0072). In 22 (44 %) patients, adverse events (AEs) of all grades were observed, and 8 (16 %) patients showed AEs grade 3/4 (predominantly thrombocythemia and neutropenia). None of the patients discontinued asciminib treatment due to AEs.

Conclusion. Asciminib demonstrated highly promising efficacy in previously TKI-treated patients with T315I mutation (200 mg BID) and without it (40 mg BID). Asciminib can be regarded as therapeutic option after failure of other TKIs. Different doses of asciminib were equally well tolerated, which makes it applicable for patients with intolerance to other TKIs and also provides ground for considering dose increases in non-responders. Good prospects are also expected for studying asciminib efficacy at earlier treatment stages (in first or second lines) as well as in combination with ATP-binding TKIs in CML patients with insufficient response to TKI treatment.

Keywords: chronic myeloid leukemia, asciminib, resistance, third-line therapy, managed access program.

Received: September 22, 2022

Accepted: December 18, 2022

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TV Antonova¹, MS Nozhkin¹, DA Lioznov^1,2

¹ IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022

² AA Smorodintsev Research Institute of Influenza, 15/17 Professora Popova ul., Saint Petersburg, Russian Federation, 197376

For correspondence: Prof. Tamara Vasilevna Antonova, MD, PhD, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022; e-mail: antonovatv28@yandex.ru

For citation: Antonova TV, Nozhkin MS, Lioznov DA. Chronic Hepatitis С and Oncohematological Diseases. Clinical oncohematology. 2023;16(1):46–53. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-46-53

ABSTRACT

This review focuses on HCV infection in oncohematological patients. High risk of hepatitis C virus (HCV) infection within this group of patients was proved by a significantly (2.0–2.5 times) higher HCV infection rate in non-Hodgkin’s lymphoma patients compared to population data. Besides, the review demonstrates the importance of HCV in the development and progression of B-cell non-Hodgkin’s lymphomas, which is confirmed by its tumorigenicity. The paper reviews the variant of seronegative (occult) hepatitis С, which is characterized by HCV RNA detected in liver tissue and peripheral blood mononuclear cells by highly sensitive reverse transcription PCR with the absence of serum HCV and HCV RNA antibodies. In this case, patients can present a source of infection. Seronegative hepatitis С is detected in donor blood in 2.2–3.4 % of cases. This infection variant is identified in 20–85 % of oncohematological patients, which needs to be further examined. Comorbid HCV infection is a potential prognostic factor in oncohematological diseases. Oncohematological patients with comorbid chronic hepatitis C (CHC) show considerably worse survival as compared with patients without it. HCV infection is associated with increased complication rates in both chemotherapy and hematopoietic stem cell transplantation (HSCT). Immunochemotherapy, on the other hand, affects CHC exacerbation and progression. High efficacy and good tolerability of direct-acting antiviral agents (DAA) in CHC therapy opened new prospects for their wide use in cases of comorbid diseases. HCV treatment in patients after HSCT still remains an issue. The guidelines for CHC treatment are predominantly formulated with a view to antiviral pre-HSCT therapy which is not always feasible in real-world clinical practice. The review contains examples of effective use of DAA drugs before or after HSCT and a case of antiviral treatment administered simultaneously with HSCT.

Keywords: hepatitis C virus, HCV infection, oncohematology, hematopoietic stem cell transplantation, immunochemotherapy, direct-acting antiviral agents.

Received: June 17, 2022

Accepted: December 10, 2022

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AA Petrenko^1,2, MI Kislova¹, EA Dmitrieva¹, EA Nikitin^1,2, VV Ptushkin^1,2,3

¹ SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

² Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993

³ NI Pirogov Russian National Research Medical University, 1 Ostrovityanova ul., Moscow, Russian Federation, 117997

For correspondence: Mariya Igorevna Kislova, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; e-mail: xkislovamariax@gmail.com

For citation: Petrenko AA, Kislova MI, Dmitrieva EA, et al. Combination of Ibrutinib and Venetoclax in the Therapy of Chronic Lymphocytic Leukemia: A Review of the Latest Data from Clinical Studies. Clinical oncohematology. 2023;16(1):37–45. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-37-45

ABSTRACT

New Bruton’s tyrosine kinase (BTK) inhibitors caused drastic modifications in the therapy of chronic lymphocytic leukemia (CLL). Ibrutinib, the first in its class BTK inhibitor, showed high efficacy in many clinical studies. However, the treatment with BTK inhibitors as monotherapy must not be discontinued. Ibrutinib monotherapy inevitably leads to BTK inhibitor resistance and severe adverse events, which often results in treatment failure. Inhibitor BCL-2 venetoclax combined with BTK inhibitor can increase the therapy efficacy due to the synergetic effect of these agents on different CLL cell populations. Combined therapy potentially providing fixed-duration treatment can yield deeper responses. The present review focuses on ibrutinib and venetoclax combination, summarizes the latest data from clinical studies, and deals with feasibility of combined therapy in terms of its efficacy and safety profile.

Keywords: ibrutinib, BTK inhibitors, venetoclax, BCL-2 inhibitors, targeted agents, chronic lymphocytic leukemia.

Received: October 17, 2022

Accepted: November 10, 2022

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AS Luchinin

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

For correspondence: Aleksander Sergeevich Luchinin, MD, PhD, 72 Krasnoarmeiskaya ul., Kirov, Russian Federation, 610027; Tel.: +7(919)506-87-86; e-mail: glivec@mail.ru

For citation: Luchinin AS. Prognostic Models in Medicine. Clinical oncohematology. 2023;16(1):27–36. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-27-36

ABSTRACT

Medical prognostic (prediction) models (MPM) are essential in modern healthcare. They determine health and disease risks and are created to improve diagnosis and treatment outcomes. All MPMs fall into two categories. Diagnostic medical models (DMM) aim at assessing individual risk for a disease present, whereas predictive medical models (PMM) evaluate the risk for development of a disease and its complications in future. This review discusses DMM and PMM characteristics, conditions for their elaboration, criteria for medical application, also in hematology, as well as challenges of their creation and quality check.

Keywords: prognostic model, artificial intelligence.

Received: September 13, 2022

Accepted: December 7, 2022

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MV Marchenko, YuN Kuznetsov, AV Lapina, IA Mikhailova, TA Bykova, TS Shchegoleva, VV Baikov, AD Kulagin

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

For correspondence: Mariya Viktorovna Marchenko, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-65; e-mail: mv_bogomolova@mail.ru

For citation: Marchenko MV, Kuznetsov YuN, Lapina AV, et al. WHIM Syndrome: A Literature Review and a Report of Two Cases in One Family. Clinical oncohematology. 2023;16(1):14–26. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-14-26

ABSTRACT

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) is a rare genetic disease associated with activating germline mutations in the gene encoding chemokine receptor CXCR4. WHIM syndrome is manifested by neutropenia, lymphopenia, infections, and degenerative changes of mature neutrophils with bone marrow myeloid hyperplasia (myelokathexis). Some patients show hypogammaglobulinemia, persistent cutaneous, genital, or elsewhere localized warts. There are also cases of congenital heart defects. The present paper extensively analyzes genetic basis, pathophysiology, clinical manifestations, and diagnosis of WHIM syndrome as well as its treatment options. The paper reports two cases in one family.

Keywords: WHIM syndrome, CXCR4, warts, hypogammaglobulinemia, infections, myelokathexis.

Received: August 30, 2022

Accepted: December 2, 2022

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SV Semochkin^1,2

¹ PA Gertsen Moscow Oncology Research Institute, branch of the NMRC of Radiology, 3 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

² NI Pirogov Russian National Research Medical University, 1 Ostrovityanova ul., Moscow, Russian Federation, 117997

For correspondence: Prof. Sergei Vyacheslavovich Semochkin, MD, PhD, 3 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; e-mail: semochkin_sv@rsmu.ru

For citation: Semochkin SV. CAR-T Therapy of Multiple Myeloma, Based on the of Congresses ASH-2021 and ASCO-2022. Clinical oncohematology. 2023;16(1):1–13. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-1-13

ABSTRACT

Current treatment of multiple myeloma (ММ) based on proteasome inhibitors, immunomodulating drugs, and monoclonal antibodies has, to a certain extent, reached the limit of its potential. Despite considerable clinical advance, ММ still remains a chronic incurable disease. Tumor-specific T-cell therapy with chimeric antigen receptor (CAR) is a new evolution step towards achieving MM cure. Today, B-cell maturation antigen (BCMA) is regarded as the primary target of CAR-T treatment of MM. This receptor is mainly expressed on the surface of tumor plasma cells in ММ as well as in B-cells of late differentiation stages and normal plasma cells. In 2021–2022, two CAR-T drugs, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), were approved for clinical use in the USA and the European Union for patients with relapsed/refractory MM. The studies of these drugs yielded encouraging clinical results. Other antigen (GPRC5D, SLAMF7) cell-based drugs are now in early stages of development. The present review is concerned with latest advances in CAR-T therapy for MM reported at the recent congresses ASH-2021 and ASCO-2022. The review comprehensively discusses the results of the KarMMa (ide-cel, stage II) and CARTITUDE-1 (cilta-cel, stage IB/II) studies. It also provides historical background of CAR-Т cell generation as well as preclinical and on-going clinical trial data on MM. It outlines potential failure causes and prospects of further improvement of the new technology.

Keywords: CAR-T therapy, multiple myeloma, chimeric antigen receptor, B-cell maturation antigen.

Received: June 17, 2022

Accepted: December 2, 2022

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AA Danilenko, SV Shakhtarina, NA Falaleeva

AF Tsyb Medical Radiological Research Centre, branch of the NMRC of Radiology, 4 Koroleva ul., Obninsk, Kaluga Region, Russian Federation, 249036

For correspondence: Anatolii Aleksandrovich Danilenko, MD, PhD, 4 Koroleva ul., Obninsk, Kaluga Region, Russian Federation, 249036; Tel.: +7(909)250-18-10; e-mail: danilenkoanatol@mail.ru

For citation: Danilenko AA, Shakhtarina SV, Falaleeva NA. Acute Myeloid Leukemias After the Treatment of Classical Hodgkin’s Lymphoma: A Literature Review. Clinical oncohematology. 2022;15(4):414–23. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-414-423

ABSTRACT

Second malignant tumors occurring in classical Hodgkin’s lymphoma (cHL) patients after treatment include mainly solid neoplasms and far more rarely acute myeloid leukemias (AML). At the same time, a relative risk of developing secondary AML substantially exceeds the risks of second (solid) tumors, and the efficacy of secondary AML treatment is considerably lower compared to the outcomes of primary AML treatment. All that implies the importance and relevance of this issue. The present literature review discusses the epidemiology of developing secondary AMLs in patents after cHL treatment. In addition to that, it focuses on modern drugs and technologies for effective treatment of secondary AMLs.

Keywords: classical Hodgkin’s lymphoma, secondary acute myeloid leukemias.

Received: April 15, 2022

Accepted: August 28, 2022

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EE Tolstykh¹, OS Chuvadar², AA Semenova¹, NA Kupryshina¹, OP Kolbatskaya¹, YuI Klyuchagina¹, OA Kolomeitsev¹, GS Tumyan¹, NN Tupitsyn¹

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

² Center of Clinical Oncology and Hematology, 4a Semashko ul., Simferopol, Republic of Crimea, Russian Federation, 295026

For correspondence: Prof. Nikolai Nikolaevich Tupitsyn, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(925)537-15-82; e-mail: nntca@yahoo.com

For citation: Tolstykh EE, Chuvadar OS, Semenova AA, et al. The Importance of Complementary Immunological Markers in the Diagnosis of Minimal Residual Disease in Multiple Myeloma. Clinical oncohematology. 2022;15(4):388–95. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-388-395

ABSTRACT

Background. The population of non-tumor plasma cells in healthy subjects’ bone marrow is known to be fairly heterogeneous. Among them, there may be a small number of CD19–, CD56+, CD45– plasma cells which differ from the main bulk of the normal plasmacytic cells by the lack of CD19 and CD45 expression and the presence of CD56 expression. It is the fact which makes the monitoring of minimal residual disease (MRD) especially challenging in multiple myeloma (MM) since normal and aberrant plasma cells should be compared. For this reason, a study of such complementary diagnostic markers as CD27, CD28, CD117, and CD81 is extremely important.

Aim. To analyze the role of complementary diagnostic markers (CD27, CD28, CD117, and CD81) of MRD in MM patients at different disease stages.

Materials & Methods. The present study enrolled 62 MM patients aged 31–76 years (median 58 years); 25 women and 37 men. The analysis focused on morphological and immunophenotypic properties of bone marrow plasma cells. MRD was detected by 8-color flow cytometry with the use of FACSCanto II Flow Cytometer (USA) based on EuroFlow standards.

Results. At the stage of primary diagnosis of MM, the immunophenotype of plasma cells was analyzed in all 62 patients using two 8-color panels recommended by the EuroFlow Consortium (2012). In accordance with primary immunophenotyping data, MRD was evaluated on the basis of not only the main diagnostic markers of plasma cells (CD38, CD138, CD45, CD56, and CD19), but also the complementary ones, such as CD27, CD28, CD117, and CD81. The study was basically conducted after induction therapy and upon remission. With cut-off > 0.01 % of aberrant plasma cells, the MRD incidence was the following: 91.0 % with CD27, 90.6 % with CD28, 87.0 % with CD117, and 96.7 % with CD81 markers. Respectively, no MRD was detected in 9.0 % with CD27, 9.4 % with CD28, 13.0 % with CD117, and 3.3 % with CD81 markers.

Conclusion. Using the set of complementary markers including CD27, CD28, CD117, and CD81 allows to establish a more accurate MRD status in MM, i.e. either negative or positive one, taking into account the expression of basic antigens CD38, CD138, CD45, CD56, and CD19.

Keywords: multiple myeloma, minimal residual disease, plasma cells, bone marrow, multicolor flow cytometry.

Received: March 2, 2022

Accepted: August 30, 2022

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