AUTOIMMUNE THROMBOCYTOPENIA

Classical Hodgkin Lymphoma: Tumor Structure and Prognostic Value of the Immune Microenvironment

AUTOIMMUNE THROMBOCYTOPENIA

AA Gusak, KV Lepik, LV Fedorova, VV Markelov, VV Baykov

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: Artem Aleksandrovich Gusak, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022; e-mail: artemgusak@yandex.ru

For citation: Gusak AA, Lepik KV, Fedorova LV, Markelov VV, Baykov VV. Classical Hodgkin Lymphoma: Tumor Structure and Prognostic Value of the Immune Microenvironment. Clinical oncohematology. 2023;16(3):242–62. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-242-262

ABSTRACT

Classical Hodgkin lymphoma (cHL) is a unique malignant lymphoid neoplasm characterized by tumor (Hodgkin and Reed-Sternberg) cells in the inflammatory and immunosuppressive microenvironment. The cHL microenvironment is a complex dynamic environment with immune cells, stromal elements, and extracellular matrix components, all of them interacting with each other and with tumor cells. This interaction basically underlies both disease progression and response to therapy. Currently, there is a growing interest in studying the structure and functions of cHL microenvironment, its prognostic value, and the potential of its components to be used as new therapeutic targets. During the last decade, the outcomes of refractory cHL treatment have considerably improved, in particular due to the administration of such PD-1 inhibitors as nivolumab and pembrolizumab. High cHL sensitivity to anti-PD-1 therapy can be accounted for by the PD-1/PD-L1-associated niche being formed in the tumor tissue as a result of intensive PD-L1 expression by tumor cells and macrophages as well as the expression of its PD-1 receptor by T-cells and M2-macrophages. More and more information becomes available about the possible mechanisms of antitumor response in anti-PD-1 treated cHL patients which seems to contradict the traditional understanding of CD8-mediated response in solid tumors. Cytotoxic effects of anti-PD-1 therapy in cHL tissues are likely to result from the interaction between tumor cells, macrophages, and CD4-positive Т-lymphocytes. This review discusses structural and regulatory relationships between tumor cells and microenvironment components, deals with new therapy approaches using various microenvironment components as targets, and summarizes currently available knowledge on prognosis based on the study of cHL microenvironment.

Keywords: classical Hodgkin lymphoma, microenvironment, immune checkpoints, macrophage polarization, immunosuppressive niche.

Received: April 12, 2023

Accepted: June 25, 2023

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Perspectives for the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma

AUTOIMMUNE THROMBOCYTOPENIA

SV Semochkin1,2

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. Perspectives for the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma. Clinical oncohematology. 2023;16(3):229–41. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-229-241

ABSTRACT

In recent decades, the progress in multiple myeloma (MM) treatment has been linked to a clearer insight into the biology of this disease and practical application of new pharmaceutical classes, such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (MABs). Modern IMiDs (lenalidomide and pomalidomide) are thalidomide derivatives which despite the similarity of chemical structure show only a relative cross-resistance. Lenalidomide is a second-generation immunomodulator with high anti-tumor activity and a favorable safety profile. In 2006, the use of lenalidomide combined with dexamethasone (Rd regimen) was approved by FDA (USA) for the treatment of relapsed/refractory MM, and 9 years later, in 2015, for newly diagnosed MM. During 2015–2019, the treatment of relapsed MM applied the newly developed regimens involving Rd combined with bortezomib (VRd), carfilzomib (KRd), ixazomib (IRd), elotuzumab (ERd), and daratumumab (DRd), the so-called triplets. Pomalidomide is a third-generation drug used in lenalidomide-refractory patients. For patients with relapsed/refractory MM who received at least two therapy lines with lenalidomide and bortezomib, regimens with 3 drugs were introduced which include pomalidomide and dexamethasone combined with elotuzumab (EPd), isatuximab (Isa-Pd), and daratumumab (DPd). In 2010, the molecular target of IMiD action was discovered, that is protein cereblon (CRBN), a component of CRBN E3 ligase enzyme complex. The insight into this mechanism provided the basis for developing a new family of thalidomide derivatives which are now called CRBN E3 ligase modulators (CELMoDs). In phase I/II trials, two drugs belonging to this group (iberdomide and mezigdomide) showed promising activity in MM refractory to three classes of antitumor drugs (IMiDs, PIs, and anti-CD38 MABs). The present review is focused on prospective studies of IMiDs and CELMoDs at different stages of MM treatment.

Keywords: multiple myeloma, immunomodulatory drugs, cereblon E3 ligase modulators, lenalidomide, pomalidomide, iberdomide, mezigdomide.

Received: January 25, 2023

Accepted: May 28, 2023

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Статистика Plumx английский

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The Prognostic Role of Genetic Aberrations in Mantle Cell Lymphoma: A Literature Review and Clinical Experience

AUTOIMMUNE THROMBOCYTOPENIA

EV Kleina1, SV Voloshin1,2, YuS Vokueva1, OD Petukhova1, EV Motyko1, MP Bakai1, DV Kustova1, AN Kirienko1, SYu Linnikov1, EV Karyagina3, OS Uspenskaya4, IS Zyuzgin5, SV Sidorkevich1, IS Martynkevich1

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

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

3 Municipal Hospital No. 15, 4 Avangardnaya ul., Saint Petersburg, Russian Federation, 198205

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

5 NN Petrov National Medical Cancer Research Center, 68 Leningradskaya ul., Pesochnyi pos., Saint Petersburg, Russian Federation, 197758

For correspondence: Elizaveta Vyacheslavovna Kleina, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024; e-mail: elizabeth.kleina@gmail.com

For citation: Kleina EV, Voloshin SV, Vokueva YuS, et al. The Prognostic Role of Genetic Aberrations in Mantle Cell Lymphoma: A Literature Review and Own Experience. Clinical oncohematology. 2023;16(2):213–26. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-213-226

ABSTRACT

Mantle cell lymphoma (MCL) is a type of peripheral B-cell non-Hodgkin’s lymphoma characterized by constitutive cyclin D1 overexpression leading to cell-cycle dysregulation and disruption of DNA damage repair. Apart from the typical translocation t(11;14)(q13;q32) and more rare variants, such as t(2;11)(p11;q13) and t(11;22)(q13;q11), a considerable number of patients quite often show secondary molecular and chromosomal aberrations underlying heterogeneity of the clinical course of MCL. Among a wide range of molecular genetic abnormalities, particular attention during the last years has been concentrated on studying the so-called double-hit MCL within a subgroup of patients with translocations involving CCND1 and MYC genes. Double-hit MCL is distinguished with rapid progression and tumor generalization at the time of diagnosis. Poor prognosis and low survival rates in most MCL patients call for the fastest possible diagnosis. Morphological and immunohistochemical as well as genetic methods (standard cytogenetic technique and fluorescence in situ hybridization) contribute to improving the quality of evidence-based diagnosis. The results of comprehensive diagnostic studies optimize prognosis assessment and treatment decision making in clinic.

Keywords: mantle cell lymphoma, double-hit MCL, karyotype, genetic aberrations, prognostic factors.

Received: August 16, 2022

Accepted: February 27, 2023

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Ibrutinib Efficacy in First-Line Therapy of High-Risk Patients Vs. Second- and Third-Line Therapies of Resistant Chronic Lymphocytic Leukemia

AUTOIMMUNE THROMBOCYTOPENIA

NV Kurkina1,2, EA Repina1, PV Volkova1, AA Repin1

1 NP Ogarev National Research Mordovia State University, 68 Bolshevistskaya ul., Saransk, Russian Federation, 430005

2 Republican Clinical Hospital No. 4, 32 Ul’yanova ul., Saransk, Russian Federation, 430032

For correspondence: Nadezhda Viktorovna Kurkina, MD, PhD, 32 Ul’yanova ul., Saransk, Russian Federation, 430032; Tel.: +7(927)172-48-63; e-mail: nadya.kurckina@yandex.ru

For citation: Kurkina NV, Repina EA, Volkova PV, Repin AA. Ibrutinib Efficacy in First-Line Therapy of High-Risk Patients Vs. Second- and Third-Line Therapies of Resistant Chronic Lymphocytic Leukemia. Clinical oncohematology. 2023;16(2):209–12. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-209-212

ABSTRACT

Risk stratification appears to be the most valid criterion in decision-making regarding optimal specific therapy in chronic lymphocytic leukemia (CLL). The CLL International Prognostic Index takes account of unfavorable cytogenetic abnormalities (del(17p)/del(11q) and/or TP53 gene mutations) as well as the mutation status of immunoglobulin heavy chain variable (IGHV) region genes. Unmutated V(H)-status is commonly associated with such prognostically unfavorable genetic markers as del(17p)/del(11q), trisomy 12, and TP53 mutation. The combination of unmutated V(H)-status with unfavorable karyotype abnormalities (del(17p)/del(11q)) negatively affects the prognosis and overall survival rate. Besides, in high-risk CLL, the efficacy of therapy is rather low, and the development of refractoriness is possible. Targeted therapy (Bruton tyrosine kinase inhibitors) both in first line and in resistant CLL considerably increases the probability of achieving long-term remission. The present paper provides the comparative analysis of clinical and hematological efficacy and tolerability of ibrutinib in first-line CLL therapy of high-risk patients as well as second- and third-line therapies of resistant CLL. Ibrutinib shows high efficacy and low toxicity. First-line ibrutinib treatment results in a faster response and effectively reduces the probability of CLL progression. Second- and third-line ibrutinib treatment allows to overcome CLL resistance without impairing patients’ quality of life.

Keywords: chronic lymphocytic leukemia, high-risk group, deletion del(17p), TP53 gene mutation, ibrutinib, efficacy, toxicity.

Received: October 9, 2022

Accepted: February 28, 2023

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Plasma Cell-Free DNA in Patients with Diffuse Large B-Cell and B-Cell High-Grade (Double Hit/Triple Hit) Lymphomas

AUTOIMMUNE THROMBOCYTOPENIA

SYu Smirnova, EE Nikulina, NG Gabeeva, DA Koroleva, SA Tatarnikova, AK Smol’yaninova, EG Gemdzhian, EE Zvonkov, AB Sudarikov

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

For correspondence: Svetlana Yurevna Smirnova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(926)879-65-94; e-mail: smirnova-s-ju@yandex.ru

For citation: Smirnova SYu, Nikulina EE, Gabeeva NG, et al. Plasma Cell-Free DNA in Patients with Diffuse Large B-Cell and B-Cell High-Grade (Double Hit/Triple Hit) Lymphomas. Clinical oncohematology. 2023;16(2):200–8. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-200-208

ABSTRACT

Aim. To study plasma cell-free DNA (pcfDNA) concentration and B-cell clonality in patients with diffuse large B-cell (DLBCL) and B-cell high-grade lymphomas prior to and at different stages of chemotherapy as well as the correlation between the data obtained and clinical and laboratory parameters.

Materials & Methods. The study enrolled 23 DLBCL patients and 7 healthy donors (HD). Plasma was prepared from whole blood by centrifugation, pcfDNA was isolated with the commercial kit Qiagen (Germany). The concentration of pcfDNA was determined using fluorometer Qubit (USA). В-cell clonality was estimated by immunoglobulin gene analysis (BIOMED-2 protocol) in the tumor tissue and bone marrow core biopsy specimens obtained on diagnosis date as well as in the pcfDNA at 5 end points: prior to chemotherapy and after cycles 1, 2, 3, and 4.

Results. Prior to therapy, all DLBCL patients showed significantly higher pcfDNA concentration than HD. Immunochemotherapy cycle 1 resulted in considerable increase in pcfDNA concentration. After cycle 2 and subsequent cycles, pcfDNA concentration gradually decreased. After cycle 4, the mean pcfDNA concentration was comparable with that of HD. In 95 % of patients В-cell clonality in pcfDNA corresponded to that identified in the tumor specimen. After immunochemotherapy cycle 1, В-cell clonality was detected in 50 % of patients, after cycle 2 it was shown by 15 %. Only 1 female patient retained В-cell clonality after therapy cycles 3 and 4. In HD, no В-cell clonality in pcfDNA was identified. Prior to therapy, the analysis revealed no correlation of either pcfDNA concentration or В-cell clonality in pcfDNA with age, sex, tumor spread, presence or absence of extranodal lesions, proliferation index Ki-67, and lactate dehydrogenase concentration.

Conclusion. In patients with malignant hematological tumors, pcfDNA seems to be an interesting, easily accessible biological material deserving further investigation. Any studies of pcfDNA require long-term dynamical analysis and standardized methods of collection, storage and processing of the data obtained. In the long run, with more and more information, pcfDNA can become an important diagnostic marker of tumor heterogeneity and a reliable relapse predictor.

Keywords: cell-free DNA, plasma, diffuse large B-cell lymphoma, B-cell high-grade lymphoma, liquid biopsy.

Received: October 5, 2022

Accepted: March 3, 2023

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Long-Term Results of Classical Hodgkin’s Lymphoma Treatment in Real-World Clinical Practice: Experience of Novosibirsk Hematological Unit

AUTOIMMUNE THROMBOCYTOPENIA

MS Voitko1,2, TI Pospelova1,2, IN Nechunaeva2, YaYu Shebunyaeva1

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

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

For correspondence: Mariya Sergeevna Voitko, MD, PhD, 21 Polzunova ul., Novosibirsk, Russian Federation, 630051; e-mail: voytko.marie@yandex.ru

For citation: Voitko MS, Pospelova TI, Nechunaeva IN, Shebunyaeva YaYu. Long-Term Results of Classical Hodgkin’s Lymphoma Treatment in Real-World Clinical Practice: Experience of Novosibirsk Hematological Unit. Clinical oncohematology. 2023;16(2):192–9. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-192-199

ABSTRACT

Aim. To assess the long-term results of classical Hodgkin’s lymphoma (cHL) treatment in Novosibirsk in real-world clinical practice.

Materials & Methods. The study enrolled 408 cHL patients treated and followed-up at the hematological unit of the Novosibirsk Municipal Clinical Hospital No. 2 from January 2008 to December 2021. The median age of patients was 33 years (range 26–44 years). Among them 223 (54.7 %) female and 185 (45.3 %) male patients. There were more patients with cHL stages III (n = 103; 25.2 %) and IV (n = 120; 29.4 %) than with stage II, which was identified in 185 (45.4 %) patients. ABVD regimen was administered to 132 (32.3 %) patients, 47 (11.5 %) patients received ABVD escalated to BEACOPP. BEACOPP therapy was performed in 229 (56.2 %) patients. Subsequent radiotherapy was assigned to 202 (49.5 %) patients. Second-line therapy was required by 89 (21.8 %) patients with relapsed and resistant cHL.

Results. The 10-year overall survival (OS) was 81 %, and the 5-year OS was 91 %. Similar progression-free survival (PFS) rates were 86 % and 77 %, respectively. The 10-year PFS in patients with stage II was 87 %, while in patients with stages II (mediastinal bulky mass), III and IV, it was only 69 % (p = 0.002). The 10-year OS in patients with localized stages was 91 %, and in patients with generalized stages it was 79 % (p = 0.0006). The 10-year OS in patients less than 45 years of age was 88 %, and in patients more than 45 years of age it was 69 %. The 10-year PFS in patients less than 45 years of age was 84 %, and in the older age group it was 60 % (p = 0.001).

Conclusion. The study results demonstrate high rates of long-term survival of cHL patients and are well comparable with the data of other study groups. Nevertheless, scientific research should be continued to develop optimal risk-adapted programs of cHL chemotherapy and to define further prospects for improving the treatment outcomes of this malignant tumor.

Keywords: classical Hodgkin’s lymphoma, overall survival, progression-free survival, immediate and long-term treatment results.

Received: October 28, 2022

Accepted: March 2, 2023

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Статистика Plumx английский

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Dynamics of SARS-CoV-2 RNA Detection in Patients and Employees of the National Research Center for Hematology During the First Two Years of the Novel COVID-19 Pandemic

AUTOIMMUNE THROMBOCYTOPENIA

OG Starkova, DS Tikhomirov, AYu Krylova, IO Snezhko, EN Ovchinnikova, OA Aleshina, TA Tupoleva, TV Gaponova

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

For correspondence: Oksana Gazimagomedovna Starkova, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(966)189-57-12; e-mail: oksanastar2006@rambler.ru

For citation: Starkova OG, Tikhomirov DS, Krylova AYu, et al. Dynamics of SARS-CoV-2 RNA Detection in Patients and Employees of the National Research Center for Hematology During the First Two Years of the Novel COVID-19 Pandemic. Clinical oncohematology. 2023;16(2):186–91. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-186-191

ABSTRACT

Background. COVID-19 required fundamental changes in healthcare management, also in medical care for oncological and hematological patients. Visits to healthcare organizations were minimized, 75 % of doctor appointments were converted to telemedicine consultations. The solutions aimed at preventing further spread of COVID-19 included establishing of observational units, distinguishing between patient and employee flows, regular SARS-CoV-2 RNA testing, reducing hospital stays and transferring patients with positive COVID-19 tests to the remodeled hospitals specializing in the novel coronavirus infection, as well as providing only emergency medical treatment and, as far as feasible, converting systemic chemotherapy to per os treatment, etc.

Aim. To assess SARS-CoV-2 RNA detection dynamics at the National Research Center for Hematology from April 2020 to January 2022 during the implementation of epidemic control measures.

Materials & Methods. The study was based on SARS-CoV-2 RNA testing of naso- and oropharyngeal samples obtained from patients and employees of the National Research Center for Hematology (hereafter referred to as Center). Besides, bronchoalveolar lavage fluid, lung tissue biopsies, and sputum were examined for SARS-CoV-2 RNA. The study was performed at the Center’s Virusology Department with the use of Sintol reagent kit “ПЦР-РВ-2019-nCov”.

Results. The study was based on 107,470 tests: 58,141 (54 %) of employees and 45,126 (46 %) of patients; 35,508 (33 %) of men and 71,962 (67 %) of women. In 1318 cases SARS-CoV-2 RNA was detected which accounted for 1.15 % of total test number. In the groups of employees/patients, virus detection rate was 1.42 %/1.09 % (p < 0.001), and in male/female groups it was 1.3 %/1.2 %, respectively (p = 0.154). The rate of infection in the groups of tumor and non-tumor hematological patients, as proved by SARS-CoV-2 RNA testing, was 1.24 % and 0.92 %, respectively (p = 0.147). In employees and patients of the Center, a wave-like virus detection rate was observed. The largest number of infections was registered in April-June 2020 (79 patients and 170 employees), October-December 2020 (126 patients and 190 employees), and January 2022 (59 patients and 203 employees), which corresponded to the first, second, and fifth COVID-19 waves in Russia.

Conclusion. The analysis of data obtained at the National Research Center for Hematology demonstrated a wave-like SARS-CoV-2 RNA detection rate in employees and patients of the Center, which corresponded to the general trend in Russia. The SARS-CoV-2 RNA detection rate did not depend on sex of subjects under study and was not significantly different in the groups of tumor and non-tumor hematological patients. Although the patients in hematological hospital are more exposed to the risk of severe infectious complications, they showed laboratory markers for COVID-19 less frequently than the Center employees.

Keywords: COVID-19, SARS-CoV-2 RNA, novel coronavirus infection, hematological patients, tumor and non-tumor hematological diseases.

Received: September 5, 2022

Accepted: March 7, 2023

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The Prognostic Value of Somatic Mutations of Epigenetic Regulation Genes in Acute Myeloid Leukemias in Real-World Clinical Practice: Results of an Observational Non-Interventional Prospective Interregional Study

AUTOIMMUNE THROMBOCYTOPENIA

AA Shatilova1, IG Budaeva1, AV Petukhov1, SA Silonov1, AE Ershova1, TS Nikulina1, YuD Matvienko1, YuV Mirolyubova1, KV Bogdanov1, LV Anchukova2, YuS Neredko3, SYu Tyasko3, OE Ochirova4, AG Karpova4, ER Vasil’eva5, OD Serdyuk6, DA Yaskulskii6, DV Bukin7, YuA Alekseeva1, EG Lomaia1, LL Girshova1

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

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

3 Stavropol Krai Clinical Oncology Dispensary, 182a Oktyabrskaya ul., Stavropol, Russian Federation, 355001

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

5 Perm Krai Clinical Hospital, 85 Pushkina ul., Perm, Russian Federation, 614990

6 Clinical Oncology Dispensary No. 1, 146 Dimitrova ul., Krasnodar, Russian Federation, 350040

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

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, Petukhov AV, et al. The Prognostic Value of Somatic Mutations of Epigenetic Regulation Genes in Acute Myeloid Leukemias in Real-World Clinical Practice: Results of an Observational Non-Interventional Prospective Interregional Study. Clinical oncohematology. 2023;16(2):174–85. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-174-185

ABSTRACT

Aim. To assess the rate of DNMT3A, IDH1, IDH2, and ASXL1 gene mutations and their effect on the prognosis both as isolated findings and in combination with well-known chromosomal aberrations and gene mutations in newly diagnosed acute myeloid leukemia (AML) patients from some regions of the Russian Federation.

Materials & Methods. The study enrolled 83 patients with newly diagnosed AML from 22 regions of the Russian Federation, who underwent molecular genetic examination for detecting IDH1 (R132), IDH2 (R140), ASXL1, and DNMT3A gene mutations with droplet digital PCR and Sanger sequencing methods.

Results. The mutation rate in DNMT3A was 16.7 %, in IDH1 (R132) it was 6 %, in IDH2 (R140) it was 9.6 %, and in ASXL1 it was 6 %. The R140 mutation in IDH2 correlated with the older age of patients. The mutations in IDH1 (R132), IDH2 (R140), and DNMT3A showed a significant association with mutated NPM1. The mutations in IDH1 (R132), IDH2 (R140) were reported to occur significantly more often in patients with normal karyotype. The IDH1 (R132) and IDH2 (R140) mutations appeared to have a favorable effect on AML prognosis, which is most likely to be associated with a high rate of their compatibility with NPM1 mutation. The mutated type of DNMT3A had a negative effect on overall survival of patients with NPM1 mutation. The mutation in ASXL1 also appeared to be an unfavorable prognostic factor for overall survival of patients with wild type NPM1.

Conclusion. A high rate of mutation occurrence in epigenetic regulation genes as well as the prognostic potential of these mutations in AML necessitate the need for determining the mutation status of DNMT3A, IDH1, IDH2, and ASXL1 in the context of primary diagnosis in real-world clinical practice.

Keywords: acute myeloid leukemias, IDH, DNMT3A, ASXL1, epigenetic regulation genes.

Received: September 25, 2022

Accepted: March 1, 2023

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Efficacy and Toxicity of Induction Therapy in Patients with Newly Diagnosed Systemic AL Amyloidosis: Results of a Prospective Single-Center Clinical Study

AUTOIMMUNE THROMBOCYTOPENIA

IG Rekhtina, VA Khyshova, MV Solov’ev, LP Mendeleeva

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

For correspondence: Viktoriya Aleksandrovna Khyshova, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(983)413-02-00; e-mail: viktoria2102@icloud.com

For citation: Rekhtina IG, Khyshova VA, Solov’ev MV, Mendeleeva LP. Efficacy and Toxicity of Induction Therapy in Patients with Newly Diagnosed Systemic AL Amyloidosis: Results of a Prospective Single-Center Clinical Study. Clinical oncohematology. 2023;16(2):166–73. (In Russ).

DOI: 10.21320/2500-2139-2023-16-2-166-173

ABSTRACT

Aim. To assess the outcomes of induction therapy in patients with newly diagnosed systemic AL Amyloidosis (AL-А).

Materials & Methods. The prospective single-center clinical study enrolled 60 patients (32 women and 28 men) with newly diagnosed systemic AL-A stage I/IIIA. The median age was 59 years (range 34–74 years). In 57 patients, BorСyDex (bortezomib, cyclophosphamide, dexamethasone) was used as first-line therapy. RCd regimen (lenalidomide, cyclophosphamide, dexamethasone) was administered to 3 patients. Patients with the lack of efficacy or pronounced toxicity (n = 24) received second-line induction therapy with lenalidomide or melphalan combined with dexamethasone. High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) was administered to 11 (18 %) patients.

Results. Hematologic targeted response (complete remission [CR] and very good partial remission [VGPR]) to BorCyDex was achieved in 62 % of patients. As a result of all lines of induction therapy, including auto-HSCT, targeted response increased to 69 %, specifically in 7/51 (14 %) patients with stringent CR (sCR), 8/51 (16 %) patients with CR, and 20/51 (39 %) patients with VGPR. Renal response after BorCyDex was registered in 10/38 (26 %) patients, 6/31 (19 %) patients showed heart response, and in 4/5 (80 %) patients liver response was reported. All therapy lines with auto-HSCT led to organ response (in ≥ 1 organ) in 15/46 (32 %) patients. Clinical response was shown by all patients with achieved sCR, by 67 % of patients with CR, and 47 % with VGPR (p = 0.04). With lower hematologic response rates, no clinical improvement was observed. With follow-up duration of 36 months, the median disease-free survival (without signs of hematologic and clinical progression) was not achieved. The 3-year overall survival was 80 %. Mortality during induction therapy was 10 % (6 patients died, including 2 patients with COVID-19). The planned 6 courses of BorCyDex could be completed only in 13 (23 %) out of 55 patients. During the induction therapy using BorCyDex, 4 patients died. The treatment was discontinued in 7/55 (12 %) patients due to its inefficacy and in 22/55 (39 %) patients because of severe peripheral and autonomic polyneuropathy. Nine (16 %) out of 55 patients with the achieved hematologic response showed excessive NT-proBNP elevation, which was accompanied by cardiovascular complications and provided ground for chemotherapy withdrawal.

Conclusion. Low organ recovery rate remains the most challenging issue for AL-A treatment. Hematologic response depth (achieved CR) is a critical factor in achieving clinical effect. The obtained data confirmed high toxicity of BorCyDex regimen in AL-A patients. Despite the advances in AL-А therapy which are associated with the use of proteasome inhibitors, treatment of this disease calls for new and more effective approaches.

Keywords: AL Amyloidosis, bortezomib, lenalidomide, efficacy, toxicity.

Received: October 31, 2022

Accepted: March 3, 2023

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