Background. The gene therapy based on hematopoietic cell xenotransplantation is becoming a powerful and universally applied therapeutic strategy in an ever-expanding range of human diseases. One of the current issues in implementing the techniques of genome modification in hematopoietic stem cells (HSCs) into clinical practice is to assure the quality and safety of gene and cell therapy products for human use. This is achieved by animal model testing at the stage of preclinical studies. With this purpose in view, NBSGW mice seem to be a unique and promising model for human HSC engraftment without pre-conditioning. Aim. To test the NBSGW mouse model for human HSC engraftment, to optimize the methods of assessing the state of the animals and monitoring the chimerism level for translational preclinical development of HSC-based products for gene and cell therapy. Materials & Methods. The xenograft models of NBSGW mice were generated using the samples of the selected peripheral blood CD34+ HSCs from a healthy donor. Serial transplantation was performed by intravenous injection of bone marrow cells from primary recipients with a high chimerism level. Engraftment efficiency was evaluated by flow cytofluorometry (FCF) and droplet digital PCR (ddPCR). Subpopulation pattern of human cell engraftment was assessed by FCF. Results. The tested HSC transplantation regimen is characterized by favorable toxicity profile. In the entire study sample of mice, the FCF analysis showed a long-term engraftment of human cells with a high chimerism level (23.5–93.6 %) in the bone marrow of the animals, also after serial transplantation, which was confirmed by ddPCR. The B-lineage differentiation cells predominated in all tested samples (of peripheral blood, bone marrow, and spleen) from mice after primary and serial transplantation. The ddPCR assay can be used as an additional tool for validating the level of human cell engraftment determined by FCF. Conclusion. NBSGW mice present a promising reference model for preclinical development of gene and cell therapy products based on human primary HSCs with a modified genome.

Background: Previous data of clinical trials demonstrated high efficacy of bispecific antibody glofitamab (G) in the therapy of patients with refractory aggressive B-cell non-Hodgkin lymphomas (B-NHL). More than 70% of patients who achieve CR maintain a response within a year according to clinical studies [M. Hutchings et al., 2021]. At the moment, it is required to study this issue in the framework of real clinical practice. Methods: This study included 24 pts with r/r B-NHL who were treated with G within the Russian Named Patient Program. G was prescribed in escalated regimen: 2.5 mg D8C1, 10 mg D15C1, 30 mg D1C2-12. Anti-CD20 antibody was administrated 1 week before G therapy initiation. Efficacy was analyzed by PET-CT after C3, C7 and C12 using Lugano criteria. Adverse events (AEs) were graded according to NCI CTCAE 5.0. Results: Median age at G initiation was 47 (27-70), male/female ratio—8/16 (33%/67%). Median number of therapy lines before G was 3 (3-8). Prior autologous SCT was performed in 6 (25%) pts, polatuzumab vedotin in 7 (29%) pts. All patients had active disease at G initiation, ECOG > 1 was in 6 (25%) pts, B symptoms in 5 (21%) pts and bulky disease in 7 (29%) pts. Median follow up was 11 (1-21) months. At analysis all pts discontinued therapy due to therapy completion (n = 9, 38%), PD (n = 8, 33%), severe COVID-19 (n = 5, 21%) and other reason (n = 2, 8%). Median number of cycles was 7 (2–12). Overall response rate was 71% (complete response (CR) n = 14, 58%; partial response n = 3, 13%). Nine patients died during G therapy including 6 (18%) pts due to PD and 3 pts—severe COVID-19. Median OS in all patients was not reached, 1-year OS was 62.5% (CI 95%: 40.3-78.4); median PFS was 10.8 months (CI 95%: 3.7-NA), 1-year PFS 50% (CI 95%: 29.1-67.8). Fourteen patients (58%) achieved CR during G therapy. Median follow up in this group was 12 (8-21) months. At the moment of analysis 1 of 14 pts had a disease relapse and started additional therapy and 1 pt died due to severe COVID-19 pneumonia in CR. Median OS and PFS in patients with CR were not reached, 1-year OS was 92.9% (CI 95%: 59.1–99), 1-year PFS 85.7% (CI 95%: 53.9–96.2). AEs were presented in 24 (100%) pts including grade 3-4 AEs in 13 (62.5%) and grade 5 AEs (COVID-19) in 3 (12.5%) pts. CRS developed in 13 (54%) pts (grade 1-2 n = 12, grade 3 n = 1). Viral infections occurred in 14 (58%) pts including COVID-19, cytomegalovirus and Varicella zoster virus. In all patients who had an insufficient response to G therapy the allo-HSCT was considered. However, at the moment of analysis only 1 patient was undergone allo-HSCT after additional therapy. Conclusions: G therapy demonstrated favorable activity with frequent and durable CR in real practice. At the same time, adverse events were observed in all patients, therefore clinical caution is needed during G treatment considering risk of CRS syndrome and cases of severe viral infections. Encore Abstract—previously submitted to EHA 2023 Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy No conflicts of interests pertinent to the abstract.

Objective. To study epidemiology and impact of colonization by multidrug-resistant Gram-negative bacteria (MDRGNB) on bloodstream infections (BSI) during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Materials and Methods. The retrospective study included 288 patients received the first allo-HSCT between 2018 and 2019. The median age was 32 (18–66) years, male – 53% (n = 152). The majority of patients had acute leukemia – 62% (n = 178) and received transplant from matched unrelated – 42% (n = 120) or haploidentical donor – 26% (n = 75). Relapse of underlying disease at the moment of all-HSCT was registered in 23% (n = 66) of patients. Results. Colonization of non-sterile sites before allo-HSCT by at least one MDRGNB was detected in 28% (n = 64). In most cases resistance is due to extended spectrum beta-lactamases (ESBL) – 86% (n = 55), while carbapenemases in combination with ESBL were detected in 14% (n = 9) of patients. After allo-HSCT the colonization was significantly higher than before transplantation (n = 161, 56%, p = 0.001), mainly due to carbapenemase- and ESBL-producing bacteria – 73% (n = 118) (p = 0.001). BSI in the early period after transplantation developed in 26% (n = 76), and in 56% (n = 43) was caused by MDRGNB. The etiology of BSI included K. pneumoniae – 51% in mostly cases. The etiology of BSI was the same bacteria that colonized non-sterile sites 2 weeks before the detection bacteria in bloodstream in 69% (n = 30) patients. Colonization by MDRGNB was associated with the development of BSI (p < 0.0001). The 100-day overall survival (OS) after all-HSCT was significantly lower in patients with colonization of non-sterile sites by MDRGNB compared with patients without colonization (60.6% vs 88.2%, p = 0.001). Conclusions. Colonization of MDRGNB after allo-HSCT reached 56%. K. pneumoniae was predominant etiology in both colonization and bloodstream infections. Colonization by MDRGNB was associated with the development of BSI and decreased OS after allo-HSCT.

Introduction. The risk of developing Hodgkin lymphoma (HL) with HIV infection is higher than in the general population, and the course of the disease itself is more aggressive. Currently, there is no unified approach to the treatment of HIV-related HL, and data on its epidemiology in the Russian Federation are limited.The objective was to study epidemiological characteristics, the used therapeutic tactics and the results of treatment for HIV-related HL.Methods and materials. The multicenter retrospective study included 46 patients with HIV- related HL treated in 9 centers of the Russian Federation. Descriptive statistics methods were used, the analysis of overall survival (OS) and progression-free survival (PFS) was performed using the Kaplan–Meier method.Results. HIV-related HL is more often represented by an advanced stage, B-symptoms, and extranodal lesions. The ABVD regimen was used as the first-line therapy in 60 % for HIV-related HL. The overall response to therapy was 81.6 %, and the 2-year OS and PFS were 85 % and 49 %, respectively. Factors that worsened OS were CD4+˂266 cells/mcL and general somatic status ECOG≥2.

Topic: 22. Stem cell transplantation - Clinical Background: There are limited data on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients with prior COVID-19. Aims: Our goal was to assess the outcomes of allogeneic HSCT in patients with prior COVID-19 infection. Methods: This single-center retrospective study included 54 adult patients who received allo-HSCT from July 2020 to September 2021 after previous COVID-19. The median age was 33 years (18–76), there were 30 (55.6%) females and 24 (44.4%) males. The underlying disease were AML (n=22, 40.8%), ALL (n=17, 31.5%), MDS (n=6, 11.1%), AA (n=4, 7.4%), CML (n=3, 5.5%) and HL (n=2, 3.7%). The median follow-up was 231 days (11 - 518). Control group included 122 patients without history of COVID-19 underwent allo-HSCT during the same period. The median age was 35 years (18 – 69) and the median follow-up time - 252 days (13 – 604). We assessed the cumulative incidence (CI) of neutrophil engraftment, acute/chronic graft-versus-host disease (GVHD) and also overall survival (OS), progression-free survival (PFS), relapse incidence (RI), non-relapse mortality (NRM). Results: The median time from COVID-19 onset to the diagnosis of underlying disease was 129.5 days (-183 - 5135). To the date of COVID-19 manifestation 23 (42.6%) patients were in remission of the underlying disease, 18 (33.3%) in relapse/ progression and remaining 13 (24.1%) had a simultaneous manifestation. The median time of COVID-19 onset since the last chemotherapy was 11 days (0 - 616). 26 patients required hospitalization due to SARS-CoV-2 infection (48.1%), 17 was outpatient (31.5%) and 11 – course of disease remains unknown (20.4%). The median time from COVID-19 to allo-HSCT was 211 days (31 - 447). None of the patients had recurrent COVID-19 during hospitalization. Due to HSCT date the standard risk patients represented the largest subgroup (n=40, 74.1%), followed by salvage risk subgroup of patients (n=14, 25.9%). Donors were haploidentical – 16 (29.6%), MUD – 16 (29.6%), MMUD – 11 (20.4%) and MRD – 11 (20.4%). The source of HSC: PBSC – 41 (75.9%) and BM – 13 (24.1%). RIC and MAC were used in 41 (75.9%) and 13 (24.1%) recipients, respectively. Majority of patients (n=48, 88.9%) received posttransplantation cyclophosphamide based GVHD prophylaxis. The CI of engraftment is 94.4% (95% CI 83,8 – 98,2%). The median time was 20 days (13 - 28). The CI of acute GVHD was 35,1% (95% CI 22,8 – 47,8%). The CI of chronic GVHD was 26,7% (95% CI 13,8 – 41,5%). The main complications of post-transplant period included venous thrombosis (n = 7, 12.9%), TMA (n=1, 1.85%), VOD (n=1, 1.85%), bloodstream infections (n=30, 55.5%), pneumonia (n=11, 20.3%), soft tissue infections (n=8, 14.8%), viral infections (n=30, 55.5%), invasive mycoses (n=6, 11.1%). The 200-day RI, NRM, OS and PFS were 9,7% (95% CI 3,6 – 19,7%), 14,8% (95% CI 7,0 – 25,6%), 78,4% (95% CI 64,2 – 87,4%) and 75,4% (95% CI 61,3 – 84,9%) respectively. The control group demonstrated the same short-term outcomes of allo-HSCT: 200-day RI – 10,3% (95% CI 5,6 – 16,7%), NRM – 17% (95% CI 10,8 – 24,3%), OS – 78,5% (95% CI 69,9 – 85%) and PFS – 72,6% (95% CI 63,5 – 79,8%). Summary/Conclusion: Allo-HSCT is feasible in patients with a history of COVID-19 and characterized by common post-transplant complications. The history of COVID-19 did not affect the 6 months results of allo-HSCT. Nevertheless, further studies are required in subgroups of patients with different consequences of COVID-19. Keywords: COVID-19, Allogeneic hematopoietic stem cell transplant

Anti CD20/CD3 bispecific antibody glofitamab (G) demonstrated high efficacy and acceptable toxicity profile in patients with aggressive r/r B-NHL. Nevertheless, the number of patients and conditions in clinical trials is limited, which requires further study of the G safety in real clinical practice. This study included 28 pts with r/r B-NHL who were treated with G from May 2021 to August 2022 within the Russian Named Patient Program. G was prescribed in escalated regimen: 2.5 mg D8C1, 10 mg D15C1, 30 mg D1C2-12. Anti-CD20 antibody was administrated in D1C1. Efficacy was analyzed by PET-CT (Lugano criteria). Adverse events (AEs) were graded according to NCI CTCAE 5.0. Median age at G initiation was 50 (21-83), male/female ratio - 11/17 (39/61%). Median number of therapy lines before G was 3 (2-8). ECOG>1 at G initiation was in 7 (25%), B symptoms in 6 (21%) and bulky disease in 8 (29%) pts. Median follow-up was 6 (1-16) mo. At analysis 22 (79%) pts discontinued therapy due to PD (n=10, 36%), severe COVID-19 (n=5, 18%), therapy completion (n=5, 18%), other reason (n=2, 7%). Median number of cycles was 6 (1-12). ORR was 67% (56% CR, 11% PR). Eight pts died during G therapy including 5 (18%) pts due to PD. AEs were present in 27 (96%) pts including gr 3-4 in 14 (43%) and gr 5 in 3 (11%) pts (Table). Any grade COVID-19 was revealed in 9 (32%) pts. Three (11%) pts died due to severe COVID-19. Anti-SARS-CoV-2 antibodies were introduced in 14 (50%) pts: in 6 (21%) pts after Covid-19 and in 8 (29%) pts as a Covid-19 prophylaxis. There were no cases of severe Covid-19 after prophylaxis with antibodies. Other viral infections have also been observed: gr 1-2 VZV in 3 (11%), gr 4 CMV pneumonia in 1 (4%) pts.Table: 97PAll AEs27 (96%)Any gradeGrade 3-4Grade 5Hematologic AEsNeutropenia17 (61%)8 (29%)noAnemia14 (50%)3 (11%)noThrombocytopenia7 (25%)1 (4%)noInfectionCovid-1910 (36%)4 (14%)3 (11%)VZV3 (11%)nonoCMV pneumonia1 (4%)1 (4%)noImmunologicalCRS15 (54%)1 (4%)noTumor flare6 (21%)2 (8%)noOtherHeadache1 (4%)1 (4%)no Open table in a new tab G demonstrated high efficacy in patients with r/r B-NHL. However, the wide range of toxicities has also been demonstrated including a high rate of viral infections. Anti-SARS-CoV-2 antibodies and standard viral prophylaxis should be considered in this patient group.

Background: Patients with HIV infection have a significantly higher risk of developing cancer than the general population. In the era of antiretroviral therapy (ART) the cancer risk and mortality have been decreased, however, the risk of developing Hodgkin lymphoma (HL) increased. The ART allows treating HIV-infected patients with lymphomas with protocols for patients in the general population. Withal the data on the results of the treatment HL in patients with HIV controversy. Aims: To study epidemiology and evaluate the results of the treatment of HL in patients with HIV in national multicenter study. Methods: The study included 45 patients with HL in patients with HIV who received treatment in 9 Russian centers from 2007 to 2021. The median follow-up was 9 months (1-129). Patients and treatment characteristics were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated within two years from the diagnosis using the Kaplan-Meier method. Results: The median age was 39 years (25-66), men - 25 (55.6%), women - 20 (44.4%). Histological variants of HL in most cases were represented by nodular sclerosis (56%) and mixed-cell variant (41%). The advanced stage of the disease (3-4 Ann Arbor) was observed in 72.7% of patients, B-symptoms at the onset of the disease - 68.2%. The majority of patients (97.7%) received ART at the diagnosis of HL. The median number of CD4+ cells/µl at the onset of HL was 352.8 (50-692) cells/μl. General somatic status at the start of chemotherapy ECOG 0-1 - 34 (82.9%), ECOG≥2 - 7 (17.1%). As the first line of therapy, patients with localized stages of HL received ABVD (75%) and BEACOPP (25%), with advanced stages - ABVD (61.3%) and BEACOPP (38.7%). The median courses of first-line therapy were 4 (1-10). Radiation therapy in first-line therapy was performed in 4 patients (8.9%). The structure of response to first-line therapy were complete response - 51.4%, partial response - 25.7%, disease stabilization - 2.9%, disease progression - 20%. Fourteen and 8 patients received second and third-line therapy, respectively. Autologous hematopoietic stem cell transplantation was performed in 6 patients - the only 42.8% of patients with relapsed / refractory HL. OS in the study group was 81%, PFS - 38% (median PFS - 23 months). The level of CD4+ cells at the onset of HL less than 250/µl was associated with a statistically significant worsening of OS during 1 year (50% vs 100%, p=0.014). Factors such as gender, age, stage of the disease, ECOG status, the presence of B-symptoms at the onset of the disease, and the treatment regimen did not statistically significantly affect the two years OS and PFS from the diagnosis of HL in patients with HIV. Summary/Conclusion: The national multicenter study allowed characterization of HL in patients with HIV and evaluation of the efficacy of first-line therapy, which was found to be lower than in the general population. The level of CD4+ cells was the only factor that affect 2-year OS. The obtained data can form the basis for further prospective studies aimed at improving the results of HL treatment in HIV-infected patients.

Objective. To study the features of invasive aspergillosis (IA) due to A. non-fumigatus versus A. fumigatus in adult (≥ 18 years) recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2016-2021. Materials and methods. The study included 33 patients with IA caused by A. non-fumigatus (n = 20) and A. fumigatus (n = 13). A comparative analysis of cases of IA, the results of therapy and outcomes in patients after allo-HSCT in the RM Gorbacheva Research Institute was performed. Diagnostic criteria EORTC / MSGERC 2020 were used. Results. Invasive aspergillosis caused by A. non-fumigatus made up the majority (60.6 %) of IA cases with an identified pathogen registered in patients after allo-HSCT in the period from 2016 to 2021. The main etiological agents in the A. non-fumigatus group were A. niger in 13 (65 %) patients, A. flavus – in 4 (20 %). The median day of diagnosis of A. non-fumigatus IAwas + 110 days (17–2093), for A. fumigatus it was + 46 days (2–866) (p = 0.171). Overall 12-week survival was 55 % and 59.2 % in the A. non-fumigatus and A. fumigatus groups, respectively (p = 0.617). The majority of patients in both the A. fumigatus (n = 10, 77 %) and A. non-fumigatus (n = 16, 80 %) groups received voriconazole as initial antifungal therapy. Second-linetherapy was required in 2 (10 %) patients with A. non-fumigatus IA: liposomal amphotericin B and echinocandins with or with-out posaconazole, and 2 (15 %) patients in the A. fumigatus group: liposomal amphotericin B and voriconazole in combination with echinocandins. A comparative analysis showed that in patients from the two groups, none of the assessed signs (gender, age, underlying disease, disease status at the time of transplantation, time from diagnosis to allo-HSCT, source of hematopoietic stem cells, conditioning regimen, donor type, antifungal prophylaxis, cytomegalovirus reactivation, severe acute and chronic graft-versus-host disease) did not differ significantly. Conclusions. A. niger is the main causative agent of IA caused by A. non-fumigatus. Patients characteristics, their treatment and outcomes did not differ significantly between the A. non-fumigatus and A. fumigatus groups.

Background. Plasmablastic lymphoma (PBL) is a rare lympho-proliferative disease which is almost exclusively associated with immunodeficiency. Most ample experience of chemotherapy and hematopoietic stem cells transplantation (HSCT) in this lymphoma variant has been accumulated in HIV-positive patients. Aim. To describe the current approaches to PBL diagnosis and treatment in HIV-positive patients as well as to provide the results of the first multi-center retrospective study on PBL epidemiology and therapy efficacy in HIV-positive patients in the Russian Federation. Materials & Methods. The study included 26 HIV-positive patients with PBL who were treated and followed-up at 5 Russian centers during 2012-2019. The present study is a part of multi-center retrospective study on lymphoma epidemiology in HIV-positive patients in Russia. Results. PBL accounted for 9.5 % of all lymphomas in HIV-positive patients enrolled in multi-center retrospective study on lymphoma epidemiology in HIV-positive patients in Russia. Epidemiological characteristics of these patients corresponded to those described in previously published literature: the disease being diagnosed mainly at late stages (88 %), oral and nasal mucosa lesions with a common involvement of facial bones (65 %), and lack of optimal HIV-infection control (66.7 %). Most commonly, the patients received EPOCH-like treatment as first-line therapy (50 %). However, the efficacy of primary therapy appeared to be low. Overall survival (OS) and progression-free survival (PFS) during a year after first-line therapy onset was 57 % and 46 %, respectively. Bortezomib included in first-line therapy was associated with a trend to a more favorable prognosis. Half of patients showed a lymphoma relapse or progression after first-line therapy. Most used second-line regimen was DHAP. Overall response to second-line therapy was 38.5 %. After second-line therapy onset, 1-year OS and PFS were 26 % and 15 %, respectively. Conclusion. HIV-positive patients with PBL have poor prognosis. Efforts to improve the prognosis for HIV-positive patients with PBL should be aimed at increasing the efficacy of first-line therapy and should involve the use of intensive chemotherapy regimens with bortezomib. The role of auto-and allo-HSCTs in the treatment of PBL has not been clearly determined, however, PBL patients, despite their HIV-infec-tion, should be regarded as auto-HSCT-eligible in the first remission and allo-HSCT-eligible in case of relapse. Further prospective multi-center studies are needed to optimize the treatment of HIV-positive patients with PBL.

Актуальность. Плазмобластная лимфома (ПБЛ) относится к редким вариантам лимфопролиферативных заболеваний и встречается почти исключительно на фоне иммунодефицитных состояний. Наибольший опыт химиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК) при данном варианте лимфомы накоплен именно у пациентов с ВИЧ-инфекцией. Цель. Представить современные подходы к диагностике и терапии ПБЛ у пациентов с ВИЧ-инфекцией, а также результаты первого многоцентрового ретроспективного исследования эпидемиологии и эффективности терапии ПБЛ у ВИЧ-инфицированных пациентов в Российской Федерации. Материалы и методы. В исследование включено 26 пациентов с ПБЛ и ВИЧ-инфекцией, получавших лечение или наблюдавшихся в 2012–2019 гг. в 5 российских центрах. Настоящее исследование является частью многоцентрового ретроспективного исследования по изучению эпидемиологии лимфом у пациентов с ВИЧ-инфекцией в России. Результаты. ПБЛ составила 9,5 % всех лимфом у ВИЧ-инфицированных пациентов, включенных в многоцентровое ретроспективное исследование по изучению эпидемиологии лимфом у пациентов с ВИЧ-инфекцией в России. Эпидемиологические характеристики включенных пациентов соответствовали ранее опубликованным работам: диагностика преимущественно на поздних стадиях заболевания (88 %), поражение слизистых оболочек полости рта и носа, часто с вовлечением костей лицевого скелета (65 %), отсутствие оптимального контроля ВИЧ-инфекции (66,7 %). В качестве первой линии пациентам чаще всего проводилась EPOCH-подобная терапия (50 %). Однако эффективность первичной терапии была неудовлетворительная. Общая выживаемость (ОВ) и выживаемость без прогрессирования (ВБП) в течение 1 года после начала первой линии терапии составили 57 и 46 % соответственно. Включение бортезомиба в первую линию терапии связано с тенденцией к более благоприятному прогнозу. У половины пациентов регистрируется рецидив или прогрессирование лимфомы после первичного лечения. Наиболее часто используемым режимом второй линии терапии была схема DHAP. Общий ответ на терапию второй линии 38,5 %. После начала второй линии терапии 1-летние ОВ и ВБП составили 26 и 15 % соответственно. Заключение. Пациенты с ПБЛ на фоне ВИЧ-инфекции имеют неблагоприятный прогноз. Усилия по улучшению прогноза пациентов с ПБЛ на фоне ВИЧ-инфекции должны быть направлены на повышение эффективности первой линии терапии и предполагают включение интенсивных схем химиотерапии с использованием бортезомиба. Место аутоТГСК и аллоТГСК в терапии ПБЛ четко не определено, однако пациентов с ПБЛ, несмотря на ВИЧ-инфекцию, следует рассматривать как кандидатов на аутоТГСК в первой ремиссии и на аллоТГСК в случае развития рецидива. Необходимы проспективные многоцентровые исследования с целью оптимизировать лечение пациентов с ПБЛ на фоне ВИЧ-инфекции.

INTRODUCTION: Since 2020, the number of patients with complications after a new coronavirus infection (COVID-19) has increased, including mycoses. Mucormycosis ranks third in the frequency of detection among invasive mycoses in patients with reduced immunity. Acute and chronic invasive fungal rhinosinusitis is the most severe and dangerous variant of the disease.OBJECTIVE: To analyze the features of the osteodestructive process of invasive mucormycosis, its relationship with blood supply, the dynamics of the process under the influence of treatment.MATERIALS AND METHODS: The study evaluated changes in the bone structures of the skull, soft tissues of the facial region, brain, and thorax in a group of 10 patients (62.3±11.4 y.o.) examined in the clinic of maxillofacial surgery and the clinic otorhinolaryngology in the post- covid period. The results of cone-beam computed tomography (Sirona) of the maxillofacial region, Xray computed tomography Optima 540 CT (General Electric) of the maxillofacial region and thoracic cavity organs, magnetic resonance imaging (GE Signa HDxt) of the brain and maxillofacial region with intravenous administration of a paramagnetic contrast agent were analyzed.RESULTS: In all cases, osteolytic lesions as a classical manifestations of invasive mucormycosis, were revealed in: alveolar processes of the upper jaws and walls of the maxillary sinuses in 100% of cases; palatine processes — 90%; nasal septum, walls of the ethmoid sinuses and walls the orbits — 70%; walls of the sphenoid sinus — 50%; pterygoid processes and zygomatic bone — 40%; the body of the sphenoid bone, nasal bones, frontal bones — 30%; the alveolar part of the mandible and temporal bone — 10%. All patients underwent surgery with resection of the affected bones — 100%, while 7 out of 10 patients received antimycotic therapy. When assessing the revealed changes in dynamics in all patients in the long-term postoperative period, sclerosis of small foci of destruction, a decrease in the extent of bone defects, a decrease in the size of sequesters, hyperostosis of the walls of the paranasal sinuses, cells ethmoid sinuses of the after sequestrectomy were noted. There were no fatal cases among the 10 patients we observed at the time of publication.CONCLUSION: The combination of anatomical features and the state of blood supply contributes to the development of invasive mucormycosis of the bones of the facial skull and the RCT data help with determining treatment tactics, the volume of surgery, and assessing dynamics in the early and long-term postoperative period.

Objective. To assess the course and outcomes of COVID-19 in recipients of allogeneic and autologous hematopoietic stem cell transplant (HSCT). Materials and Methods. The retrospective study included 44 adult recipients (allogeneic – 33 [75%] and autologous – 11 [25%] of HSCT who diagnosed with COVID-19 after transplantation. Group mostly represented by acute leukemia – 18 (41%) and lymphoma – 10 (22.7%). The median follow-up time since the development of COVID-19 was 231 days (1–818 days), after HSCT – 507.5 days (14–3723 days). Overall and progression-free survival was assessed using the Kaplan–Meier and Log-Rank method. We also evaluated the characteristics of the course of a new coronavirus infection. Results. Median time for the development of COVID-19 from the moment of HSCT was 122.5 days (-1–3490 days). Twelve patients (27.2%) were in grade 3–4 neutropenia at the time of COVID-19 diagnosis, 16 (36.4%) patients were in grade 1–2 neutropenia. Sixteen (48.4%) allo-HSCT recipients had active graft-versus-host disease (GVHD) at the time of COVID-19 development. Disease severity was mild in 19 (43.2%) and moderate in 13 (29.5%) patients. Overall, 200-day survival from the onset of COVID-19 was 78.8% (95% CI [63.1–88.4]). Anemia (p = 0.02) and thrombocytopenia (p = 0.01) significantly decrease OS in patients with COVID-19 after HSCT. Patients with GVHD at the time of COVID-19 onset had a better survival rate (p = 0.02). The timing of COVID-19 development after HSCT did not affect outcomes. Conclusions. The key points of the course of COVID-19 in HSCT recipients are the presence of cytopenia and graft-versus-host disease. Overall survival was 78.8%.

Background: Nivolumab 3 mg/kg was shown to be effective in patients with relapsed and refractory classic Hodgkin lymphoma (r/r cHL). However, previously obtained data on pharmacokinetics, as well as financial toxicity of therapy, raised the issue of studying necessity of efficacy of reduced doses of PD-1 inhibitors. Efficacy of nivolumab 40 mg has previously been demonstrated in patients with r/r cHL in a prospective phase 2 study (Lepik KV et al., 2020). Continued accumulation of experience in the use of low-dose PD-1 inhibitors in patients with r/r cHL is required to support previous data. Aims: To compare the efficacy of nivolumab (Nivo) 40 mg therapy with 3 mg/kg for patients with r/r cHL. Methods: The Nivo40 trial (NCT03343665) expanded prospective cohort of patients (group 1, n=50) treated with Nivo 40 mg was compared with the retrospective group 2 (n=116) of patients treated with Nivo 3 mg/kg. Patients characteristics are demonstrated in the Table 1. The response was evaluated every 3 months by PET-CT using LYRIC criteria. Adverse events (AE) were analyzed by NCI CTCAE 4.0.3. Overall response rate, progression-free survival (PFS) and overall survival (OS) were compared between group 1 and 2. During the survival analysis the PFS was censored by the time of additional therapy initiation. - Variable Nivo 40 mgN=50 Nivo 3 mg/kgN=116 p Median age, years (range) 36 (20-54) 38 (14-65) 0.129 Male/female, n (%) 17/33 (34/66) 56/60 (48/52) 0.089 Primary chemoresistance, n (%) 38 (76) 74 (64) 0.124 Early relapse, n (%) 7 (14) 14 (12) 0.731 Prior autologous stem cell transplantation, n (%) 17 (34) 44 (38) 0.630 Prior brentuximab vedotin, n (%) 18 (36) 62 (53) 0.039 Therapy lines before Nivo therapy, n (range) 4 (1-8) 5 (2-10) 0.011 B symptoms at Nivo therapy initiation, n (%) 26 (52) 71 (61) 0.269 Disease stage at Nivo therapy initiation, n (%) 2 8 (16) 11 (9) 0.294 3 5 (10) 7 (6) 4 37 (74) 97 (84) Progression at Nivo therapy initiation, n (%) 46 (92) 92 (79) 0.272 ECOG status at Nivo therapy initiation, n (%) 0-1 31 (62) 70 (60) 0.758 2 14 (28) 29 (25) 3 4 (8) 14 (12) 4 1 (2) 2 (2) Results: Median follow up was 44 (11-55) months in group 1 and 60 (6-70) months in group 2. Median Nivo cycles was 19 (2-49) and 20 (1-32) respectively. The best response to Nivo therapy was detected at 6 (2-24) and 6 (1-27) cycles respectively. Overall response rate was 66% in group 1 and 67% in group 2. The structure of response in group 1 was: complete response (CR) in 38% of patients, partial response (PR) in 28%, stable disease (SD) in 6%, indeterminate response (IR) in 22% and progressive disease (PD) in 6%; in group 2: CR in 34%, PR in 33%, SD in 5%, IR in 20% and PD in 8%. Median OS was not achieved in both groups, 3-year OS was 97,8% and 96,5% respectively (p=0.356). Median PFS was 21,9 months (95%CI: 16,75-27,05) in group 1 and 18,8 months (95%CI: 13,44-24,16) in group 2, 3-year PFS was 25,6% and 27% respectively (p=0.356). Additional therapy after Nivo monotherapy was started in 78% of patients after Nivo 40 mg and in 84% after Nivo 3 mg/kg. Allogeneic stem cell transplantation after Nivo therapy was performed in 5 (10%) patients in group 1 and in 26 (22%) patients in group 2. Any grade adverse events were detected in 66% of patients in group 1 and in 79% in group 2 (p=0.068), 3-4 grade AE were detected in 10% and 19% respectively (p=0.151). Summary/Conclusion: Nivolumab 40 mg therapy is comparable to the standard dose of 3 mg/kg in terms of overall response rate as well as survival in patients with r/r cHL. However, a direct comparison of different doses of nivolumab in a prospective study is required.

Objective. To study risk factors, etiology, clinical signs and treatment outcomes of invasive aspergillosis (IA) and mucormycosis combination (IAM) in children. Materials and Methods. A retrospective review of Saint-Petersburg register (1998–2021) of patients with IA was done and children with IAM were included. EORTC/MSGERG 2019 criteria were used for diagnosing and treatment results evaluation of invasive mycosis. We presented a clinical case of IAM in a child with acute lymphoblastic leukemia relapse. Results. A total of 12 children with IAM were included. They accounted 8% of all pediatric patients with invasive aspergillosis (n = 152). IAM was diagnosed in children with hematological malignancies and solid tumors from 4 to 16 years (median age – 11.5 years), mostly in girls (83%). Main risk factors of IAM were prolonged lymphopenia (75%, median 22 days) and neutropenia (67%, median 30 days) due to chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. The predominant etiological agents of IA were Aspergillus niger (33%), A. nidulans (33%) and A. fumigatus (17%), of mucormycosis – Lichtheimia corymbifera (50%) and Rhizomucor spp. (50%). Based on EORTC/MSGERG 2019 criteria, «proven» mucormycosis was diagnosed in 83% of patients, «probable» – in 17%. «Probable» IA was found in 100% of patients. The most common clinical sites of IAM were the lungs (75%) and paranasal sinuses (43%), multifocal involvement was revealed in 33% of patients. Mucormycosis developed during antifungal therapy of IA in 83% of patients. Antifungal therapy of mucormycosis received 75% of patients (amphotericin B lipid complex – 89%, posaconazole – 78%, caspofungin – 33%), combined antifungal therapy – 33%, surgery – 50%; combination of surgical and antifungal treatment was used in 42% of patients. The overall 12-week survival was 77.8%. The use of combined surgical and antifungal treatment significantly improved the survival of children with IAM (p = 0.023). Conclusions. Mucormycosis was diagnosed in 8% of children with IA. IAM developed mostly in patients with hematological malignancies (83%), prolonged lymphopenia (75%) and neutropenia (67%) against the background of chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. In 83% of patients mucormycosis was diagnosed during antifungal therapy for IA. The development of IAM increased overall 12-week mortality (50%). The combination of antifungal therapy with surgical treatment significantly improved prognosis of IAM (p = 0.023).

The aim of the work is to attract the attention of specialists: dentists, oncologists, hematologists to thorough sanitation of the oral cavity of patients preparing for chemotherapy treatment, to transplantation of hematopoietic stem cells. Two clinical cases described in the article were observed at the R.M. Gorbacheva First Saint-Petersburg State Medical University from 2010 to 2019. They confirm the possibility of the occurrence of infectious complications with damage to the maxillofacial region caused by rare pathogens of invasive mycosis, which debuted as an odontogenic inflammatory process. The success of the treatment of Invasive Mycosis depends on early diagnosis and antimycotic therapy; active surgical tactics in relation to the affected tissues in a controlled course of the underlying disease and the restoration of effective hematopoiesis.

Since SARS-CoV-2 infection heavily affects vulnerable populations including those with immune suppression, it is of special value to study clinical course, treatment outcomes, and immunity in patients (pts) with hematological (hem) malignancies. CHRONOS19 is an ongoing observational study in adult pts (≥18 years) with hem diseases (malignant or non-malignant) and COVID-19 in Russia. This web-based registry collected de-identified data from 15 centers all over the country at 30, 90, and 180 days after lab-confirmed or suspected (based on CT and/or clinical symptoms) COVID-19 diagnosis. The primary endpoint was 30-day all-cause mortality. As of data cut-off on April 14, 2021, 626 pts were enrolled in the study; 562 were eligible for primary endpoint assessment, n (%): M/F 271 (48%) / 291 (52%), median age 56 [18-90] years, malignant disease in 516 (92%) pts, among them induction phase / relapse or refractory / remission / NA in 180 (35%) / 120 (23%) / 187 (36%) / 29 (6%) pts. Thirty-day all-cause mortality in pts with hem malignancies was 19%; 83% of deaths were due to COVID-19 complications. No increase of hem disease relapse rate after COVID-19 was observed at Day 90 or Day 180, although 180-day data was still not mature at the time of analysis. IgG to SARS-CoV-2 was detected in 84% of pts with hem malignancies (167/199). The highest rate of detected antibody immunity was found in pts with chronic myeloproliferative neoplasms (100%; 13/13), HL (100%; 12/12), and multiple myeloma (97%; 34/35), the lowest – in pts with CLL (62%; 8/13) and NHL (60%; 6/10 and 56%; 10/18 for low-grade and high-grade lymphoma, respectively). igG detection rate in CD20+ lymphoma (60%) was significantly lower than in HL or T-cell lymphoma (p=0.004). Pts with ECOG 0-2 throughout the disease had a high rate of antibody immunity (90%; 104/116) vs. those with ECOG 3-4 at the time of COVID-19 diagnosis (77.5%; 31/40) or with worsening of ECOG to 3-4 during the disease (78%; 36/46). Five cases of SARS-CoV-2 re-infection were described. Pts with hem malignancies and COVID-19 have higher mortality than the general population. Low post-disease antibody immunity to SARS-CoV-2 and cases of re-infection may justify vaccination of these pts and warrant further research.

AbstractCurrently, the relevance of the issues of diagnosis and treatment of invasive fungal diseases has increased significantly due to the pandemic of a new coronavirus infection COVID-19 and the massive use of corticosteroids for the treatment. The key success factors in the outcome of invasive fungal diseases are early diagnosis and treatment, including the applying of an adequate systemic antifungal therapy and surgical treatment. Extensive areas of mycotic lesions of the facial bones and paranasal sinuses are lifethreatening conditions due to anatomical proximity to brain structures and a high risk of dissemination of I invasive fungal diseases with a fatal outcome. The objective of this work was to study the risk factors, possible pathogenesis, diagnosis and treatment strategy of invasive fungal diseases of the orofacial region in convalescents of COVID-19. We present case-series data on six patients in the clinics of maxillofacial surgery and otorhinolaryngology of the Pavlov First Saint Petersburg State Medical University over the period of 2021–2022. Predisposing factors, clinical and radiological symptoms, features of diagnosis, therapy and surgical strategy were analyzed. The presented observations confirm the relevance and danger of complications after a COVID-19 in the form of the development of invasive fungal diseases with damage to the maxillofacial region caused by mucormycetes and Aspergillus spp., as well as importance of early diagnosis and treatment.

Classical Hodgkin lymphoma (cHL) is characterized by the unique tumor microenvironment (TME) rich in immune cells. One of the explanations for the depressed antitumor response in cHL is hyperexpression of inhibitory immune checkpoint receptors on T cells as well as increased proportion of M2 macrophages (M2) in TME. The presence of high number of M2 has been demonstrated to worsen the prognosis of patients treated with standard chemotherapy, while data regarding the prognostic value of TME features in patients treated with PD-1 inhibitors is limited. This retrospective study included 61 primary tumor samples from pts with r/r HL, treated with Nivo, and 15 repeated samples obtained during relapse or progression of disease after immunotherapy. The PFS and the best overall response (BOR) depending on the proportion of cells positive for CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT, c-MAF in the TME in primary and sequential biopsies were analyzed. Immunohistochemical staining was performed with Bond III (Leica Biosystems). The antibody cocktail (CD163/c-MAF) was used for identification of M2. The response to Nivo was assessed by PET-CT with LYRIC. ROC analysis established 8,5% cut-off value for CD163 expression and 11,5% for CD68 expression, dividing patients with high and low number of positive cells. In the CD163low group, 4-year PFS was 24,1% (95% CI 9,3%-42,6%) with a median PFS of 11,6 months (95% CI 7,2-24,8); in the CD163high group - 42,6% (95% CI 20,2%-63,4%) with a median of 24,8 months (95% CI 20,4 - NA), p = 0,0086. Complete remission (CR) achievement as BOR to Nivo was associated with a lower level of M2 in primary biopsies (p = 0.047). In the analysis of sequential samples, an increase of PD- 1+ and LAG-3+ T-cells and depletion of CD68+ and CD163+ cells in repeated biopsies was observed (median PD-1–1.0% vs 7.0%; LAG-3–5.0% vs 8.0%; CD68–10.0% vs 7.0%; CD163–9.0% vs 3.0%, p<0,05). We found that low number of CD163+ cells in primary samples were associated with inferior PFS during Nivo therapy, while a lower level of M2 was correlated with achievement of CR. In repeated biopsies after Nivo therapy the cell profile in the TME changed: number of PD-1+ and Lag-3+ T-cells increased and number of CD68+ and CD163+ macrophages decreased.

Over the last decade, the introduction of new antifungal drugs and diagnostic procedures has improved the prognosis of hematological patients with invasive fungal disease (IFD), primarily invasive aspergillosis. Despite effective antifungal prophylaxis against the most common IFD caused by Aspergillus spp., rates of IFD due to rare pathogens being resistant to most antifungal drugs, including mucormycosis have been increased. The main group of patients having a high risk of mucormycosis is deeply immunocompromised patients who received chemotherapy for acute leukemia, patients undergoing allogeneic bone marrow transplantation, or treated with corticosteroids for graft-versushost disease. Currently, the urgency of this complication is significantly higher due to COVID-19 pandemic and extensive use of corticosteroids for the treatment of COVID-19. Despite the fact that the criteria for the diagnosis of IFD EORTC/MSG 2008 and 2020 have been developed and implemented into practice in most countries, mucormycosis still remains a difficult-to-diagnose IFD, where the factor of rapid diagnosis is a main factor of treatment success. Medications available for the treatment of IFD include polyenes, triazoles, and echinocandins. For a long time, the drug of choice for the treatment of mucormycosis was liposomal amphotericin B. However, a new effective drug has been approved for the treatment of both mucormycosis and IFD, caused by multiple pathogens – isavuconazole. This review presents new data on the epidemiology of mucormycosis, diagnosis approaches and current international treatment guidelines.