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To date, the impact of the tumor microenvironment on the prognosis of patients with classic Hodgkin lymphoma (cHL) during anti-PD-1 therapy has been studied insufficiently. This retrospective study included 61 primary samples of lymph nodes from patients who had relapsed/refractory (r/r) cHL and were treated with nivolumab. Repeated samples were obtained in 15 patients at relapse or disease progression after immunotherapy. Median follow-up was 55 (13–63) months. The best overall response rate and progression-free survival (PFS) were analyzed depending on the expression of CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT, CD163/c-maf in the tumor microenvironment in primary and sequential biopsies. The combination of CD163/c-maf antibodies was used for the identification of M2 macrophages (M2). A low number of macrophages in primary samples was associated with inferior PFS during nivolumab treatment (for CD163-positive cells p = 0.0086; for CD68-positive cells p = 0.037), while a low number of M2 with higher PFS (p = 0.014). Complete response was associated with a lower level of M2 (p = 0.011). In sequential samples (before and after nivolumab therapy) an increase in PD-1 (p = 0.011) and LAG-3 (p = 0.0045) and a depletion of CD68 (p = 0.057) and CD163 (p = 0.0049)-positive cells were observed. The study expands understanding of the cHL microenvironment structure and dynamics during nivolumab therapy in patients with r/r cHL.
Background.Most patients with primary CNS lymphoma (PCNSL), an aggressive extranodal lymphoma confined to the CNS, have a poor prognosis in spite of development of chemotherapy regimens. First-line treatment consists of high-dose methotrexate-based (HD-MTX) regimen followed by consolidation with autologous stem cell transplantation or whole brain radiotherapy. Given that this tumor manifests predominantly in older patients with median age of 65 years, many patients are unable to tolerate intensive chemotherapy. Moreover, most patients eventually present with relapsed or refractory (r/r) disease. Relapse or refractory (r/r) PCNSL has a poor prognosis with median overall survival not exceeding 3.5 months (Langner-Lemercier et al, 2016) and these patients should be offered a clinical trial whenever possible. These groups are in need of safe, tolerable and effective therapeutic approaches. Primary testicular lymphoma (PTL) shares biological and clinical similarities with PCNSL and often present with CNS involvement. Such patients are also in need of new approaches, especially if they are refractory or not suitable to HD-MTX. Given high PD-1/PD-L1 expression in tumor microenvironment (Berghoff, 2014), immune checkpoint inhibitors were successfully tested in r/r PCNSL and PTL setting. However, data are still scarce and limited to case series (Nayak et al., 2017; Graber et al. 2020). Here we present Pavlov University experience of the treatment of PCNSL and PTL with CNS involvement with PD-1 inhibitor nivolumab. Methods.Eight patients, 2 men and 6 women, with PCNSL and one patient with PTL with CNS involvement treated at the Pavlov University between 2017 and 2020 were included into analysis. Median age at a diagnosis was 62 (28-66) years. Two patients (22%) had ECOG score 3-4 and therefore could not be considered for intensive MTX containing frontline treatment. In all of the cases the tumor histological type was diffuse large B-cell lymphoma. All patients had parenchymal involvement: 7 patients had multifocal disease; deep structures were involved in 2 patients. One patient had leptomeningeal involvement. Nivolumab was used in a first-line setting in 2 patients (22%). In 7 (78%) patients with relapsed/refractory disease, the median number of treatment lines prior to nivolumab was 1 (1-7). Nivolumab was given every 2 weeks in the 100 mg dose. Adverse events were defined according to NCI CTC-AE 5.0. Results.At the time of analysis, the median follow-up was 18 (3-44) months. Median number of nivolumab cycles was 10 (2-23). Seven (78%) patients had an objective response: complete response in 3 patients (33.3%) and partial response in 4 patients (44.4%). Two patients (22.2%) were refractory to treatment. Two-year overall survival (OS) was 44% with median OS of 12 months. Two-year progression-free survival (PFS) was 26% with median of PFS 12 months. Оne responder had a moderate increase of tumor volume on MRI after two months of therapy followed by complete disappearance of brain lesions on sequential imaging at 4 months after treatment initiation. Nivolumab therapy appeared safe with only one patient (11%) having severe adverse event, namely grade 3 alanine aminotransferase and aspartate aminotransferase increase. Conclusion.Nivolumab appears to be safe and effective therapy in PCNSL and PTL with CNS involvement both in first-line and r/r setting. However, in our cohort majority of patients relapsed that suggest that consolidation therapy after remission induction with nivolumab may be crucial for long-term remissions. We also demonstrate that pseudoprogression might be also observed in PCNSL during immunotherapy. Large-scale trials are needed to generate strong evidence for the use of PD-1 inhibitors in PCNSL. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Nivolumab is an anti-PD-1 inhibitor approved for classical Hodgkin lymphoma. There is early clinical data suggesting the efficiency of nivolumab in PCNS lymphoma (Nayak, 2017)
Objectives Therapy of patients with relapsed and refractory classic Hodgkin lymphoma (r/r cHL) after PD-1 inhibitors failure remains an unresolved issue. The aim of this study was to evaluate the efficacy and safety of the combination of nivolumab with brentuximab vedotin (Nivo + BV) after nivolumab monotherapy failure. Methods This study retrospectively analyzed 21 patients with r/r cHL who were treated with the combination of Nivo + BV after Nivo failure. The response was evaluated by PET-CT scan according to the LYRIC criteria. Adverse events (AEs) were assessed according to NCI CTCAE v.4.03. Results Median follow-up was 19 (9-47) months. The ORR was 57%. The median OS was not reached, 24 month OS was 80% (95% CI 50-93%). Median PFS was 12 months with 24 month PFS of 31% (95% CI 12-53%). Any grade AEs were observed in 12 patients (63%), 3-4 grade AEs in 2 patients (10%). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after Nivo + BV was performed in 8 (38%) patients. The median time between Nivo + BV and allo-HSCT was 8 (5-21) months. Conclusions Combination of Nivo + BV in r/r cHL after nivolumab monotherapy failure is potentially an effective and safe approach.
Актуальность и цели. Не менее 1 / 3 больных с диффузной B-крупноклеточной лимфомой (ДВКЛ) демонстрируют резистентность к терапии первой линии. Возможности иммунохимиотерапии R-CHOP признаются неудовлетворительными у пациентов из группы высокого риска. Использование опций, предполагающих увеличение дозоинтенсивности лечения или включение аутоТГСК в первую линию, не подкреплено результатами контролируемых исследований. В этом контексте в настоящей работе рассматриваются возможности, проблемы и неудачи терапии первой линии с учетом длительного наблюдения за популяцией пациентов с ДВКЛ в Волгоградской области. Материалы и методы. С 2004 по 2017 г. в популяционный регистр отделения гематологии ГБУЗ «Волгоградский областной клинический онкологический диспансер» были включены все первичные больные ДВКЛ-492 человека: 235 (48 %) мужчин, 257 (52 %) женщин, в возрасте 18-88 лет. Средний и медиана возраста составили 59 и 61 год соответственно. Терапию CHOP получило 206 (42 %) больных, R-CHOP-223 (45 %). Другие режимы, включая программы NHL-BFM-90 и R-DA-EPOCH, применялись только у 63 (13 %) пациентов. Терапию второй и третьей линий получило 145 (30 %) и 54 (11 %) больных соответственно. Значение международного прогностического индекса (IPI) и иммуноморфоло
Цель. Исследование взаимосвязи непосредственной эффективности лечения лимфомы из клеток зоны мантии, неудач первой линии и прямых затрат, зависящих от выбора терапии первой линии. Методы. С 2008 по 2016 г. проведено сравнительное одноцентровое контролируемое исследование эффективности и токсичности режима R-hyper-CVAD-R-HD-AraC (n = 16). Группу контроля составили пациенты, получавшие 6-8 циклов R-CHOP (n = 39). Доза цитарабина снижена в сравнении с оригинальным режимом до 1 г/м 2 2 раза в сутки в течение 2 дней. Дозы препаратов в блоке R-hyper-CVAD были стандартными. Курс R-HD-AraC начинался на 28-й день от начала R-hyper-CVAD. В группе R-hyper-CVAD-R-HD-AraC характеристика пациентов была следующая: медиана возраста 56 лет (диапазон 40-66 лет), старше 60 лет-6 (38 %), мужчины-12 (75 %), стадия IV-12 (75 %), «bulky»-7 (44 %), вовлечение костного мозга-11 (69 %), высокий риск по MIPI b-8 (50 %), бластоидный вариант-7 (44 %). Только 2 пациента из группы R-hyper-CVAD-R-HD-AraC получили высокодозную консолидацию с трансплантацией аутологичных ГСК. ТГСК в контрольной группе не выполнялась. Результаты сравнительного анализа скорректированы по возрасту. По остальным значимым факторам сравниваемые группы были сопоставимы. Результаты. Все пациенты основной (исследуемой) группы получили по 3 блока R-hyper-CVAD и 3 блока R-HD-AraC. Частота полных ремиссий была значимо выше, чем в контрольной группе,-12 (75 %) vs 14 (36 %).
Randomized multicenter trials in the area of hematopoietic stem cell transplantation (HSCT) face considerable challenges, therefore, their amount is relatively small. Most clinical guidelines are based on the data of multicenter registry studies or well-controlled prospective single-center non-randomized studies. To determine the criteria of a well-controlled single-center trial the results of which can be confi rmed by a multicenter analysis, the total of 44 groups of patients from 22 cooperative studies in collaboration with EBMT were analyzed. The results of these studies were compared with single-center data and the results of the planned studies of RM Gorbacheva Scientifi c Research Institute of Pediatric Oncology, Hematology and Transplantation. In 43 % of cases signifi cant diff erences were observed. The probability of diff erences did not decrease with an increasing number of patients in the single-center groups, but became higher (odds ratio 1.037; 95% confi dence interval 1.001-1.074; p = 0.046), which highlights the diff erences in methods of single- and multicenter trials. While analyzing the reasons for signifi cant diff erences the following necessary criteria for high-quali ty single-center trials in the area of HSCT were formulated: 1) conditioning regimens and graft-versus-host disease prophylaxis (if they are not subject of the study) need to be consistent with the most frequently used practices; 2) groups of patients should be status-homogeneous; 3) the trial must not include patients treated more than 5 years before the analysis; 4) patients should receive current antitumor therapy at pre- and post-transplantation stages; 5) each compared group should include more than 30-40 patients
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.
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