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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 %).
A sufficient subgroup of patients encounters pain syndrome in the course of cytostatic chemotherapy (ChT), either with or without hematopoietic stem cell transplantation (HSCT). Over this time period, severe thrombocytopenia and leucopenia may develop, thus limiting the opportunities for non-steroidal anti-inflammatory drugs (NSAID). As recommended by WHO, administration of strong opioids to children is possible in moderate pain and inefficiency of NSAIDs. In this case, second step of the pain relief ladder is absent, i.e., codeine application. However, the recommendations do not exclude usage of tramadol, which is widely applied in pediatrics. Our aim was to evaluate relative safety and efficiency of tramadol and morphine in managment of moderate pain in children after HSCT and ChT. Patients and methods The study included analysis of 159 children admitted to the ICU pain management team with complaints for weak or moderate pain (form 3 to 6 points on an age-matched scale). The age of patients was from 1 to 17 years, with a median of 8 years old. All the patients did not receive opioids (were opioid naïve) within 30 days before inclusion to the study. The drugs were injected by continuous infusion at the inpatient clinic. In the first group (n=118), standard tramadol doses were administered as the 1st-line therapy (0.2 to 0.3 mg/kg/h). The patients form 2nd group (n=41) were administered low-dose morphine (0.01 to 0.019 mg/kg/h). Treatment efficiency was assessed by FLACC verbal scores, Wong-Baker Faces Pain Rating Scale, or visual analogue scale and quality of life. Statistical evaluation was performed by means of SPSS software, using a nonparametric Chi-square criterion. Results When administered tramadol as a first-line therapy, it was efficient in ca. 40.7% of cases (n=48). With low-dose morphine, the response rate proved to be 58.5% (n=24). One patient (0.8%) received tramadol when transferred to other institution. The second-line therapy (strong opioids) was administered due to lack of efficiency, or poor drug acceptability during the first-line treatment. It was observed in 53.4% of group 1 (n=63), and in 39% (n=16) of morphine-treated patients (group 2). Side effects due to tramadol administration were observed in 5.1% of cases (n=6). When administered low-dose morphine, only 1 female patient (2.4%) developed intestinal paresis which resolved after the therapy cancellation. Upon statistical evaluation, no significant differences were revealed between the groups. Conclusion Both medical drugs have shown similar efficiency and safety when applied for jugulating weak or moderate nociceptive pain after cytostatic chemotherapy and HSCT in pediatric patients.
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.
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