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Hu M, Zhang T, Liu B, Guo Q, Zhao B, Lin J, Lv Z, Wang R. Association of rituximab use with adverse events in adults with lymphoma or autoimmune disease: a single center experience. Front Med (Lausanne) 2025; 12:1567886. [PMID: 40351469 PMCID: PMC12061919 DOI: 10.3389/fmed.2025.1567886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Objective Rituximab (RTX) is a chimeric human/murine CD20 monoclonal antibody, which has been administered in treating hematological malignancies and various autoimmune disorders. This study aimed to present our center's experience in RTX use in adults with lymphoma and autoimmune diseases (AID) including primary membranous nephropathy (pMN), as well as therapeutic effects of RTX on clinical outcome of pMN patients. Methods A total of 761 Chinese patients were retrospectively included, who received RTX treatment at Shandong Provincial Hospital between January 1st, 2017 and December 31st, 2021, with person time of exposure spanning between their first dose of RTX and last follow-up date or the end of the study period. Results Adverse events (AEs) occurred in 487 patients (64.0%), with a majority of infection (309, 40.6%) and a minority of non-infectious AEs (178, 23.4%); and the incidences of AEs were higher in lymphoma patients (381, 65.8%) than that in AID patients (106, 58.2%). Respiratory infections (215, 28.3%), gastrointestinal infections (49, 6.4%), urinary tract infections (41, 5.4%), cutaneous and mucosal infections (31, 4.1%), and infections in the abdominal cavity or pleurisy (4, 0.5%) were the leading types of infections. Cancer diagnosis [hazard ratio (HR), 3.926; 95% confidence interval (CI), 1.730-8.913] and prophylactic sulfamethoxazole/trimethoprim (SMZ/TMP) administration (HR, 3.793; 95% CI, 1.101-13.069) were associated with increased risk of infections. Immediate non-infectious AEs included anaphylaxis (44, 5.8%) and infusion reactions (99, 13.0%). Long-term non-infectious AEs included hypogammaglobulinemia (106, 28.6%), neutropenia (11, 5.5%) and interstitial lung disease (1, 0.1%). Female sex (HR, 0.515; 95% CI, 0.289-0.918) and cancer diagnosis (HR, 0.126; 95% CI, 0.049-0.323) were associated with higher risk of hypogammaglobulinemia. In 74 pMN patients, 13 (17.6%) patients experienced infections, with 2 cases of non-infectious AEs (2.7%). 6-month follow-up showed remission was achieved in 45 patients (60.8%), either as initial (61.0%) or alternative therapy (60.7%), without significant impacts on kidney function (p > 0.05). Conclusion Our findings indicated AEs were common during RTX treatment, particularly in lymphoma patients, most of which were moderate and mild, highlighting a whole-process monitoring, timely interference and caring. And RTX was a safe and effective therapeutic option for pMN either as initial or alternative therapy in adult Chinese patients.
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Affiliation(s)
- Mengsi Hu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingwei Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
| | - Bing Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qi Guo
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Bing Zhao
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jiangong Lin
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Pedersen LS, Klausen NN, Jensen JF, Bacevičius ED, Brown P, Mészáros Jørgensen J, Larsen TS, Poulsen CB, Clausen MR, Schou Pedersen R, Gang AO, Westermann R, Kristensen S, Dreyer LW, El‐Galaly TC, Jakobsen LH. The long-term risk of immune-related conditions in survivors of diffuse large B-cell lymphoma: A Danish nationwide registry study. EJHAEM 2025; 6:e1070. [PMID: 39866948 PMCID: PMC11756995 DOI: 10.1002/jha2.1070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 01/28/2025]
Abstract
Background There is limited knowledge of the long-term effects on the immune system after treatment for diffuse large B-cell lymphoma (DLBCL). Methods This study included DLBCL patients from the Danish Lymphoma Registry who obtained complete remission (CR) after (R)-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like immunochemotherapy. Each R+ CHOP-like treated patient was matched to five comparators from the Danish background population and furthermore compared to R- CHOP-like treated patients. Incidence rate ratios (IRRs) and risk differences (RDs) were calculated for a wide range of infections, autoimmune conditions, and immune deficiencies (AC-IDs) combined and by subtypes. Results R+ CHOP-like treated patients had a higher risk of infections overall (IRR 1.5, 95% confidence interval [CI] 1.4-1.7: 10-year RD 5.0%, 95% CI 2.2%-7.8%) and for a majority of the subtypes than matched comparators. Likewise, they had a higher risk of AC-IDs overall (IRR 1.4, 95% CI 1.1-1.7; RD 0.8%, 95% CI 0.7%-2.2%) than matched comparators, however only of clinical relevance for three subtypes; autoimmune diseases of the endocrine system, sarcoidosis and immune deficiencies. The addition of rituximab to CHOP-like therapy did not alter the incidence rates (IR) of infections overall (IRR 1.1, 95% CI 0.9-1.3) or AC-IDs overall (IRR 0.8, 95% CI 0.5-1.3) compared to CHOP-like therapy alone, although the IR for respiratory infections was significantly elevated (IRR 1.5, 95% CI 1.1-2.1). However, an increased use of IVIG treatment was observed among R+ CHOP survivors. Conclusion R-CHOP-like treated patients face an increased risk of infections and AC-IDs overall compared with the background population. The risk of infections and AC-IDs did not change overall after the addition of rituximab to CHOP, however, an increased risk of respiratory infections is notable. These findings could highlight the need for expanded vigilance and prophylaxis strategies.
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Affiliation(s)
- Laura Schou Pedersen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark
| | - Nadja Nørholm Klausen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark
| | - Jonas Faartoft Jensen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark
| | | | - Peter Brown
- Department of HaematologyRigshospitaletCopenhagenDenmark
| | | | | | | | | | | | | | - Rasmus Westermann
- Department of RheumatologyCenter of Rheumatic Research Aalborg (CERRA)Aalborg University HospitalAalborgDenmark
| | - Salome Kristensen
- Department of RheumatologyCenter of Rheumatic Research Aalborg (CERRA)Aalborg University HospitalAalborgDenmark
- Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Lene Wohlfahrt Dreyer
- Department of RheumatologyCenter of Rheumatic Research Aalborg (CERRA)Aalborg University HospitalAalborgDenmark
- Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Tarec Christoffer El‐Galaly
- Department of HaematologyAarhus University HospitalAarhusDenmark
- Department of HaematologyOdense University HospitalOdenseDenmark
- Department of Cancer EpidemiologyKarolinska InstitutetStockholmSweden
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
- Department of Clinical EpidemiologyAarhus University HospitalAarhusDenmark
- Department of Molecular MedicineAarhus University HospitalAarhusDenmark
| | - Lasse Hjort Jakobsen
- Department of Haematology, Clinical Cancer Research CenterAalborg University HospitalAalborgDenmark
- Department of Mathematical SciencesAalborg UniversityAalborgDenmark
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Nie Y, Zhang N, Li J, Wu D, Yang Y, Zhang L, Bai W, Jiang N, Qiao L, Huang C, Zhou S, Tian X, Li M, Zeng X, Peng L, Zhang W. Hypogammaglobulinemia and Infection Events in Patients with Autoimmune Diseases Treated with Rituximab: 10 Years Real-Life Experience. J Clin Immunol 2024; 44:179. [PMID: 39150626 DOI: 10.1007/s10875-024-01773-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/23/2024] [Indexed: 08/17/2024]
Abstract
OBJECTIVES To investigate predictors of hypogammaglobulinemia (HGG) and severe infection event (SIE) in patients with autoimmune disease (AID) receiving rituximab (RTX) therapy. METHODS This was a retrospective study conducted in a tertiary medical center in China. Predictors of HGG or SIE were assessed using Cox analysis. Restricted cubic spline (RCS) analysis was applied to examine the correlation between glucocorticoid (GC) maintenance dose and SIE. RESULTS A total of 219 patients were included in this study, with a cumulative follow-up time of 698.28 person-years. Within the study population, 117 patients were diagnosed with connective tissue disease, 75 patients presented with ANCA-associated vasculitis, and 27 patients exhibited IgG4-related disease. HGG was reported in 63.3% of the patients, where an obvious decline in IgG and IgM was shown three months after RTX initiation. The rate of SIE was 7.2 per 100 person-years. An increase in the GC maintenance dose was an independent risk factor for both hypo-IgG (HR 1.07, 95% CI 1.02-1.12, p = 0.003) and SIE (HR 1.06, 95% CI 1.02-1.1, p = 0.004). Further RCS analysis identified 7.48 mg/d prednisone as a safe threshold dose for patients who underwent RTX treatment to avoid a significantly increased risk for SIE. CONCLUSION HGG was relatively common in RTX-treated AID patients. Patients with chronic lung disease or who were taking ≥ 7.5 mg/d prednisone during RTX treatment were at increased risk for SIE and warrant attention from physicians.
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Affiliation(s)
- Yuxue Nie
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Nianyi Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Jingna Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Di Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Yunjiao Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Li Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Wei Bai
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Nan Jiang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Lin Qiao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Can Huang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Shuang Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Xinping Tian
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Linyi Peng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China.
| | - Wen Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, The Ministry of Education Key Laboratory, Beijing, China.
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Dong J, Xu Z, Guo X, Ye F, Fan C, Gao J, Gao Y, Yang L. Effect of rituximab on immune status in children with aggressive mature B-cell lymphoma/leukemia-a prospective study from CCCG-BNHL-2015. Heliyon 2024; 10:e27305. [PMID: 38495131 PMCID: PMC10943340 DOI: 10.1016/j.heliyon.2024.e27305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/19/2024] Open
Abstract
Background Limited research has been conducted on the impact of rituximab on immune function and the incidence of side effects in children undergoing combination chemotherapy for aggressive mature B-cell lymphoma/leukemia. Methods Clinical data from 85 patients with primary pediatric aggressive mature B-cell lymphoma/leukemia, treated according to the Chinese Children's Cancer Group (CCCG)-mature B-cell non-Hodgkin lymphoma (BNHL)-2015 protocol from June 1, 2015, to December 1, 2022, were collected from three tertiary medical centers in China. Patients with pre-existing malignancies or primary immune deficiencies (PIDs) were excluded. Results Between June 1, 2015, and December 1, 2022, 85 patients (65 [76.5%] boys and 20[23.5%] girls; mean age, 6.95 years) were enrolled, and immune data at baseline during follow-up were analyzed. At the end of chemotherapy, a higher proportion of patients in the R4 group exhibited a decrease in peripheral blood CD3- CD19+ B cells (20[100%] of 20 vs 13[47.8%] of 18, p = 0.04), CD3+ T cells (21[91.3%] of 23 vs 14[60.9%] of 23, p = 0.016), and serum IgM (14[60.9%] of 23 vs 4[17.4%] of 23, p = 0.003) compared to the R3 group. However, these differences were no longer statistically significant six months after chemotherapy administration. The combination of rituximab with AA was associated with a higher incidence of significant thrombocytopenia (49[81.7%] of 60 vs 29[52.7%] of 55, p = 0.001) and infection (35[58.3%] of 60 vs 17[30.9%] of 55, p = 0.003) compared to AA alone. Furthermore, the combination of rituximab with BB was linked to a higher incidence of significant thrombocytopenia (32[52.5%] of 61 vs 31[31.0%] of 100, p = 0.007) compared to BB alone. Conclusions While the effects of rituximab in combination with intense chemotherapy for childhood aggressive mature B-cell lymphoma/leukemia on children's immune function generally recovers within six months it may still prolong the recovery from immunoglobulinemia, posing a risk of secondary infections. Further studies are required to identify children with potential primary immunodeficiencies.
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Affiliation(s)
- Jiajia Dong
- Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China
| | - Zhou Xu
- Department of Hematology/Oncology, School of Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China
| | - Xia Guo
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Disease of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Fanghua Ye
- Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China
| | - Chenying Fan
- Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China
| | - Ju Gao
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Disease of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yijin Gao
- Department of Hematology/Oncology, School of Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China
| | - Liangchun Yang
- Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China
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Criscuolo M, Fracchiolla N, Farina F, Verga L, Pagano L, Busca A. A review of prophylactic regimens to prevent invasive fungal infections in hematology patients undergoing chemotherapy or stem cell transplantation. Expert Rev Hematol 2023; 16:963-980. [PMID: 38044878 DOI: 10.1080/17474086.2023.2290639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/29/2023] [Indexed: 12/05/2023]
Abstract
INTRODUCTION The recent introduction of targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors, and immunotherapies has improved the cure rate of hematologic patients. The implication of personalized treatment on primary antifungal prophylaxis will be discussed. AREAS COVERED We reviewed the literature for clinical trials reporting the rate of invasive fungal infections during targeted and cellular therapies and stem cell transplant, and the most recent international guidelines for primary antifungal prophylaxis. EXPERT OPINION As the use of personalized therapies is growing, the risk of invasive fungal infection has emerged in various clinical settings. Therefore, it is possible that the use of mold-active antifungal prophylaxis would spread in the next years and the risk of breakthrough infections would increase. The introduction of new antifungal agents in the clinical armamentarium is expected to reduce clinical unmet needs concerning the management of primary antifungal prophylaxis and improve outcome of patients.
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Affiliation(s)
- Marianna Criscuolo
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Nicola Fracchiolla
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | | | | | - Livio Pagano
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Alessandro Busca
- Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Department of Oncology, SSCVD Trapianto di Cellule Staminali Torino, Torino, Italy
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Alexander S, Aupérin A, Bomken S, Csóka M, Kazanowska B, Chiang AK, Andres M, Uyttebroeck A, Burke GAA, Zsiros J, Pillon M, Bollard CM, Mussolin L, Verdu-Amoros J, Neven B, Barkauskas DA, Wheatley K, Patte C, Gross TG, Minard-Colin V. Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial. Lancet Haematol 2023; 10:e445-e457. [PMID: 37094596 PMCID: PMC10350968 DOI: 10.1016/s2352-3026(23)00062-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND Survival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial. METHODS The Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing. FINDINGS From Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106 vs 53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53-5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75 vs 36 [64%] of 56, OR 13·33 [3·71-47·84], p<0·0001), and hypogammaglobulinemia (67 [71%] of 95 vs 37 [47%] of 79, OR 2·72 [1·45-5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94 vs 16 [25%] of 63, OR 3·64 [1·81-7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164 vs nine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23-5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 for Streptococcus pneumoniae (pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration. INTERPRETATION Children with high-risk mature B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab were at risk of prolonged hypogammaglobulinemia, although severe infections were rare. Strategies for immunoglobulin replacement and revaccination are needed. FUNDING Clinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network in England, Children's Cancer Foundation Hong Kong, US National Cancer Institute, F Hoffmann-La Roche.
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Affiliation(s)
- Sarah Alexander
- Division of Pediatric Haematology/Oncology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
| | - Anne Aupérin
- Biostatistics and Epidemiology Office, Gustave Roussy, INSERM U1018 Oncostat, Labelled Ligue Contre le Cancer, Université Paris-Saclay, Villejuif, France
| | - Simon Bomken
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; The Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Monika Csóka
- Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Bernarda Kazanowska
- Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland
| | - Alan K Chiang
- Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Mara Andres
- Department of Pediatric Hematology and Oncology, University of Valencia, Valencia, Spain
| | - Anne Uyttebroeck
- Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium
| | - G A Amos Burke
- Department of Paediatric Haematology, Oncology, and Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - József Zsiros
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
| | - Marta Pillon
- Maternal and Child Health Department, Padova University, Padova, Italy
| | - Catherine M Bollard
- Center for Cancer and Immunology Research, Children's National Hospital and The George Washington University, Washington, DC, USA
| | - Lara Mussolin
- Maternal and Child Health Department, Padova University, Padova, Italy; Unit of Oncohematology, Stem Cell Transplant and Gene Therapy, Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
| | - Jaime Verdu-Amoros
- Department of Pediatric Hematology and Oncology, University Hospital Valencia, Valencia, Spain
| | - Bénédicte Neven
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Unit of Pediatric Immunology, Haematology and Rheumatology, Paris Cité University, Imagine Institute, Paris, France
| | - Donald A Barkauskas
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, California, LA, USA
| | - Keith Wheatley
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Catherine Patte
- Departments of Pediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Thomas G Gross
- Center for Cancer and Blood Disorders, Children's Hospital of Colorado, Aurora, CO, USA
| | - Véronique Minard-Colin
- Departments of Pediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France; INSERM U1015, Gustave Roussy, Université Paris-Saclay, Villejuif, France
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7
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Modeling and affinity maturation of an anti-CD20 nanobody: a comprehensive in-silico investigation. Sci Rep 2023; 13:582. [PMID: 36631511 PMCID: PMC9834265 DOI: 10.1038/s41598-023-27926-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/10/2023] [Indexed: 01/12/2023] Open
Abstract
B-cell Non-Hodgkin lymphomas are the malignancies of lymphocytes. CD20 is a membrane protein, which is highly expressed on the cell surface of the B-cells in NHL. Treatments using monoclonal antibodies (mAbs) have resulted in failure in some cases. Nanobodies (NBs), single-domain antibodies with low molecular weights and a high specificity in antigen recognition, could be practical alternatives for traditional mAbs with superior characteristics. To design an optimized NB as a candidate CD20 inhibitor with raised binding affinity to CD20, the structure of anti-CD20 NB was optimized to selectively target CD20. The 3D structure of the NB was constructed based on the optimal templates (6C5W and 5JQH), and the key residues were determined by applying a molecular docking study. After identifying the key residues, some mutations were introduced using a rational protocol to improve the binding affinity of the NB to CD20. The rational mutations were conducted using the experimental design (Taguchi method). Six residues (Ser27, Thr28, Phe29, Ile31, Asp99, and Asn100) were selected as the key residues, and five residues were targeted for rational mutation (Trp, Phe, His, Asp, and Tyr). Based on the mutations suggested by the experimental design, two optimized NB structures were constructed. NB2 showed a remarkable binding affinity to CD20 in docking studies with a binding energy of - 853 kcal/mol. The optimized NB was further evaluated using molecular dynamics simulation. The results revealed that CDR1 (complementarity determining regions1) and CDR3 are essential loops for recognizing the antigen. NB2 could be considered as a potential inhibitor of CD20, though experimental evaluations are needed to confirm it.
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8
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Chen L, Li C, Bai H, Li L, Chen W. Use of modeling and simulation to predict the influence of triazole antifungal agents on the pharmacokinetics of zanubrutinib and acalabrutinib. Front Pharmacol 2022; 13:960186. [PMID: 36299883 PMCID: PMC9588929 DOI: 10.3389/fphar.2022.960186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Bruton’s tyrosine kinase (BTK) inhibitors are commonly used in the targeted therapy of B-cell malignancies. It is reported that myelosuppression and fungal infections might occur during antitumor therapy of BTK inhibitors, therefore a combination therapy with triazole antifungals is usually required. Objective: To evaluate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on the pharmacokinetics of BTK inhibitors (zanubrutinib, acalabrutinib) and to quantify the drug-drug interactions (DDIs) between them. Methods: The physiologically-based pharmacokinetic (PBPK) models were developed based on pharmacokinetic parameters and physicochemical data using Simcyp® software. These models were validated using clinically observed plasma concentrations data which based on existing published studies. The successfully validated PBPK models were used to evaluate and predict potential DDIs between BTK inhibitors and different triazoles. BTK inhibitors and triazole antifungal agents were simulated by oral administration. Results: Simulated plasma concentration-time profiles of the zanubrutinib, acalabrutinib, voriconazole, fluconazole, and itraconazole are consistent with the clinically observed profiles which based on existing published studies, respectively. The exposures of BTK inhibitors increase by varying degrees when co-administered with different triazole antifungals. At multiple doses regimen, voriconazole, fluconazole and itraconazole may increase the area under plasma concentration-time curve (AUC) of zanubrutinib by 127%, 81%, and 48%, respectively, and may increase the AUC of acalabrutinib by 326%, 119%, and 264%, respectively. Conclusion: The PBPK models sufficiently characterized the pharmacokinetics of BTK inhibitors and triazole antifungals, and were used to predict untested clinical scenarios. Voriconazole exhibited the greatest influence on the exposures of BTK inhibitors. The dosage of zanubrutinib or acalabrutinib need to be reduced when co-administered with moderate CYP3A inhibitors.
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Affiliation(s)
- Lu Chen
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Chao Li
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Hao Bai
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Lixian Li
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Wanyi Chen
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing University, Chongqing, China
- *Correspondence: Wanyi Chen,
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9
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Ogiso A, Mizuno T, Ito K, Mizokami F, Tomita A, Yamada S. Use of benzodiazepines is the risk factor for infection in patients aged 80 years or older with diffuse large B-cell lymphoma: A single-institution retrospective study. PLoS One 2022; 17:e0269362. [PMID: 35687536 PMCID: PMC9187058 DOI: 10.1371/journal.pone.0269362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 05/20/2022] [Indexed: 11/30/2022] Open
Abstract
Background The number of patients aged 80 years or older with diffuse large B-cell lymphoma (DLBCL) is increasing, and the incidence rate of the disease in this population group reaches up to 20%. The risk of infection is higher in older patients than in other patients. Although hypnotic drugs are frequently detected as potentially inappropriate medications, it is unclear whether hypnotic drugs affect the occurrence of infection during chemotherapy. Here, we investigated whether the use of hypnotic drugs is associated with infection during first-line chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) aged 80 years or older. Methods Japanese patients aged 80 years or older with diffuse large B-cell lymphoma who had received first-line chemotherapy at Fujita Health University Hospital from January 2005 to March 2020 were enrolled in this retrospective cohort study. The primary study outcome was the identification of the risk factor for infection during first-line chemotherapy. Results This study included 65 patients received first-line chemotherapy. The proportion of patients with National Comprehensive Cancer Network-international prognostic index ≥ 6 was higher in the infection group than in the non-infection group. The relative dose intensity of each anticancer drug (cyclophosphamide, adriamycin, and vincristine) and dose of prednisolone did not significantly differ between the two groups. Multivariate analysis showed that the use of benzodiazepines was a risk factor for infection (odds ratio, 4.131 [95% confidence interval: 1.225–13.94], P = 0.022). Conclusion DLBCL patients using benzodiazepines should be monitored for infection symptoms during chemotherapy.
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Affiliation(s)
- Anna Ogiso
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tomohiro Mizuno
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, Japan
- * E-mail:
| | - Kaori Ito
- Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Fumihiro Mizokami
- Department of Pharmacy, National Center for Geriatrics and Gerontology, Obu, Japan
| | - Akihiro Tomita
- Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Shigeki Yamada
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, Japan
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10
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Noreña I, Fernández-Ruiz M, Aguado JM. Is there a real risk of bacterial infection in patients receiving targeted and biological therapies? ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2022; 40:266-272. [PMID: 35577446 DOI: 10.1016/j.eimce.2020.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 10/06/2020] [Indexed: 06/15/2023]
Abstract
Over the past decades, the advent of targeted and biological therapies has revolutionized the management of cancer and autoimmune, hematological and inflammatory conditions. Although a large amount of information is now available on the risk of opportunistic infections associated with some of these agents, the evidence regarding the susceptibility to bacterial infections is more limited. Biological agents have been shown to entail a variable risk of bacterial infections in pivotal randomized clinical trials and post-marketing studies. Recommendations on risk minimization strategies and therapeutic interventions are therefore scarce and often based on expert opinion, with only a few clear statements for some particular agents (i.e. meningococcal vaccination for patients receiving eculizumab). In the present review the available information regarding the incidence of and risk factors for bacterial infection associated with the use of different groups of biological agents is summarized according to their mechanisms of action, and recommendations based on this evidence are provided. Additional information coming from clinical research and real-world studies is required to address unmet questions in this emerging field.
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Affiliation(s)
- Ivan Noreña
- Teaching and Training Unit, Division of Infectious Diseases and Tropical Medicine, LMU University Hospital Munich, Munich, Germany.
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; School of Medicine, Universidad Complutense. Madrid, Spain
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11
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Szpakowski JL, Tucker LY, Baer DM, Pauly MP. Hepatotoxicity during legacy cancer chemotherapy in patients infected with hepatitis C virus: A retrospective cohort study. CANADIAN LIVER JOURNAL 2022; 5:43-60. [PMID: 35990784 PMCID: PMC9231429 DOI: 10.3138/canlivj-2021-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 08/13/2021] [Indexed: 11/04/2023]
Abstract
BACKGROUND The rates and causes of significant hepatotoxicity with cancer chemotherapy (CCT) in patients infected with hepatitis C virus (HCV) are incompletely characterized. METHODS We compared rates of grade 3 or 4 hepatotoxicity, defined as elevated transaminases, during CCT in patients who are mono-infected with HCV compared with rates in controls matched on demographics, diagnosis, and rituximab use. We excluded patients with hepatobiliary cancers, hepatitis B virus or human immunodeficiency virus infection. Hepatotoxicity was attributed to a medical cause, cancer progression, or CCT, including HCV flare. RESULTS Patients with HCV (n = 196) had a higher rate of cirrhosis than the 1,130 matched controls (21.9% versus 4%; P <0.001). Their higher rate of overall hepatotoxicity (8.7% versus 4.5% of controls, P = 0.01) was due to higher rate of CCT-related hepatotoxicity (4.1% versus 1.2%, P = 0.01). On multivariable analysis, the largest risk factor for overall hepatotoxicity was cirrhosis, and the only risk factor for CCT-related hepatotoxicity was HCV infection. Among those with HCV, the only significant risk factor for hepatotoxicity was rituximab use. Hepatotoxicity caused by CCT delayed or altered treatment in only 3 HCV patients and 1 control (1.5% versus 0.1%, P = 0.01). CONCLUSIONS Most patients with HCV can safely be treated with cancer chemotherapy. Cirrhosis and HCV infection contributed to increased hepatotoxicity in subjects on CCT. Among HCV patients, rituximab use was the major risk factor for increased hepatotoxicity. Hepatotoxicity due to CCT itself rarely altered or delayed CCT. Nonetheless, HCV-positive patients should be monitored carefully during CCT.
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Affiliation(s)
| | - Lue-Yen Tucker
- Division of Research, Kaiser Permanente, Oakland, California, USA
| | - David M Baer
- Kaiser Permanente Medical Center, Oakland, California, USA
| | - Mary Pat Pauly
- Kaiser Permanente Medical Center, Sacramento, California, USA
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12
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Little JS, Weiss ZF, Hammond SP. Invasive Fungal Infections and Targeted Therapies in Hematological Malignancies. J Fungi (Basel) 2021; 7:1058. [PMID: 34947040 PMCID: PMC8706272 DOI: 10.3390/jof7121058] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 01/02/2023] Open
Abstract
The use of targeted biologic therapies for hematological malignancies has greatly expanded in recent years. These agents act upon specific molecular pathways in order to target malignant cells but frequently have broader effects involving both innate and adaptive immunity. Patients with hematological malignancies have unique risk factors for infection, including immune dysregulation related to their underlying disease and sequelae of prior treatment regimens. Determining the individual risk of infection related to any novel agent is challenging in this setting. Invasive fungal infections (IFIs) represent one of the most morbid infectious complications observed in hematological malignancy. In recent years, growing evidence suggests that certain small molecule inhibitors, such as BTK inhibitors and PI3K inhibitors, may cause an increased risk of IFI in certain patients. It is imperative to better understand the impact that novel targeted therapies might have on the development of IFIs in this high-risk patient population.
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Affiliation(s)
- Jessica S. Little
- Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
| | - Zoe F. Weiss
- Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
| | - Sarah P. Hammond
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
- Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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13
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García-Vidal C, Vázquez L, Jarque I. [Relevance of liposomal amphotericin B in the treatment of invasive fungal infections in patients with hematologic malignancies]. Rev Iberoam Micol 2021; 38:61-67. [PMID: 33994104 DOI: 10.1016/j.riam.2021.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 12/20/2022] Open
Abstract
Liposomal amphotericin B (L-AmB) has been a key cornerstone for the management of invasive fungal infections (IFI) caused by a wide array of molds and yeasts during the last three decades. Multiple studies performed over this period have generated a large body of evidence on its efficacy and safety, becoming the main antifungal agent in the management of IFI in patients with hematologic malignancies in several not mutually exclusive clinical settings. First, L-AmB is the most commonly used antifungal agent in patients undergoing intensive chemotherapy for acute leukemia and high-risk myelodysplastic syndrome, as well as in hematopoietic stem cell transplant recipients. Additionally, due to the administration of newer targeted therapies (such as monoclonal antibodies or small molecule inhibitors), opportunistic mold infections are increasingly being reported in patients with hematologic malignancies usually considered low-risk for IFI. These agents usually have a high drug-drug interaction potential, being triazoles, commonly used for antifungal prophylaxis, included. Finally, patients developing breakthrough IFI because of either subtherapeutic concentrations of antifungal prophylactic drugs in blood or selection of resistant strains, require broad spectrum antifungal therapy, usually with an antifungal of a different class. In both situations, L-AmB remains as the best option for early antifungal therapy.
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Affiliation(s)
| | - Lourdes Vázquez
- Servicio de Hematología, Hospital Universitario, Salamanca, España
| | - Isidro Jarque
- Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, España.
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14
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Gkrania-Klotsas E, Kumararatne DS. Serious Infectious Complications After Rituximab Therapy in Patients With Autoimmunity: Is This the Final Word? Clin Infect Dis 2021; 72:738-742. [PMID: 32067045 DOI: 10.1093/cid/ciaa131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 02/14/2020] [Indexed: 11/14/2022] Open
Affiliation(s)
- Effrossyni Gkrania-Klotsas
- Department of Infectious Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.,Department of Clinical Immunology, Cambridge University Hospitals, Cambridge, United Kingdom
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15
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Kyriakidis I, Vasileiou E, Rossig C, Roilides E, Groll AH, Tragiannidis A. Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies. J Fungi (Basel) 2021; 7:186. [PMID: 33807678 PMCID: PMC7999508 DOI: 10.3390/jof7030186] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/27/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022] Open
Abstract
Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children with hematologic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and axicabtagene ciloleucel), CD20 (rituximab and biosimilars, 90Y-ibritumomab tiuxetan, ofatumumab, and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (brentuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (90Y-labelled BW 250/183), CD248 (ontuxizumab) and immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications.
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Affiliation(s)
- Ioannis Kyriakidis
- Pediatric and Adolescent Hematology-Oncology Unit, 2nd Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (I.K.); (E.V.)
| | - Eleni Vasileiou
- Pediatric and Adolescent Hematology-Oncology Unit, 2nd Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (I.K.); (E.V.)
| | - Claudia Rossig
- Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, D-48149 Münster, Germany;
| | - Emmanuel Roilides
- Infectious Diseases Unit, Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, 3rd Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece;
| | - Andreas H. Groll
- Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, Infectious Disease Research Program, University Children’s Hospital Münster, D-48149 Münster, Germany;
| | - Athanasios Tragiannidis
- Pediatric and Adolescent Hematology-Oncology Unit, 2nd Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece; (I.K.); (E.V.)
- Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, Infectious Disease Research Program, University Children’s Hospital Münster, D-48149 Münster, Germany;
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16
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Ruiz-Camps I, Aguilar-Company J. Risk of infection associated with targeted therapies for solid organ and hematological malignancies. Ther Adv Infect Dis 2021; 8:2049936121989548. [PMID: 33680453 PMCID: PMC7897815 DOI: 10.1177/2049936121989548] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/26/2020] [Indexed: 12/15/2022] Open
Abstract
Higher risks of infection are associated with some targeted drugs used to treat solid organ and hematological malignancies, and an individual patient’s risk of infection is strongly influenced by underlying diseases and concomitant or prior treatments. This review focuses on risk levels and specific suggestions for management, analyzing groups of agents associated with a significant effect on the risk of infection. Due to limited clinical experience and ongoing advances in these therapies, recommendations may be revised in the near future. Bruton tyrosine kinase (BTK) inhibitors are associated with a higher rate of infections, including invasive fungal infection, especially in the first months of treatment and in patients with advanced, pretreated disease. Phosphatidylinositol 3-kinase (PI3K) inhibitors are associated with an increased risk of Pneumocystis pneumonia and cytomegalovirus (CMV) reactivation. Venetoclax is associated with cytopenias, respiratory infections, and fever and neutropenia. Janus kinase (JAK) inhibitors may predispose patients to opportunistic and fungal infections; need for prophylaxis should be assessed on an individual basis. Mammalian target of rapamycin (mTOR) inhibitors have been linked to a higher risk of general and opportunistic infections. Breakpoint cluster region-Abelson (BCR-ABL) inhibitors are associated with neutropenia, especially over the first months of treatment. Anti-CD20 agents may cause defects in the adaptative immune response, hypogammaglobulinemia, neutropenia, and hepatitis B reactivation. Alemtuzumab is associated with profound and long-lasting immunosuppression; screening is recommended for latent infections and prevention strategies against CMV, herpesvirus, and Pneumocystis infections. Checkpoint inhibitors (CIs) may cause immune-related adverse events for which prolonged treatment with corticosteroids is needed: prophylaxis against Pneumocystis is recommended.
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Affiliation(s)
- Isabel Ruiz-Camps
- Infectious Diseases Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Juan Aguilar-Company
- Infectious Diseases Department and Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
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17
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Luo C, Wu G, Huang X, Ma Y, Zhang Y, Song Q, Xie M, Sun Y, Huang Y, Huang Z, Hou Y, Xu S, Chen J, Li X. Efficacy and safety of new anti-CD20 monoclonal antibodies versus rituximab for induction therapy of CD20 + B-cell non-Hodgkin lymphomas: a systematic review and meta-analysis. Sci Rep 2021; 11:3255. [PMID: 33547368 PMCID: PMC7864901 DOI: 10.1038/s41598-021-82841-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 01/20/2021] [Indexed: 12/25/2022] Open
Abstract
Rituximab combined with chemotherapy is the first-line induction therapy of CD20 positive B-cell non-Hodgkin lymphomas (CD20+ B-NHL). Recently new anti-CD20 monoclonal antibodies (mAbs) have been developed, but their efficacy and safety compared with rituximab are still controversial. We searched MEDLINE, Embase, and Cochrane Library for eligible randomized controlled trials (RCTs) that compared new anti-CD20 mAbs with rituximab in induction therapy of B-NHL. The primary outcomes are progression-free survival (PFS) and overall survival (OS), additional outcomes include event-free survival (EFS), disease-free survival (DFS), overall response rate (ORR), complete response rate (CRR) and incidences of adverse events (AEs). Time-to-event data were pooled as hazard ratios (HRs) using the generic inverse-variance method and dichotomous outcomes were pooled as odds ratios (ORs) using the Mantel-Haenszel method with their respective 95% confidence interval (CI). Eleven RCTs comprising 5261 patients with CD20+ B-NHL were included. Compared with rituximab, obinutuzumab significantly prolonged PFS (HR 0.84, 95% CI 0.73-0.96, P = 0.01), had no improvement on OS, ORR, and CRR, but increased the incidences of serious AEs (OR 1.29, 95% CI 1.13-1.48, P < 0.001). Ofatumumab was inferior to rituximab in consideration of ORR (OR 0.73, 95% CI 0.55-0.96, P = 0.02), and had no significant differences with rituximab in regard to PFS, OS and CRR. 131I-tositumomab yielded similar PFS, OS, ORR and CRR with rituximab. 90Y-ibritumomab tiuxetan increased ORR (OR 3.07, 95% CI 1.47-6.43, P = 0.003), but did not improve PFS, DFS, OS and CRR compared with rituximab. In conclusion, compared with rituximab in induction therapy of CD20+ B-NHL, obinutuzumab significantly improves PFS but with higher incidence of AEs, ofatumumab decreases ORR, 90Y-ibritumomab tiuxetan increases ORR.
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Affiliation(s)
- Chengxin Luo
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Guixian Wu
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiangtao Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yanni Ma
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yali Zhang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qiuyue Song
- Department of Health Statistics, Third Military Medical University, Chongqing, China
| | - Mingling Xie
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yanni Sun
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yarui Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhen Huang
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yu Hou
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Shuangnian Xu
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Jieping Chen
- Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
- Key Laboratory of Cancer Immunotherapy of Chongqing, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Xi Li
- Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, Chongqing, China.
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Noreña I, Fernández-Ruiz M, Aguado JM. Is there a real risk of bacterial infection in patients receiving targeted and biological therapies? Enferm Infecc Microbiol Clin 2020; 40:S0213-005X(20)30398-0. [PMID: 33339658 DOI: 10.1016/j.eimc.2020.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/03/2020] [Accepted: 10/06/2020] [Indexed: 11/03/2022]
Abstract
Over the past decades, the advent of targeted and biological therapies has revolutionized the management of cancer and autoimmune, hematological and inflammatory conditions. Although a large amount of information is now available on the risk of opportunistic infections associated with some of these agents, the evidence regarding the susceptibility to bacterial infections is more limited. Biological agents have been shown to entail a variable risk of bacterial infections in pivotal randomized clinical trials and post-marketing studies. Recommendations on risk minimization strategies and therapeutic interventions are therefore scarce and often based on expert opinion, with only a few clear statements for some particular agents (i.e. meningococcal vaccination for patients receiving eculizumab). In the present review the available information regarding the incidence of and risk factors for bacterial infection associated with the use of different groups of biological agents is summarized according to their mechanisms of action, and recommendations based on this evidence are provided. Additional information coming from clinical research and real-world studies is required to address unmet questions in this emerging field.
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Affiliation(s)
- Ivan Noreña
- Teaching and Training Unit, Division of Infectious Diseases and Tropical Medicine, LMU University Hospital Munich, Munich, Germany.
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain; School of Medicine, Universidad Complutense. Madrid, Spain
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High-dose rituximab in combination with autologous stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma. Med Clin (Barc) 2020; 155:235-241. [PMID: 32173075 DOI: 10.1016/j.medcli.2019.11.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 11/12/2019] [Accepted: 11/28/2019] [Indexed: 11/23/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate the efficacy and toxicity of high-dose rituximab (HD-R) in combination with autologous stem cell transplantation (auto-SCT) in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). METHODS There were 22 patients in the HD-R group, to whom rituximab was administered during stem cell mobilization (375mg/m2 1 day before and 7 days after chemotherapy) and after transplantation (1000mg/m2 on days +1 and +8). In the control group, the procedure was the same as that in the HD-R group but without rituximab. We observed the safety, tolerability, adverse effects and immune reconstitution of HD-R therapy. The log-rank test, univariate analysis and multivariate Cox regression analysis were used to evaluate the effect of HD-R on survival. RESULTS In total, 22 relapsed or refractory DLBCL patients were treated with HD-R. No dose-limiting toxicities were observed except for CD19+ B cell reconstruction in the first 6 months after SCT. There were 20 relapsed or refractory DLBCL patients in the control group. The 3-year progression-free survival (PFS) and overall survival (OS) greatly improved in the HD-R group compared to that in the control group (63.8% vs. 35.0%, P=0.028 and 80.1% vs. 50.0%, P=0.035, respectively). The univariate and multivariate analyses demonstrated that HD-R and the time to relapse were independent prognostic factors for OS and PFS. CONCLUSION HD-R in combination with auto-SCT is a feasible and promising treatment for patients with relapsed or refractory DLBCL.
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20
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Martin Paez Y, Bennett JL, Subramanian PS, Pelak VS. Considerations for the Treatment of Inflammatory Neuro-Ophthalmologic Disorders During the COVID-19 Pandemic. J Neuroophthalmol 2020; 40:305-314. [PMID: 32804456 PMCID: PMC7418184 DOI: 10.1097/wno.0000000000001016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The initiation and continuation of immune-based therapies to treat and prevent complications of inflammatory neuro-ophthalmologic disorders during the 2019 novel coronavirus (COVID-19) pandemic is the subject of considerable debate. In each case, a treatment decision must be reached based on best clinical practices for the disorder, patient comorbidities, the current state of knowledge about the pathogenesis and infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the utilization of hospital and community resources. Unfortunately, the evidence needed to standardize the decision-making process for each neuro-ophthalmologic disorder is currently absent and is likely to require months or years to develop based on the accrual of robust international data sets. In this article, we review the current understanding of SARS-CoV-2 and COVID-19 complications to provide a framework for approaching the treatment of inflammatory neuro-ophthalmic disorders during the COVID-19 viral pandemic.
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Affiliation(s)
- Yosbelkys Martin Paez
- Departments of Ophthalmology (YMP, JLB, PSS, VSP), Neurology (YMP, JLB, PSS, VSP), and Neurosurgery (PSS), University of Colorado School of Medicine, Aurora, Colorado; and Programs in Neuroscience and Immunology (JLB), University of Colorado School of Medicine, Aurora, Colorado
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21
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Wang H, Yan S, Liu H, Li L, Song J, Wang G, Wang H, Wu Y, Shao Z, Fu R. Infection risk in autoimmune hematological disorders with low-dose rituximab treatment. J Clin Lab Anal 2020; 34:e23455. [PMID: 32794271 PMCID: PMC7595891 DOI: 10.1002/jcla.23455] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 06/07/2020] [Accepted: 06/12/2020] [Indexed: 12/12/2022] Open
Abstract
Background Rituximab has been widely used in many autoimmune diseases. Aim To evaluate the infection risk of rituximab in autoimmune hematological disorders. Methods Retrospectively studied and compared the clinical data of 89 patients in our hospital who used low‐dose rituximab (group R) or pulse cyclophosphamide (group C) for their refractory/relapsed autoimmune hematological diseases from January 2011 to January 2017. The kinds of their diseases included autoimmune hemolytic disease (AIHA), Evans syndrome, and idiopathic thrombocytopenic purpura (ITP). All patients chose either rituximab treatment or cyclophosphamide treatment on their own considerations. Findings The median follow‐up time was six months in group R and four months in group C. After treatments, the patients in group R showed higher white blood cell (WBC) count and neutrophil count than group C (P = .020, P = .037). CD20‐positive B cells in group R remained at a very low level after rituximab treatment and need about 15 months to return to normal level, which was longer than group C (six months). The incidence of infection in these two groups has no significant difference, which was 34.7% (17/30) in group R and 32.5% (13/28) in group C (P = .976). Tuberculosis infections after rituximab treatment were found in three patients for the first time. Conclusion The G‐CSF, nadir WBC count, and IgA level were protective factors of infection during rituximab treatment. Low‐dose rituximab therapy in autoimmune hematological diseases does not increase infection risk compared with cyclophosphamide.
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Affiliation(s)
- Honglei Wang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Siyang Yan
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lijuan Li
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jia Song
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Guojin Wang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Huaquan Wang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuhong Wu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zonghong Shao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
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22
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Davis JS, Ferreira D, Paige E, Gedye C, Boyle M. Infectious Complications of Biological and Small Molecule Targeted Immunomodulatory Therapies. Clin Microbiol Rev 2020; 33:e00035-19. [PMID: 32522746 PMCID: PMC7289788 DOI: 10.1128/cmr.00035-19] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks. Contrary to the hope that these more specific agents would have minimal and predictable infectious sequelae, infectious complications have emerged as a major stumbling block for many of these agents. Furthermore, the growing number and complexity of available biologic agents makes it difficult for clinicians to maintain current knowledge, and most review articles focus on a particular target disease or class of agent. In this article, we review the current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents, aiming to create a single resource relevant to a broad range of clinicians and researchers. For each of 19 classes of agent, we discuss the mechanism of action, the risk and types of infectious complications, and recommendations for prevention of infection.
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Affiliation(s)
- Joshua S Davis
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
| | - David Ferreira
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Emma Paige
- Department of Infectious Diseases, Alfred Hospital, Melbourne, VIC, Australia
| | - Craig Gedye
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
- Department of Oncology, Calvary Mater Hospital, Newcastle, NSW, Australia
| | - Michael Boyle
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
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Clausen MR, Ulrichsen SP, Juul MB, Poulsen CB, Iversen B, Pedersen PT, Madsen J, Pedersen RS, Josefsson PL, Gørløv JS, Nørgaard M, d'Amore F. Prognostic significance of infectious episodes occurring during first-line therapy for diffuse large B-cell lymphoma - A nationwide cohort study. Hematol Oncol 2020; 38:318-325. [PMID: 32239673 DOI: 10.1002/hon.2734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 02/04/2020] [Accepted: 03/08/2020] [Indexed: 11/10/2022]
Abstract
Infections during first-line therapy for DLBCL are often associated with chemotherapy dose reductions and increased mortality. Systemic infections have also been suggested as beneficial promotors of immunological responses. However, whether there is an association between the timing of an infectious episode and outcome during treatment has not yet been clarified. We investigated how the occurrence and timing of infectious episodes during the first line of treatment for "de novo" DLBCL influenced patient outcome. We used data on DLBCL patients from the Danish Lymphoma Registry, the Danish National Patient Registry, and the Danish National Pathology Registry. Infections were categorized according to type (ICD-10) and time of occurrence after treatment start. "Early" infections were defined as occurring between days 7 and 42 and "late" infections between days 100 and 150 from treatment start. Patients experiencing both "early and late" infections were categorized separately. We used multivariable Cox regression and Kaplan-Meier estimates to assess the association between infections and survival adjusting for NCCN-IPI, sex, comorbidity, and rituximab treatment. We identified 3546 patients, median age 65 years (IQR 56,73). Infectious episodes occurred in 1171 (33%) patients, of which 666 had "early," 303 "late," and 202 both "early and late" events. Patients without registered infections had a 5-year overall survival (OS) rates of 74%. Those with "early," "late," or "early+late" had 5-year OS of 65%, 62%, and 53%, respectively. Compared with patients without any registered infections, hazard rate ratios (HR) were 1.24 (95% CI 1.05-1.47), 1.32 (95% CI 1.06-1.63), and 1.59 (95% CI 1.27-2.00), respectively, in the multivariable model. We observed that infectious episodes during first-line treatment for "de novo" DLBCL occurred in 44% of the patients. Irrespective of timing, patients with infectious episodes had an inferior outcome compared to those without. Outcome patterns were similar for patients registered with sepsis.
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Affiliation(s)
- Michael R Clausen
- Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | - Sinna P Ulrichsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Maja B Juul
- Department of Hematology, Odense University Hospital, Odense, Denmark
| | | | - Brian Iversen
- Department of Hematology, Sygehus Lillebaelt, Vejle, Denmark
| | - Per T Pedersen
- Department of Hematology, Sydvestjysk Sygehus, Esbjerg, Denmark
| | - Jakob Madsen
- Department of Hematology, Aalborg University Hospital, Aalborg, Denmark
| | | | - Pär L Josefsson
- Department of Hematology, Herlev University Hospital, Herlev, Denmark
| | - Jette S Gørløv
- Department of Hematology, Rigshospitalet, Copenhagen, Denmark
| | - Mette Nørgaard
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Francesco d'Amore
- Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
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Riesgo de infección asociada a nuevas terapias para el tratamiento de los síndromes linfoproliferativos. Med Clin (Barc) 2020; 154:101-107. [DOI: 10.1016/j.medcli.2019.07.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 12/18/2022]
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Santos JE, Fiel D, Santos R, Vicente R, Aguiar R, Santos I, Amoedo M, Pires C. Rituximab use in adult glomerulopathies and its rationale. ACTA ACUST UNITED AC 2019; 42:77-93. [PMID: 31904761 PMCID: PMC7213927 DOI: 10.1590/2175-8239-jbn-2018-0254] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 09/23/2019] [Indexed: 01/26/2023]
Abstract
Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.
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Affiliation(s)
| | - David Fiel
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Ricardo Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rita Vicente
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rute Aguiar
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Iolanda Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Manuel Amoedo
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Carlos Pires
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
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26
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Santos JE, Fiel D, Santos R, Vicente R, Aguiar R, Santos I, Amoedo M, Pires C. Rituximab use in adult glomerulopathies and its rationale. JORNAL BRASILEIRO DE NEFROLOGIA : 'ORGAO OFICIAL DE SOCIEDADES BRASILEIRA E LATINO-AMERICANA DE NEFROLOGIA 2019. [PMID: 31904761 DOI: 10.1590/2175-8239-] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.
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Affiliation(s)
| | - David Fiel
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Ricardo Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rita Vicente
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Rute Aguiar
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Iolanda Santos
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Manuel Amoedo
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
| | - Carlos Pires
- Departamento de Nefrologia, Hospital Espírito Santo de Évora, Évora, Portugal
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Atkins S, He F. Chemotherapy and Beyond: Infections in the Era of Old and New Treatments for Hematologic Malignancies. Infect Dis Clin North Am 2019; 33:289-309. [PMID: 30935703 DOI: 10.1016/j.idc.2019.01.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Treatment options for hematologic malignancies have been rapidly expanding in the past decade, resulting in better survival outcomes for many patients. Infection is an important cause of morbidity and mortality in this patient population. Cytotoxic chemotherapy has well-studied infectious risks related to the degree and duration of myelosuppression. Targeted therapies and immunotherapies have less clearly predictable infectious risk and diverse effects on immune function. This review discusses contemporary management of hematologic malignancies, followed by special discussion of novel agents, including signaling/small molecule inhibitors, monoclonal antibodies, immunomodulators, and immunotherapies, for treatment of hematologic malignancies with focus on infectious risk.
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Affiliation(s)
- Sarah Atkins
- Department of Internal Medicine, University of Minnesota, 420 Delaware Street Southeast, MMC 284, Minneapolis, MN 55455, USA
| | - Fiona He
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, 420 Delaware Street Southeast, MMC 480, Minneapolis, MN 55455, USA.
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29
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Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease‐modifying antirheumatic drugs. Int J Rheum Dis 2018; 22:574-582. [PMID: 30338649 DOI: 10.1111/1756-185x.13401] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 08/29/2018] [Accepted: 09/08/2018] [Indexed: 02/06/2023]
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30
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Silva-Fernández L, De Cock D, Lunt M, Low AS, Watson KD, BSRBR-RA Contributors Group, Symmons DPM, Hyrich KL. Serious infection risk after 1 year between patients with rheumatoid arthritis treated with rituximab or with a second TNFi after initial TNFi failure: results from The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Rheumatology (Oxford) 2018; 57:1533-1540. [PMID: 28968862 PMCID: PMC6105920 DOI: 10.1093/rheumatology/kex304] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 07/03/2017] [Indexed: 12/05/2022] Open
Abstract
Objectives Both TNF inhibitors (TNFi) and rituximab (RTX), a B-cell depleting biologic, can disrupt the immune system in RA. RTX is licensed in Europe for use following TNFi failure. However, safety data on serious infections (SIs) are scarce for RTX in daily practice. This analysis aims to compare the risk of SIs in the first year after a switch to either TNFi or RTX in patients who have failed a first TNFi. Methods This study included patients with RA registered with the British Society for Rheumatology Biologics Register (BSRBR-RA) who switched to either a second TNFi or RTX after failing a first TNFi. Patients were followed until first SI, treatment discontinuation, last recorded follow-up or the end of the first year after the switch, whichever came first. SI was defined as requiring hospitalization, intravenous antibiotics or resulting in death. The risk of first SI was compared between TNFi and RTX using Cox proportional hazard models adjusted using propensity scores using inverse probability of treatment weighting. Results This analysis included 3419 TNFi and 1396 RTX patients contributing 2765 and 1224 person-years (pyrs), respectively. SI occurred in 164 (4.8%) TNFi and 81 (5.8%) RTX patients giving a crude rate of 59 and 66 SI/1000 pyrs, respectively. The adjusted hazard ratio for SI was 1.0 (95% CI: 0.7, 1.4). Conclusion The risk of SIs was comparable over the first year of treatment between TNFi and RTX treatment in patients who had failed a single prior TNFi.
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Affiliation(s)
- Lucía Silva-Fernández
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- Rheumatology Department, Complexo Hospitalario Universitario de Ferrol, Ferrol (A Coruña), Spain
| | - Diederik De Cock
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Mark Lunt
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Audrey S Low
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Kath D Watson
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Deborah P M Symmons
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Machester, UK
| | - Kimme L Hyrich
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Machester, UK
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Ali K, Sial AA, Baig MT, Baig N, Ansari SH, Shamsi TS. Detection of the Incidence of HBV, HCV Infection and Febrile Neutropenia Associated With CHOP With or Without Rituximab in Diffuse Large B-Cell Lymphoma-Treated Patients. Hosp Pharm 2018; 53:194-197. [PMID: 30147140 DOI: 10.1177/0018578717741394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Background: Reactivation of hepatitis B virus (HBV) and hepatitis C virus (HCV) and febrile neutropenia (FN) are common in diffuse large B-cell lymphoma (DLBCL) patients undergoing cyclophosphamide, hydroxyrubicin, Oncovin, and prednisolone (CHOP) or cyclophosphamide, hydroxyrubicin, Oncovin, prednisolone - rituximab containing (R-CHOP) chemotherapy. This ultimately leads to delaying the therapy, increasing hospital stay, and raising the pharmacoeconomic burden on patients. Aim and Objective: The aim of this study was to determine the incidence of HBV and HCV infection and febrile neutropenia in DLBCL patients treated with R-CHOP and CHOP. Methodology: This was an institutional approved study in which patient records from a private hospital, specialized in hematology and oncology (Karachi, Pakistan), were reviewed retrospectively from 2014 to 2016. Patients aged above 18 years with known diagnosis of DLBCL who underwent CHOP-21 or R-CHOP-21 chemotherapy regimen were included. Baseline blood chemistry and liver function tests along with the data regarding HBV (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [anti-HBs]), HCV (antibody anti-HCV), and febrile neutropenia were collected from patient records. Results: In total, 35 cases of DLBCL were treated during a 3-year period (ie, from 2014 to 2016), of which 16 were on CHOP-21 regimen whereas 19 were treated with R-CHOP-21. Of the 19 patients who underwent R-CHOP chemotherapy, only 2 (10%) patients were HBsAg reactive. Before commencing the second cycle, 2 (10%) patients reported to hospital with fever and had hematological (low neutrophil count) and microbiological (Escherichia coli) proven febrile neutropenia. The incidence of HBV infection post treatment was lower in group treated with CHOP (1 patient showed HBsAg reactivity).
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Affiliation(s)
- Kashif Ali
- National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan.,Dow University of Health Sciences, Karachi, Pakistan
| | | | | | - Nida Baig
- Dow University of Health Sciences, Karachi, Pakistan
| | - Saqib Hussain Ansari
- National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan
| | - Tahir Sultan Shamsi
- National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan
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ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect 2018; 24 Suppl 2:S71-S82. [PMID: 29447988 DOI: 10.1016/j.cmi.2018.02.003] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 01/28/2018] [Accepted: 02/03/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD19, CD20 and CD52 and to suggest preventive recommendations. SOURCES Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT Although CD19-targeted agents (blinatumomab or inebilizumab) are not associated with an increased risk of infection, they may cause IgG hypogammaglobulinaemia and neutropenia. The requirement for prolonged intravenous infusion of blinatumomab may increase the risk of catheter-associated bloodstream infections. Infection remains the most common non-haematological adverse effect of anti-CD20 monoclonal antibodies, including severe respiratory tract infection, hepatitis B virus (HBV) reactivation and varicella-zoster virus infection. Screening for chronic or resolved HBV infection is recommended for patients receiving anti-CD20 monoclonal antibodies. Antiviral prophylaxis should be offered for 12-18 months to hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/anti-hepatitis B core antibody (HBc)-positive patients. Anti-Pneumocystis prophylaxis should be considered in patients receiving concomitant chemotherapy, particularly steroids. Alemtuzumab (anti-CD52) increases the risk of infections, in particular among leukaemia and solid organ transplant patients. These populations benefit from anti-Pneumocystis prophylaxis, prevention strategies for cytomegalovirus infection, and screening for HBV, hepatitis C virus and tuberculosis. Antiviral prophylaxis for at least 6-12 months should be provided for HBsAg-positive patients. IMPLICATIONS As there are limited clinical data for many of the reviewed agents, special attention must be given to promptly detect and report emerging infectious complications.
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A Case of Rituximab-Induced Necrotizing Fasciitis and a Review of the Literature. Case Rep Hematol 2017; 2017:6971027. [PMID: 29082050 PMCID: PMC5634570 DOI: 10.1155/2017/6971027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 08/22/2017] [Indexed: 11/25/2022] Open
Abstract
Necrotizing fasciitis is a fulminant soft tissue infection characterized by rapid progression and high mortality. Rituximab is a generally well-tolerated immunosuppresive medication used for B-cell malignancies and some rheumatological disorders. We report a case of a 69-year-old male with chronic lymphocytic leukemia who suffered necrotizing fasciitis of his left lower extremity secondary to Clostridium septicum 7 weeks after treatment with rituximab. Despite immediate intravenous antimicrobial therapy and emergent fasciotomy with extensive debridement, his hospital course was complicated by septic shock and he required an above-the-knee amputation. Physicians need to be aware of the possibility of necrotizing fasciitis in patients presenting with skin infections after rituximab therapy.
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Li PH, Lau CS. Secondary antibody deficiency and immunoglobulin replacement. HONG KONG BULLETIN ON RHEUMATIC DISEASES 2017. [DOI: 10.1515/hkbrd-2017-0001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Abstract
Antibody deficiencies can be either primary or secondary, leading to significant morbidity and mortality without appropriate management. Secondary antibody deficiency can be due to various diseases or iatrogenic causes, especially with the use of immunosuppressive agents such as B-cell depleting therapies. Unlike its primary counterpart, little is known regarding the management of secondary antibody deficiency and it remains an underappreciated entity. This is a growing concern with the growing numbers of patients on various immunosuppressant therapies and increasing survivors of autoimmune diseases and haematological malignancies. In this report, we review the diagnosis and management of secondary antibody deficiency, especially after rituximab-induced hypogammaglobulinemia.
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Affiliation(s)
- Philip H. Li
- Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital , University of Hong Kong , Hong Kong , Hong Kong
| | - Chak-Sing Lau
- Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital , University of Hong Kong , Hong Kong , Hong Kong
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Abstract
In patients with membranous nephropathy, alkylating agents (cyclophosphamide or chlorambucil) alone or in combination with steroids achieve remission of nephrotic syndrome more effectively than conservative treatment or steroids alone, but can cause myelotoxicity, infections, and cancer. Calcineurin inhibitors can improve proteinuria, but are nephrotoxic. Most patients relapse after treatment withdrawal and can become treatment dependent, which increases the risk of nephrotoxicity. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain- containing protein 7A (THSD7A) antigens provides a clear pathophysiological rationale for interventions that specifically target B-cell lineages to prevent antibody production and subepithelial deposition. The anti-CD20 monoclonal antibody rituximab is safe and achieves remission of proteinuria in approximately two-thirds of patients with membranous nephropathy. In those with PLA2R-related disease, remission can be predicted by anti-PLA2R antibody depletion and relapse by antibody re-emergence into the circulation. Thus, integrated evaluation of serology and proteinuria could guide identification of affected patients and treatment with individually tailored protocols. Nonspecific and toxic immunosuppressive regimens will fall out of use. B-cell modulation by rituximab and second-generation anti-CD20 antibodies (or plasma cell-targeted therapy in anti-CD20 resistant forms of disease) will lead to a novel therapeutic paradigm for patients with membranous nephropathy.
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[Infection risks in multiple sclerosis therapy by infusion of disease modifying drugs]. DER NERVENARZT 2016; 86:971-7. [PMID: 26187545 DOI: 10.1007/s00115-015-4388-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The increased risk of developing infections when using disease-modifying drugs for treatment of multiple sclerosis (MS) is a major challenge in the daily clinical routine. In the growing field of treatment options specific knowledge of treatment-related risks of infections and appropriate preventive and countermeasures is mandatory. Current clinical experience shows that an individual risk stratification is necessary when choosing treatment options and while monitoring during and after treatment administration. The determination of the individual risk of infection in the context of serial use of disease-modifying drugs remains a challenging issue. In addition to the mechanisms of action, the warning notices and current recommendations on infection prophylaxis when using intravenous disease-modifying drugs, such as alemtuzumab, natalizumab and mitoxantron, are presented in detail.
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Zhou Y, Lower EE, Li H, Baughman RP. Clinical management of pulmonary sarcoidosis. Expert Rev Respir Med 2016; 10:577-91. [DOI: 10.1586/17476348.2016.1164602] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Abstract
Immunomodulatory and immunosuppressive treatments for multiple sclerosis (MS) are associated with an increased risk of infection, which makes treatment of this condition challenging in daily clinical practice. Use of the expanding range of available drugs to treat MS requires extensive knowledge of treatment-associated infections, risk-minimizing strategies and approaches to monitoring and treatment of such adverse events. An interdisciplinary approach to evaluate the infectious events associated with available MS treatments has become increasingly relevant. In addition, individual stratification of treatment-related infectious risks is necessary when choosing therapies for patients with MS, as well as during and after therapy. Determination of the individual risk of infection following serial administration of different immunotherapies is also crucial. Here, we review the modes of action of the available MS drugs, and relate this information to the current knowledge of drug-specific infectious risks and risk-minimizing strategies.
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Fabrizi F, Cresseri D, Fogazzi GB, Moroni G, Passerini P, Martin P, Messa P. Rituximab therapy for primary glomerulonephritis: Report on two cases. World J Clin Cases 2015; 3:736-742. [PMID: 26301235 PMCID: PMC4539414 DOI: 10.12998/wjcc.v3.i8.736] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 12/30/2014] [Accepted: 06/19/2015] [Indexed: 02/05/2023] Open
Abstract
The evidence in the medical literature on the efficacy and safety of rituximab therapy for primary glomerulonephritis is limited and controversial. We describe two male Caucasian patients with rapidly progressive kidney failure due to primary proliferative glomerulonephritis. Both of them received high-dose intravenous corticosteroids and oral cyclophosphamide with limited benefit. The first patient (hepatitis C virus-negative mixed cryoglobulinemia) underwent plasma-exchange with intravenous immunoglobulins; he showed significant benefit on kidney function (he became dialysis independent with serum creatinine going back to 1.6 mg/dL) after one rituximab pulse even if urinary abnormalities were still present. No improvement in renal function or urinary changes occurred in the second patient. Both these individuals developed sepsis over the follow-up, the first patient died two months after rituximab therapy. This report is in keeping with the occurrence of severe infections after rituximab therapy in patients with renal impairment at baseline and concomitant high-dose steroids.
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Poudrier J, Soulas C, Chagnon-Choquet J, Burdo T, Autissier P, Oskar K, Williams KC, Roger M. High expression levels of BLyS/BAFF by blood dendritic cells and granulocytes are associated with B-cell dysregulation in SIV-infected rhesus macaques. PLoS One 2015; 10:e0131513. [PMID: 26107380 PMCID: PMC4479440 DOI: 10.1371/journal.pone.0131513] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 06/03/2015] [Indexed: 12/22/2022] Open
Abstract
Dendritic cells (DCs) modulate B-cell survival and differentiation, mainly through production of growth factors such as B lymphocyte stimulator (BLyS/BAFF). In recent longitudinal studies involving HIV-1-infected individuals with different rates of disease progression, we have shown that DCs were altered in number and phenotype in the context of HIV-1 disease progression and B-cell dysregulations were associated with increased BLyS/BAFF expression in plasma and by blood myeloid DCs (mDCs) in rapid and classic progressors but not in HIV-1-elite controllers (EC). Suggesting that the extent to which HIV-1 disease progression is controlled may be linked to BLyS/BAFF expression status and the capacity to orchestrate B-cell responses. Herein, longitudinal analyses of simian immunodeficiency virus (SIV)-infected rhesus macaques also revealed increased expression of BLyS/BAFF by blood mDCs as soon as day 8 and throughout infection. Strikingly, granulocytes presented the highest BLyS/BAFF expression profile in the blood of SIV-infected macaques. BLyS/BAFF levels were also increased in plasma and correlated with viral loads. Consequently, these SIV-infected animals had plasma hyperglobulinemia and reduced blood B-cell numbers with altered population frequencies. These data underscore that BLyS/BAFF is associated with immune dysregulation in SIV-infected rhesus macaques and suggest that BLyS/BAFF is a key regulator of immune activation that is highly conserved among primates. These findings emphasize the potential importance of this SIV-infected primate model to test whether blocking excess BLyS/BAFF has an effect on the overall inflammatory burden and immune restoration.
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Affiliation(s)
- Johanne Poudrier
- Laboratoire d’immunogénétique, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Canada
- Département de Microbiologie, Infectiologie et Immunologie de l‘Université de Montréal, Montréal, Canada
- * E-mail: (JP); (MR)
| | | | - Josiane Chagnon-Choquet
- Laboratoire d’immunogénétique, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Canada
- Département de Microbiologie, Infectiologie et Immunologie de l‘Université de Montréal, Montréal, Canada
| | - Tricia Burdo
- Boston College, Boston, MA, United States of America
| | | | - Kathryn Oskar
- Boston College, Boston, MA, United States of America
| | | | - Michel Roger
- Laboratoire d’immunogénétique, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Canada
- Département de Microbiologie, Infectiologie et Immunologie de l‘Université de Montréal, Montréal, Canada
- * E-mail: (JP); (MR)
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Bockenstedt MM, Boggiatto PM, Jones DE. Characterization of the B cell response to Leishmania infection after anti-CD20 B cell depletion. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:6192-6202. [PMID: 26261496 PMCID: PMC4525830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 05/25/2015] [Indexed: 06/04/2023]
Abstract
Anti-CD20 depletion therapies targeting B cells are commonly used in malignant B cell disease and autoimmune diseases. There are concerns about the ability of B cells to respond to infectious diseases acquired either before or after B cell depletion. There is evidence that the B cell response to existing or acquired viral infections is compromised during treatment, as well as the antibody response to vaccination. Our laboratory has an experimental system using co-infection of C3H mice with both Leishmania major and Leishmania amazonensis that suggests that the B cell response is important to healing infected mice. We tested if anti-CD20 treatment would completely restrict the B cell response to these intracellular pathogens. Infected mice that received anti-CD20 B cell depletion therapy had a significant decrease in CD19(+) cells within their lymph nodes and spleens. However, splenic B cells were detected in depleted mice and an antigen-specific antibody response was produced. These results indicate that an antigen-specific B cell response towards intracellular pathogens can be generated during anti-CD20 depletion therapy.
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Affiliation(s)
- Marie M Bockenstedt
- Department of Veterinary Pathology and Preventive Medicine, Iowa State University1600 S 16th St, Ames, IA 50011, USA
| | - Paola M Boggiatto
- Department of Veterinary Microbiology, College of Veterinary Medicine, Iowa State University1600 S 16th St, Ames, IA 50011, USA
| | - Douglas E Jones
- Department of Veterinary Pathology and Preventive Medicine, Iowa State University1600 S 16th St, Ames, IA 50011, USA
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Hornbeak DM, Thorne JE. Immunosuppressive therapy for eye diseases: Effectiveness, safety, side effects and their prevention. Taiwan J Ophthalmol 2015; 5:156-163. [PMID: 29018691 PMCID: PMC5602133 DOI: 10.1016/j.tjo.2015.03.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 03/25/2015] [Accepted: 03/30/2015] [Indexed: 12/17/2022] Open
Abstract
Ocular inflammation is a significant cause of ocular morbidity and visual impairment. Topical, periocular, intraocular, and systemic corticosteroids are highly effective for treating appropriate forms of ocular inflammation. However, their use may be constrained by local and/or systemic side effects, especially if long-term therapy is required. As a result, immunosuppressive agents increasingly have been used to manage ocular inflammation alongside or in place of corticosteroids. The four categories of agents used today are antimetabolites [primarily methotrexate, mycophenolate mofetil (MMF), and azathioprine]; T-cell inhibitors (usually cyclosporine, less often tacrolimus or sirolimus); alkylating agents (cyclophos-phamide and chlorambucil); and biologic agents [tumor necrosis factor (TNF) inhibitors, lymphocyte inhibitors, and interleukin inhibitors]. The primary goals of immunosuppressive therapy are (1) to control inflammation when corticosteroids fail to do so; (2) to prevent corticosteroid-induced toxicity when the necessary corticosteroid dosage exceeds the desired or safe level (corticosteroid sparing); and (3) to treat specific high-risk uveitis syndromes known to respond poorly to corticosteroids alone. Growing evidence shows the effectiveness of immunosuppressive drugs in achieving these goals, as well as improved visual function, prevention of ocular complications, and in some cases even disease remission. However, these agents also have side effects, which must be considered in each patient's management. In this report, we summarize the effectiveness and safety of immunosuppressive drug therapy utilized in the treatment of ocular inflammatory diseases.
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Affiliation(s)
- Dana M Hornbeak
- Division of Ocular Immunology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jennifer E Thorne
- Division of Ocular Immunology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Hua Q, Zhu Y, Liu H. Severe and fatal adverse events risk associated with rituximab addition to B-cell non-Hodgkin's lymphoma (B-NHL) chemotherapy: a meta-analysis. J Chemother 2015; 27:365-70. [PMID: 25872413 DOI: 10.1179/1973947815y.0000000025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE Rituximab is a monoclonal antibody targetting the CD20 antigen with the ability to increase overall remission (OR) in B-cell non-Hodgkin's lymphoma (B-NHL). A systematic review and meta-analysis were conducted to determine the risk of the most clinically relevant severe and fatal adverse events (AEs) associated with the use of rituximab in the treatment of B-NHL. PATIENTS AND METHODS We included phase III clinical trials that used chemotherapy in combination with rituximab or chemotherapy alone as for B-NHL. Statistical analyses were conducted to calculate summary risk ratio (RR) of the relevant severe and fatal AEs related with rituximab. RESULTS Eight randomised controlled clinical trials were included in this meta-analysis. Summary RR obtained showed no statistically significant rituximab-associated increased risk in 13 severe adverse events (SAEs) (infection, fever, anaemia, thrombocytopaenia, granulocytopenia, liver toxicity, cardiac toxicity, neurologic toxicity, lung toxicity, mucositis, nausea/vomiting, diarrhoea, alopecia) except leukocytopenia (36.4% versus 31%; RR = 1.13; 95%CI, 1.01-1.27; P = 0.03). The incidences of fatal AEs showed noteworthy difference between rituximab group and control group (RR = 1.45; 95% CI, 1.04-2.02; P = 0.03). CONCLUSION This meta-analysis indicates that there was no proof of statistically higher incidence of most SAEs in rituximab containing group compared with chemotherapy alone. However, fatal infections were more frequently observed in patients who received rituximab. Considering the low-incidence infection-induced death during the treatment period, the effects of rituximab on infections need further investigation.
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Affiliation(s)
- Qingling Hua
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University , Hefei, China
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Abstract
The interface of multiple sclerosis (MS) and infection occurs on several levels. First, infectious disease has been postulated as a potential trigger, if not cause, of MS. Second, exacerbation of MS has been well-documented as a consequence of infection, and, lastly, infectious diseases have been recognized as a complication of the therapies currently employed in the treatment of MS. MS is a disease in which immune dysregulation is a key component. Examination of central nervous system (CNS) tissue of people affected by MS demonstrates immune cell infiltration, activation and inflammation. Therapies that alter the immune response have demonstrated efficacy in reducing relapse rates and evidence of brain inflammation on magnetic resonance imaging (MRI). Despite the altered immune response in MS, there is a lack of evidence that these patients are at increased risk of infectious disease in the absence of treatment or debility. Links between infections and disease-modifying therapies (DMTs) used in MS will be discussed in this review, as well as estimates of occurrence and ways to potentially minimize these risks. We address infection in MS in a comprehensive fashion, including (1) the impact of infections on relapse rates in patients with MS; (2) a review of available infection data from pivotal trials and postmarketing studies for the approved and experimental DMTs, including frequency, types and severity of infections; and (3) relevant risk minimization strategies, particularly as they pertain to progressive multifocal leukoencephalopathy (PML).
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Cravedi P, Remuzzi G, Ruggenenti P. Rituximab in primary membranous nephropathy: first-line therapy, why not? Nephron Clin Pract 2014; 128:261-9. [PMID: 25427622 DOI: 10.1159/000368589] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The ideal treatment of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) is still a matter of debate. This is a major issue since these patients may progress to end-stage kidney disease (ESKD) in 5-10 years. Steroids, alkylating agents, and calcineurin inhibitors have been suggested to achieve NS remission and prevent ESKD in this population. Treatment benefits, however, are uncertain and are often offset by serious adverse events (SAEs). Evidence that B cells play a crucial role in the pathogenesis of the disease, both as precursors of autoantibody-producing cells and as antigen-presenting cells, provided the background for explorative studies testing the role of B cell-depletion therapy with the monoclonal antibody rituximab. This approach aimed at selectively inhibiting disease mechanisms without the devastating consequences of unspecific immunosuppression. Finding that rituximab safely ameliorated NS in 8 patients with primary MN fueled a series of observational studies that uniformly confirmed the safety/efficacy profile of rituximab in this context. Although head-to-head comparisons in randomized clinical trials are missing, comparative analyses between series of homogeneous patient cohorts clearly show at least similar efficacy of rituximab as compared to steroid plus alkylating agents. Moreover, data confirm the dramatically superior safety profile of rituximab that actually appears to be associated with a rate of SAEs even lower than that observed with conservative therapy. Rituximab is also effective in patients resistant to other treatments and its cost-effectiveness is further increased when treatment is titrated to circulating B cells. Recently identified pathogenic antibodies against the M type phospholipase A2 receptor will likely provide a novel tool to monitor disease activity and drive rituximab therapy, at least in a subset of patients. Newly developed anti-CD20 antibodies could represent a valuable option for those who fail rituximab therapy. Steroids, alkylating agents, and calcineurin inhibitors should likely be abandoned.
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Affiliation(s)
- Paolo Cravedi
- Icahn School of Medicine at Mount Sinai, New York, N.Y., USA
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Park S, Kang CI, Chung DR, Peck KR, Kim WS, Kim SJ. Clinical Significance of Non-neutropenic Fever in the Management of Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab-CHOP: Comparison with Febrile Neutropenia and Risk Factor Analysis. Cancer Res Treat 2014; 47:448-57. [PMID: 25648098 PMCID: PMC4506109 DOI: 10.4143/crt.2014.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 05/10/2014] [Indexed: 01/15/2023] Open
Abstract
Purpose Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard chemotherapy in diffuse large B-cell lymphoma (DLBCL) patients. Although febrile neutropenia (FN) is the major toxicity of this regimen, non-neutropenic fever (NNF) becomes an emerging issue. Materials and Methods We analyzed clinical features and outcomes of febrile complications from 397 patients with newly diagnosed DLBCL who were registered in the prospective cohort study. They had completed R-CHOP between September 2008 and January 2013. Results Thirty-nine patients (9.8%) had NNF whereas 160 patients (40.3%) had FN. Among them, 24 patients (6.0%) had both during their treatment. Compared to frequent occurrence of initial FN after the first cycle (> 50% of total events), more than 80% of NNF cases occurred after the third cycle. Interstitial pneumonitis comprised the highest proportion of NNF cases (54.8%), although the causative organism was not identified in the majority of cases. Thus, pathogen was identified in a limited number of patients (n=9), and Pneumocystis jiroveci pneumonia (PJP) was the most common. Considering that interstitial pneumonitis without documented pathogen could be clinically diagnosed with PJP, the overall rate of PJP including probable cases was 4.5% (18 cases from 397 patients). The NNF-related mortality rate was 10.3% (four deaths from 39 patients with NNF) while the FN-related mortality rate was only 1.3%. Conclusion NNF was observed with incidence of 10% during R-CHOP treatment, and showed different clinical manifestations with respect to the time of initial episode and causes.
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Affiliation(s)
- Silvia Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Cheol-In Kang
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Doo Ryeon Chung
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyong Ran Peck
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Makatsori M, Kiani-Alikhan S, Manson AL, Verma N, Leandro M, Gurugama NP, Longhurst HJ, Grigoriadou S, Buckland M, Kanfer E, Hanson S, Ibrahim MAA, Grimbacher B, Chee R, Seneviratne SL. Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. QJM 2014; 107:821-8. [PMID: 24778295 DOI: 10.1093/qjmed/hcu094] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. METHODS We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. RESULTS We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. CONCLUSION With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.
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Affiliation(s)
- M Makatsori
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - S Kiani-Alikhan
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - A L Manson
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - N Verma
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - M Leandro
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - N P Gurugama
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - H J Longhurst
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - S Grigoriadou
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - M Buckland
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - E Kanfer
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - S Hanson
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - M A A Ibrahim
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - B Grimbacher
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - R Chee
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - S L Seneviratne
- From the Allergy Department, Royal Brompton and Harefield NHS Trust, London, UK, Department of Immunology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK, Department of Immunology, Barts Health NHS Trust, London, UK, Department of Immunology, Royal Free London NHS Foundation Trust, London, UK, Department of Rheumatology, University College London Hospital, London, UK, King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, UK, Department of Haematology, Imperial College Healthcare NHS Trust, London, UK and Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
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McQuillan AD, Macdonald WBG, Turner JH. Phase II study of first-line (131)I-rituximab radioimmunotherapy in follicular non-Hodgkin lymphoma and prognostic (18)F-fluorodeoxyglucose positron emission tomography. Leuk Lymphoma 2014; 56:1271-7. [PMID: 25065701 DOI: 10.3109/10428194.2014.949260] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
First-line (131)I-anti-CD20 radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) achieves durable remission with low toxicity. The phase II INITIAL study comprised 68 patients with follicular NHL followed up to 7 years (median 4 years) after outpatient (131)I-rituximab radioimmunotherapy (RIT) in conjunction with rituximab, followed by maintenance therapy for 1 year. Baseline and 3-month (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) imaging, analyzed according to Deauville criteria, was used to evaluate response and predict prognosis. The overall response rate at 3 months was 99%, with 88% achieving Deauville category 1-3. These satisfactory responders did not reach median time-to-next-treatment, versus a median of 29 months for a category 4-5 response (p < 0.0001). Grade IV hematological toxicity (9%) was self-limited without clinical sequelae. (131)I-rituximab radioimmunotherapy in newly diagnosed, advanced stage, symptomatic follicular NHL is an effective, practical and affordable alternative to existing conventional chemotherapies, with lower toxicity and durable remissions. Response assessment at 3 months by (18)F-FDG PET Deauville five-point scale permits prognostic stratification.
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Nissen JC, Hummel M, Brade J, Kruth J, Hofmann WK, Buchheidt D, Reinwald M. The risk of infections in hematologic patients treated with rituximab is not influenced by cumulative rituximab dosage - a single center experience. BMC Infect Dis 2014; 14:364. [PMID: 24992940 PMCID: PMC4227097 DOI: 10.1186/1471-2334-14-364] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 06/18/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Rituximab, a monoclonal antibody directed against CD20, is approved for the treatment of CD20-positive B-cell Non-Hodgkin's lymphoma and rheumatologic disorders. Due to its potent activity in depleting CD20-positive lymphocytes, the influence on opportunistic infections is still under discussion. Thus, we analyzed the impact of rituximab either as monotherapy or in combination with other chemotherapeutic regimens to elucidate its role in contributing to infectious complications. METHODS The records of consecutive patients (n = 125, 141 treatment episodes) treated with rituximab alone or in combination with chemotherapy and corticosteroids were analyzed retrospectively for the incidence, spectrum and outcome of infections during treatment and 6 months after the last course of rituximab. Univariate analysis of cofactors such as steroid medication, antiinfective prophylaxis, underlying disease and remission status were performed. RESULTS Altogether 80 therapy episodes were associated with infections, the median number of infections per patient being 1 (range 1-7). The number of infectious complications was significantly higher in patients receiving a combination of rituximab and chemotherapy compared to rituximab monotherapy (p < 0.001). There was no statistically significant difference regarding number of rituximab courses or cumulative rituximab dosage between episodes with and without infections, respectively.Mean cumulative prednisone dosage between the cohort with infections and the one without infections showed a trend towards higher dosage of prednisone in the patients with infections (mean difference 441 mg, p > 0.14). CONCLUSIONS Rituximab in induction treatment, either as monotherapy or combined with chemotherapy by itself does not increase the incidence or change the spectrum of infections in hematologic patients. However the possible influence of higher dosages of concomitant steroid medication on frequency of infections suggests that a heightened awareness of the potential for infectious complications should be applied to patients receiving higher doses of glucocorticoids in combination with other therapeutic regimens.
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Affiliation(s)
| | | | | | | | | | - Dieter Buchheidt
- Department of Hematology and Oncology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.
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50
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Winkelmann A, Loebermann M, Reisinger EC, Zettl UK. Multiple sclerosis treatment and infectious issues: update 2013. Clin Exp Immunol 2014; 175:425-38. [PMID: 24134716 DOI: 10.1111/cei.12226] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2013] [Indexed: 01/13/2023] Open
Abstract
Immunomodulation and immunosuppression are generally linked to an increased risk of infection. In the growing field of new and potent drugs for multiple sclerosis (MS), we review the current data concerning infections and prevention of infectious diseases. This is of importance for recently licensed and future MS treatment options, but also for long-term established therapies for MS. Some of the disease-modifying therapies (DMT) go along with threats of specific severe infections or complications, which require a more intensive long-term monitoring and multi-disciplinary surveillance. We update the existing warning notices and infectious issues which have to be considered using drugs for multiple sclerosis.
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Affiliation(s)
- A Winkelmann
- Department of Neurology, University of Rostock, Rostock, Germany
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