Association between the incidence of infusion-related reactions by obinutuzumab and the dose of corticosteroid as premedication: A multicenter retrospective cohort study

Association between the incidence of infusion-related reactions by obinutuzumab and the dose of corticosteroid as premedication: A multicenter retrospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association between the incidence of infusion-related reactions by obinutuzumab and the dose of corticosteroid as premedication: A multicenter retrospective cohort study Tatsuya Ohtsubo, Kazuhiro Yamamoto, Saori Matumoto, Kaori Ito, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4883642/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Premedication with corticosteroids is recommended for prophylaxis against infusion-related reactions (IRRs) caused by obinutuzumab despite a lack of solid evidence regarding the dose of corticosteroids. Methods We investigated the incidence of IRRs in the high-dose (patients who received 100 mg or higher of prednisolone, 80 mg or higher of methylprednisolone, or 16.5 mg or higher of dexamethasone) and low-dose (patients who received a dose lower than that in those groups or those who take hydrocortisone) corticosteroid groups. Results The incidence of IRRs in the high-dose and low-dose corticosteroid groups at the initial administration of obinutuzumab was 27.0% (41/152) and 48.4% (31/64), respectively, indicating that the high-dose group had a lower incidence of IRRs ( p = 0.002). The incidence of IRRs at the initial administration of obinutuzumab was significantly associated with the administration of first-generation histamine 1 receptor antagonist (odds ratio = 3.70, 95% confidence interval: 1.47–9.28; reference: second-generation histamine 1 receptor antagonist), hydrocortisone (odds ratio = 6.49, 95% confidence interval: 1.53–27.46; reference: dexamethasone), and methylprednisolone (odds ratio = 1.38, 95% confidence interval:1.10–12.16; reference: dexamethasone), although no association was found with the lower dose of corticosteroids. Conclusions Higher doses of corticosteroids as premedication can reduce the incidence of IRRs by obinutuzumab than lower doses. Dexamethasone may be a better choice for IRRs prophylaxis rather than hydrocortisone or methylprednisolone, and second-generation histamine 1 receptor antagonists may be a better choice rather than first-generation drugs. Introduction Obinutuzumab is a humanized anti-CD20 monoclonal antibody that is widely used for CD20-positive follicular lymphoma and chronic lymphocytic leukemia (including small lymphocytic lymphoma). In the GALLIUM study [ 1 ], which included patients with follicular lymphoma, patients who received obinutuzumab-based immunochemotherapy showed longer progression-free survival than those who received rituximab-based immunochemotherapy, making obinutuzumab-based immunochemotherapy a standard therapy for CD20-positive follicular lymphoma [ 2 ]. However, infusion-related reactions (IRRs) are observed as serious and frequent adverse events associated with obinutuzumab administration, which tend to occur during the initial administration [ 1 , 3 ]. The incidence of IRRs in the obinutuzumab and rituximab groups in the GALLIUM study was 59% and 49% for all grades, respectively, and 11% and 5% for grades 3–5, respectively [ 1 ]. Obinutuzumab may result in the occurrence of IRRs more frequently than rituximab. Premedication with antipyretic analgesics, histamine 1 receptor antagonists, and corticosteroids is recommended for preventing IRRs caused by obinutuzumab [ 4 , 5 ]. The Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommend 100 mg of prednisolone, 20 mg of dexamethasone, or 80 mg of methylprednisolone with respect to corticosteroids and state that hydrocortisone should not be used because it is not effective for IRRs prophylaxis in the package insert of obinutuzumab [ 4 , 5 ]. However, corticosteroids are expected to be used at reduced doses for reasons such as diabetic comorbidity or to avoid serious infections. There is no published data for the dose of corticosteroids used in clinical trials, and no dosing regimen of corticosteroids has been established. Therefore, we aimed to standardize premedication with corticosteroids at the initial administration of obinutuzumab and investigate the association between the dose of corticosteroids and IRRs incidence. Methods 1. Patients Patients treated with obinutuzumab as initial therapy for primary or relapsed CD20-positive follicular lymphoma from August 1, 2018, to October 31, 2021, at collaborating institutions were included. The exclusion criteria were as follows: patients who take antipyretic analgesics (including nonsteroidal anti-inflammatory drugs), histamine 1 receptor antagonists, or corticosteroids other than those included in the regimen used before obinutuzumab administration and those who were not given corticosteroids as premedication on the same day as obinutuzumab administration. 2. Definition of the high-dose and low-dose corticosteroid groups The high-dose group comprised patients who received 100 mg or higher of prednisolone, 80 mg or higher of methylprednisolone, or 16.5 mg or higher of dexamethasone as premedication. The low-dose group comprised patients who received a dose lower than that in the high-dose group or those who took hydrocortisone. Because dexamethasone preparations in Japan are marked with the content of dexamethasone without phosphate, the cutoff value for low or high dexamethasone dose in this study was defined as 16.5 mg, which is treated the same as 20 mg of dexamethasone phosphate. The corticosteroid equivalent was set as 20 mg of hydrocortisone, 5 mg of prednisolone, 4 mg of methylprednisolone, and 0.75 mg of dexamethasone in equal doses [ 6 ]. 3. Definition of IRRs IRRs incidence was determined from a physician’s documentation in the electronic medical record that IRRs (e.g., anaphylaxis, hypotension, nausea, chills, bronchospasm, pharyngeal or throat irritation, wheezing, laryngeal edema, atrial fibrillation, tachycardia, and hypersensitivity) occurred during obinutuzumab administration. In cases where there was no description regarding the incidence of IRRs in medical records, the attending physician performed a retrospective evaluation. The severity of IRRs was assessed by referring to the physician’s medical record. If no record was available regarding severity, each principal investigator assessed it based on “Infusion related reaction” in Common Terminology Criteria for Adverse Events version 5.0. 4. Statistical analysis Continuous variables are presented as means (standard deviations) and were compared using Student’s t-test. Nominal variables are presented as numbers and percentages and were compared using the chi-square test. Univariable and multivariable logistic regression analyses were performed on patients without missing values to explore the risk of developing IRRs with obinutuzumab. The explanatory variables were staging (AnnArbor classification), B symptoms, sIL-2R, LDH, dosage and type of corticosteroid, and type of histamine antagonist [ 7 – 9 ]. Statistical analyses were performed using Statistical Package for the Social Sciences (version 23.0; IBM Corp., New York) with a significance level of 5%. Results 1. Patient characteristics Of the 220 patients who received obinutuzumab as initial therapy for CD20-positive follicular lymphoma, 216 were included, excluding four patients who did not receive corticosteroids as premedication on the same day as obinutuzumab administration. The patient backgrounds in the high- and low-dose corticosteroid groups are shown in Table 1 . The number of patients in the high- and low-dose groups was 152 and 64, respectively. The high-dose group had a significantly lower age and a significantly lower percentage of patients with clinical stage III or higher than the low-dose group. Furthermore, the high-dose group had a significantly higher percentage of patients with PS of 0 and untreated patients, significantly higher ALP levels, and a higher percentage of patients with azole antifungal drug use. The details of corticosteroids, histamine 1 receptor antagonists, and antipyretic analgesics used as premedication are shown in Table 2 . The most commonly used corticosteroid was dexamethasone [n = 151 (69.9%)]. The most commonly used histamine 1 receptor antagonist and antipyretic analgesic were d-chlorpheniramine maleate [n = 96 (44.4%)] and acetaminophen [n = 125 (57.9%)], respectively. Table 1 Comparison of patient characteristics between high-dose and low-dose corticosteroid groups High dose (n = 152) Low dose (n = 64) p -value Age [Mean (SD)] 66.4 (10.3) 69.9 (9.2) 0.019 Sex, [n (%)] Male 77 (50.7) 35 (54.7) 0.59 PS [n (%)] 0 115 (75.6) 31 (48.4) 0.034 ≧ 1 36 (23.7) 20 (31.3) Unknown 1 (0.7) 13 (20.3) Ann Arbor Staging [n (%)] < Ⅲ 35 (23.0) 5 (7.8) 0.012 ≧Ⅲ 114 (75.0) 55 (85.9) Unknown 3 (2.0) 4 (6.3) Line [n (%)] Untreated 94 (61.8) 29 (45.3) 0.025 Relapsed 58 (38.2) 35 (54.7) BM involvement [n (%)] Yes 56 (36.8) 29 (45.3) 0.066 No 90 (59.3) 26 (40.6) Unknown 6 (3.9) 9 (14.1) Splenomegaly [n (%)] Yes 32 (21.1) 12 (18.8) 0.67 No 118 (77.6) 52 (81.2) Unknown 2 (1.3) 0 (0) B symptoms [n (%)] Yes 20 (13.2) 10 (15.6) 0.29 No 129 (84.8) 41 (64.1) Unknown 3 (2.0) 13 (20.3) ALP (U/L) (Mean, SD) 224.6 (150.8) 182.2 (91.1) 0.042 sIL-2R (U/mL) (Mean, SD) 1925.6 (2948.2) 2602.4 (4091.1) 0.17 LDH (U/L) (Mean, SD) 211.8 (74.5) 229.3 (105.2) 0.17 Hb (g/dL) (Mean, SD) 12.7 (1.8) 12.8 (2.1) 0.81 Combination regimen [n (%)] Bendamustin 127 (83.6) 58 (90.6) 0.282 CHOP 21 (13.8) 4 (6.3) CVP 4 (2.6) 2 (3.1) Concomitant drugs [n (%)] Aprepitant 58 (38.2) 21 (32.8) 0.46 Azole antifungal drugs 25 (16.4) 3 (4.7) 0.02 Macrolide antibiotics 1 (0.7) 0 (0) 0.52 Types of corticosteroids [n (%)] DEX 120 (79.0) 31 (48.4) < 0.01 HDC 0 (0) 28 (43.8) PSL 11 (7.2) 3 (4.7) mPSL 21 (13.8) 2 (3.1) Types of histamine antagonists [n (%)] First generations 74 (48.7) 56 (87.5) < 0.01 Second generations 67 (44.1) 8 (12.5) First and second concomitant 11 (7.2) 0 (0) PS: performance status, BM: bone marrow, ALP: alkaline phosphatase, sIL-2R: soluble interleukin-2 receptor, LDH: lactate dehydrogenase, Hb: hemoglobin, CHOP: cyclophosphamide, doxorubicin, vincristine, prednisolone, CVP: cyclophosphamide, vincristine, prednisolone, DEX: dexamethasone, HDC: hydrocortisone, PSL: prednisolone, mPSL: methylprednisolone Table 2 Summary of premedications for administration of Obinutuzumab Category Drug Dose Administration route n Corticosteroid DEX 3.3 mg i.v. 3 6.6 mg i.v. 26 9.9 mg i.v. 2 16.5 mg i.v. 32 19 mg i.v. 11 19.8 mg i.v. 68 33mg i.v. 9 HDC 15 mg i.v. 1 100 mg i.v. 10 200 mg i.v. 16 500 mg i.v. 1 PSL 60 mg p.o. 2 70 mg p.o. 1 100 mg 100mg p.o. i.v. 6 5 mPSL 40 mg i.v. 1 62.5 mg i.v. 1 80 mg i.v. 18 100 mg i.v. 1 125 mg i.v. 1 250 mg i.v. 1 Antipyretic analgesics Acetaminophen 400 mg p.o. 12 500 mg p.o. 57 600 mg p.o. 24 800 mg p.o. 3 900 mg p.o. 6 1000 mg p.o. 6 1000 mg i.v. 17 Diclofenac 25 mg p.o. 5 Loxoprofen 60 mg p.o. 86 Antihistamine d-Chlorpheniramine maleate (First generation) 2 mg p.o. 4 4 mg p.o. 1 5 mg i.v. 59 6 mg p.o. 30 12 mg p.o. 2 Diphenhydramine hydrochloride (First generation) 30 mg p.o. 25 40 mg p.o. 1 50 mg p.o. 8 Epinastine (Second generation) 20 mg p.o. 62 Mequitadine (Second generation) 3 mg p.o. 3 Levocetirizine hydrochloride (Second generation) 2.5 mg p.o. 1 5 mg p.o. 9 Hydroxyzine pamoate (First generation) and levocetirizine hydrochloride (Second generation) 25 mg 5 mg p.o. 11 DEX: dexamethasone, HDC: hydrocortisone, PSL: prednisolone, mPSL: methylprednisolone 2. IRRs incidence according to the corticosteroid dose group The number of patients who had IRRs in the high-dose corticosteroid group was 41 (27.0%), which was significantly lower than that in the low-dose group [n = 31 (48.4%), p = 0.002] (Table 3 ). The severity of IRRs incidence in the high-dose group was grade 1 in 14 patients, grade 2 in 23 patients, and grade 3 in 4 patients, whereas, in the low-dose group, the severity of IRRs incidence was grade 1 in 8 patients, grade 2 in 20 patients, and grade 3 in 3 patients. Supplemental Table 1 shows the background of the 151 patients who received dexamethasone as premedication in the high- and low-dose corticosteroid groups. In the subgroup for the use of dexamethasone, the number of patients who had IRRs in the high- and low-dose groups was 26 (21.7%) and 10 (32.3%), respectively, with no significant difference ( p = 0.22). The severity of IRRs in the high-dose group was grade 1 in 7 patients, grade 2 in 15 patients, and grade 3 in 4 patients. In the low-dose group, the severity of IRRs was grade 1 in 3 patients, grade 2 in 5 patients, and grade 3 in 2 patients. Table 3 Incidence of the infusion‑related reactions according to the dose of corticosteroid as premedication High dose (n = 152) Low dose (n = 64) p -value IRRs (any grade), n (%) 41 (27.0) 31 (48.4) 0.002 Grade 0 111 33 - Grade 1 14 8 - Grade 2 23 20 - Grade 3 4 3 - IRRs: infusion‑related reactions 3. Associated factors for the development of IRRs Excluding 30 patients with missing values from 216 eligible patients, we explored associated factors for the incidence of IRRs in 186 patients. Multivariable logistic regression analysis showed that first-generation histamine 1 receptor antagonist use as premedication [odds ratio (OR) = 3.70, 95% confidence interval (CI): 1.47–9.28; reference: second-generation histamine 1 receptor antagonist use], hydrocortisone use as premedication [OR = 6.49, 95% CI: 1.53–27.46; reference: dexamethasone], and methylprednisolone use as premedication [OR = 1.38, 95% CI: 1.10–12.16; reference: dexamethasone] were significantly associated with the incidence of IRRs during initial obinutuzumab administration (Table 4 ). Low corticosteroid doses were not associated with the incidence of IRRs [OR = 0.83, 95% CI: 0.31–2.21] in the multivariable analysis. Prednisolone equivalent was not associated with the incidence of IRRs [OR = 0.99, 95% CI: 0.99–1.00] (Supplemental Table 2). Table 4 Logistic regression analysis Univariable analysis Multivariable analysis Variables Category OR (95% CI) p -values OR (95% CI) p -values AnnArbor classification ≥ Ⅲ 3.04 (1.20–7.73) 0.02 2.12 (0.74–6.06) 0.16 B symptoms + 2.94 (1.31–6.59) 0.01 1.38 (0.52–3.64) 0.52 sIL-2R (U/mL) - 1.0 (1.0–1.0) 0.35 1.0 (1.0–1.0) 0.15 LDH (U/L) - 1.0 (0.99–1.0) 0.25 1.0 (0.99–1.0) 0.08 Dosage of corticosteroids Low dose 2.10 (1.03–4.20) 0.04 0.83 (0.31–2.21) 0.71 Types of corticosteroids DEX Reference - Reference - HDC 6.88 (2.19–21.57) < 0.01 6.49 (1.53–27.46) 0.010 PSL 4.01 (1.26–12.78) 0.02 2.65 (0.70–10.00) 0.15 mPSL 3.44 (1.20–9.88) 0.02 1.38 (1.10–12.16) 0.035 Types of histamine antagonists Second generations Reference - Reference - First generations 4.58 (2.06–10.19) < 0.01 3.70 (1.47–9.28) < 0.01 First and second concomitant 3.75 (0.91–15.41) 0.07 2.55 (0.51–12.86) 0.26 sIL-2R, soluble interleukin-2 receptor; LDH, lactate dehydrogenase; DEX, dexamethasone; HDC, Hydrocortisone; PSL, prednisolone; mPSL, methylprednisolone Discussion We found that the incidence of IRRs in patients with high-dose corticosteroids was lower than that in those with low-dose corticosteroids administered as premedication for obinutuzumab. Furthermore, we demonstrated that the administration of first-generation histamine 1 receptor antagonists and hydrocortisone or methylprednisolone may be factors in the IRRs incidence by obinutuzumab. This is the first report findings regarding corticosteroid dose for prophylaxis of IRRs induced by obinutuzumab. This study demonstrated that the use of high-dose corticosteroids is an effective prophylactic method against IRRs. The high-dose group in this study was defined based on FDA recommendations, suggesting that the use of sufficient corticosteroids over the recommended dose is important for preventing IRRs. Studies have suggested that corticosteroids have a dose-dependent effect on IRRs prophylaxis and that intravenously administered dexamethasone has a dose-dependent effect on preventing IRRs in the case of trastuzumab administration [10]. Although the report targeted patients who received trastuzumab therapy, this report supports the dose-dependent effect of corticosteroids on IRRs. Moreover, although some patient backgrounds significantly differed between the high- and low-dose groups in this study, they were not identified as risk factors for IRRs incidence in a previous study including patients treated with rituximab [7–9]; therefore, it is likely that those factors did not affect the incidence of IRRs. Although high tumor volume and bone marrow involvement may be risk factor for IRRs incidence in patients receiving obinutuzumab [11, 12], no significant differences in sIL-2R or LDH and bone marrow involvement were observed between the two groups in this study. The concomitant use of azole antifungals has been reported to potentiate the effects of corticosteroids [13]. In this study, a higher percentage of patients in the high-dose group received concomitant azole antifungals; although the data suggest that increased corticosteroid exposure is effective in suppressing IRRs, the possibility that the use of concomitant azole antifungals contributed to the lower incidence of IRRs in the high-dose group cannot be ruled out. In this study, the comparison groups were divided according to the dose and type of corticosteroid medication; prednisolone equivalent was not associated with IRRs incidence (Supplemental Table 2). To exclude the effect of corticosteroid type, a post hoc analysis in the subgroup of patients with dexamethasone administration showed no difference in IRRs incidence between the high- and low-dose groups. However, the sample size is too small to reproduce the same incidence ratios in the high- and low-dose groups in the overall population and to detect differences with sufficient statistical power; therefore, further study is necessary. Furthermore, prednisolone equivalent may not reflect accurate titers [6], and equivalent based on uniform criteria may not be significant covariates for IRRs. Although the cutoff dose value was set lower than the recommended value, the high-dose group was more effective than the low-dose group, and we believe that the results support the recommendations from the FDA and EMA. The use of hydrocortisone and methylprednisolone was shown to be factors in the incidence of IRRs versus the use of dexamethasone. No data are available in the FDA and EMA package inserts to support the use of hydrocortisone in reducing IRRs. In this study, 96.4% of the patients fell into the low-dose group when the hydrocortisone doses were converted to prednisolone equivalent values. In contrast, 91.3% of patients who received methylprednisolone fell into the high-dose group when the dose was converted to prednisolone equivalent; therefore, differences in the pharmacological and pharmacokinetic profiles of each corticosteroid in addition to the dose may have influenced the incidence of IRRs. Although dexamethasone is known to have a longer biological half-life than hydrocortisone or methylprednisolone [6], the reasons for high efficacy of dexamethasone on IRRs prevention should be examined in detail in the future. In addition to cytokine-induced infusion reactions, hypersensitivity, which is an allergic reaction, is also known to occur after rituximab administration [14]. Hypersensitivity has been reported to account for 5–10% of the overall post-dose reactions [15, 16]. These events are difficult to differentiate from IRRs by medical examination because of their similar symptoms, and the outcomes collected in this study may include a mixture of these events. Succinate esters are known as inducers of hypersensitivity [17]. Injectable corticosteroids are manufactured as succinate or phosphate esters because corticosteroids are insoluble in water. Hydrocortisone, prednisolone, and methylprednisolone injectables are succinate esters. Therefore, these drugs may have increased the frequency of hypersensitivity. The result that prednisolone was not identified as a factor in the incidence of IRRs may be attributed to the fact that 64.3% (9/14) of patients who received prednisolone as premedication were administered prednisolone orally. The frequency of hypersensitivity as the phenotype of IRRs in this study is unknown and requires further study. The administration of first-generation histamine 1 receptor antagonists was shown to be a possible factor for the incidence of IRRs. No studies have examined the effect of histamine 1 receptor antagonist on obinutuzumab-induced IRRs. A study comparing the histamine 1 receptor antagonists fexofenadine and bepotastine in terms of efficacy as IRRs countermeasures during the initial administration of rituximab reported that bepotastine significantly suppressed the incidence of IRRs compared with fexofenadine [18], suggesting that differences in pharmacokinetics and other aspects of histamine 1 receptor antagonists affect the incidence of IRRs. Studies investigating the preventive effect of diphenhydramine and cetirizine on IRRs in patients who received rituximab and other anticancer therapies have demonstrated that cetirizine may be a viable alternative for diphenhydramine in preventing IRRs [19]. A randomized controlled trial is ongoing to evaluate the efficacy of bepotastine besilate compared with hydroxyzine pamoate on IRR [20]. First-generation histamine 1 receptor antagonists are contraindicated in patients with prostatic hypertrophy and glaucoma, and their central nervous system depressant effects cause side effects, such as drowsiness and dizziness. Although the reasons why second-generation histamine 1 receptor antagonists are more effective as IRRs countermeasures than first-generation histamine 1 receptor antagonists have not been examined, it was considered desirable to use second-generation histamine 1 receptor antagonists, which have less anticholinergic and central nervous system depressant effects than first-generation histamine 1 receptor antagonists, from the perspective of side effects. Factors for the incidence of IRRs by rituximab have been reported to includehigh LDH and sIL-2R level, low hemoglobin level, presence of B symptoms and bone marrow infiltration, indolent lymphoma, and bulky disease [7–9]. High tumor volume may be risk factor for IRRs incidence in patients receiving obinutuzumab [11]. In this study, factors that could reflect tumor volume, such as staging, B symptoms, sIL-2R, and LDH, were examined but not identified as factors. The Groupe d'Etude des Lymphomes Folliculaires has developed criteria for predicting tumor volume in follicular lymphoma [21], which included B symptoms, but not sIL-2R or LDH. It was considered possible that the level of sIL-2R and LDH are unlikely to immediately reflect tumor volume because follicular lymphoma progressesslowly. This study has several limitations. This study was a retrospective survey, and collecting data using a uniform evaluation method for IRRs was impossible. In the GALLIUM study, the incidence of IRRs in the obinutuzumab and rituximab groups was 59% and 49%, respectively [1]. Other retrospective studies on IRRs caused by rituximab have reported IRRs incidence rates of 32.9% [7] and 37.9% [8] at the initial administration of rituximab. Two retrospective studies for IRRs caused by obinutuzumab have reported IRRs incidence rates of 36% [22] and 55.6% [12], at the time of initial obinutuzumab administration. The incidence of IRRs in this study was 33.3%, which is comparable to those reported in previous retrospective studies, although it differs from clinical trials in which precise evaluation can be performed. The possibility that IRRs may be underestimated in real-world data is an important limitation in this study. Furthermore, logistic regression analysis was performed on 186 patients. The seven factors were selected as explanatory variables in the multivariable analysis with reference to clinical findings from previous reports. However, IRRs occurred in 57 patients, which may have reduced the reliability and robustness of the analysis. Bone marrow infiltration was not selected as an explanatory variable in the logistic regression analysis due to missing these examination data. In conclusion, higher corticosteroid doses during the initial administration of obinutuzumab can reduce the incidence of IRRs. Furthermore, it was suggested that dexamethasone may be more effective than hydrocortisone or methylprednisolone, and second-generation histamine 1 receptor antagonists may be more effective than first-generation agents in preventing IRR. Declarations Author contribution Tatsuya Ohtsubo and Kazuhiro Yamamoto were involved in the design of the study. Tatsuya Ohtsubo performed the statistical analysis and was advised by Kazuhiro Yamamoto and Satoshi Dote. Tatsuya Ohtsubo and Saori Matumotoand Kaori Itoand Yuzuka Sasaand Kosuke Tomishimaand Satoshi Doteand Katuya Makiharaand Yoshinori Wakasugiand Tsutomu Mitsuieand Kouhei Yamagiwaand Kazuo Satoand Hiroki Hasegawacollected data.All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Ethics approval This study conformed to the provisions of the Declaration of Helsinki. The Institutional Review Board of Japanese Red Cross Kyoto Daini Hospital approved the study protocol (Approval No. S2021-25) Consent to participate A summary of the study and consent to publication were declared available so that each participant could refuse to participate in the study at any time. 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J Allergy Clin Immunol Pract 3:175–185 Kamm GL, Hagmeyer KO (1999) Allergic-type reactions to corticosteroids, Ann Pharmacother 33:451–460 Matsui N, Ishihara N, Mochizuki Y, Tamaki H, Nishimura N, Naora K (2019) Inhibitory effect on rituximab-induced infusion reaction by premedication with fexofenadine or Bepotastine. Jpn J Pharm Health Care Sci 45:396–403 Durham CG, Thotakura D, Sager L, Foster J, Herrington JD (2019) Cetirizine versus diphenhydramine in the prevention of chemotherapy-related hypersensitivity reactions. J Oncol Pharm Pract 25:1396–1401 Kitahiro Y, Yamamoto K, Yakushijin K, Ioroi T, Tanda M, Itohara K, Omura T, Minami H, Yano I (2024) The Efficacy of Bepotastine Besilate Compared With Hydroxyzine Pamoate for Preventing Infusion Reactions to the First Dose of Rituximab in Patients With Non-Hodgkin Lymphoma: Protocol for a Phase II, Double-Blind, Multicenter Randomized Trial. JMIR Res Protoc 13:e54882 Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, Straetmans N, Tilly H, Tabah I, Solal-Céligny P (1997) Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 15:1110–1117 Kuromatsu M, Kajita T, Taruno M, Nishikawa Y, Akasaka T, Okuno T (2021) Search for risk factors influencing the occurrence of infusion reaction after initial treatment with obinutuzumab. Jpn J Pharm Health Care Sci 47:631–638 Additional Declarations No competing interests reported. Supplementary Files SupplementalTable.docx Supplemental material Supplemental Table 1 Comparison of patient characteristics between high-dose and low-dose groups in patients using dexamethasone Supplemental Table 2 Logistic regression analysis Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4883642","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":339941303,"identity":"fa16ad8a-6bde-4b33-8f2e-9b9c04bb32fe","order_by":0,"name":"Tatsuya Ohtsubo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYDACCSBmbGBgkJc/fADElSFCCzNYi4ThDLYEEJeHeC0MN3gMQHzCWvil+w9/5t1hU8c4u+fzqxs1FjwM7IePbsCnRXLOYTZp3jNpEuwyZ7dZ5xwDOownLe0GPi0GN5LZmHnbDkswNuRuM85hA2qR4DEjpIX5M0gLw4GcZ8Y5/4jTwiAN1nIjh/lxbhsRWiRnJJtJzj2TJrmx55gZc26fBA8bIb/wSyQ+/vB2hw2/PHvz48853+rk+NkPH8OrBRmwSYBJYpWDAPMHUlSPglEwCkbByAEAX1REeWA0s5QAAAAASUVORK5CYII=","orcid":"","institution":"Japanese Red Cross Society Kyoto Daini Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Ohtsubo","suffix":""},{"id":339941304,"identity":"03a74b7b-3e03-4caf-96ab-3e6c502be231","order_by":1,"name":"Kazuhiro Yamamoto","email":"","orcid":"","institution":"Okayama University","correspondingAuthor":false,"prefix":"","firstName":"Kazuhiro","middleName":"","lastName":"Yamamoto","suffix":""},{"id":339941306,"identity":"924b90bc-85ca-40f6-a047-ce06298637f1","order_by":2,"name":"Saori Matumoto","email":"","orcid":"","institution":"Japanese Red Cross Osaka Hospital","correspondingAuthor":false,"prefix":"","firstName":"Saori","middleName":"","lastName":"Matumoto","suffix":""},{"id":339941308,"identity":"07d0711c-d477-4e1c-b0e9-059d8b143f52","order_by":3,"name":"Kaori Ito","email":"","orcid":"","institution":"Meijo University","correspondingAuthor":false,"prefix":"","firstName":"Kaori","middleName":"","lastName":"Ito","suffix":""},{"id":339941309,"identity":"93845b62-a812-4458-a954-dcc9b75457b1","order_by":4,"name":"Yuzuka Sasa","email":"","orcid":"","institution":"Kindai University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuzuka","middleName":"","lastName":"Sasa","suffix":""},{"id":339941310,"identity":"05a44d4d-88cd-4755-bdd4-27100a89c2f7","order_by":5,"name":"Kosuke Tomishima","email":"","orcid":"","institution":"Japanese Red Cross Kyoto Daiichi Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kosuke","middleName":"","lastName":"Tomishima","suffix":""},{"id":339941312,"identity":"1878c3a6-47a0-480f-859b-a3a67c0394d2","order_by":6,"name":"Satoshi Dote","email":"","orcid":"","institution":"Kyoto Katsura Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Dote","suffix":""},{"id":339941313,"identity":"258d58a1-044a-43fb-bd44-9cdee51e2177","order_by":7,"name":"Katuya Makihara","email":"","orcid":"","institution":"Yodogawa Christian Hospital","correspondingAuthor":false,"prefix":"","firstName":"Katuya","middleName":"","lastName":"Makihara","suffix":""},{"id":339941314,"identity":"62477789-5bb8-435f-b026-fedd3625adec","order_by":8,"name":"Yoshinori Wakasugi","email":"","orcid":"","institution":"Shiga University of Medical Science Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshinori","middleName":"","lastName":"Wakasugi","suffix":""},{"id":339941315,"identity":"685eb217-b968-4604-9416-e0002011cec4","order_by":9,"name":"Tsutomu Mitsuie","email":"","orcid":"","institution":"Japanese Red Cross Otsu Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tsutomu","middleName":"","lastName":"Mitsuie","suffix":""},{"id":339941316,"identity":"37427a3f-5e95-4687-a134-b4ec1586834c","order_by":10,"name":"Kouhei Yamagiwa","email":"","orcid":"","institution":"Saiseikai Siga Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kouhei","middleName":"","lastName":"Yamagiwa","suffix":""},{"id":339941317,"identity":"7de8902d-43bb-4f8b-b70f-c7aa0f272c26","order_by":11,"name":"Kazuo Sato","email":"","orcid":"","institution":"Japan Baptist Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kazuo","middleName":"","lastName":"Sato","suffix":""},{"id":339941318,"identity":"4dd881e9-5694-45aa-9b0c-b0918b784f7f","order_by":12,"name":"Hiroki Hasegawa","email":"","orcid":"","institution":"Rakuwakai Otowa Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroki","middleName":"","lastName":"Hasegawa","suffix":""},{"id":339941319,"identity":"18ddbc33-4c00-4af2-beca-857c1ab63a3d","order_by":13,"name":"Nobuhiko Uoshima","email":"","orcid":"","institution":"Japanese Red Cross Society Kyoto Daini Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nobuhiko","middleName":"","lastName":"Uoshima","suffix":""},{"id":339941320,"identity":"1f9f9d23-31d7-483d-88b3-9be4e887090b","order_by":14,"name":"Yumi Kitahiro","email":"","orcid":"","institution":"Kobe University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yumi","middleName":"","lastName":"Kitahiro","suffix":""},{"id":339941321,"identity":"2d8f77aa-517e-46f5-b043-1d56ad3ea457","order_by":15,"name":"Kanji Tomogane","email":"","orcid":"","institution":"Japanese Red Cross Society Kyoto Daini Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kanji","middleName":"","lastName":"Tomogane","suffix":""}],"badges":[],"createdAt":"2024-08-09 01:29:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4883642/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4883642/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83282551,"identity":"22edcc02-2be7-4096-b9ca-7cf70b9bff4a","added_by":"auto","created_at":"2025-05-22 10:38:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":990599,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4883642/v1/94507185-fa83-4fc1-b39d-da024f594a76.pdf"},{"id":64216057,"identity":"f7e88fc8-d793-4928-bf7b-43dd674def19","added_by":"auto","created_at":"2024-09-10 09:36:50","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22625,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplemental Table 1 Comparison of patient characteristics between high-dose and low-dose groups in patients using dexamethasone\u003c/p\u003e\n\u003cp\u003eSupplemental Table 2 Logistic regression analysis\u003c/p\u003e","description":"","filename":"SupplementalTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-4883642/v1/0a0233412983690af7a4bdd7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between the incidence of infusion-related reactions by obinutuzumab and the dose of corticosteroid as premedication: A multicenter retrospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eObinutuzumab is a humanized anti-CD20 monoclonal antibody that is widely used for CD20-positive follicular lymphoma and chronic lymphocytic leukemia (including small lymphocytic lymphoma). In the GALLIUM study [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], which included patients with follicular lymphoma, patients who received obinutuzumab-based immunochemotherapy showed longer progression-free survival than those who received rituximab-based immunochemotherapy, making obinutuzumab-based immunochemotherapy a standard therapy for CD20-positive follicular lymphoma [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, infusion-related reactions (IRRs) are observed as serious and frequent adverse events associated with obinutuzumab administration, which tend to occur during the initial administration [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The incidence of IRRs in the obinutuzumab and rituximab groups in the GALLIUM study was 59% and 49% for all grades, respectively, and 11% and 5% for grades 3\u0026ndash;5, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Obinutuzumab may result in the occurrence of IRRs more frequently than rituximab. Premedication with antipyretic analgesics, histamine 1 receptor antagonists, and corticosteroids is recommended for preventing IRRs caused by obinutuzumab [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommend 100 mg of prednisolone, 20 mg of dexamethasone, or 80 mg of methylprednisolone with respect to corticosteroids and state that hydrocortisone should not be used because it is not effective for IRRs prophylaxis in the package insert of obinutuzumab [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, corticosteroids are expected to be used at reduced doses for reasons such as diabetic comorbidity or to avoid serious infections. There is no published data for the dose of corticosteroids used in clinical trials, and no dosing regimen of corticosteroids has been established. Therefore, we aimed to standardize premedication with corticosteroids at the initial administration of obinutuzumab and investigate the association between the dose of corticosteroids and IRRs incidence.\u003c/p\u003e"},{"header":"Methods","content":"\n\u003ch3\u003e1. Patients\u003c/h3\u003e\n\u003cp\u003ePatients treated with obinutuzumab as initial therapy for primary or relapsed CD20-positive follicular lymphoma from August 1, 2018, to October 31, 2021, at collaborating institutions were included. The exclusion criteria were as follows: patients who take antipyretic analgesics (including nonsteroidal anti-inflammatory drugs), histamine 1 receptor antagonists, or corticosteroids other than those included in the regimen used before obinutuzumab administration and those who were not given corticosteroids as premedication on the same day as obinutuzumab administration.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2. Definition of the high-dose and low-dose corticosteroid groups\u003c/h2\u003e \u003cp\u003eThe high-dose group comprised patients who received 100 mg or higher of prednisolone, 80 mg or higher of methylprednisolone, or 16.5 mg or higher of dexamethasone as premedication. The low-dose group comprised patients who received a dose lower than that in the high-dose group or those who took hydrocortisone. Because dexamethasone preparations in Japan are marked with the content of dexamethasone without phosphate, the cutoff value for low or high dexamethasone dose in this study was defined as 16.5 mg, which is treated the same as 20 mg of dexamethasone phosphate. The corticosteroid equivalent was set as 20 mg of hydrocortisone, 5 mg of prednisolone, 4 mg of methylprednisolone, and 0.75 mg of dexamethasone in equal doses [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3. Definition of IRRs\u003c/h2\u003e \u003cp\u003eIRRs incidence was determined from a physician\u0026rsquo;s documentation in the electronic medical record that IRRs (e.g., anaphylaxis, hypotension, nausea, chills, bronchospasm, pharyngeal or throat irritation, wheezing, laryngeal edema, atrial fibrillation, tachycardia, and hypersensitivity) occurred during obinutuzumab administration. In cases where there was no description regarding the incidence of IRRs in medical records, the attending physician performed a retrospective evaluation. The severity of IRRs was assessed by referring to the physician\u0026rsquo;s medical record. If no record was available regarding severity, each principal investigator assessed it based on \u0026ldquo;Infusion related reaction\u0026rdquo; in Common Terminology Criteria for Adverse Events version 5.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e4. Statistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables are presented as means (standard deviations) and were compared using Student\u0026rsquo;s t-test. Nominal variables are presented as numbers and percentages and were compared using the chi-square test. Univariable and multivariable logistic regression analyses were performed on patients without missing values to explore the risk of developing IRRs with obinutuzumab. The explanatory variables were staging (AnnArbor classification), B symptoms, sIL-2R, LDH, dosage and type of corticosteroid, and type of histamine antagonist [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Statistical analyses were performed using Statistical Package for the Social Sciences (version 23.0; IBM Corp., New York) with a significance level of 5%.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e1. Patient characteristics\u003c/h2\u003e \u003cp\u003eOf the 220 patients who received obinutuzumab as initial therapy for CD20-positive follicular lymphoma, 216 were included, excluding four patients who did not receive corticosteroids as premedication on the same day as obinutuzumab administration. The patient backgrounds in the high- and low-dose corticosteroid groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The number of patients in the high- and low-dose groups was 152 and 64, respectively. The high-dose group had a significantly lower age and a significantly lower percentage of patients with clinical stage III or higher than the low-dose group. Furthermore, the high-dose group had a significantly higher percentage of patients with PS of 0 and untreated patients, significantly higher ALP levels, and a higher percentage of patients with azole antifungal drug use. The details of corticosteroids, histamine 1 receptor antagonists, and antipyretic analgesics used as premedication are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The most commonly used corticosteroid was dexamethasone [n\u0026thinsp;=\u0026thinsp;151 (69.9%)]. The most commonly used histamine 1 receptor antagonist and antipyretic analgesic were d-chlorpheniramine maleate [n\u0026thinsp;=\u0026thinsp;96 (44.4%)] and acetaminophen [n\u0026thinsp;=\u0026thinsp;125 (57.9%)], respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of patient characteristics between high-dose and low-dose corticosteroid groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigh dose (n\u0026thinsp;=\u0026thinsp;152)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow dose (n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge [Mean (SD)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.4 (10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69.9 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77 (50.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (54.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePS [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e115 (75.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e≧\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (23.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (20.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnn Arbor Staging [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt; Ⅲ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (23.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e≧Ⅲ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (85.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLine [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUntreated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (61.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (45.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRelapsed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (38.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (54.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBM involvement [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (45.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (59.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (40.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (14.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenomegaly [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118 (77.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (81.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB symptoms [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e129 (84.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (64.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (20.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP (U/L) (Mean, SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e224.6 (150.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e182.2 (91.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esIL-2R (U/mL) (Mean, SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1925.6 (2948.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2602.4 (4091.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH (U/L) (Mean, SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e211.8 (74.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e229.3 (105.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb (g/dL) (Mean, SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.7 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.8 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination regimen [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBendamustin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e127 (83.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (90.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.282\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant drugs [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAprepitant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (38.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (32.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzole antifungal drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacrolide antibiotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of corticosteroids [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120 (79.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (7.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emPSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of histamine antagonists [n (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst generations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (48.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecond generations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (44.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst and second concomitant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (7.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003ePS: performance status, BM: bone marrow, ALP: alkaline phosphatase, sIL-2R: soluble interleukin-2 receptor, LDH: lactate dehydrogenase, Hb: hemoglobin, CHOP: cyclophosphamide, doxorubicin, vincristine, prednisolone, CVP: cyclophosphamide, vincristine, prednisolone, DEX: dexamethasone, HDC: hydrocortisone, PSL: prednisolone, mPSL: methylprednisolone\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of premedications for administration of Obinutuzumab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDose\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdministration route\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"19\" rowspan=\"20\"\u003e \u003cp\u003eCorticosteroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eDEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.3 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.6 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.9 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.8 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eHDC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e500 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 mg\u003c/p\u003e \u003cp\u003e100mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003emPSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e250 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"8\" rowspan=\"9\"\u003e \u003cp\u003eAntipyretic analgesics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003eAcetaminophen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e400 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e500 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e600 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e800 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e900 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1000 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1000 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiclofenac\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoxoprofen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"12\" rowspan=\"13\"\u003e \u003cp\u003eAntihistamine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003ed-Chlorpheniramine maleate\u003c/p\u003e \u003cp\u003e(First generation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ei.v.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eDiphenhydramine hydrochloride\u003c/p\u003e \u003cp\u003e(First generation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEpinastine\u003c/p\u003e \u003cp\u003e(Second generation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMequitadine\u003c/p\u003e \u003cp\u003e(Second generation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLevocetirizine hydrochloride\u003c/p\u003e \u003cp\u003e(Second generation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHydroxyzine pamoate\u003c/p\u003e \u003cp\u003e(First generation) and\u003c/p\u003e \u003cp\u003elevocetirizine hydrochloride\u003c/p\u003e \u003cp\u003e(Second generation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 mg\u003c/p\u003e \u003cp\u003e5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.o.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eDEX: dexamethasone, HDC: hydrocortisone, PSL: prednisolone, mPSL: methylprednisolone\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2. IRRs incidence according to the corticosteroid dose group\u003c/h2\u003e \u003cp\u003eThe number of patients who had IRRs in the high-dose corticosteroid group was 41 (27.0%), which was significantly lower than that in the low-dose group [n\u0026thinsp;=\u0026thinsp;31 (48.4%), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002] (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The severity of IRRs incidence in the high-dose group was grade 1 in 14 patients, grade 2 in 23 patients, and grade 3 in 4 patients, whereas, in the low-dose group, the severity of IRRs incidence was grade 1 in 8 patients, grade 2 in 20 patients, and grade 3 in 3 patients. Supplemental Table\u0026nbsp;1 shows the background of the 151 patients who received dexamethasone as premedication in the high- and low-dose corticosteroid groups. In the subgroup for the use of dexamethasone, the number of patients who had IRRs in the high- and low-dose groups was 26 (21.7%) and 10 (32.3%), respectively, with no significant difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.22). The severity of IRRs in the high-dose group was grade 1 in 7 patients, grade 2 in 15 patients, and grade 3 in 4 patients. In the low-dose group, the severity of IRRs was grade 1 in 3 patients, grade 2 in 5 patients, and grade 3 in 2 patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence of the infusion‑related reactions according to the dose of corticosteroid as premedication\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh dose (n\u0026thinsp;=\u0026thinsp;152)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow dose (n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIRRs (any grade), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eIRRs: infusion‑related reactions\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3. Associated factors for the development of IRRs\u003c/h2\u003e \u003cp\u003eExcluding 30 patients with missing values from 216 eligible patients, we explored associated factors for the incidence of IRRs in 186 patients. Multivariable logistic regression analysis showed that first-generation histamine 1 receptor antagonist use as premedication [odds ratio (OR)\u0026thinsp;=\u0026thinsp;3.70, 95% confidence interval (CI): 1.47\u0026ndash;9.28; reference: second-generation histamine 1 receptor antagonist use], hydrocortisone use as premedication [OR\u0026thinsp;=\u0026thinsp;6.49, 95% CI: 1.53\u0026ndash;27.46; reference: dexamethasone], and methylprednisolone use as premedication [OR\u0026thinsp;=\u0026thinsp;1.38, 95% CI: 1.10\u0026ndash;12.16; reference: dexamethasone] were significantly associated with the incidence of IRRs during initial obinutuzumab administration (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Low corticosteroid doses were not associated with the incidence of IRRs [OR\u0026thinsp;=\u0026thinsp;0.83, 95% CI: 0.31\u0026ndash;2.21] in the multivariable analysis. Prednisolone equivalent was not associated with the incidence of IRRs [OR\u0026thinsp;=\u0026thinsp;0.99, 95% CI: 0.99\u0026ndash;1.00] (Supplemental Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e \u003cb\u003eLogistic regression analysis\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eUnivariable analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eMultivariable analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-values\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-values\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnnArbor classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge; Ⅲ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.04 (1.20\u0026ndash;7.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.12 (0.74\u0026ndash;6.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.94 (1.31\u0026ndash;6.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.38 (0.52\u0026ndash;3.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esIL-2R (U/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0 (1.0\u0026ndash;1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.0 (1.0\u0026ndash;1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0 (0.99\u0026ndash;1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.0 (0.99\u0026ndash;1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDosage of corticosteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.10 (1.03\u0026ndash;4.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.83 (0.31\u0026ndash;2.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of corticosteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHDC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.88 (2.19\u0026ndash;21.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.49 (1.53\u0026ndash;27.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.01 (1.26\u0026ndash;12.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.65 (0.70\u0026ndash;10.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emPSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.44 (1.20\u0026ndash;9.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.38 (1.10\u0026ndash;12.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of histamine antagonists\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSecond generations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFirst generations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.58 (2.06\u0026ndash;10.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.70 (1.47\u0026ndash;9.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFirst and second concomitant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.75 (0.91\u0026ndash;15.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.55 (0.51\u0026ndash;12.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003esIL-2R, soluble interleukin-2 receptor; LDH, lactate dehydrogenase; DEX, dexamethasone; HDC, Hydrocortisone; PSL, prednisolone; mPSL, methylprednisolone\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe found that the incidence of IRRs in patients with high-dose corticosteroids was lower than that in those with low-dose corticosteroids administered as premedication for obinutuzumab. Furthermore, we demonstrated that the administration of first-generation histamine 1 receptor antagonists and hydrocortisone or methylprednisolone may be factors in the IRRs incidence by obinutuzumab. This is the first report findings regarding corticosteroid dose for prophylaxis of IRRs induced by obinutuzumab.\u003c/p\u003e\n\u003cp\u003eThis study demonstrated that the use of high-dose corticosteroids is an effective prophylactic method against IRRs. The high-dose group in this study was defined based on FDA recommendations, suggesting that the use of sufficient corticosteroids over the recommended dose is important for preventing IRRs. Studies have suggested that corticosteroids have a dose-dependent effect on IRRs prophylaxis and that intravenously administered dexamethasone has a dose-dependent effect on preventing IRRs in the case of trastuzumab administration [10]. Although the report targeted patients who received trastuzumab therapy, this report supports the dose-dependent effect of corticosteroids on IRRs. Moreover, although some patient backgrounds significantly differed between the high- and low-dose groups in this study, they were not identified as risk factors for IRRs incidence in a previous study including patients treated with rituximab [7\u0026ndash;9]; therefore, it is likely that those factors did not affect the incidence of IRRs. Although high tumor volume and bone marrow involvement may be risk factor for IRRs incidence in patients receiving obinutuzumab [11, 12], no significant differences in sIL-2R or LDH and bone marrow involvement were observed between the two groups in this study. The concomitant use of azole antifungals has been reported to potentiate the effects of corticosteroids [13]. In this study, a higher percentage of patients in the high-dose group received concomitant azole antifungals; although the data suggest that increased corticosteroid exposure is effective in suppressing IRRs, the possibility that the use of concomitant azole antifungals contributed to the lower incidence of IRRs in the high-dose group cannot be ruled out.\u003c/p\u003e\n\u003cp\u003eIn this study, the comparison groups were divided according to the dose and type of corticosteroid medication; prednisolone equivalent was not associated with IRRs incidence (Supplemental Table\u0026nbsp;2). To exclude the effect of corticosteroid type, a post hoc analysis in the subgroup of patients with dexamethasone administration showed no difference in IRRs incidence between the high- and low-dose groups. However, the sample size is too small to reproduce the same incidence ratios in the high- and low-dose groups in the overall population and to detect differences with sufficient statistical power; therefore, further study is necessary. Furthermore, prednisolone equivalent may not reflect accurate titers [6], and equivalent based on uniform criteria may not be significant covariates for IRRs. Although the cutoff dose value was set lower than the recommended value, the high-dose group was more effective than the low-dose group, and we believe that the results support the recommendations from the FDA and EMA.\u003c/p\u003e\n\u003cp\u003eThe use of hydrocortisone and methylprednisolone was shown to be factors in the incidence of IRRs versus the use of dexamethasone. No data are available in the FDA and EMA package inserts to support the use of hydrocortisone in reducing IRRs. In this study, 96.4% of the patients fell into the low-dose group when the hydrocortisone doses were converted to prednisolone equivalent values. In contrast, 91.3% of patients who received methylprednisolone fell into the high-dose group when the dose was converted to prednisolone equivalent; therefore, differences in the pharmacological and pharmacokinetic profiles of each corticosteroid in addition to the dose may have influenced the incidence of IRRs. Although dexamethasone is known to have a longer biological half-life than hydrocortisone or methylprednisolone [6], the reasons for high efficacy of dexamethasone on IRRs prevention should be examined in detail in the future. In addition to cytokine-induced infusion reactions, hypersensitivity, which is an allergic reaction, is also known to occur after rituximab administration [14]. Hypersensitivity has been reported to account for 5\u0026ndash;10% of the overall post-dose reactions [15, 16]. These events are difficult to differentiate from IRRs by medical examination because of their similar symptoms, and the outcomes collected in this study may include a mixture of these events. Succinate esters are known as inducers of hypersensitivity [17]. Injectable corticosteroids are manufactured as succinate or phosphate esters because corticosteroids are insoluble in water. Hydrocortisone, prednisolone, and methylprednisolone injectables are succinate esters. Therefore, these drugs may have increased the frequency of hypersensitivity. The result that prednisolone was not identified as a factor in the incidence of IRRs may be attributed to the fact that 64.3% (9/14) of patients who received prednisolone as premedication were administered prednisolone orally. The frequency of hypersensitivity as the phenotype of IRRs in this study is unknown and requires further study.\u003c/p\u003e\n\u003cp\u003eThe administration of first-generation histamine 1 receptor antagonists was shown to be a possible factor for the incidence of IRRs. No studies have examined the effect of histamine 1 receptor antagonist on obinutuzumab-induced IRRs. A study comparing the histamine 1 receptor antagonists fexofenadine and bepotastine in terms of efficacy as IRRs countermeasures during the initial administration of rituximab reported that bepotastine significantly suppressed the incidence of IRRs compared with fexofenadine [18], suggesting that differences in pharmacokinetics and other aspects of histamine 1 receptor antagonists affect the incidence of IRRs. Studies investigating the preventive effect of diphenhydramine and cetirizine on IRRs in patients who received rituximab and other anticancer therapies have demonstrated that cetirizine may be a viable alternative for diphenhydramine in preventing IRRs [19]. A randomized controlled trial is ongoing to evaluate the efficacy of bepotastine besilate compared with hydroxyzine pamoate on IRR [20]. First-generation histamine 1 receptor antagonists are contraindicated in patients with prostatic hypertrophy and glaucoma, and their central nervous system depressant effects cause side effects, such as drowsiness and dizziness. Although the reasons why second-generation histamine 1 receptor antagonists are more effective as IRRs countermeasures than first-generation histamine 1 receptor antagonists have not been examined, it was considered desirable to use second-generation histamine 1 receptor antagonists, which have less anticholinergic and central nervous system depressant effects than first-generation histamine 1 receptor antagonists, from the perspective of side effects.\u003c/p\u003e\n\u003cp\u003eFactors for the incidence of IRRs by rituximab have been reported to includehigh LDH and sIL-2R level, low hemoglobin level, presence of B symptoms and bone marrow infiltration, indolent lymphoma, and bulky disease [7\u0026ndash;9]. High tumor volume may be risk factor for IRRs incidence in patients receiving obinutuzumab [11]. In this study, factors that could reflect tumor volume, such as staging, B symptoms, sIL-2R, and LDH, were examined but not identified as factors. The Groupe d\u0026apos;Etude des Lymphomes Folliculaires has developed criteria for predicting tumor volume in follicular lymphoma [21], which included B symptoms, but not sIL-2R or LDH. It was considered possible that the level of sIL-2R and LDH are unlikely to immediately reflect tumor volume because follicular lymphoma progressesslowly.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. This study was a retrospective survey, and collecting data using a uniform evaluation method for IRRs was impossible. In the GALLIUM study, the incidence of IRRs in the obinutuzumab and rituximab groups was 59% and 49%, respectively [1]. Other retrospective studies on IRRs caused by rituximab have reported IRRs incidence rates of 32.9% [7] and 37.9% [8] at the initial administration of rituximab. Two retrospective studies for IRRs caused by obinutuzumab have reported IRRs incidence rates of 36% [22] and 55.6% [12], at the time of initial obinutuzumab administration. The incidence of IRRs in this study was 33.3%, which is comparable to those reported in previous retrospective studies, although it differs from clinical trials in which precise evaluation can be performed. The possibility that IRRs may be underestimated in real-world data is an important limitation in this study. Furthermore, logistic regression analysis was performed on 186 patients. The seven factors were selected as explanatory variables in the multivariable analysis with reference to clinical findings from previous reports. However, IRRs occurred in 57 patients, which may have reduced the reliability and robustness of the analysis. Bone marrow infiltration was not selected as an explanatory variable in the logistic regression analysis due to missing these examination data.\u003c/p\u003e\n\u003cp\u003eIn conclusion, higher corticosteroid doses during the initial administration of obinutuzumab can reduce the incidence of IRRs. Furthermore, it was suggested that dexamethasone may be more effective than hydrocortisone or methylprednisolone, and second-generation histamine 1 receptor antagonists may be more effective than first-generation agents in preventing IRR.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution\u0026nbsp;\u003c/strong\u003eTatsuya Ohtsubo and Kazuhiro Yamamoto were involved in the design of the study. Tatsuya Ohtsubo performed the statistical analysis and was advised by Kazuhiro Yamamoto and Satoshi Dote.\u0026nbsp;Tatsuya Ohtsubo\u0026nbsp;and\u0026nbsp;Saori Matumotoand\u0026nbsp;Kaori Itoand\u0026nbsp;Yuzuka Sasaand\u0026nbsp;Kosuke Tomishimaand\u0026nbsp;Satoshi Doteand\u0026nbsp;Katuya Makiharaand\u0026nbsp;Yoshinori Wakasugiand\u0026nbsp;Tsutomu Mitsuieand\u0026nbsp;Kouhei Yamagiwaand\u0026nbsp;Kazuo Satoand\u0026nbsp;Hiroki Hasegawacollected data.All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003eThis study conformed to the provisions of the Declaration of Helsinki. The Institutional Review Board of Japanese Red Cross Kyoto Daini Hospital approved the study protocol (Approval No. S2021-25)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003eA summary of the study and consent to publication were declared available so that each participant could refuse to participate in the study at any time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analyzed during the current study are available from the first author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e All authors have reviewed and approved the final version of the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e There are no conflicts of interest to disclose in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMarcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněn\u0026yacute; M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W (2017) Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377:1331\u0026ndash;1344\u003c/li\u003e\n\u003cli\u003eNational Comprehensive Cancer Network Inc (2024) NCCN Clinical Practices in Oncology; B-Cell Lymphomas-Verssion2; 2024 April 30, 2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Date accessed: July 17, 2024.\u003c/li\u003e\n\u003cli\u003eCheson BD, Chua N, Mayer J, Dueck G, Trněn\u0026yacute; M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben JG, Lennard A, Lugtenburg PJ, Fingerle-Rowson GF, Mattiello F, Knapp A, Sehn LH (2018) Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus Bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol 36:2259\u0026ndash;2266\u003c/li\u003e\n\u003cli\u003eFood \u0026amp; Drug Administration. Drugs @FDA: FDA-Approved Drugs. obinutuzumab drug label. November, 2013. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125486s034lbl.pdf. Date accessed: July 17, 2024.\u003c/li\u003e\n\u003cli\u003eEuropean Medical Agency. Drugs @EMA: EMA-Approved Drugs. obinutuzumab drug label. July, 2014. Available from: https://www.ema.europa.eu/en/documents/product-information/gazyvaro-epar-product-information_en.pdf. Date accessed: July 17, 2024.\u003c/li\u003e\n\u003cli\u003eLiu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, Brown JP, Cohen A, Kim H (2013) A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 9:30\u003c/li\u003e\n\u003cli\u003eHayama T, Miura K, Uchiike A, Nakagawa M, D Tsutsumi, Sakagami M, Yoshida Y, Takei M (2017) A clinical prediction model for infusion-related reactions to rituximab in patients with B cell lymphomas. Int J Clin Pharm 39:380\u0026ndash;385\u003c/li\u003e\n\u003cli\u003eTachi T, Yasuda M, Usui K, Umeda M, Nagaya K, Osawa T, Ichihashi A, Noguchi Y, Goto H, Kasahara S, Takahashi T, Goto C, Teramachi H (2015) Risk factors for developing infusion reaction after rituximab administration in patients with B-cell non-Hodgkin\u0026rsquo;s lymphoma. Pharmazie 70:674\u0026ndash;677\u003c/li\u003e\n\u003cli\u003eHong J, Kim JY, Ahn HK, Lee SM, Sym SJ, Park J, Cho EK, Ahn JY, Park S, Lee SP, Shin DB, Lee JH (2013) Bone marrow involvement is predictive of infusion related reaction during rituximab administration in patients with B cell lymphoma. Support Care Cancer 21:1145\u0026ndash;1152\u003c/li\u003e\n\u003cli\u003eGoto E, Hata T, Nishihara M, Neo M, Iwamoto M, Kimura K, Goto M, Rikitake Y (2023) Preventive effect of dexamethasone premedication on the development of infusion-related reaction in breast cancer patients receiving trastuzumab. Br J Clin Pharmacol 89:2102\u0026ndash;2112\u003c/li\u003e\n\u003cli\u003eFreeman CL, Morschhauser F, Sehn L, Dixon M, Houghton R, Lamy T, Fingerle-Rowson G, Wassner-Fritsch E, Gribben JG, Hallek M, Salles G, Cartron G (2015) Cytokine release in patients with CLL treated with obinutuzumab and possible relationship with infusion-related reactions. Blood 126: 2646\u0026ndash;2649\u003c/li\u003e\n\u003cli\u003eMasamoto Y, Taoka K, Maki H, Kurokawa M (2022) Bone marrow involvement is a risk factor for infusion-realated reactions in patients with follicular lymphoma treated by obinutuzumab,Annals of Hematology. Ann Hematol 101:2795\u0026ndash;2797\u003c/li\u003e\n\u003cli\u003eVaris T, Kivist\u0026ouml; KT, Backman JT, Neuvonen PJ (2000) The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect Clin Pharmacol Ther 68:487\u0026ndash;494\u003c/li\u003e\n\u003cli\u003eFouda GE, Bavbek S (2020) Rituximab hypersensitivity; from clinical presentation to management. Front Pharmacol 11:572863\u003c/li\u003e\n\u003cli\u003eBrennan PJ, Rodriguez Bouza TR, Hsu FI, Sloane DE, Castells MC (2009) Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol 124:1259\u0026ndash;1266\u003c/li\u003e\n\u003cli\u003eGalv\u0026atilde;o VR, Castells MC (2015) Hypersensitivity to biological agents\u0026mdash;Updated diagnosis, management, and treatment. J Allergy Clin Immunol Pract 3:175\u0026ndash;185\u003c/li\u003e\n\u003cli\u003eKamm GL, Hagmeyer KO (1999) Allergic-type reactions to corticosteroids, Ann Pharmacother 33:451\u0026ndash;460\u003c/li\u003e\n\u003cli\u003eMatsui N, Ishihara N, Mochizuki Y, Tamaki H, Nishimura N, Naora K (2019) Inhibitory effect on rituximab-induced infusion reaction by premedication with fexofenadine or Bepotastine. Jpn J Pharm Health Care Sci 45:396\u0026ndash;403\u003c/li\u003e\n\u003cli\u003eDurham CG, Thotakura D, Sager L, Foster J, Herrington JD (2019) Cetirizine versus diphenhydramine in the prevention of chemotherapy-related hypersensitivity reactions. J Oncol Pharm Pract 25:1396\u0026ndash;1401\u003c/li\u003e\n\u003cli\u003eKitahiro Y, Yamamoto K, Yakushijin K, Ioroi T, Tanda M, Itohara K, Omura T, Minami H, Yano I (2024) The Efficacy of Bepotastine Besilate Compared With Hydroxyzine Pamoate for Preventing Infusion Reactions to the First Dose of Rituximab in Patients With Non-Hodgkin Lymphoma: Protocol for a Phase II, Double-Blind, Multicenter Randomized Trial. JMIR Res Protoc 13:e54882\u003c/li\u003e\n\u003cli\u003eBrice P, Bastion Y, Lepage E, Brousse N, Ha\u0026iuml;oun C, Moreau P, Straetmans N, Tilly H, Tabah I, Solal-C\u0026eacute;ligny P (1997) Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d\u0026apos;Etude des Lymphomes Folliculaires. Groupe d\u0026rsquo;Etude des Lymphomes de l\u0026rsquo;Adulte. J Clin Oncol 15:1110\u0026ndash;1117\u003c/li\u003e\n\u003cli\u003eKuromatsu M, Kajita T, Taruno M, Nishikawa Y, Akasaka T, Okuno T (2021) Search for risk factors influencing the occurrence of infusion reaction after initial treatment with obinutuzumab. Jpn J Pharm Health Care Sci 47:631\u0026ndash;638\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4883642/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4883642/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePremedication with corticosteroids is \u0026nbsp;recommended for prophylaxis against infusion-related reactions (IRRs) caused \u0026nbsp;by obinutuzumab despite a lack of solid evidence regarding the dose of \u0026nbsp;corticosteroids.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe investigated the incidence of IRRs in the high-dose (patients who received 100 mg or higher of prednisolone, 80 mg or higher of methylprednisolone, or 16.5 mg or higher of dexamethasone) and low-dose (patients who received a dose lower than that in those groups or those who take hydrocortisone) corticosteroid groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence of IRRs in the high-dose and low-dose corticosteroid groups at the initial administration of obinutuzumab was 27.0% (41/152) and 48.4% (31/64), respectively, indicating that the high-dose group had a lower incidence of IRRs (\u003cem\u003ep \u003c/em\u003e= 0.002). The incidence of IRRs at the initial administration of obinutuzumab was significantly associated with the administration of first-generation histamine 1 receptor antagonist (odds ratio = 3.70, 95% confidence interval: 1.47–9.28; reference: second-generation histamine 1 receptor antagonist), hydrocortisone (odds ratio = 6.49, 95% confidence interval: 1.53–27.46; reference: dexamethasone), and methylprednisolone (odds ratio = 1.38, 95% confidence interval:1.10–12.16; reference: dexamethasone), although no association was found with the lower dose of corticosteroids.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHigher doses of corticosteroids as premedication can reduce the incidence of IRRs by obinutuzumab than lower doses. Dexamethasone may be a better choice for IRRs prophylaxis rather than hydrocortisone or methylprednisolone, and second-generation histamine 1 receptor antagonists may be a better choice rather than first-generation drugs.\u003c/p\u003e","manuscriptTitle":"Association between the incidence of infusion-related reactions by obinutuzumab and the dose of corticosteroid as premedication: A multicenter retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-10 09:36:46","doi":"10.21203/rs.3.rs-4883642/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"83c22133-71a2-4a79-a2a7-d5af2b704f5e","owner":[],"postedDate":"September 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-22T10:38:10+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-10 09:36:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4883642","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4883642","identity":"rs-4883642","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}