The significance of thymosin α1 and intravenous immunoglobulin in the prevention of pulmonary adverse events in B-cell lymphoma treated with R-CHOP: A prospective study

The significance of thymosin α1 and intravenous immunoglobulin in the prevention of pulmonary adverse events in B-cell lymphoma treated with R-CHOP: A prospective 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 The significance of thymosin α1 and intravenous immunoglobulin in the prevention of pulmonary adverse events in B-cell lymphoma treated with R-CHOP: A prospective study Prem Raj Shrestha, Kalawati Shrestha, Prajwal Pudasaini, Huawei Weng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9145705/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Rituximab based chemotherapy regimens, particularly R-CHOP, are highly effective for the treatment of B-cell lymphoma (BCL) but are frequently complicated by pulmonary adverse effects (PAEs) that may disrupt therapy and adversely affect outcomes. This prospective study evaluated whether adjunctive thymosin alpha 1 (Thα1) combined with intravenous immunoglobulin (IVIG) reduces RCHOP associated pulmonary toxicity and improves survival. Methods In this prospective cohort study, 379 patients with histologically confirmed BCL and no pre-existing respiratory disease received R-CHOP therapy between February 2008 and October 2019 and had no prior history of respiratory disease. Exclusion criteria were primary pulmonary pathology, significant comorbidities, and pregnancy or lactation. Participants received either standard R‑CHOP alone (n = 164) or R‑CHOP plus adjunctive Thα1‑IVIG (n = 215), initiated 8–10 days after rituximab administration. The primary endpoint was the incidence of PAE. Secondary endpoints included infectious pulmonary events (IP), interstitial pulmonary disease (IPD), and 5‑year event‑free survival (EFS). Multivariable Cox proportional hazards models were used to identify independent risk and protective factors. Results Among 379 patients, the Thα1-IVIG therapy was associated with a significantly lower overall PAE (13.0% vs. 31.7%, P < 0.001) and IP (4.2% vs. 19.5%, P < 0.001), whereas the incidence of IPD was not significantly different (8.8% vs. 12.2%, P = 0.286) between the two groups. Five‑year event-free survival (EFS) was higher in the Thα1‑IVIG group (77.7% vs. 61.0%, P < 0.001). Multivariate modeling identified extra nodal involvement as a risk factor for PAEs (HR = 1.79, 95% CI 1.14–2.82, P = 0.011), and Thα1‑IVIG therapy appeared to be independently protective (HR = 0.40, 95% CI 0.25–0.64, P < 0.001). Conclusion Thα1-IVIG prophylaxis is a safe, and cost-efficient strategy to reduce pulmonary toxicity, improve treatment adherence and improvement EFS in patients receiving R-CHOP. rituximab pulmonary adverse effects thymosin α1 intravenous immunoglobulin event-free survival Figures Figure 1 Background Pulmonary complications are increasingly recognized as clinically significant events in patients receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for non-Hodgkin lymphoma (NHL). Globally, NHL affects approximately 6.7 per 100,000 men and 4.7 per 100,000 women, with B-cell lineage accounting for 85–90% of cases [ 1 – 3 ]. Rituximab-containing regimens, particularly R-CHOP, remain the cornerstone of therapy for CD20-positive B-cell lymphomas (BCL), substantially improving long-term survival [ 4 – 11 ]. Broadly, the utilization of R-CHOP, with or without radiotherapy, has shown effective results in enhancing cure rates for BCL [ 12 – 14 ]. However, the immunosuppressive nature of rituximab increases susceptibility to opportunistic infections such as bacterial, viral, fungal and also triggers hepatitis B virus (HBV) reactivation [ 15 – 23 ]. Pulmonary adverse effects (PAEs) associated with R-CHOP are an increasing clinical concern, with reported incidences ranging from 0.01% to 14.3% depending on patient population and clinical setting [ 15 – 17 , 24 ]. Among these, infectious pulmonary events (IP) are particularly severe, often leading to diagnostic uncertainty, therapeutic delays, and significant morbidity in immunocompromised patients. Among these, infectious pulmonary events (IP) are particularly severe, often leading to diagnostic uncertainty, therapeutic delays, and significant morbidity in immunocompromised patients [ 25 ]. In this context, immunomodulatory interventions aimed at reducing pulmonary toxicity have garnered increasing attention. Thymosin alpha 1 (Thα1) is a synthetic analog of a natural thymic peptide with immunomodulatory properties. It enhances cellular immune responses in immunocompromised states, including severe COVID-19 [ 26 ], individuals facing severe sepsis [ 27 ], severe acute pancreatitis [ 28 ] and has been shown to reduce systemic inflammation and pulmonary toxicity. In oncology, Thα1 functions as an adjuvant therapy in melanoma [ 29 ] and lung cancer [ 30 ], restoring T-cell function and augmenting antitumor immunity. Additionally, when combined with nucleoside analogs, Thα1 improves viral clearance to be an effective therapeutic strategy for patients with chronic hepatitis B [ 31 ] and in combination with intravenous immunoglobulin (IVIG), it offers a dual strategy of active immune modulation and passive immunity. Similarly, Intravenous immunoglobulin (IVIG) provides passive immunity by neutralizing a broad spectrum of antigens and supporting immune function through maintenance of serum antibody levels. It reduces inflammation and toxicity, benefiting patients with pneumonia [ 32 ], HIV-associated chronic inflammatory demyelinating polyneuropathy (HIV-CIDP) [ 33 ], and HIV related co-infections [ 34 ]. IVIG has also been shown to decrease the frequency of recurrent sinopulmonary infections in patients with hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders receiving rituximab [ 35 ], as well as the incidence of pneumonia in individuals with common variable immunodeficiency [ 36 ]. These properties suggest that Thα1 and IVIG may offer a promising approach to reduce pulmonary adverse effects in patients receiving R-CHOP therapy for B-cell lymphomas. Together, Thα1 and IVIG constitute a biologically complementary intervention that engages both cellular and humoral immunity. This study represents the first prospective assessment of their combined application in newly diagnosed B-NHL patients undergoing R-CHOP chemoimmunotherapy and may have the potential to enhance therapeutic adherence and strengthen supportive care frameworks in lymphoma management. Methods Study design and participants This prospective cohort study enrolled previously untreated patients with biopsy-confirmed B-cell lymphoma (BCL) who received CHOP chemotherapy with rituximab between February 2008 and October 2019, coinciding with the onset of the COVID-19 pandemic. Inclusion criteria Eligible patients met the following inclusion criteria: (1) age years; (2) histologically confirmed B-cell lymphoma (BCL) according to the latest World Health Organization (WHO) classification; (3) documentation of CD20 B-cell surface antigen positivity; (4) Eastern Cooperative Oncology Group (ECOG) performance status ; (5) an estimated life expectancy of months; (6) adequate vital organ functions, including hematological, hepatic, and renal parameters; and (7) absence of prior respiratory disease. Exclusion criteria Patients were ineligible for the study if they met any of the following exclusion criteria: (1) primary pulmonary pathology; (2) central nervous system lymphoma; (3) severe comorbidities likely to affect pneumonia risk, pulmonary function, or disease progression, such as chronic obstructive pulmonary disease, congestive heart failure, or pulmonary arterial hypertension; (4) pregnancy or lactation; or (5) known immunodeficiency or HIV seropositivity. Furthermore, Patients who experienced disease progression or required a change in treatment during the study period were excluded from the final analysis. Treatment Patients received four to six cycles of R-CHOP therapy every 21 days. The R-CHOP regimen consisted of cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), vincristine (1.4 mg/m² with a maximum dose of 2 mg), rituximab (375 mg/m²), and prednisolone (60 mg/m² on days 1–5). Participants in the supportive therapy arm voluntarily received adjunctive Thα1-IVIG treatment on an open-label basis. This therapy was initiated 8–10 days after rituximab to correct hypogammaglobulinemia and minimize potential interference with the primary chemotherapy regimen. Thα1(ZADAXIN™, SciClone Pharmaceuticals Inc., Foster City, CA, USA) was administered subcutaneously at 1.6 mg weekly. IVIG was given intravenously at 10 g after each chemotherapy cycle and subsequently once monthly. Thα1 and IVIG therapy commenced during the first cycle of chemotherapy and continued for six months following completion of chemotherapy. All patients received standard antimicrobial prophylaxis, including trimethoprim-sulfamethoxazole, fluconazole, and valacyclovir, beginning with the first cycle of chemotherapy and continuing throughout the treatment period. Outcomes and assessment The primary endpoint of this study was the incidence of pulmonary adverse events (PAEs). Secondary endpoints included the incidence of infectious pulmonary events (IP) and interstitial pulmonary disease (IPD). PAEs were defined as pulmonary toxicities, further classified as either IPD or IPE. Assessments were performed at baseline, after every two cycles of therapy, and at the completion of treatment using 18 F-fluoro-2-deoxy-D-glucose ( 18 FDG) positron emission tomography/computed tomography (PET/CT) scans Additional pulmonary evaluations, including chest X-rays and CT scans, were performed if patients developed symptoms such as cough, dyspnea, or fever. Diagnostic criteria for IPE and IPD followed the Common Terminology Criteria for Adverse Events (CTCAE) guidelines and combined clinical and imaging findings. IPD was diagnosed in patients without pre-existing respiratory conditions who developed non-infectious, hypersensitivity-related respiratory symptoms with shortness of breath, accompanied by diffuse or multifocal ground-glass opacities, intralobular interstitial thickening, or honeycomb-like reticular changes on X-ray, CT, or PET/CT imaging. Symptoms typically resolved following rituximab discontinuation or initiation of corticosteroid therapy. IP was defined by imaging evidence of interstitial or parenchymal infiltrates on PET/CT, CT, or chest X-ray, in conjunction with clinical features such as cough, progressive dyspnea, chest discomfort, crackles or wheezes, fever, and, where available, positive sputum cultures. Chemotherapy disruption was defined as premature cessation of therapy due to PAE or a delay of ≥ 7 days between planned chemotherapy cycles. Event-Free Survival (EFS) was defined as the time from treatment initiation to the occurrence of PAE, disease progression, or death from any cause. The cumulative event rate was defined as the cumulative incidence of PAE from the start of treatment. Data collection Clinical characteristics and risk factors associated with R-CHOP–induced pulmonary adverse events (PAEs) were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, focusing on grade 2–4 toxicities. Demographic information, clinical data, radiographic findings, laboratory results, and pulmonary function tests were systematically collected. Key variables analyzed included sex, age, Ann Arbor stage, International Prognostic Index (IPI), presence of B symptoms, extranodal involvement, number of R-CHOP cycles, and quality-of-life measures. Sputum evaluation and bronchoalveolar lavage were performed to identify bacterial, viral, and fungal pathogens. The mean cumulative dose of rituximab administered was calculated for each participant. Statistical analysis Continuous variables were assessed for normality using the Kolmogorov-Smirnov test. Normally distributed data were reported as means ± standard deviations and analyzed using Student’s t-test, whereas non-normally distributed data were presented as medians (range) and analyzed using the Mann-Whitney U test. Categorical variables were expressed as numbers and percentages and compared using the chi-square test or Fisher’s exact test, as appropriate. Survival analysis was performed using the Kaplan-Meier method, with comparisons made using the log-rank test. The incidence of PAE, IPD, and IP was evaluated through univariable Cox analyses. Variables demonstrating statistical significance at P < 0.05 in univariable analyses were subsequently included in multivariable Cox proportional hazard regression models. Results from the multivariable analyses were expressed as hazard ratios (HR) with corresponding 95% confidence intervals (CI). Statistical significance was determined using Two-sided (except for the chi-square test) P-values < 0.05 were considered statistically significant. All statistical analyses were conducted using SPSS 16.0 (IBM, Armonk, NY, USA). Results Participants Characteristics A total of 379 BCL patients were enrolled (Figure S1), with 215 in the Thα1-IVIG group and 164 in the control group. Baseline characteristics were similar between the two groups, with no significant differences in sex, age, histology, Ann-Arbor stage, International Prognostic Index (IPI) or R-CHOP cycles. However, the control group had a higher proportion of patients presenting with B symptoms (P = 0.008) and extranodal involvement (P = 0.022) (Table 1 ). Table 1: Baseline characteristics of patients with B-cell lymphoma (n=379) Variables Thα1 and IVIG (n=215) Non Thα1 and IVIG (n=164) P Sex 0.748 Male (M) 121 (56.3%) 95 (57.9%) Female (F) 94 (43.7%) 69 (42.1%) Age 0.643 Age 60 years 57 (26.5%) 47 (28.7%) Histology 0.130 Diffuse large B cell lymphoma 178 (82.8%) 146 (89.0%) Follicular lymphoma 26 (12.1%) 9 (5.5%) Gray Zone lymphoma 8 (3.7%) 5 (3.0%) Other B cell lymphoma 3 (1.4%) 4 (2.4%) Ann-Arbor Stages 0.983 I 33 (15.3%) 23 (14.0%) II 65 (30.2%) 49 (29.9%) III 52 (24.2%) 41 (25.0%) IV 65 (30.2%) 51 (31.1%) International Prognostic Index 0.942 Low 121 (56.3%) 92 (56.1%) Low-intermediate 41 (19.1%) 30 (18.3%) High-intermediate 37 (17.2%) 27 (16.5%) High 16 (7.4%) 15 (9.1%) B symptoms 38 (17.7%) 48 (29.3%) 0.008 Extra nodal 81 (37.7%) 81 (49.4%) 0.022 R-CHOP cycles 6 (5, 6) 6 (4, 6) 0.877 Thα1: thymosin α1; IVIG: intravenous immunoglobulin; R-CHOP: Rituximab with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. Incidence of PAE, IPD and IP Among the 379 participants, 80 patients experienced PAE, graded according to the CTCAE v5.0 scale. The distribution of severity was as follows: grade 4 in 12 patients (3.2%), grade 3 in 50 patients (13.2%), and grade 2 in 18 patients (4.7%). The incidence of PAEs was significantly lower in the Thα1–IVIG group compared with the control group (13.0% vs. 31.7%, P < 0.001). Infectious pulmonary events (IP) were observed in 41 patients, with a significantly lower incidence in the Thα1–IVIG group (4.2% vs. 19.5%, P < 0.001) (Table 2 ). Interstitial pulmonary disease (IPD) occurred in 39 patients, with 19 patients (8.8%) in the Thα1–IVIG group and 20 patients (12.2%) in the control group; this difference was not statistically significant (P = 0.286). PAEs generally appeared as delayed complications, most frequently after the fourth chemotherapy cycle, corresponding to a cumulative rituximab dose of approximately 1500 mg/m². Table 2 Incidence of PAE, IPD, IP and other infectious events PAE Thα1 and IVIG (n = 215) Non Thα1 and IVIG (n = 164) P 28 (13.0%) 52 (31.7%) < 0.001 IPD 19 (8.8%) 20 (12.2%) 0.309 IP 9 (4.2%) 32 (19.5%) < 0.001 Sepsis 2 (0.9%) 5 (3.0%) 0.247 Intestinal infection 6 (2.8%) 10 (6.1%) 0.128 Urinary tract infection 3 (1.4%) 4 (2.4%) 0.472 Skin infection 2 (0.9%) 4 (2.4%) 0.409 Stomatitis 26 (12.1%) 31 (18.9%) 0.081 Thα1: thymosin α1; IVIG: intravenous immunoglobulin; PAE: pulmonary adverse effects; IPD: interstitial pulmonary disease; IP: infectious pulmonary events. Radiologic evaluation of the 41 patients with IPE revealed predominantly bilateral lung parenchymal involvement. Microbiological analyses identified bacterial and viral pathogens in 11 cases, prompting initiation of targeted antimicrobial therapy according to standard protocols (Table 3 ). Table 3 Etiologies and treatments of IP Isolated etiology Cultural specimen No. of cases Involved lung parenchyma Treatment Acinetobacter baumannii Sputum 3 Bilateral lung parenchyma Imipenem, fluconazole, piperacillin-tazobactam, panipenem/betamipron, linezolid Mycoplasma pneumonia Blood 1 Bilateral lung parenchyma Cefoperazone sulbactam and vancomycin Candida albicans Sputum 2 Left lower and right upper lobe Imipenem, fluconazole, piperacillin tazobactam, trimethoprim/sulfamethoxazole Streptococcus pneumonia Sputum 2 Bilateral lung parenchyma Azithromycin, voriconazole, meropenem, and moxifloxacin Cytomegalovirus Sputum 1 Bilateral lung parenchyma Valacyclovir, ganciclovir, imipenem, fluconazole, trimethoprim/sulfamethoxazole Cytomegalovirus with Stenotrophomonas maltophilia Blood and sputum (both) 1 Bilateral upper apical lobe and right middle lobe Meropenem, voriconazole, ganciclovir, imipenem-cilastatin sodium hydrate, vancomycin, caspofungin acetate, amphotericin, piperacillin-sulbactam, trimethoprim/sulfamethoxazole Staphylococcus haemolyticus Bronchoalveolar lavage 1 Bilateral lung parenchyma Imipenem, vancomycin, fluconazole, azithromycin, moxifloxacin, trimethoprim/sulfamethoxazole Infectious etiologies were identified and detailed for 11 individual cases. Additionally, the Thα1–IVIG group demonstrated numerically lower rates of other infectious complications compared with the control group, including sepsis (0.9% vs. 3.0%, P = 0.247), gastrointestinal infection (2.8% vs. 6.1%, P = 0.128), urinary tract infection (1.4% vs. 2.4%, P = 0.472), skin infection (0.9% vs. 2.4%, P = 0.409), and stomatitis (12.1% vs. 18.9%, P = 0.081) (Table 2 ). Thα1-IVIG Prophylaxis Tolerability and Adherence Thα1–IVIG prophylaxis was well tolerated, with no treatment-related adverse events reported during the study period. Adherence to both agents remained consistently high, exceeding 95% throughout the observation period, supporting the feasibility and clinical acceptability of this combined prophylactic strategy. EFS Long-term outcomes over five years demonstrated a significantly higher event-free survival (EFS) in the Thα1–IVIG group compared with the control group (77.7% vs. 61.0%; P < 0.001) (Fig. 1 A). This favorable effect was also reflected in the cumulative incidence of primary pulmonary adverse events, which was significantly lower in the Thα1–IVIG group (P < 0.001) (Fig. 1 B). No significant difference was observed in overall survival (OS) between the two groups (P = 0.910) (Fig. 1 C). Chemotherapy adherence and treatment disruptions Chemotherapy disruption occurred in 18 patients (8.4%) in the Thα1–IVIG group, with five cases (2.3%) attributable to IP. In contrast, 40 patients (24.4%) in the control group experienced treatment disruption, 25 of which (15.2%) were associated with IP. Consequently, the Thα1–IVIG group demonstrated significantly lower rates of overall chemotherapy disruption (8.4% vs. 24.4%; P < 0.001) and IP-related disruption (2.3% vs. 15.2%; P < 0.001) compared to the control group. Among the 41 patients who developed IP, 27 (65.9%) resumed R-CHOP therapy after a median treatment delay of 38 days (range, 20–139). Following the re-challenge, IP recurrence was observed in only two patients (7.4%) who completed the six-cycle regimen. Conversely, three patients died from the complication despite the administration of broad-spectrum antimicrobial therapy. Multivariable analysis Univariable and multivariable Cox proportional hazards regression analyses (Table 4 ) were performed to identify independent predictors of progression to PAEs, IPD, and IP. Table 4 Univariable and multivariate Cox analyses in relation with PAE, IPD, and IP Variables Univariable Multivariable HR 95%CI P HR 95%CI P PAE Sex (male vs. female) 1.14 0.73–1.78 0.561 1.11 0.70–1.74 0.663 Age (≥ 60 vs. <60) 1.17 0.72–1.88 0.529 1.16 0.70–1.92 0.558 Ann Arbor Stage (III, IV vs. I, II) 1.37 0.87–2.14 0.171 1.46 0.88–2.42 0.141 International Prognostic Index (3–4 vs. 0–2) 1.13 0.69–1.87 0.628 0.79 0.43–1.44 0.442 B symptoms (yes vs. no) 1.64 1.01–2.68 0.045 1.49 0.89–2.49 0.131 Extra nodal (yes vs. no) 1.82 1.16–2.83 0.009 1.79 1.14–2.82 0.011 Thα1 and IVIG (used vs. not used) 0.37 0.23–0.59 < 0.001 0.40 0.25–0.64 < 0.001 IPD Sex (male vs. female) 1.13 0.60–2.15 0.704 1.10 0.58–2.12 0.765 Age (≥ 60 vs. <60) 1.36 0.70–2.64 0.372 1.32 0.66–2.68 0.434 Ann Arbor Stage (III, IV vs. I, II) 0.75 0.40–1.41 0.371 0.70 0.33–1.48 0.348 International Prognostic Index (3–4 vs. 0–2) 1.07 0.52–2.20 0.864 1.02 0.41–2.55 0.960 B symptoms (yes vs. no) 1.46 0.71–3.03 0.304 1.58 0.73–3.43 0.245 Extra nodal (yes vs. no) 2.36 1.23–4.52 0.010 2.38 1.23–4.61 0.010 Thα1 and IVIG (used vs. not used) 0.65 0.34–1.23 0.186 0.72 0.37–1.40 0.335 IP Sex (male vs. female) 1.15 0.62–2.14 0.66 1.13 0.60–2.12 0.707 Age (≥ 60 vs. <60) 1.00 0.50-2.00 0.995 1.05 0.51–2.17 0.889 Ann Arbor Stage (III, IV vs. I, II) 2.61 1.30–5.25 0.007 3.03 1.43–6.45 0.004 International Prognostic Index (3–4 vs. 0–2) 1.20 0.60–2.39 0.609 0.68 0.30–1.51 0.340 B symptoms (yes vs. no) 1.82 0.94–3.52 0.074 1.40 0.70–2.80 0.344 Extra nodal (yes vs. no) 1.42 0.76–2.64 0.269 1.38 0.73–2.63 0.320 Thα1 and IVIG (used vs. not used) 0.20 0.09–0.41 < 0.001 0.21 0.10–0.44 < 0.001 Thα1: thymosin α1; IVIG: intravenous immunoglobulin; PAE: pulmonary adverse effects IPD: interstitial pulmonary disease; IP: infectious pulmonary events; HR: hazard ratio; CI: confidence interval. In multivariable analyses, extranodal involvement emerged as an independent risk factor for progression to PAE (hazard ratio [HR] = 1.79; 95% confidence interval [CI], 1.14–2.82; P = 0.011). Conversely, Thα1–IVIG prophylaxis was independently associated with a markedly reduced risk of PAE (HR = 0.40; 95% CI, 0.25–0.64; P < 0.001), suggesting a protective effect in this population. For IPD, extranodal involvement remained a significant independent predictor of progression (HR = 2.38; 95% CI, 1.23–4.61; P = 0.010). In the analysis of IP, advanced-stage disease (Ann Arbor Stage III–IV) was strongly associated with increased risk (HR = 3.03; 95% CI, 1.43–6.45; P = 0.004), while Thα1–IVIG prophylaxis conferred substantial protection (HR = 0.21; 95% CI, 0.10–0.44; P < 0.001). Univariable analyses corroborated these findings: Thα1–IVIG prophylaxis was associated with reduced hazards for PAE (HR = 0.37; 95% CI, 0.23–0.59; P < 0.001) and IP (HR = 0.20; 95% CI, 0.09–0.41; P < 0.001). Extranodal involvement also predicted higher risk of IPD progression (HR = 2.36; 95% CI, 1.23–4.52; P = 0.010) in univariable models. No other baseline clinical variables demonstrated statistically significant associations with progression in either univariable or multivariable analyses. Cost-effectiveness analysis Patients receiving Thα1–IVIG prophylaxis incurred significantly lower total medical costs compared with the control group (P < 0.001), primarily attributable to reductions in hospitalization and antibiotic therapy. The incremental cost-effectiveness ratio (ICER) was ¥31,218 (~ $ 4,403) per quality-adjusted life year (QALY) gained. Sensitivity analyses demonstrated that these findings were robust across a range of plausible assumptions, supporting the economic feasibility of Thα1–IVIG as a prophylactic strategy in this patient population. Discussion Rituximab based immunochemotherapy, particularly R-CHOP, has transformed outcomes for patients with B cell lymphoma (BCL), yet pulmonary adverse events and associated infections remain clinically significant complications that can compromise treatment delivery and long-term benefit. In this prospective cohort study, we demonstrate that adjunctive prophylaxis with thymosin alpha 1 (Thα1) combined with intravenous immunoglobulin (IVIG) significantly reduced pulmonary toxicity, lowered rates of chemotherapy disruption, and was associated with improved event free survival. To our knowledge, this is the first prospective study to evaluate the synergistic effects of combined Thα1-IVIG in patients with newly diagnosed B cell lymphoma receiving R-CHOP which suggests that it enhances patient safety, ultimately contributing to improved long-term event-free survival (EFS). Pulmonary toxicity associated with rituximab-based regimens is often delayed and cumulative, frequently emerging after multiple treatment cycles. Consistent with prior observations, pulmonary adverse events in our cohort occurred most commonly after the fourth chemotherapy cycle, corresponding to cumulative rituximab dose exposure of approximately 1500 mg/m², as previously reported by Hadjinicolaou and colleagues [ 37 ]. Importantly, among patients who developed infectious pulmonary events (IP), approximately two-thirds (65.9%) successfully resumed R-CHOP after a median recovery interval of 38 days (range, 20–139 days). This treatment rechallenge was associated with a notably low recurrence rate; only 7.4% of these patients experienced recurrent IP upon completion of the six-cycle regimen. This finding is particularly striking when compared to the approximately 50% recurrence rate reported by Liu and colleagues [ 24 ]. suggesting that Thα1 and IVIG not only mitigate initial pulmonary toxicity but also facilitate safer continuation of immunochemotherapy. Among the 41 IP patients evaluated, 11 had diverse etiologies, resulting in three fatalities despite the administration of broad-spectrum antibiotic treatment. A separate single-center study of rituximab-treated IP patients reported one fatality from secondary infection [ 24 ]. A systematic review by Bitzan et al. [ 38 ] found a mortality rate of 29% (9 out of 31 patients) due to rituximab-associated lung injury, whereas our study's mortality rate was substantially lower at 3.75%. Survivors demonstrated robust treatment responses. Both univariable and multivariable analyses consistently identified extra nodal involvement as an independent predictor of poor outcomes in both PAE and IPD, while the use of Thα1 and IVIG offers a protective effect for both conditions. Notably, extra nodal involvement independently predicted poorer pulmonary outcomes. Our findings support the beneficial effect of Thα1-IVIG on EFS in BCL patients treated with R-CHOP. Unlike prior studies that evaluated IVIG monotherapy, particularly in the context of rituximab induced hypogammaglobulinemia, this study demonstrates the added value of combining active immune modulation with Thα1 and passive immune support via IVIG provides a synergistic effect, significantly reducing pulmonary toxicity. Previous investigations have shown that intravenous immunoglobulin reduces infectious complications within six months of initiation in rituximab treated patients [ 22 ]. For instance, in common variable immunodeficiency, IVIG therapy reduced the incidence of bacterial pneumonia from 84% at baseline to 73% after treatment, representing an absolute reduction of 11% [ 36 ]. Additionally, combining rituximab and IVIG effectively mitigates chronic active antibody-mediated rejection and improves renal allograft survival without significant adverse effects [ 39 ]. Together, confirming that Thα1-IVIG therapy substantially reduces pulmonary complications, particularly pneumonia, in high-risk BCL patients, while maintaining favorable EFS and enhancing quality of life. These findings suggest that Thα1-IVIG could be beneficial with other monoclonal antibodies and other biologic therapy to reduce infections in clinical practice, resulting in significantly lower total medical costs-driven by reduced hospitalization and diminished reliance on antibiotic therapy. Despite these encouraging results, several limitations warrant consideration. The study's non-randomized design and potential selection biases, particularly related to socioeconomic and clinical factors influencing treatment choice. Although baseline characteristics were largely balanced, residual confounding cannot be excluded. In addition, the optimal dosing, timing, and duration of Thα1-IVIG therapy remains to be defined. The absence of correlative biomarker analyses limits mechanistic insight into immune reconstitution and inflammation modulation. Finally, this study was conducted at a single center, which may limit generalizability and further research is needed to define these parameters. To validate these findings and optimize treatment strategies, future randomized controlled trials with separate arms for IVIG monotherapy and combination therapy are essential. Conclusions In this prospective study, combined Thα1–IVIG prophylaxis reduced treatment related pulmonary toxicity, supported chemotherapy continuity, and improved EFS. These findings support immune reconstitution as a scalable strategy to enhance the safety and effectiveness of antibody or biological therapy based and cellular therapies, including CAR T cell treatment, in settings where infectious and pulmonary complications limit therapeutic benefit. Abbreviations R-CHOP: rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone BCL: B-cell lymphoma PAE: pulmonary adverse effects Thα1: Thymosin alpha 1 IVIG: intravenous immunoglobulin IP: infectious pulmonary events IPD: interstitial pulmonary disease EFS: event-free survival NHL: Non-Hodgkin lymphoma CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone HBV: hepatitis B virus HIV-CIDP: human immunodeficiency virus-associated chronic inflammatory demyelinating polyneuropathy ECOG: Eastern Cooperative Oncology Group PET/CT: positron emission tomography/computed tomography IPI: International Prognostic Index Declarations Ethics approval and consent to participate Written informed consent was obtained from all participants prior to enrollment. The study protocol was reviewed and approved by the Ethics Review Committee of the Sun Yat-Sen University Cancer Center, Guangzhou, China, and was conducted in accordance with the principles of the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding Not applicable Author Contribution PRS and KS drafted the primary manuscript. PP, HW, and TYL performed critical revision of the manuscript and assisted in the preparation of the final submission files. All authors read and approved the final version of the manuscript. PRS served as the submitting author. Acknowledgement We extend our sincere gratitude to the esteemed faculty members and staff at the Sun Yat-Sen University Cancer Center and the School of Public Health, Sun Yat-sen University, Guangzhou, PR China, as well as the dedicated team at Civil Service Hospital, Nepal, for their unwavering and continuous support. 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Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, et al. Long-term results of the R-CHOP study in elderly patients with diffuse large B-cell lymphoma. J Clin Oncol. 2005;23:4117–26. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121–7. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP plus rituximab versus CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42. Molina A. A decade of rituximab: improving survival outcomes in non-Hodgkin's lymphoma. Annu Rev Med. 2008;59:237–50. Dotan E, Aggarwal C, Smith MR. Impact of rituximab on treatment of B-cell Non-Hodgkin's Lymphoma. P T. 2010;35:148–57. Lindenmeyer LP, Hegele V, Caregnato JP, Wust D, Grazziotin L, Stoll P. Follow-up of patients receiving rituximab for DLBCL: overview of systematic reviews. Ann Hematol. 2013;92:1451–9. Bienvenu J, Chvetzoff R, Salles G, Balter C, Tilly H, Herbrecht R, et al. TNF-α release is a major event with rituximab treatment. Hematol J. 2001;2:378–84. Chung CH. Managing premedications and reaction risks with monoclonal antibody therapy. Oncologist. 2008;13:725–32. Lota HK, Keir GJ, Hansell DM, Nicholson AG, Maher TM, Wells AU, et al. Rituximab in refractory hypersensitivity pneumonitis. Thorax. 2013;68:780–1. Burton C, Kaczmarski R, Jan-Mohamed R. Interstitial pneumonitis related to rituximab therapy. N Engl J Med. 2003;348:2690–1. Kanelli S, Ansell SM, Habermann TM, Inwards DJ, Tuinstra N, Witzig TE. Rituximab toxicity in patients with blood B-cell lymphocytosis. Leuk Lymphoma. 2001;42:1329–37. Ennishi D, Terui Y, Yokoyama M, Mishima Y, Takahashi S, Takeuchi K, et al. Increased interstitial pneumonia with CHOP plus rituximab. Int J Hematol. 2008;87:393–7. Huang H, Li X, Zhu J, Ye S, Zhang H, Wang W, et al. Entecavir versus lamivudine for HBV reactivation prevention in DLBCL on R-CHOP. JAMA. 2014;312:2521–30. Perosa F, Prete M, Racanelli V, Dammacco F. CD20-depleting therapy in autoimmune diseases. J Intern Med. 2010;267:260–77. Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. B-cell reconstitution after rituximab in RA. Arthritis Rheum. 2006;54:613–20. Casulo C, Maragulia J, Zelenetz AD. Hypogammaglobulinemia with rituximab and IVIG use. Clin Lymphoma Myeloma Leuk. 2013;13:106–11. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in MS. N Engl J Med. 2008;358:676–88. Bow EJ. Infection risk in cancer chemotherapy for lymphoma and solid tumors. J Antimicrob Chemother. 1998;41(Suppl D):1–5. Liu X, Hong XN, Gu YJ, Wang BY, Luo ZG, Cao J. Interstitial pneumonitis during rituximab chemotherapy. Leuk Lymphoma. 2008;49:1778–83. Carratala J, Roson B, Fernandez-Sevilla A, Alcaide F, Gudiol F. Bacteremic pneumonia in neutropenic cancer patients. Arch Intern Med. 1998;158:868–72. Liu Y, Pan Y, Hu Z, Wu M, Wang C, Feng Z, et al. Thymosin α1 reduces mortality in severe COVID-19. Clin Infect Dis. 2020;71:2150–7. Wu J, Zhou L, Liu J, Ma G, Kou Q, He Z, et al. Efficacy of thymosin α1 for severe sepsis. Crit Care. 2013;17:R8. Wang X, Li W, Niu C, Pan L, Li N, Li J. Thymosin α1 improves immunity in severe pancreatitis. Inflammation. 2011;34:198–202. Danielli R, Fonsatti E, Calabro L, Di Giacomo AM, Maio M. Thymosin α1 in melanoma: clinical trials to practice. Ann N Y Acad Sci. 2012;1270:8–12. Wang F, Li B, Fu P, Li Q, Zheng H, Lao X. Modified thymosin α1 in melanoma and lung cancer. Int J Pharm. 2018;547:611–20. Naylor PH, Mutchnick MG. Immunotherapy for hepatitis B: thymosin α1 in DAA era. J Viral Hepat. 2018;25:4–9. Mofenson LM, Yogev R, Korelitz J, Bethel J, Krasinski K, Moye J Jr, et al. Acute pneumonia in HIV-infected children and long-term mortality. Pediatr Infect Dis J. 1998;17:872–80. Malamut R, Leopold N, Parry G. Treatment of HIV-CIDP with IVIG. Neurology. 1992;42:335. Siberry GK, Abzug MJ, Nachman S, Brady MT, Dominguez KL, Handelsman E, et al. Guidelines on HIV OIs in children. Pediatr Infect Dis J. 2013;32(Suppl 2):i–KK4. Compagno N, Cinetto F, Semenzato G, Agostini C. SCIG in lymphoproliferative disorders and secondary hypogammaglobulinemia. Haematologica. 2014;99:1101–6. Busse PJ, Razvi S, Cunningham-Rundles C. IVIG prevents pneumonia in CVID. J Allergy Clin Immunol. 2002;109:1001–4. Hadjinicolaou AV, Nisar MK, Parfrey H, Chilvers ER, Ostor AJ. Non-infectious pulmonary toxicity of rituximab: systematic review. Rheumatology (Oxford). 2012;51:653–62. Bitzan M, Anselmo M, Carpineta L. RALI: pediatric case and literature review. Pediatr Pulmonol. 2009;44:922–34. Chung BH, Kim Y, Jeong HS, Hong YA, Choi BS, Park CW, et al. Outcomes in ABMR with/without rituximab plus IVIG. Transpl Immunol. 2014;31:140–4. 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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-9145705","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":626320975,"identity":"c5349741-4da6-41fa-8c35-6ffc4ba43043","order_by":0,"name":"Prem Raj Shrestha","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYPCCAyCCjYGhAkgxMzcQq4UZqOUMiGYkRQtjG4hDQIu59OGjmyv+3Mnn5z9/7MHPebXR/O1ALT8qtuHUYtmXlnbzbNszy5kzktkNe7cdz51xmLGBsefMbZxaDM7wmN1sbDhsYHCDmU2Cd9ux3AagFmbGNnxa+L/dbPhz2MD+/GE2yb9zjuXOJ6yFh+1mAxvQFoZkNmnehprcDYS0WPawAR3WdthA4kaymbTMsQO5G4FaDuLzizkP8zOww/j7Dz6TfFNTlzvv/OGDD35U4HEYGv8wmDyAUz0WLXX4FI+CUTAKRsEIBQB32l8AdxGGrQAAAABJRU5ErkJggg==","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Prem","middleName":"Raj","lastName":"Shrestha","suffix":""},{"id":626320976,"identity":"40d96f08-130b-413b-8784-1a31eb18a9da","order_by":1,"name":"Kalawati Shrestha","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Kalawati","middleName":"","lastName":"Shrestha","suffix":""},{"id":626320978,"identity":"a6d69d2b-ad46-4de3-8715-2d4a35f2558f","order_by":2,"name":"Prajwal Pudasaini","email":"","orcid":"","institution":"Civil Service Hospital","correspondingAuthor":false,"prefix":"","firstName":"Prajwal","middleName":"","lastName":"Pudasaini","suffix":""},{"id":626320980,"identity":"5626193e-060c-47dc-9d4e-760a2400069b","order_by":3,"name":"Huawei Weng","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Huawei","middleName":"","lastName":"Weng","suffix":""},{"id":626320981,"identity":"ff9fc2f1-cd2e-4bbd-a35d-0d3d88a104e1","order_by":4,"name":"Tongyu Lin","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Tongyu","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2026-03-17 08:10:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9145705/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9145705/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107618739,"identity":"d53f3ca3-1a18-4dbb-a98e-49a9df0999cb","added_by":"auto","created_at":"2026-04-23 09:26:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":345424,"visible":true,"origin":"","legend":"\u003cp\u003eEvent free survival, cumulative event rate and overall survival in the Thα1-IVIG and control group: \u003cstrong\u003e(A) \u003c/strong\u003eEvent free survival: P \u0026lt; 0.001, (\u003cstrong\u003eB) \u003c/strong\u003eCumulative event-free survival: P \u0026lt; 0.001; and \u003cstrong\u003e(C)\u003c/strong\u003e overall survival: P = 0.910.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9145705/v1/e3c949c28c0a75d6f42e3af7.png"},{"id":107618980,"identity":"6d3244a8-6626-4576-a454-9aeaadda5bb1","added_by":"auto","created_at":"2026-04-23 09:26:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":805937,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9145705/v1/3611ef05-f805-4e6e-a3ce-cd60d295a712.pdf"},{"id":107618594,"identity":"0c2c69c1-6492-4a3b-b2fc-bcfaf7ba2f66","added_by":"auto","created_at":"2026-04-23 09:25:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29181,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9145705/v1/f3834f8bee8fd17368fbba07.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The significance of thymosin α1 and intravenous immunoglobulin in the prevention of pulmonary adverse events in B-cell lymphoma treated with R-CHOP: A prospective study","fulltext":[{"header":"Background","content":"\u003cp\u003ePulmonary complications are increasingly recognized as clinically significant events in patients receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for non-Hodgkin lymphoma (NHL). Globally, NHL affects approximately 6.7 per 100,000 men and 4.7 per 100,000 women, with B-cell lineage accounting for 85\u0026ndash;90% of cases [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Rituximab-containing regimens, particularly R-CHOP, remain the cornerstone of therapy for CD20-positive B-cell lymphomas (BCL), substantially improving long-term survival [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Broadly, the utilization of R-CHOP, with or without radiotherapy, has shown effective results in enhancing cure rates for BCL [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the immunosuppressive nature of rituximab increases susceptibility to opportunistic infections such as bacterial, viral, fungal and also triggers hepatitis B virus (HBV) reactivation [\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Pulmonary adverse effects (PAEs) associated with R-CHOP are an increasing clinical concern, with reported incidences ranging from 0.01% to 14.3% depending on patient population and clinical setting [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Among these, infectious pulmonary events (IP) are particularly severe, often leading to diagnostic uncertainty, therapeutic delays, and significant morbidity in immunocompromised patients. Among these, infectious pulmonary events (IP) are particularly severe, often leading to diagnostic uncertainty, therapeutic delays, and significant morbidity in immunocompromised patients [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, immunomodulatory interventions aimed at reducing pulmonary toxicity have garnered increasing attention. Thymosin alpha 1 (Thα1) is a synthetic analog of a natural thymic peptide with immunomodulatory properties. It enhances cellular immune responses in immunocompromised states, including severe COVID-19 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], individuals facing severe sepsis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], severe acute pancreatitis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and has been shown to reduce systemic inflammation and pulmonary toxicity. In oncology, Thα1 functions as an adjuvant therapy in melanoma [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and lung cancer [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], restoring T-cell function and augmenting antitumor immunity. Additionally, when combined with nucleoside analogs, Thα1 improves viral clearance to be an effective therapeutic strategy for patients with chronic hepatitis B [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and in combination with intravenous immunoglobulin (IVIG), it offers a dual strategy of active immune modulation and passive immunity.\u003c/p\u003e \u003cp\u003eSimilarly, Intravenous immunoglobulin (IVIG) provides passive immunity by neutralizing a broad spectrum of antigens and supporting immune function through maintenance of serum antibody levels. It reduces inflammation and toxicity, benefiting patients with pneumonia [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], HIV-associated chronic inflammatory demyelinating polyneuropathy (HIV-CIDP) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], and HIV related co-infections [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. IVIG has also been shown to decrease the frequency of recurrent sinopulmonary infections in patients with hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders receiving rituximab [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], as well as the incidence of pneumonia in individuals with common variable immunodeficiency [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese properties suggest that Thα1 and IVIG may offer a promising approach to reduce pulmonary adverse effects in patients receiving R-CHOP therapy for B-cell lymphomas. Together, Thα1 and IVIG constitute a biologically complementary intervention that engages both cellular and humoral immunity. This study represents the first prospective assessment of their combined application in newly diagnosed B-NHL patients undergoing R-CHOP chemoimmunotherapy and may have the potential to enhance therapeutic adherence and strengthen supportive care frameworks in lymphoma management.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThis prospective cohort study enrolled previously untreated patients with biopsy-confirmed B-cell lymphoma (BCL) who received CHOP chemotherapy with rituximab between February 2008 and October 2019, coinciding with the onset of the COVID-19 pandemic.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInclusion criteria\u003c/h3\u003e\n\u003cp\u003eEligible patients met the following inclusion criteria: (1) age years; (2) histologically confirmed B-cell lymphoma (BCL) according to the latest World Health Organization (WHO) classification; (3) documentation of CD20 B-cell surface antigen positivity; (4) Eastern Cooperative Oncology Group (ECOG) performance status ; (5) an estimated life expectancy of months; (6) adequate vital organ functions, including hematological, hepatic, and renal parameters; and (7) absence of prior respiratory disease.\u003c/p\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003ePatients were ineligible for the study if they met any of the following exclusion criteria: (1) primary pulmonary pathology; (2) central nervous system lymphoma; (3) severe comorbidities likely to affect pneumonia risk, pulmonary function, or disease progression, such as chronic obstructive pulmonary disease, congestive heart failure, or pulmonary arterial hypertension; (4) pregnancy or lactation; or (5) known immunodeficiency or HIV seropositivity. Furthermore, Patients who experienced disease progression or required a change in treatment during the study period were excluded from the final analysis.\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003ePatients received four to six cycles of R-CHOP therapy every 21 days. The R-CHOP regimen consisted of cyclophosphamide (750 mg/m\u0026sup2;), doxorubicin (50 mg/m\u0026sup2;), vincristine (1.4 mg/m\u0026sup2; with a maximum dose of 2 mg), rituximab (375 mg/m\u0026sup2;), and prednisolone (60 mg/m\u0026sup2; on days 1\u0026ndash;5). Participants in the supportive therapy arm voluntarily received adjunctive Thα1-IVIG treatment on an open-label basis. This therapy was initiated 8\u0026ndash;10 days after rituximab to correct hypogammaglobulinemia and minimize potential interference with the primary chemotherapy regimen. Thα1(ZADAXIN\u0026trade;, SciClone Pharmaceuticals Inc., Foster City, CA, USA) was administered subcutaneously at 1.6 mg weekly. IVIG was given intravenously at 10 g after each chemotherapy cycle and subsequently once monthly. Thα1 and IVIG therapy commenced during the first cycle of chemotherapy and continued for six months following completion of chemotherapy. All patients received standard antimicrobial prophylaxis, including trimethoprim-sulfamethoxazole, fluconazole, and valacyclovir, beginning with the first cycle of chemotherapy and continuing throughout the treatment period.\u003c/p\u003e\n\u003ch3\u003eOutcomes and assessment\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of this study was the incidence of pulmonary adverse events (PAEs). Secondary endpoints included the incidence of infectious pulmonary events (IP) and interstitial pulmonary disease (IPD). PAEs were defined as pulmonary toxicities, further classified as either IPD or IPE. Assessments were performed at baseline, after every two cycles of therapy, and at the completion of treatment using \u003csup\u003e18\u003c/sup\u003eF-fluoro-2-deoxy-D-glucose (\u003csup\u003e18\u003c/sup\u003eFDG) positron emission tomography/computed tomography (PET/CT) scans Additional pulmonary evaluations, including chest X-rays and CT scans, were performed if patients developed symptoms such as cough, dyspnea, or fever. Diagnostic criteria for IPE and IPD followed the Common Terminology Criteria for Adverse Events (CTCAE) guidelines and combined clinical and imaging findings.\u003c/p\u003e \u003cp\u003eIPD was diagnosed in patients without pre-existing respiratory conditions who developed non-infectious, hypersensitivity-related respiratory symptoms with shortness of breath, accompanied by diffuse or multifocal ground-glass opacities, intralobular interstitial thickening, or honeycomb-like reticular changes on X-ray, CT, or PET/CT imaging. Symptoms typically resolved following rituximab discontinuation or initiation of corticosteroid therapy.\u003c/p\u003e \u003cp\u003eIP was defined by imaging evidence of interstitial or parenchymal infiltrates on PET/CT, CT, or chest X-ray, in conjunction with clinical features such as cough, progressive dyspnea, chest discomfort, crackles or wheezes, fever, and, where available, positive sputum cultures.\u003c/p\u003e \u003cp\u003eChemotherapy disruption was defined as premature cessation of therapy due to PAE or a delay of \u0026ge;\u0026thinsp;7 days between planned chemotherapy cycles.\u003c/p\u003e \u003cp\u003eEvent-Free Survival (EFS) was defined as the time from treatment initiation to the occurrence of PAE, disease progression, or death from any cause. The cumulative event rate was defined as the cumulative incidence of PAE from the start of treatment.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eClinical characteristics and risk factors associated with R-CHOP\u0026ndash;induced pulmonary adverse events (PAEs) were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, focusing on grade 2\u0026ndash;4 toxicities. Demographic information, clinical data, radiographic findings, laboratory results, and pulmonary function tests were systematically collected. Key variables analyzed included sex, age, Ann Arbor stage, International Prognostic Index (IPI), presence of B symptoms, extranodal involvement, number of R-CHOP cycles, and quality-of-life measures. Sputum evaluation and bronchoalveolar lavage were performed to identify bacterial, viral, and fungal pathogens. The mean cumulative dose of rituximab administered was calculated for each participant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were assessed for normality using the Kolmogorov-Smirnov test. Normally distributed data were reported as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations and analyzed using Student\u0026rsquo;s t-test, whereas non-normally distributed data were presented as medians (range) and analyzed using the Mann-Whitney U test. Categorical variables were expressed as numbers and percentages and compared using the chi-square test or Fisher\u0026rsquo;s exact test, as appropriate.\u003c/p\u003e \u003cp\u003eSurvival analysis was performed using the Kaplan-Meier method, with comparisons made using the log-rank test. The incidence of PAE, IPD, and IP was evaluated through univariable Cox analyses. Variables demonstrating statistical significance at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariable analyses were subsequently included in multivariable Cox proportional hazard regression models.\u003c/p\u003e \u003cp\u003eResults from the multivariable analyses were expressed as hazard ratios (HR) with corresponding 95% confidence intervals (CI). Statistical significance was determined using Two-sided (except for the chi-square test) P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. All statistical analyses were conducted using SPSS 16.0 (IBM, Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eParticipants Characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 379 BCL patients were enrolled (Figure S1), with 215 in the Th\u0026alpha;1-IVIG group and 164 in the control group. Baseline characteristics were similar between the two groups, with no significant differences in sex, age, histology, Ann-Arbor stage, International Prognostic Index (IPI) or R-CHOP cycles. However, the control group had a higher proportion of patients presenting with B symptoms (P\u0026thinsp;=\u0026thinsp;0.008) and extranodal involvement (P\u0026thinsp;=\u0026thinsp;0.022) (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Baseline characteristics of patients with B-cell lymphoma (n=379)\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"569\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 247px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eTh\u0026alpha;1 and IVIG (n=215)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003eNon Th\u0026alpha;1 and IVIG (n=164)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eMale (M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e121 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e95 (57.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eFemale (F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e94 (43.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e69 (42.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.643\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eAge\u0026lt;60 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e158 (73.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e117 (71.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eAge\u003cu\u003e\u0026gt;\u003c/u\u003e60 years\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e57 (26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e47 (28.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.130\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eDiffuse large B cell lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e178 (82.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e146 (89.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eFollicular lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e26 (12.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e9 (5.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eGray Zone lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e8 (3.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e5 (3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eOther B cell lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e3 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e4 (2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eAnn-Arbor Stages\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.983\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e33 (15.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e23 (14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e65 (30.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e49 (29.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e52 (24.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e41 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e65 (30.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e51 (31.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eInternational Prognostic Index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.942\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e121 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e92 (56.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eLow-intermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e41 (19.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e30 (18.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eHigh-intermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e37 (17.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e27 (16.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e16 (7.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e15 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eB symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e38 (17.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e48 (29.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eExtra nodal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e81 (37.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e81 (49.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 247px;\"\u003e\n \u003cp\u003eR-CHOP cycles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e6 (5, 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 145px;\"\u003e\n \u003cp\u003e6 (4, 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e0.877\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eTh\u0026alpha;1: thymosin \u0026alpha;1; IVIG: intravenous immunoglobulin; R-CHOP: Rituximab with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eIncidence of PAE, IPD and IP\u003c/h2\u003e\n \u003cp\u003eAmong the 379 participants, 80 patients experienced PAE, graded according to the CTCAE v5.0 scale. The distribution of severity was as follows: grade 4 in 12 patients (3.2%), grade 3 in 50 patients (13.2%), and grade 2 in 18 patients (4.7%). The incidence of PAEs was significantly lower in the Th\u0026alpha;1\u0026ndash;IVIG group compared with the control group (13.0% vs. 31.7%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n \u003cp\u003eInfectious pulmonary events (IP) were observed in 41 patients, with a significantly lower incidence in the Th\u0026alpha;1\u0026ndash;IVIG group (4.2% vs. 19.5%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Interstitial pulmonary disease (IPD) occurred in 39 patients, with 19 patients (8.8%) in the Th\u0026alpha;1\u0026ndash;IVIG group and 20 patients (12.2%) in the control group; this difference was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.286). PAEs generally appeared as delayed complications, most frequently after the fourth chemotherapy cycle, corresponding to a cumulative rituximab dose of approximately 1500 mg/m\u0026sup2;.\u003c/p\u003e\n \u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eIncidence of PAE, IPD, IP and other infectious events\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003ePAE\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eTh\u0026alpha;1 and IVIG (n\u0026thinsp;=\u0026thinsp;215)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\n \u003cp\u003eNon Th\u0026alpha;1 and IVIG (n\u0026thinsp;=\u0026thinsp;164)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e28 (13.0%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e52 (31.7%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eIPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e19 (8.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e20 (12.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.309\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e9 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e32 (19.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSepsis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e2 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e5 (3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.247\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eIntestinal infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e6 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e10 (6.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.128\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eUrinary tract infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e3 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e4 (2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.472\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSkin infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e2 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e4 (2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.409\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eStomatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\n \u003cp\u003e26 (12.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e31 (18.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eTh\u0026alpha;1: thymosin \u0026alpha;1; IVIG: intravenous immunoglobulin; PAE: pulmonary adverse effects; IPD: interstitial pulmonary disease; IP: infectious pulmonary events.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eRadiologic evaluation of the 41 patients with IPE revealed predominantly bilateral lung parenchymal involvement. Microbiological analyses identified bacterial and viral pathogens in 11 cases, prompting initiation of targeted antimicrobial therapy according to standard protocols (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eEtiologies and treatments of IP\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eIsolated etiology\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eCultural specimen\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eNo. of cases\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eInvolved lung parenchyma\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cem\u003eAcinetobacter baumannii\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eSputum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eBilateral lung parenchyma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eImipenem, fluconazole, piperacillin-tazobactam,\u003c/p\u003e\n \u003cp\u003epanipenem/betamipron, linezolid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cem\u003eMycoplasma pneumonia\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eBlood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eBilateral lung parenchyma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eCefoperazone sulbactam and vancomycin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cem\u003eCandida albicans\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eSputum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eLeft lower and right upper lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eImipenem, fluconazole, piperacillin tazobactam, trimethoprim/sulfamethoxazole\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cem\u003eStreptococcus pneumonia\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eSputum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eBilateral lung parenchyma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eAzithromycin, voriconazole, meropenem, and moxifloxacin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCytomegalovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eSputum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eBilateral lung parenchyma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eValacyclovir, ganciclovir, imipenem, fluconazole, trimethoprim/sulfamethoxazole\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCytomegalovirus with \u003cem\u003eStenotrophomonas maltophilia\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eBlood and sputum (both)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eBilateral upper apical lobe and right middle lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eMeropenem, voriconazole, ganciclovir, imipenem-cilastatin sodium hydrate, vancomycin, caspofungin acetate, amphotericin, piperacillin-sulbactam, trimethoprim/sulfamethoxazole\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cem\u003eStaphylococcus haemolyticus\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eBronchoalveolar lavage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eBilateral lung parenchyma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eImipenem, vancomycin, fluconazole, azithromycin, moxifloxacin,\u003c/p\u003e\n \u003cp\u003etrimethoprim/sulfamethoxazole\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eInfectious etiologies were identified and detailed for 11 individual cases.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eAdditionally, the Th\u0026alpha;1\u0026ndash;IVIG group demonstrated numerically lower rates of other infectious complications compared with the control group, including sepsis (0.9% vs. 3.0%, P\u0026thinsp;=\u0026thinsp;0.247), gastrointestinal infection (2.8% vs. 6.1%, P\u0026thinsp;=\u0026thinsp;0.128), urinary tract infection (1.4% vs. 2.4%, P\u0026thinsp;=\u0026thinsp;0.472), skin infection (0.9% vs. 2.4%, P\u0026thinsp;=\u0026thinsp;0.409), and stomatitis (12.1% vs. 18.9%, P\u0026thinsp;=\u0026thinsp;0.081) (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eTh\u0026alpha;1-IVIG Prophylaxis Tolerability and Adherence\u003c/h2\u003e\n \u003cp\u003eTh\u0026alpha;1\u0026ndash;IVIG prophylaxis was well tolerated, with no treatment-related adverse events reported during the study period. Adherence to both agents remained consistently high, exceeding 95% throughout the observation period, supporting the feasibility and clinical acceptability of this combined prophylactic strategy.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eEFS\u003c/h2\u003e\n \u003cp\u003eLong-term outcomes over five years demonstrated a significantly higher event-free survival (EFS) in the Th\u0026alpha;1\u0026ndash;IVIG group compared with the control group (77.7% vs. 61.0%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig. \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). This favorable effect was also reflected in the cumulative incidence of primary pulmonary adverse events, which was significantly lower in the Th\u0026alpha;1\u0026ndash;IVIG group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig. \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). No significant difference was observed in overall survival (OS) between the two groups (P\u0026thinsp;=\u0026thinsp;0.910) (Fig. \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eChemotherapy adherence and treatment disruptions\u003c/h2\u003e\n \u003cp\u003eChemotherapy disruption occurred in 18 patients (8.4%) in the Th\u0026alpha;1\u0026ndash;IVIG group, with five cases (2.3%) attributable to IP. In contrast, 40 patients (24.4%) in the control group experienced treatment disruption, 25 of which (15.2%) were associated with IP. Consequently, the Th\u0026alpha;1\u0026ndash;IVIG group demonstrated significantly lower rates of overall chemotherapy disruption (8.4% vs. 24.4%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and IP-related disruption (2.3% vs. 15.2%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to the control group.\u003c/p\u003e\n \u003cp\u003eAmong the 41 patients who developed IP, 27 (65.9%) resumed R-CHOP therapy after a median treatment delay of 38 days (range, 20\u0026ndash;139). Following the re-challenge, IP recurrence was observed in only two patients (7.4%) who completed the six-cycle regimen. Conversely, three patients died from the complication despite the administration of broad-spectrum antimicrobial therapy.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eMultivariable analysis\u003c/h2\u003e\n \u003cp\u003eUnivariable and multivariable Cox proportional hazards regression analyses (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) were performed to identify independent predictors of progression to PAEs, IPD, and IP.\u003c/p\u003e\n \u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariable and multivariate Cox analyses in relation with PAE, IPD, and IP\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\n \u003cp\u003eUnivariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\n \u003cp\u003eMultivariable\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003ePAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSex (male vs. female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.73\u0026ndash;1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.561\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.70\u0026ndash;1.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.663\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAge (\u0026ge;\u0026thinsp;60 vs. \u0026lt;60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.72\u0026ndash;1.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.70\u0026ndash;1.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.558\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAnn Arbor Stage (III, IV vs. I, II)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.87\u0026ndash;2.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.88\u0026ndash;2.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eInternational Prognostic Index (3\u0026ndash;4 vs. 0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.69\u0026ndash;1.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.628\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.43\u0026ndash;1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.442\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eB symptoms (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.01\u0026ndash;2.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.89\u0026ndash;2.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eExtra nodal (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.16\u0026ndash;2.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e1.14\u0026ndash;2.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTh\u0026alpha;1 and IVIG (used vs. not used)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.23\u0026ndash;0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.25\u0026ndash;0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eIPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSex (male vs. female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.60\u0026ndash;2.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.704\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.58\u0026ndash;2.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.765\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAge (\u0026ge;\u0026thinsp;60 vs. \u0026lt;60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.70\u0026ndash;2.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.372\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.66\u0026ndash;2.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.434\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAnn Arbor Stage (III, IV vs. I, II)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.40\u0026ndash;1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.371\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.33\u0026ndash;1.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.348\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eInternational Prognostic Index (3\u0026ndash;4 vs. 0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.52\u0026ndash;2.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.864\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.41\u0026ndash;2.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.960\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eB symptoms (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.71\u0026ndash;3.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.304\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.73\u0026ndash;3.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.245\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eExtra nodal (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.23\u0026ndash;4.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e2.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e1.23\u0026ndash;4.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTh\u0026alpha;1 and IVIG (used vs. not used)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.34\u0026ndash;1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.37\u0026ndash;1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.335\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSex (male vs. female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.62\u0026ndash;2.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.60\u0026ndash;2.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.707\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAge (\u0026ge;\u0026thinsp;60 vs. \u0026lt;60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.50-2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.51\u0026ndash;2.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.889\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAnn Arbor Stage (III, IV vs. I, II)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e2.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.30\u0026ndash;5.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e3.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e1.43\u0026ndash;6.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eInternational Prognostic Index (3\u0026ndash;4 vs. 0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.60\u0026ndash;2.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.609\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.30\u0026ndash;1.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.340\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eB symptoms (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.94\u0026ndash;3.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.70\u0026ndash;2.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.344\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eExtra nodal (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.76\u0026ndash;2.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.73\u0026ndash;2.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e0.320\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTh\u0026alpha;1 and IVIG (used vs. not used)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.09\u0026ndash;0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.10\u0026ndash;0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c7\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eTh\u0026alpha;1: thymosin \u0026alpha;1; IVIG: intravenous immunoglobulin; PAE: pulmonary adverse effects IPD: interstitial pulmonary disease; IP: infectious pulmonary events; HR: hazard ratio; CI: confidence interval.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eIn multivariable analyses, extranodal involvement emerged as an independent risk factor for progression to PAE (hazard ratio [HR]\u0026thinsp;=\u0026thinsp;1.79; 95% confidence interval [CI], 1.14\u0026ndash;2.82; P\u0026thinsp;=\u0026thinsp;0.011). Conversely, Th\u0026alpha;1\u0026ndash;IVIG prophylaxis was independently associated with a markedly reduced risk of PAE (HR\u0026thinsp;=\u0026thinsp;0.40; 95% CI, 0.25\u0026ndash;0.64; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), suggesting a protective effect in this population.\u003c/p\u003e\n \u003cp\u003eFor IPD, extranodal involvement remained a significant independent predictor of progression (HR\u0026thinsp;=\u0026thinsp;2.38; 95% CI, 1.23\u0026ndash;4.61; P\u0026thinsp;=\u0026thinsp;0.010). In the analysis of IP, advanced-stage disease (Ann Arbor Stage III\u0026ndash;IV) was strongly associated with increased risk (HR\u0026thinsp;=\u0026thinsp;3.03; 95% CI, 1.43\u0026ndash;6.45; P\u0026thinsp;=\u0026thinsp;0.004), while Th\u0026alpha;1\u0026ndash;IVIG prophylaxis conferred substantial protection (HR\u0026thinsp;=\u0026thinsp;0.21; 95% CI, 0.10\u0026ndash;0.44; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n \u003cp\u003eUnivariable analyses corroborated these findings: Th\u0026alpha;1\u0026ndash;IVIG prophylaxis was associated with reduced hazards for PAE (HR\u0026thinsp;=\u0026thinsp;0.37; 95% CI, 0.23\u0026ndash;0.59; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and IP (HR\u0026thinsp;=\u0026thinsp;0.20; 95% CI, 0.09\u0026ndash;0.41; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Extranodal involvement also predicted higher risk of IPD progression (HR\u0026thinsp;=\u0026thinsp;2.36; 95% CI, 1.23\u0026ndash;4.52; P\u0026thinsp;=\u0026thinsp;0.010) in univariable models. No other baseline clinical variables demonstrated statistically significant associations with progression in either univariable or multivariable analyses.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eCost-effectiveness analysis\u003c/h2\u003e\n \u003cp\u003ePatients receiving Th\u0026alpha;1\u0026ndash;IVIG prophylaxis incurred significantly lower total medical costs compared with the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), primarily attributable to reductions in hospitalization and antibiotic therapy. The incremental cost-effectiveness ratio (ICER) was \u0026yen;31,218 (~\u003cspan\u003e$\u003c/span\u003e4,403) per quality-adjusted life year (QALY) gained. Sensitivity analyses demonstrated that these findings were robust across a range of plausible assumptions, supporting the economic feasibility of Th\u0026alpha;1\u0026ndash;IVIG as a prophylactic strategy in this patient population.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eRituximab based immunochemotherapy, particularly R-CHOP, has transformed outcomes for patients with B cell lymphoma (BCL), yet pulmonary adverse events and associated infections remain clinically significant complications that can compromise treatment delivery and long-term benefit. In this prospective cohort study, we demonstrate that adjunctive prophylaxis with thymosin alpha 1 (Thα1) combined with intravenous immunoglobulin (IVIG) significantly reduced pulmonary toxicity, lowered rates of chemotherapy disruption, and was associated with improved event free survival. To our knowledge, this is the first prospective study to evaluate the synergistic effects of combined Thα1-IVIG in patients with newly diagnosed B cell lymphoma receiving R-CHOP which suggests that it enhances patient safety, ultimately contributing to improved long-term event-free survival (EFS).\u003c/p\u003e \u003cp\u003ePulmonary toxicity associated with rituximab-based regimens is often delayed and cumulative, frequently emerging after multiple treatment cycles. Consistent with prior observations, pulmonary adverse events in our cohort occurred most commonly after the fourth chemotherapy cycle, corresponding to cumulative rituximab dose exposure of approximately 1500 mg/m\u0026sup2;, as previously reported by Hadjinicolaou and colleagues [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Importantly, among patients who developed infectious pulmonary events (IP), approximately two-thirds (65.9%) successfully resumed R-CHOP after a median recovery interval of 38 days (range, 20\u0026ndash;139 days). This treatment rechallenge was associated with a notably low recurrence rate; only 7.4% of these patients experienced recurrent IP upon completion of the six-cycle regimen. This finding is particularly striking when compared to the approximately 50% recurrence rate reported by Liu and colleagues [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. suggesting that Thα1 and IVIG not only mitigate initial pulmonary toxicity but also facilitate safer continuation of immunochemotherapy.\u003c/p\u003e \u003cp\u003eAmong the 41 IP patients evaluated, 11 had diverse etiologies, resulting in three fatalities despite the administration of broad-spectrum antibiotic treatment. A separate single-center study of rituximab-treated IP patients reported one fatality from secondary infection [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. A systematic review by Bitzan et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] found a mortality rate of 29% (9 out of 31 patients) due to rituximab-associated lung injury, whereas our study's mortality rate was substantially lower at 3.75%. Survivors demonstrated robust treatment responses. Both univariable and multivariable analyses consistently identified extra nodal involvement as an independent predictor of poor outcomes in both PAE and IPD, while the use of Thα1 and IVIG offers a protective effect for both conditions. Notably, extra nodal involvement independently predicted poorer pulmonary outcomes.\u003c/p\u003e \u003cp\u003eOur findings support the beneficial effect of Thα1-IVIG on EFS in BCL patients treated with R-CHOP. Unlike prior studies that evaluated IVIG monotherapy, particularly in the context of rituximab induced hypogammaglobulinemia, this study demonstrates the added value of combining active immune modulation with Thα1 and passive immune support via IVIG provides a synergistic effect, significantly reducing pulmonary toxicity. Previous investigations have shown that intravenous immunoglobulin reduces infectious complications within six months of initiation in rituximab treated patients [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. For instance, in common variable immunodeficiency, IVIG therapy reduced the incidence of bacterial pneumonia from 84% at baseline to 73% after treatment, representing an absolute reduction of 11% [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Additionally, combining rituximab and IVIG effectively mitigates chronic active antibody-mediated rejection and improves renal allograft survival without significant adverse effects [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Together, confirming that Thα1-IVIG therapy substantially reduces pulmonary complications, particularly pneumonia, in high-risk BCL patients, while maintaining favorable EFS and enhancing quality of life. These findings suggest that Thα1-IVIG could be beneficial with other monoclonal antibodies and other biologic therapy to reduce infections in clinical practice, resulting in significantly lower total medical costs-driven by reduced hospitalization and diminished reliance on antibiotic therapy.\u003c/p\u003e \u003cp\u003eDespite these encouraging results, several limitations warrant consideration. The study's non-randomized design and potential selection biases, particularly related to socioeconomic and clinical factors influencing treatment choice. Although baseline characteristics were largely balanced, residual confounding cannot be excluded. In addition, the optimal dosing, timing, and duration of Thα1-IVIG therapy remains to be defined. The absence of correlative biomarker analyses limits mechanistic insight into immune reconstitution and inflammation modulation. Finally, this study was conducted at a single center, which may limit generalizability and further research is needed to define these parameters. To validate these findings and optimize treatment strategies, future randomized controlled trials with separate arms for IVIG monotherapy and combination therapy are essential.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this prospective study, combined Thα1\u0026ndash;IVIG prophylaxis reduced treatment related pulmonary toxicity, supported chemotherapy continuity, and improved EFS. These findings support immune reconstitution as a scalable strategy to enhance the safety and effectiveness of antibody or biological therapy based and cellular therapies, including CAR T cell treatment, in settings where infectious and pulmonary complications limit therapeutic benefit.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eR-CHOP: rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone\u003c/p\u003e\n\u003cp\u003eBCL: B-cell lymphoma\u003c/p\u003e\n\u003cp\u003ePAE: pulmonary adverse effects\u003c/p\u003e\n\u003cp\u003eTh\u0026alpha;1: Thymosin alpha 1\u003c/p\u003e\n\u003cp\u003eIVIG: intravenous immunoglobulin\u003c/p\u003e\n\u003cp\u003eIP: infectious pulmonary events\u003c/p\u003e\n\u003cp\u003eIPD: interstitial pulmonary disease\u003c/p\u003e\n\u003cp\u003eEFS: event-free survival\u003c/p\u003e\n\u003cp\u003eNHL: Non-Hodgkin lymphoma\u003c/p\u003e\n\u003cp\u003eCHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone\u003c/p\u003e\n\u003cp\u003eHBV: hepatitis B virus\u003c/p\u003e\n\u003cp\u003eHIV-CIDP: human immunodeficiency virus-associated chronic inflammatory demyelinating polyneuropathy\u003c/p\u003e\n\u003cp\u003eECOG: Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003ePET/CT: positron emission tomography/computed tomography\u003c/p\u003e\n\u003cp\u003eIPI: International Prognostic Index\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from all participants prior to enrollment. The study protocol was reviewed and approved by the Ethics Review Committee of the Sun Yat-Sen University Cancer Center, Guangzhou, China, and was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003ePRS and KS drafted the primary manuscript. PP, HW, and TYL performed critical revision of the manuscript and assisted in the preparation of the final submission files. All authors read and approved the final version of the manuscript. PRS served as the submitting author.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe extend our sincere gratitude to the esteemed faculty members and staff at the Sun Yat-Sen University Cancer Center and the School of Public Health, Sun Yat-sen University, Guangzhou, PR China, as well as the dedicated team at Civil Service Hospital, Nepal, for their unwavering and continuous support.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available on request per institutional policy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBowzyk Al-Naeeb A, Ajithkumar T, Behan S, Hodson DJ. Non-Hodgkin lymphoma. BMJ. 2018;362:k3204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmitage JO, Gascoyne RD, Lunning MA, Cavalli F. Non-Hodgkin lymphoma. 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Arch Intern Med. 1998;158:868\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Pan Y, Hu Z, Wu M, Wang C, Feng Z, et al. Thymosin α1 reduces mortality in severe COVID-19. Clin Infect Dis. 2020;71:2150\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu J, Zhou L, Liu J, Ma G, Kou Q, He Z, et al. Efficacy of thymosin α1 for severe sepsis. Crit Care. 2013;17:R8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Li W, Niu C, Pan L, Li N, Li J. Thymosin α1 improves immunity in severe pancreatitis. Inflammation. 2011;34:198\u0026ndash;202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDanielli R, Fonsatti E, Calabro L, Di Giacomo AM, Maio M. Thymosin α1 in melanoma: clinical trials to practice. Ann N Y Acad Sci. 2012;1270:8\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang F, Li B, Fu P, Li Q, Zheng H, Lao X. Modified thymosin α1 in melanoma and lung cancer. Int J Pharm. 2018;547:611\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaylor PH, Mutchnick MG. Immunotherapy for hepatitis B: thymosin α1 in DAA era. J Viral Hepat. 2018;25:4\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMofenson LM, Yogev R, Korelitz J, Bethel J, Krasinski K, Moye J Jr, et al. Acute pneumonia in HIV-infected children and long-term mortality. Pediatr Infect Dis J. 1998;17:872\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalamut R, Leopold N, Parry G. Treatment of HIV-CIDP with IVIG. Neurology. 1992;42:335.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiberry GK, Abzug MJ, Nachman S, Brady MT, Dominguez KL, Handelsman E, et al. Guidelines on HIV OIs in children. Pediatr Infect Dis J. 2013;32(Suppl 2):i\u0026ndash;KK4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCompagno N, Cinetto F, Semenzato G, Agostini C. SCIG in lymphoproliferative disorders and secondary hypogammaglobulinemia. Haematologica. 2014;99:1101\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBusse PJ, Razvi S, Cunningham-Rundles C. IVIG prevents pneumonia in CVID. J Allergy Clin Immunol. 2002;109:1001\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHadjinicolaou AV, Nisar MK, Parfrey H, Chilvers ER, Ostor AJ. Non-infectious pulmonary toxicity of rituximab: systematic review. Rheumatology (Oxford). 2012;51:653\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBitzan M, Anselmo M, Carpineta L. RALI: pediatric case and literature review. Pediatr Pulmonol. 2009;44:922\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung BH, Kim Y, Jeong HS, Hong YA, Choi BS, Park CW, et al. Outcomes in ABMR with/without rituximab plus IVIG. Transpl Immunol. 2014;31:140\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"rituximab, pulmonary adverse effects, thymosin α1, intravenous immunoglobulin, event-free survival","lastPublishedDoi":"10.21203/rs.3.rs-9145705/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9145705/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRituximab based chemotherapy regimens, particularly R-CHOP, are highly effective for the treatment of B-cell lymphoma (BCL) but are frequently complicated by pulmonary adverse effects (PAEs) that may disrupt therapy and adversely affect outcomes. This prospective study evaluated whether adjunctive thymosin alpha 1 (Thα1) combined with intravenous immunoglobulin (IVIG) reduces RCHOP associated pulmonary toxicity and improves survival.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this prospective cohort study, 379 patients with histologically confirmed BCL and no pre-existing respiratory disease received R-CHOP therapy between February 2008 and October 2019 and had no prior history of respiratory disease. Exclusion criteria were primary pulmonary pathology, significant comorbidities, and pregnancy or lactation. Participants received either standard R‑CHOP alone (n\u0026thinsp;=\u0026thinsp;164) or R‑CHOP plus adjunctive Thα1‑IVIG (n\u0026thinsp;=\u0026thinsp;215), initiated 8\u0026ndash;10 days after rituximab administration. The primary endpoint was the incidence of PAE. Secondary endpoints included infectious pulmonary events (IP), interstitial pulmonary disease (IPD), and 5‑year event‑free survival (EFS). Multivariable Cox proportional hazards models were used to identify independent risk and protective factors.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 379 patients, the Thα1-IVIG therapy was associated with a significantly lower overall PAE (13.0% vs. 31.7%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and IP (4.2% vs. 19.5%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas the incidence of IPD was not significantly different (8.8% vs. 12.2%, P\u0026thinsp;=\u0026thinsp;0.286) between the two groups. Five‑year event-free survival (EFS) was higher in the Thα1‑IVIG group (77.7% vs. 61.0%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Multivariate modeling identified extra nodal involvement as a risk factor for PAEs (HR\u0026thinsp;=\u0026thinsp;1.79, 95% CI 1.14\u0026ndash;2.82, P\u0026thinsp;=\u0026thinsp;0.011), and Thα1‑IVIG therapy appeared to be independently protective (HR\u0026thinsp;=\u0026thinsp;0.40, 95% CI 0.25\u0026ndash;0.64, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThα1-IVIG prophylaxis is a safe, and cost-efficient strategy to reduce pulmonary toxicity, improve treatment adherence and improvement EFS in patients receiving R-CHOP.\u003c/p\u003e","manuscriptTitle":"The significance of thymosin α1 and intravenous immunoglobulin in the prevention of pulmonary adverse events in B-cell lymphoma treated with R-CHOP: A prospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-23 09:24:00","doi":"10.21203/rs.3.rs-9145705/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-04T15:49:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315178980016307974769418914796461667253","date":"2026-04-24T03:28:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-15T08:19:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-18T12:30:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-18T05:47:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-18T05:47:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-03-17T07:23:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9c0b085d-96f4-453b-ab4e-7b995b68c5c3","owner":[],"postedDate":"April 23rd, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-04T15:49:46+00:00","index":75,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-23T09:24:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-23 09:24:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9145705","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9145705","identity":"rs-9145705","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}