Rituximab-induced Interstitial Lung Disease Research Articles

A Novel Nomogram Predicting Rituximab-Associated Interstitial Pneumonia in Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Single-Center

Background: The incidence rate of rituximab-induced interstitial lung disease (RILD) was reported to be 3.7%-16.7%. The onset of RILD was insidious, and the clinical symptoms were atypical. The course of the RILD progressed rapidly without timely treatment. However, there were no models reported to predict the risk of RILD. Herein, we investigated the incidence of RILD in consecutive patients with diffuse large B-cell lymphoma (DLBCL) and its correlation with clinicopathological features, and a novel nomogram was constructed to successfully predict the risk of RILD. Methods: The clinicopathological data of 110 consecutive patients with DLBCL who were treated in the Department of Hematology of Beijing Tongren Hospital from January 2020 to December 2022 were retrospectively collected, and all patients received first-line treatment regimens containing rituximab. The occurrence of interstitial pneumonia was assessed by chest CT or interim PET-CT. Efficacy was assessed according to Lugano criteria, and chi-square test was used to assess the difference in RILD in different characteristic groups. Results: The complete remission rate of 110 patients with DLBCL after treatment was 84.2%. Twenty-one patients (19.1%) developed RILD during treatment, and the median time of occurrence was the 4th cycle（range: 2~8). The median duration of treatment for RILD was 10 days (range: 5~60). Except for 5 patients with no obvious symptoms, all 16 patients received glucocorticoid-containing regimens, and all patients improved after treatment. The incidence of RILD was significantly higher in patients who received liposomal doxorubicin-containing regimens than those treated with adriamycin regimens (29.7% versus 13.7%, P=0.043). Smoking ( P=0.298) and advanced age ( P=0.156) were associated with a high incidence of RILD. Then we developed a RILD risk prediction model according to the risk factors, and the patients were divided into high-risk and low-risk groups, and the incidence of RILD was significantly different between the two groups ( P=0.027). Finally, a novel nomogram related to the occurrence of RILD in DLBCL patients was developed to scientifically and accurately predict the incidence of RILD. Conclusion: Patients with DLBCL should be alert to the occurrence of RILD after chemotherapy with rituximab-containing regimen, especially in smoking and elderly patients, and the prevention and monitoring of RILD should be strengthened after the application of liposomal doxorubicin.

A Case Report on Rituximab-induced Interstitial Lung Disease

A Case Report on Rituximab-induced Interstitial Lung Disease

Rituximab Induced Interstitial Lung Disease Diagnosis, Treatment Outcome, and Risk’s Factor, a Place for Transbronchial Pulmonary Cryobiopsy

Rituximab (RTX) is a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody, approved in late 1998 by the FDA. Effectively used as a single agent or combined with a chemotherapy regimen to treat lymphoma, RTX is a significant step forward in the arsenal treatment of idiopathic thrombocytopenic purpura, systemic lupus erythematous, rheumatoid arthritis, and autoimmune hemolytic anemia. Side effects of RTX are commonly seen during the first infusion in up to 50% of patients and include fever, chills, and rigors. These side effects are generally transient and related to the tumor burden, probably due to a greater degree of complement activation and proinflammatory cytokine release. Severe lung toxicity like cryptogenic organizing pneumonia, pneumonitis, and interstitial lung diseases are infrequent, with most of the knowledge coming from case reports.

Clinical analysis of rituximab-induced interstitial lung disease

Objective: To investigate the clinical characteristics, diagnosis-treatment points and prognosis of rituximab-induced interstitial lung disease (R-ILD), and to improve the recognition of this disease. Methods: The clinical data on 4 cases of R-ILD were analyzed retrospectively, and the related literatures were reviewed. The literature review was carried out respectively in Wanfang Data, CNKI and PubMed by October 2016 with"rituximab"and"interstitial lung disease"or"interstitial pneumonitis"as the search terms. Results: The all 4 patients received chemotherapy including rituximab, had respiratory symptoms after 2 to 5 cycles chemotherapy respectively. The chest computerized tomography findings of all 4 cases showed diffuse ground glass opacities. In all of the patients, the diagnosis of R-ILD was made and glucocorticoids therapy was initiated. After treatment, the clinical symptoms improved promptly and follow-up chest computerized tomography showed pulmonary lesions significantly resolved. Literature review found 48 articles (2 reviews, 6 original articles, 39 case reports and 1 other article) . 50 cases of R-ILD were collected and the chief complaint were dyspnea, cough and fever. The ground-glass pattern on the CT scan of the chest was the important feature of this disease. Therapy included glucocorticoids, discontinuation of rituximab, and any other clinically necessary measures. Conclusions: Rituximab can cause interstitial lung disease. The diagnosis relies on clinical manifestation and radiological findings. The good prognosis depends on prompt discontinuation of rituximab and treatment with glucocorticoids.

Pneumocystis pneumonia versus rituximab-induced interstitial lung disease in lymphoma patients receiving rituximab-containing chemotherapy.

It is difficult to differentiate Pneumocystis pneumonia (PCP) from rituximab-induced interstitial lung disease (RILD) in lymphoma patients with diffuse pulmonary infiltrates who are receiving rituximab-containing chemotherapy. Using a clinical scoring system, we aim to differentiate PCP from RILD who are receiving rituximab-containing chemotherapy. We reviewed the medical records of lymphoma patients who had received rituximab-containing chemotherapy between 2012 and 2015 in a tertiary hospital. Among 613 lymphoma patients receiving rituximab-containing chemotherapy, 97 (16%) had diffuse pulmonary infiltrates. Of these, 16 (16%) with an alternative diagnosis and 22 (23%) with an indeterminate diagnosis were excluded. Finally, 21 (22%) patients were classified as having PCP and the remaining 38 (39%) as having RILD. Fever, short duration of symptoms (≤5 days), systemic inflammatory response syndrome (SIRS), and severe extent of disease on CT scan (>75%) were more common in patients with PCP than in those with RILD. Clinical scores were determined using the following system: SIRS = score 1, symptom duration ≤5 days = score 1, extent of disease on CT >75% = score 4. A score of ≥2 differentiated PCP from RILD with 91% sensitivity (95% CI, 70-99) and 71% specificity (95% CI, 54-84). A clinical scoring system based on presence of SIRS, short duration of symptoms, and severe extent of disease on CT scan appears to be useful in differentiation of PCP from RILD.

TNF-α antagonist may not be suitable for severe rituximab-induced interstitial lung disease.

Rituximab-induced interstitial lung disease (R-ILD) has aroused more concern in recent years. Anti-TNF-α treatment has been suggested for the treatment of severe R-ILD, due to the plausible suggestion that its pathogenesis is related to TNF-α. This commentary aimed to comment on the role of TNF-α antagonists in R-ILD. Although most R-ILD patients respond well to glucocorticoids, other treatment options are needed for patients who are refractory to conventional treatment. Contrary to expectations, the TNF-α antagonist etanercept brought no benefit in R-ILD. Moreover, TNF-α-targeted therapies were reported to induce or exacerbate interstitial lung disease. The role of TNF-α in the pathogenesis of R-ILD is still unclear due to limited studies on its aetiology. Use of TNF-α antagonists in R-ILD is still speculative, as clinical trials do not support its efficacy. What's more, TNF-α antagonists may themselves induce interstitial lung disease with poor prognosis.

Rituximab-induced interstitial lung disease in a patient with follicular lymphoma: A rare case report.

Rituximab is a chimeric monoclonal antibody that targets CD-20 antigen expressed in more than 90% of all B cell non-Hodgkin's lymphoma (NHL). We report a case of 33-year-old female without any comorbidities, newly diagnosed with stage IIIB follicular lymphoma treated with rituximab-based chemotherapy. Patient developed exertional dyspnea and dry cough after the fourth cycle of rituximab-based chemotherapy. Diagnostic high-resolution computed tomography (HRCT) of the lungs revealed bilateral patchy ground glass opacities suggestive of interstitial lung disease (ILD). It was managed successfully with supplemental oxygen and corticosteroids with discontinuation of the Rituximab. Extensive review of the literature did not reveal ample of material on rituximab-induced ILD (RTX-ILD).

Rituximab Induced Interstitial Lung Disease in Patients with Non-Hodgkin’s Lymphoma: A Clinical Study of Six Cases and Review of the Literature

Background. Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. Aim. The aim of this prospective longitudinal study is to describe the clinical presentation, management, and response to rechallenge in patients diagnosed with rituximab induced ILD over a period of one year. Results. Out of sixteen patients with CD20 positive non-Hodgkin’s lymphoma who received rituximab along with standard chemotherapy, six patients developed features suggestive of R-ILD. Four (66.6%) of these patients had diffuse large B cell lymphoma. The median time of presentation of R-ILD was after the 3rd cycle of chemotherapy. Three patients (50%) presented with acute onset of high fever, dyspnea, and dry cough while the remaining three presented with insidious onset of dyspnea and dry cough. An infectious etiology for the respiratory illness was ruled out in all patients with an exhaustive work-up. Four patients (66.6%) responded to corticosteroid treatment and supplemental oxygen. One patient required mechanical ventilation and succumbed to ILD while another required prolonged supplemental oxygen. Two (33.3%) of patients were successfully rechallenged with rituximab under cover of corticosteroids. Conclusions. Rituximab induced lung disease is a rare but potentially fatal pulmonary toxicity which requires a high index of suspicion for early diagnosis and treatment.

Fatal interstitial lung disease induced by rituximab-containing chemotherapy, treatment with TNF-α antagonist and cytokine profiling: a case-report and review of the literature

Rituximab, an anti-CD20 monoclonal antibody, is widely used with good response for the treatment of B-cell lymphoma and various refractory autoimmune diseases. Although rituximab is effective, rare but serious pulmonary adverse reactions have been reported. We report on a case of rituximab-induced life-threatening interstitial lung disease in a patient with diffuse large B-cell lymphoma (DLBCL), and describe the patient's serum cytokine profile during anti-TNF-α treatment. A 71-year-old woman diagnosed with DLBCL was treated with three cycles of rituximab-containing chemotherapy. She developed a fatal respiratory failure, which was eventually diagnosed as rituximab-induced interstitial lung disease (R-ILD). The R-ILD in this patient did not respond to intensive steroid treatment, or to enternacept, an anti-TNF therapy. During therapy, we observed that the serum level of IL-6 was much higher at the beginning of treatment than was usual for other DLBCL patients. Levels of IL-6 and TNF-α also increased during the course of the clinical exacerbation. We undertook a literature search and reviewed similar cases of R-ILD. Although rituximab is generally effective and safe, caution is required for high-risk patients, as in our case, and as reported in several other cases in the literature. Cytokine analysis may help in identifying patients at high risk of R-ILD. Better intensive therapeutic approaches other than steroids are required even during the early stages of the complication.

Primary Cutaneous Intravascular Large B-cell Lymphoma Treated with Combination Chemotherapy and Complicated by Rituximab-induced Interstitial Lung Disease

Primary Cutaneous Intravascular Large B-cell Lymphoma Treated with Combination Chemotherapy and Complicated by Rituximab-induced Interstitial Lung Disease

Pulmonary Infiltrates in NHL Patients Receiving Rituximab Combined with Chemotherapy: 18F-Fluorodeoxyglucose Positron Emission Tomography and CT (PET-CT) Analysis and Clinical Correlates.

Abstract 3753Poster Board III-689Pulmonary infiltrates (PIs) detected in non-Hodgkins lymphoma (NHL) patients may present a diagnostic challenge. One possible etiology among patients receiving rituximab combined with chemotherapy is rituximab-induced interstitial lung disease. We studied a historical prospective cohort of consecutive patients with NHL receiving combined immunochemotherapy. This study aimed to characterize PIs by PET-CT imaging in patients with suspected rituximab associated findings and to describe their clinical correlates, including patient characteristics, underlying disease, rituximab dosing schedule and symptoms. Patients with lymphoma who received rituximab combined with chemotherapy between January 2007 and May 2009 at our institute were identified. Patients were included in the study cohort if the first (baseline) rituximab dose was administered during the study period and if they had a CT or a PET-CT scan prior to baseline and at least one PET-CT scan thereafter. All scans were analyzed by two nuclear medicine physicians and a radiologist blinded to diagnoses and treatment. Cases of therapy associated PIs were defined as patients with new or worsening PIs, with either alveolar, interstitial or ground glass appearance, with or without FDG uptake and without clinical evidence for pulmonary infection or active lymphoma. A total of 199 NHL patients were identified, 80 of whom met the pre-specified eligibility criteria. NHL categories included diffuse large B-cell lymphoma (DLBCL) (61%), follicular lymphoma (20%), mantle cell lymphoma (10%), MALT lymphoma (4%) and other/non-specified lymphoma (5%). Lymphoma involved the lungs at baseline in 36 % of the patients. Chemotherapy regimens included RCHOP-21 (60%), RCHOP-14 (29%), RCOP (9%) and RCHOP/RDHAP (3%). Therapy associated PIs were identified in 17 patients (21%), 6 of whom had accompanying symptoms. NHL categories included DLBCL (n=14) and low grade lymphoma (n=3) among PI cases. PIs were detected after an average of 3.8 rituximab cycles (range 2-8) and were described as ground glass (n=11), interstitial (n=5) or alveolar (n=6). Resolution of infiltrates in follow-up scans was detected in 6 of the 17 patients. Pulmonary manifestations included cough (n=5), dyspnea (n=3), fever (n=2) and decreased diffusion capacity on pulmonary function tests (n=3). In 4 patients symptoms resolved after treatment with corticosteroids and/or antibiotics and cessation of rituximab and one patient died shortly after improvement of symptoms. FDG uptake was observed in 9 of the cases with PIs. No association between FDG uptake and patient characteristics or symptoms was identified. The incidence of PIs was higher in patients with lymphoma involving the lungs (40% vs. 10%, p=.0009), in patients with aggressive vs. indolent lymphoma (28% vs. 10%, p= .06), in females vs. males (30% vs. 16%, p = .09) and in patients who received R-CHOP-14 vs. RCHOP-21 (26% vs. 18%, p =.5). Similarly, the incidence of symptomatic PIs was higher in patients with lymphoma involving the lungs (17.2% vs. 2.0%, p=.02), in patients who received RCHOP-14 vs. RCHOP-21 (17.0% vs 4.0% p=.07) and in females vs. males (10.8% vs. 4.7%, p= .09). In conclusion, therapy associated PIs were not a rare phenomenon in a cohort of NHL patients treated with rituximab/chemotherapy regimens, accompanying symptoms occurred in a third of them and FDG uptake was noted in over a half. PIs were more common in patients with lymphoma involving the lung, possibly due to targeted activity of rituximab in the affected lungs. Patients receiving RCHOP-14 and those with aggressive lymphoma were more prone to develop PIs. Further prospective studies are required to establish the role of rituximab, to compare between symptomatic and asymptomatic cases and to define independent risk factors. Therapy related PIs should be considered in NHL patients receiving combined rituximab and chemotherapy, especially in those developing PIs in association with the relevant predisposing factors. Disclosures:No relevant conflicts of interest to declare.

Rituximab-induced nonspecific interstitial pneumonia like reaction in a patient with idiopathic thrombocytopenic purpura

Rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody, is an effective treatment for haematological autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP). A 72-year-old man was diagnosed with idiopathic thrombocytopenic purpura (ITP). After receiving 4 cycles of rituximab in one month complete response was achieved. However, three weeks after the last infusion he presented to the haematology department with fever, productive cough and dyspnea and severe hypoxemia. HRCT of the thorax revealed patchy areas of ground glass opacities throughout both lungs and small peripheral consolidations were seen. Transbronchial biopsy showed interstitial thickening and type II pneumocyte activation with interstitial pneumonia. Bronchoalveolar lavage showed increased eosinophils. The patient was treated with three pulses of 1 gr iv methylprednisolone and then gradually switched to 15 mg of prednisolone for 3 months. The dyspnea and tachypnea gradually improved, in addition to blood oxygenation and a follow up HRCT 3 months later showed a significant resolution of lesions. Severe lung toxicity like acute respiratory distress syndrome, cryptogenic organizing pneumonia, pneumonitis, and interstitial lung disease are very rare, with most of the knowledge coming from case reports. Rituximab-induced interstitial lung disease (R-ILD) is a rare complication. To the best of our knowledge, 23 cases of R-ILD have been reported in the literature; 22 of them were treated with R-CHOP for NHL and only one was receiving rituximab for ITP. We report the second case to develop this complication for a non-malignant disorder.

Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma

Rituximab is widely used for CD20+ non-Hodgkin lymphoma (NHL). The use of rituximab has been uncommonly associated with pulmonary toxicity. We report here a single institution experience on the clinical characteristics, diagnosis, treatment and outcome of rituximab-induced interstitial lung disease. From May 2007 to February 2008, 107 patients with NHL received rituximab-containing chemotherapy. Among them, nine patients were identified who developed interstitial pneumonitis during rituximab-containing chemotherapy. The median cycles of rituximab prior to presentation was two. Most of the patients manifested with high fever, while some had dyspnea or non-productive cough. Pulmonary diffuse interstitial infiltrations were seen on computed tomography scans of all the patients. Treatment consisted of glucocorticoids with a slow taper and antibiotics against atypical pulmonary pathogens. Eight patients responded to glucocorticoid therapy and recovered, whereas one died of secondary infection. Two of the four patients who were retreated with rituximab had recurrence of interstitial pneumonitis. In conclusion, clinicians should be highly alerted of the possibility of interstitial pneumonitis in NHL patients treated with rituximab-containing regimen. Early recognition, timely establishment of diagnosis and prompt treatment with glucocorticoids in combination with empirical antibiotics are essential for a favourable clinical outcome. Retreatment with rituximab and other cytotoxic agents known to cause pulmonary toxicity should be carefully considered for risk benefit ratio.

6019 POSTER Background and methodology of the ADAGIO study–aprospective, observational, multicenter study to determine the prevalence, predictors, and mediators of non-adherence in patients treated with imatinib

Rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody, is an effective treatment for haematological autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP). A 72-year-old man was diagnosed with idiopathic thrombocytopenic purpura (ITP). After receiving 4 cycles of rituximab in one month complete response was achieved. However, three weeks after the last infusion he presented to the haematology department with fever, productive cough and dyspnea and severe hypoxemia. HRCT of the thorax revealed patchy areas of ground glass opacities throughout both lungs and small peripheral consolidations were seen. Transbronchial biopsy showed interstitial thickening and type II pneumocyte activation with interstitial pneumonia. Bronchoalveolar lavage showed increased eosinophils. The patient was treated with three pulses of 1 gr iv methylprednisolone and then gradually switched to 15 mg of prednisolone for 3 months. The dyspnea and tachypnea gradually improved, in addition to blood oxygenation and a follow up HRCT 3 months later showed a significant resolution of lesions.Severe lung toxicity like acute respiratory distress syndrome, cryptogenic organizing pneumonia, pneumonitis, and interstitial lung disease are very rare, with most of the knowledge coming from case reports. Rituximab-induced interstitial lung disease (R-ILD) is a rare complication. To the best of our knowledge, 23 cases of R-ILD have been reported in the literature; 22 of them were treated with R-CHOP for NHL and only one was receiving rituximab for ITP. We report the second case to develop this complication for a non-malignant disorder.

Rituximab‐induced interstitial lung disease

The aim of this study is to characterize rituximab-induced interstitial lung disease (R-ILD). The information on all reported cases of R-ILD was reviewed. This analysis focused on patient characteristics, underlying disease, rituximab dosing schedule, and R-ILD characteristic-like symptoms, diagnosis, treatment, and outcomes. Sixteen cases of R-ILD, including our two cases, have been reported in the literature. Commonalities include older age, clinical presentation, computerized tomography findings, pulmonary function tests, and biopsy findings. Therapy included corticosteroids and broad spectrum antibiotics. Prognosis has been variable. Patients who worsen despite corticosteroids have a poor outcome. The pathogenesis of R-ILD is largely unknown. Potential explanations for R-ILD may include the induction and release of cytotoxic substances. R-ILD is a rare but potentially fatal pulmonary toxicity due to rituximab. R-ILD should be considered in patients who present with dyspnea, fever, and cough, and there is no clear evidence of infection. Prompt diagnosis and treatment with corticosteroids is essential.

Rituximab Induced Interstitial Lung Disease.

Interstitial lung disease (ILD) secondary to monoclonal antibodies and tyrosine-kinase inhibitors have been reported. However, little is known about rituximab induced ILD. We report two cases of R-ILD.CASE 1: A 63 year-old man with DLBCL presented for cycle 6 of R-CHOP complaining of 10 days of dyspnea and fever. Prior to initiation of therapy, he had a normal lung exam along with computerized tomography (CT) of the chest. After three cycles of R-CHOP, repeat CT scans of the chest revealed a favorable response to treatment and continued disease-free lung fields. He had tachypnea, tachycardia, and a normal lung examination. Pulse oximetry on room air was 76%. A helical CT of the chest demonstrated diffuse bilateral pneumonitis with no evidence of pulmonary embolus. Bronchoscopy with bronchoalveolar lavage and biopsy revealed no infection. Biopsy showed evidence of alveolar damage and interstitial fibrosis. He responded to corticosteroids and was discharged home with supplemental oxygen. Two months later, he did not require supplemental oxygen. A CT scan of the chest showed almost complete resolution of his interstitial disease. Pulmonary function tests revealed a mild restrictive pattern with a severe diffusion defect.CASE 2: A 61 year-old man with DLBCL presented with 3 days of dyspnea, fever and cough. He was on cycle five, day 14 of R-CHOP. Prior to starting therapy, lung examination was normal and a CT of the chest showed no lung abnormalities. He had tachypnea, tachycardia, and inspiratory crackles on lung examination. Arterial blood gas revealed a pO2 of 45 mmHg. He was admitted to the hospital and started on broad spectrum antibiotics and corticosteroids. A helical CT of the chest revealed a diffuse interstitial lung pattern bilaterally consistent with interstitial pneumonitis and no pulmonary embolus. A bronchoscopy with bronchoalveolar lavage showed no infection. A lung biopsy could not be performed because of severe hypoxia. The patient required mechanical ventilation. After one week of intensive treatment the patient expired.DISCUSSION: Respiratory complications of rituximab include increased cough, rhinitis, brochospasm, dyspnea, and sinusitis. However, R-ILD is very rare. The pathogenesis of R-ILD is largely unknown. Potential explanations for R-ILD may include a direct injury to the lung tissues, unlikely, as well as the induction of cytotoxic substances. Rituximab acts by binding CD20+ B cells. Toxicity and efficacy are related to events after binding which include B cell signaling, complement activation, direct apoptosis, and antibody dependent cellular cytotoxicity. Complement activation and cytokine secretion, in particular, seems to be the causative factors in side effects associated with infusion reactions. Because of the increasing use of rituximab for a variety of disorders, it is important to recognize and appropriately treat possible fatal toxicities. Our patients presented with dyspnea and fever. In the absence of an infectious etiology further evaluation with a high-resolution CT scan of the chest or bronchoscopy with BAL and biopsy should be pursued. If evaluation suggests an ILD without clear evidence of infection, corticosteroids should be initiated and further treatment with rituximab discontinued.CONCLUSION: With the increasing use of rituximab and other monoclonal antibodies, clinicians must be aware of this rare but potentially fatal complication.