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      Characteristics of pulmonary complications in non-Hodgkin’s lymphoma patients treated with rituximab-containing chemotherapy and impact on survival

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          Abstract

          Patients with non-Hodgkin’s lymphoma (NHL) receiving rituximab-containing chemotherapy are at risk of developing respiratory complications, but comprehensive information on these complications and their impact on survival is lacking. We performed a retrospective cohort analysis on 123 NHL patients who received rituximab-containing chemotherapy between 2009 and 2016 in order to describe the incidence, etiologies and effect on survival of respiratory complications defined by new or worsening respiratory symptoms requiring diagnostic work-up or hospitalization. Thirty patients (24%) developed respiratory complications during a follow-up time of 825 (555–1338) days after chemotherapy. They had a higher prevalence of congestive heart failure and lung or pleural involvement at diagnosis as compared to patients who did not develop complications. Overall, 58 episodes of pulmonary complications were observed after median (interquartile) times from the first and last rituximab doses of 205 (75–580) days and 27 (14–163) days respectively. Infectious etiologies accounted for 75% of the respiratory complications, followed by heart failure exacerbation, lymphomatous involvement, and ARDS. Two Pneumocystis jirovecii pneumonias were observed, and no complication was ascribed to rituximab toxicity. Respiratory complications required ICU admission in 19 cases (33%) and invasive mechanical ventilation in 14 cases (24%). Using a time-dependent Cox regression analysis, we observed that the occurrence of respiratory complications was associated with a 170% increase in death hazard (hazard ratio 2.65, 95% CI 1.60–4.40, p = 0.001). In conclusion, respiratory complications in NHL patients receiving chemotherapy are relatively frequent, severe, and mostly infectious and are associated with increased mortality.

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          Most cited references26

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          Rituximab-induced lung disease: A systematic literature review.

          The anti-CD20 antibody rituximab has been reported to induce a heterogeneous spectrum of lung disorders. The aim of the present study was to critically review data on the clinical presentations, causality assessments and management strategies of lung diseases possibly related to rituximab. A systematic literature review was performed on English-language reports in PubMed until September 2008. Cases of lung diseases ascribed to rituximab (n = 45) were identified, with three time-to-onset patterns. The most common presentation was acute/subacute hypoxaemic organising pneumonia (n = 37), starting 2 weeks after the last infusion (often around the fourth cycle) and resolving, in most cases, provided glucocorticoid therapy was given early. Acute respiratory distress syndrome occurred in five patients, within a few hours and usually after the first infusion. In the remaining three patients, macronodular organising pneumonia developed insidiously long after rituximab therapy and responded to steroids. Eight patients died. Based on time to onset, symptoms, and responses to discontinuation and rechallenge with rituximab and other drugs, 13 cases were highly compatible and 32 compatible with rituximab-induced lung disease. Knowledge of these presentations of rituximab-induced lung disease should prove helpful for diagnosis and causality assessment purposes. Time-to-onset data, suggesting different pathogenic mechanisms, support closer clinical and perhaps radiological monitoring between infusions, particularly in patients with a history of reversible respiratory symptoms.
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            Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma.

            To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m2 per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle. The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score > or = 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score > or = 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score > or = 2 warrants further investigation with a randomized study.
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              Validity of the Ann Arbor staging classification for the non-Hodgkin's lymphomas.

              The Ann Arbor staging classification has proved to be valuable for Hodgkin's disease. When proposed in 1971 it was thought that it could also be applied to the non-Hodgkin's lymphomas. The diversity of the non-Hodgkin's groups, the continued evolution of histopathologic classifications, and the great frequency of advanced disease in the lymphocytic subgroups make the Ann Arbor classification of only limited value for the non-Hodgkin's lymphomas.
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                Author and article information

                Contributors
                +(1)/717-531-6984 , avandelouw@hmc.psu.edu
                Journal
                Ann Hematol
                Ann. Hematol
                Annals of Hematology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0939-5555
                1432-0584
                21 July 2018
                2018
                : 97
                : 12
                : 2373-2380
                Affiliations
                [1 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Department of Pharmacy, , Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, ; 500 University Drive, Hershey, PA 17033 USA
                [2 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Department of Public Health Sciences, , Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, ; 500 University Drive, Hershey, PA 17033 USA
                [3 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Division of Pulmonary and Critical Care Medicine, , Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, ; 500 University Drive, Hershey, PA 17033 USA
                Author information
                http://orcid.org/0000-0003-2260-2005
                Article
                3448
                10.1007/s00277-018-3448-9
                7102168
                30030570
                085f531d-5003-493d-9ec8-a4228d7d8e3b
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 8 May 2018
                : 17 July 2018
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Hematology
                lymphoma,respiratory complications,rituximab,mortality
                Hematology
                lymphoma, respiratory complications, rituximab, mortality

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