A Retrospective Study on the Incidence of Rituximab-Related Interstitial Pneumonitis In Patients Undergoing Immunochemotherapy for Non-Hodgkin Lymphoma

Rituximab is a chimeric monoclonal anti-CD20 antibody that is standard of care for the treatment of B-cell non-Hodgkin lymphoma (NHL). Recent small retrospective case series have highlighted interstitial pneumonitis (IP) as a rare but potentially fatal side effect of rituximab but the incidence of pneumotoxicity in the product monograph is reported to be < 0.03%. In clinical practice, it can be difficult to ascertain the cause of IP given that rituximab, cyclophosphamide and G-CSF are all potentially causative agents and infection is an important concern. The primary purpose of this study was to quantify the incidence of rituximab-related IP in patients receiving immunochemotherapy for NHL.

All patients with NHL who received CHOP, CVP, R-CHOP, or R-CVP in Princess Margaret Hospital between January 1, 1999 and August 30, 2009 were retrospectively reviewed with case ascertainment from a pharmacy database as well as a prospectively populated lymphoma database. Treatment was commonly administered as primary therapy. CT scans were typically performed at baseline and at the midpoint and end of treatment. Additional CT scans were performed for clinical indications (fever or pulmonary symptoms) at the discretion of the treating physicians. Patients were excluded if they did not have comparative pre- and post-treatment CT scans, T cell histology, lacked adequate clinical information in their chart, or had received additional concomitant systemic therapy. IP was defined as the appearance of new or worsened ground-glass opaciification or interlobular septal thickening on post-baseline scans, due to any underlying cause. We compared cohorts of patients who did and did not receive rituximab and documented the incidence of IP during and/or post-treatment in both groups. Concomitant G-CSF administration in each group was documented. Additionally, we compared the incidence of documented infectious IP in patients receiving chemotherapy with and without rituximab.

927 patients were reviewed with 464 excluded as per the aforementioned criteria (370 patients did not have adequate serial CT results available, 59 patients had T cell NHL). Of the 462 patients included, the rituximab-chemotherapy group (n=303; R group: R-CHOP or R-CVP) included 68% DLBCL, 16.5% FL and 6% MCL. The chemotherapy alone group (n=159, C group: CHOP or CVP) included 58% DLBCL, 17% FL and 4% MCL. The median age for the entire cohort was 56 (range 16–88) and was similar in both groups. The rate of smoking was similar in both groups (R-group: 30% vs. C-group: 34%, p=0.43) while G-CSF usage was more common in the R group (40.3 vs 29.6%, p=0.02). The rate of pulmonary CT abnormalities in the entire cohort was 18% (84/462) with a rate of 23.8% (72/303) in the R-group and 7.5% (12/159) in the C-group (p=0.0001). The rate of IP in the entire cohort defined by CT criteria was 5.6% (26/462) with a higher rate in the R group (7.3 vs. 2.5%, p=0.03). The cases were equally divided between asymptomatic IP (12 cases in total 3% R-group, 1.9% C-group, p=0.49) and symptomatic IP (14 cases in total, 4.3% R-group, 0.6% C-group, p=0.04). The rate of G-CSF use did not significantly differ between groups (p=0.21). There was not a significant difference in the incidence of IP due to bacterial infection (p=0.1889), PCP (p=0.7921), fungal infection (p=0.6913), or viral infection (p=0.3056) between the R and C groups although the number of proven infectious events were low (19 cases).

The addition of rituximab to CHOP/CVP chemotherapy significantly increases the risk of symptomatic chemotherapy-related interstitial pneumonitis (4.3% vs 0.6%). It does not appear to predispose patients to an increased risk of documented infectious interstitial pneumonitis although these events were rare in this series. Clinicians should monitor patients carefully for this uncommon toxicity as it may impact on the successful delivery of standard treatment. Further data regarding the IP cases are being collected and analyzed for outcome.

Kukreti:Celgene: Honoraria; Ortho Biotech: Honoraria; Roche: Honoraria. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Hoffman Laroche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Genzyme: Honoraria.