“One Hour” Rituximab Infusion Is Safe and Improves Patient Care and Outpatient Unit Management.

Background: Administration of the monoclonal anti-CD20 antibody Rituximab has been associated with infusional toxicity, leading to strict guidelines of use, i.e., infusion times from 4 to 6 hours. Even with pretreatment acetaminophen and diphenydramine, grade 3/4 adverse events including bronchospasm and hypotension occur in ~10% of patients with the first, and in < 2% with subsequent infusions. Presence of circulating malignant CD20 bearing cells represents a risk factor for developing grade 3/4 reactions. The pathophysiogy of this infusional toxicity is thought to be a “cytokine release syndrome” occuring within the 2 first hours of infusion. In few cases, it can be related to an anaphylactic reaction, occurring in the first minutes of infusion. Based on these observations and because infusional toxicity may be lower by the concomitant use of steroids, we established new guidelines of rituximab administration based on the number of circulating CD20+ cells, cycle number of the infusion, and allowing a total one-hour infusion time.

Methods: A 1 mg/kg dose of steroids + diphenydramine + acetaminophen were given 20 minutes before each rituximab infusion. Rituximab dose was 375 mg/m2 diluted in 500 ml bottle. In the absence of circulating CD20+ cells, patients received their first course of rituximab according to the standard recommendations (from 50 mg/h and increasing by levels of 50mg/h every 30 min) until the fifth level. Then the remaining dose was administered at 500ml/h, with a total infusion time of ~3 h. The subsequent infusions were given at 100 mg/h for 15 minutes then at 500 ml/h, i.e. in one hour. In case of circulating malignant CD20+ cells, the first rituximab administration was administrated over 2 days: 50mg/m2 in 4h on day 1, and 325mg/m2 on day 2 according to the instructions described above. The subsequent infusions were administered according the one-hour protocol.

Results: 69 patients have been treated in our outpatient unit, according to this protocol, for a total of 115 courses including 21 first cycles. Patients characteristics are as follows: median age 61 (range 26–85); 50% male; histology: 27 DLCBL including (IPI ≤1: 17 patients, IPI ≥2: 10 patients), 22 follicular, 2 mantle cell, 3 marginal zone, 2 lymphoplasmocytic, 1 Castelman disease, 11 CLL and 1 idiopathic thrombopenic purpura; treatment: R-CHOP in 51 patients, R-fludarabine/cytoxan in 15, R-chlorambucil in 1 and Rituximab alone in 2. Among the 21 first courses treatment was R-CHOP in 13, R- fludarabine/cytoxan in 3 and Rituximab in 5. No grade 3/4 toxicity was noted neither during the first nor the subsequent cycles. During the first infusion 2 patients developed grade 2, and 3 developed grade 1 reactions. One CLL patient had a grade 1 reaction after the second cycle.

Conclusions: Taking into account the presence of circulating malignant CD20+ cells, a 3h first and one-hour subsequent infusion protocol is safe and well tolerated, independently of diagnosis and chemotherapy regimen. This protocol allows a sparing of 2 to 4 hours treatment time, very convenient for patients and in outpatient unit management.