Greater Toxicity Seen With Obinutuzumab Over Rituximab in Follicular lymphoma

Compared with rituximab (Rituxan), obinutuzumab (Gazyva) is associated with greater toxicity in follicular lymphoma, according to a recent review published in Hematological Oncology. 

Rituximab, a tyle 1 anti CD20 monoclonal antibody (mAB), first became widely available in 2000. In that time, it has improved outcomes for patients with B-cell malignancies significantly increasing the median survival from approximately 10 years to approximately 15 to 20 years. obinutuzumab, a type II anti-CD20 mAB, was developed in response to “rituximab resistance.” It is meant as a second-line option for patients who become refractory to treatment or relapse. In a head to head comparison of the 2 agents in the clinical setting, obinutuzumab was found to significantly delay progression. However, while the safety profile of rituximab is well established, questions remain around how obinutuzumab’s safety profile compares.

The retrospective analysis included 5 trials totaling 4247 participants. However, only 4 trials included toxicity data, bringing the number of evaluable patients down to 3429. Follicular lymphoma patients were included in 2 of the trials, totaling 1351 participants. All studies were conducted between 2009 and 2014 and all lines of therapy were included. The primary end point of the study was the rate of grade 3/4 adverse events (AEs).

The 2 trials that included patients with follicular lymphoma were the 2017 phase 3 GALLIUM trial (NCT01332968) and the 2014 phase 2 GAUSS trial (NCT00576758). In the Gallium trial, both rituximab and obinutuzumab were given in combination with chemotherapy. In the GAUSS trial, they were used as monotherapy.

In the GALLIUM trial 595 patients were assigned to the experimental obinutuzumab arm while 597 were assigned to the control rituximab arm. The rate of grade 3/4 AEs in the experimental arm was 74.6% compared with 67.8% in the control arm. AEs reported in the both the experimental and control arms included infections (20% vs 15%), pneumonia (4.9% vs 4.3%), febrile (6.9% vs 4.8%), neutropenia (45.8% vs 39.5%), anemia (4% vs 21.7%), thrombocytopenia (6% vs 2.7%), and cardiac events (4.4% vs 2%).

In the GAUSS trial, 87 patients were randomized into the experimental obinutuzumab arm and 86 patients were randomized into the control rituximab arm. The rate of grade 3/4 AEs for both arms was 32%. AEs reported in both the experimental and control arms included (3% vs 7%) and neutropenia (3% vs 8%).

An analysis of all studies found that while the point estimate favored increased rates of grade 3/4 infection with obinutuzumab, it was not statistically significant (RR 1.17 [95% CI, 1.0-1.36], 4 trials, 3429 patients. However, obinutuzumab overall was found to associated with a significant increase of grade 3/4 AEs (RR 1.15 [95% CI, 1.09-1.2], 4 trials, 3429 patients) compared to rituximab. Specifically, obinutuzumab showed and increased risk of grade 3/4 thrombocytopenia (RR 2.8 [95% CI, 1.92-4.06], 3 trials, 3256 patients), grade 3/4 infusion related reactions (RR 2.8 [95% CI, 2.16-3.64], 4 trials, 3429 patients), and grade 3/4 cardiac events, (RR 1.65 [95% CI, 1.11-2.46], 3 trials, 3256 patients) (figures 1b-d). Rates of pneumonia were similar between the 2 agents. Additionally, no significant difference in the rate of grade 3/4 anemia (RR 1.13 [95% CI 0.84-1.52], 3 trials, 3256 patients) and grade 3/4 neutropenia (RR 1.01 [95% CI 0.93-1.11] was observed.

The 36-month mortality rate was also found to be similar between the two agents (PR 0.93 [95% CI, 0.78-1.11], 4 studies, 3429 patients). The point estimation for the rate of drug discontinuation due to an AE (RR 1.24 [95% CI, 1.0-1.54], 3 trials, 2,772 patients) was higher for obinutuzumab, but was found to not be statistically significant.

“It has been suggested that differences in efficacy and toxicity may be related to dosing. Patients received obinutuzumab at a dose of 1000 mg, whereas rituximab was given at a dose of 375 mg /m², except for CLL patients, who received 500 mg/m² from cycle 2 forward. Most regimens give three doses of obinutuzumab during the first cycle, as opposed to only one dose of rituximab, resulting in the administration of more antibody, which is of similar molecular weight to rituximab, implying a potential advantage to obinutuzumab in respect to efficacy,” study authors wrote.

^REFERENCE:

^{Amitai I, Grafter-Gvili A, Shargian-Alon L, et al. Obinutuzumab-related adverse events: A systematic review and meta-analysis. Hematol. Oncol. 2021;39(2):215-221 doi: 10.1002/hon.2828.}