Successful obinutuzumab administration after rituximab discontinuation due to intolerance in patients with hematologic disorders

TO THE EDITOR:

Rituximab has transformed the treatment of multiple hematologic disorders over the past 2 decades, leading to higher response rates and longer survival; however, drug hypersensitivity reactions (DHRs) including allergies, serum sickness, and infusion reactions remain common.^1,2 DHRs of any grade have been reported to be as high as 77%, and grade 3 or higher DHRs have been reported to occur in ∼0.5% to 10% of patients.^3,4 The rate of rituximab discontinuation because of toxicity has varied across studies.^3,4 DHRs are heterogenous and commonly associated with the first exposure to rituximab. Moderate infusion reactions are generally successfully rechallenged at lower infusion rates. For severe reactions, multiple desensitization protocols have been reported with high rates of success, though some patients have continued intolerance despite these measures. Other patients may be deemed ineligible to rechallenge with rituximab because of the type or severity of the reaction.⁴ 

Rituximab and obinutuzumab both target CD20 and lead to antibody-dependent cellular cytotoxicity and cell death of CD20 expressing B cells.⁵ Although rituximab is a type I chimeric mouse/human monoclonal antibody, obinutuzumab is a humanized type II monoclonal antibody, which replaces the mouse antibody framework with human sequences.^5-7 Humanized type II monoclonal antibodies have been shown to potentially be less immunogenic.^6,7 This could lead to a lower risk of certain DHRs because of lower foreign antigens found in humanized monoclonal antibodies.^6,7 In addition, the correlation of lower DHR with ongoing anti-CD20 therapy is hypothetically due to B-cell depletion from each cycle of anti-CD20 therapy.⁸ Theoretically, cross-reactivity in the form of DHR between anti-CD20 agents could be low because of multiple differences between each drug and previous B-cell depletion, though the practice of obinutuzumab use after rituximab intolerance is limited primarily to case reports and small case series.^9-14 Here, we report our single-center experience using off-label obinutuzumab after rituximab discontinuation from DHR or intolerance among patients with any hematologic disorder.

After the institutional review board authorization from The James Cancer Hospital at The Ohio State University, patients were identified retrospectively, based on the disease state and line of therapy at the time of administration, using an off-label pharmacy database that was used to aid in insurance approval for medications not approved by the US Food and Drug Administration. The study was conducted in accordance with the Declaration of Helsinki. In total, 21 patients from 2015 to 2022 were identified on the basis of their insurance submissions for treatment with obinutuzumab because of rituximab-induced DHR or intolerance. Four patients received insurance denial and did not receive any further anti-CD20–directed therapy. Seventeen patients received insurance approval and were treated with obinutuzumab. Patient characteristics, disease course, responses, and DHRs were assessed. All DHRs to rituximab and obinutuzumab were graded via the common terminology criteria for adverse events version 5.0 classification system, with severe DHR being categorized as a reaction with any grade ≥3. The primary outcome was the successful administration of obinutuzumab without discontinuation because of a DHR.

The median age of the cohort was 65 years (range, 38-81 years; Table 1). All anti-CD20 therapy was lymphoma-directed with the following exceptions: 1 patient with a nonmalignant disease (thrombotic thrombocytopenia purpura), 1 with multiple occurrences of Epstein-Barr virus (EBV) reactivation who required anti-CD20 therapy, and 1 with hairy cell leukemia who was administered with obinutuzumab to treat cold agglutinin hemolysis and thrombocytopenia. The median number of rituximab doses initiated before being discontinued, excluding desensitization infusions, was 2 (range, 1-11). All patients had at least a grade 3 reaction to rituximab, and 5 patients developed a grade 4 reaction, which led to discontinuation. Three patients (18%) were unsuccessfully treated with a rituximab desensitization protocol before obinutuzumab administration (Table 1). The most common type of DHR or reason for intolerance was anaphylaxis or anaphylaxis-like reactions. Serum sickness was observed among 6 patients. Other DHRs or intolerances included severe rash indicative of a true allergy, neurologic toxicity among other symptoms, and debilitating myalgia not formally diagnosed as serum sickness.

After the administration of obinutuzumab, DHRs of any grade occurred among 6 patients (35%). Grade ≥3 DHRs were uncommon, though 2 patients (12%) experienced a severe reaction. One of the grade 3 DHRs with obinutuzumab was an infusion reaction requiring rescue medications and interruption of the infusion; however, the infusion was subsequently completed. The other grade 3 DHR led to the discontinuation of obinutuzumab because of the severity of both the rituximab and obinutuzumab reactions. Overall, administration of obinutuzumab without discontinuation because of DHRs was successful for 16 of 17 patients (94%) including all 3 patients who had not successfully completed rituximab desensitization protocols.

Within the heterogeneous disease states reported in the cohort, responses to obinutuzumab were common. Seven patients had a complete response, 3 had a partial response, 1 had hemoglobin and platelet response for their cold agglutin hemolysis and thrombocytopenia, and 1 was cleared of EBV using polymerase chain reaction after EBV reactivation. Given the heterogeneity of diseases and treatment conditions associated with obinutuzumab use, clinical outcomes were not a primary outcome of this analysis.

The retrospective design and small sample size are limitations of the study. The clinical determination and diagnosis of each allergy and intolerance varied across providers. Although the definitions of DHR and intolerance defined in prospective trials were not identical among treating physicians, this does represent a real-world experience of rituximab DHR and intolerance that is commonly observed in the clinics.

To our knowledge, this is the largest published cohort of patients treated with obinutuzumab after a rituximab DHR or intolerance. Obinutuzumab administration was safe with more than 90% of the patients completing the obinutuzumab infusion. This analysis does not compare the effectiveness of rituximab desensitization with that of obinutuzumab use after rituximab DHR or intolerance. It is important to note that rituximab desensitization can be time-intensive and costly because patients are frequently admitted to the hospital and require direct nursing care during the desensitization procedure. Rituximab desensitization may not be an option for all patients based on the type or severity of the reaction. Here, we report that obinutuzumab use is an acceptable alternative after rituximab DHR or intolerance and can be safe even after failed rituximab desensitization. Further studies with a large cohort of patients are warranted to add to the growing body of evidence that obinutuzumab has low cross-reactivity in the form of DHR toward rituximab.

Contribution: T.S., J.L., T.W., and T.V. contributed to the concept and design of this study and participated in the initial draft of the manuscript; T.S. and A.L. performed the data collection; and all authors read and agreed to the final version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Timothy Schieber, Department of Pharmacy, James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, OH 43210; e-mail: timothy.schieber@osumc.edu.