Skin test-guided administration of Rituximab to reduce hypersensitivity reactions compared to standard administration in hematological malignancies – An investigator-initiated, randomized, open-label trial

Rituximab is a widely used monoclonal antibody in the treatment of hematological malignancies. However, hypersensitivity reactions (HSRs), particularly during the first infusion, remain a major clinical challenge. These reactions range from mild infusion-related symptoms to severe anaphylaxis. Current strategies to prevent such reactions (such as universal premedication and slow infusion rates) do not account for individual immune sensitivity. This trial aims to evaluate whether a personalized, skin test-guided administration strategy can reduce the incidence and severity of HSRs compared to standard rituximab infusion protocols.

This is an investigator-initiated, open-label, randomized, parallel-group, superiority trial being conducted at JIPMER, Puducherry. Eligible adult patients (aged 18 years and above), naïve to rituximab, and planned for rituximab-based chemotherapy will be randomized in a 1 to 1 ratio into two arms. In the intervention arm (Arm A), all patients will undergo skin prick testing with undiluted rituximab. If negative, intradermal testing will follow in two steps which includes first with 1 mg per mL, and if negative, then with 10 mg per mL.  A positive response is defined as a wheal diameter increase of more than equal to 3 mm. Patients with a positive skin test will receive rituximab via a standardized 12 step desensitization protocol involving three different dilutions. Those with negative tests will receive standard infusion. In the control arm (Arm B), patients will receive rituximab through standard infusion irrespective of skin test results, which are recorded for research purposes only.

All participants will be premedicated and monitored for HSRs using standardized criteria (CTCAE v5.0 and Modified Brown). The primary outcome is the incidence of HSRs during the first rituximab infusion. Secondary outcomes include severity and phenotype of reactions, frequency of infusion interruptions, correlation with serum biomarkers (IL6, tryptase), and the presence of anti-rituximab antibodies. The trial includes screening, informed consent, baseline assessment, intervention, infusion with monitoring, biomarker evaluation, and follow-up through the second cycle.