Evaluating the efficacy of montelukast in reducing the incidence and severity of monoclonal antibodies-associated infusion reactions (Phase II Study)

Abstract Introduction Monoclonal antibodies (MABs) and antibody-drug conjugates (ADCs) are increasingly utilized in hematology-oncology. However, monoclonal antibody-associated adverse events (MCAAEs) remain a limitation. These reactions persist despite advances in humanization of MABs. Mast cell stabilizers like montelukast (MKA) can reduce the incidence and severity of infusion reactions. A prior study demonstrated that adding MKA to premedication reduced MCAAEs in multiple myeloma patients receiving daratumumab. This finding encouraged off-label use of MKA with other MABs despite the lack of formal evaluation. This phase 2, single-arm study assesses the efficacy of adding oral MKA to premedication in reducing MCAAEs in patients receiving MABs for hematologic or oncologic conditions. Methods This investigator-initiated, single-arm, open-label study was conducted at a single institution and funded by an institutional research grant. Eligible subjects were ≥18 years old, initiating therapy with one of the target MABs (alone or in combination with chemotherapy), able to provide informed consent, tolerate oral MKA, and available for phone follow-up. Key exclusion criteria included treatment for non-hematologic/oncologic indications, intolerance to MKA, or history of depression. MKA is 10 mg given orally at least one hour before MAB infusion, in addition to premedication. The study permitted up to six doses (one per cycle) or until treatment discontinuation. Primary endpoints included infusion duration, frequency, and severity of infusion reactions, need for additional intra-infusion premedication, and post-infusion adverse events within 24 hours. The study initially aimed to enroll 80 subjects over two years (2020–2022), but was terminated early after enrolling 40 subjects due to the COVID-19 pandemic. All 40 subjects were included in this analysis. The study was approved by the Institutional Review Board of Community Medical Center/UCSF Fresno and registered at ClinicalTrials.gov (NCT04198623). Results Among the 40 subjects, 62.5% were female and 62.5% identified as Caucasian. Hispanics/Latinos comprised 27.5%. Seven patients (17.5%) had atopic conditions, and 15 (37.5%) reported medication allergy. The most common diagnosis was diffuse large B-cell lymphoma/Burkitt's lymphoma (30%), followed by multiple myeloma (20%) and acute myeloid leukemia (15%). The remaining patients had marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or autoimmune cytopenias (ITP/AIHA). Mean LDH was within normal limits (182 IU/L; range 99–451). A total of 198 MAB doses administered: Rituximab: 100(50.5%) Daratumumab: 42(21%) Obinutuzumab: 18(9%) Blinatumomab: 18(9%) Gemtuzumab: 14(7%) Elotuzumab: 6(3%) All patients received at least one cycle (Cycle 1), with rituximab being the most frequently used (21 patients). One rituximab patient withdrew early due to the onset of the COVID-19 pandemic and did not receive further cycles. 18 infusion reactions occurred: 14 during Cycle 1 (35%) and 4 during Cycles 2–6 (10%). Of Cycle 1 reactions, most were allergic (75%) and Grade 1–2 in severity (75%). Four patients (10%) experienced Grade 3 reactions during Cycle 1; two resulted in infusion discontinuation, and two were rescheduled. 4 patients had multiple reactions (all in Cycle 1), including two allergic and one cytokine release syndrome. Univariate analysis showed no significant association between infusion reactions and age, gender, ethnicity, LDH, diagnosis, or specific MAB used during Cycle 1. However, a history of medication allergy (p = 0.017) and presence of atopic conditions (p = 0.008) were significantly associated with a higher risk of infusion reactions. In multivariable analysis, both factors remained independently associated with Cycle 1 infusion reactions (p = 0.003). Due to the low number of events, no significant associations were identified for reactions in Cycles 2–6. Compared to published registration trial data for the included MABs, adding MKA was associated with a 43% risk reduction of infusion reactions (p < 0.001). Conclusion 10 mg MKA added to the premedication of MAB infusion is well tolerated and significantly reduces the risk of MCAAEs Patients with a history of atopy or medication allergy are at high risk for infusion reactions during the first cycle of therapy, even with MKA premedication. This subgroup may benefit from closer monitoring and further intervention strategies.