ABSTRACT
Introduction: Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator approved in multiple countries for treatment of adults with relapsing forms of MS (RMS) or moderately to severely active ulcerative colitis. Objective(s): To describe incidence rates (IRs) of treatmentemergent adverse events (TEAEs) in patients with RMS treated with ozanimod 0.92 mg in phase 3 and open-label extension (OLE) trials. Method(s): In phase 3 trials, adults with RMS were randomised to oral ozanimod 0.46 or 0.92 mg/d or intramuscular interferon beta-1a 30 mug/wk for >=12 months (SUNBEAM-NCT02294058) or 24 months (RADIANCE-NCT02047734). Completers were eligible to enrol in the ongoing OLE trial (DAYBREAK-NCT02576717) of ozanimod 0.92 mg/d. IRs and 95% confidence intervals (CI)/1000 person years (PY;100,000 PY for malignancies) were calculated for TEAEs during the pooled phase 3 trials and at yearly intervals during the OLE (2 Feb 2021 cutoff). Result(s): In patients treated with continuous ozanimod 0.92 mg (n=882), the IR [95%CI]/1000 PY decreased over time (from phase 3 to OLE >36 months) for overall TEAEs (896.1 [826.8-971.3] vs 259.1 [180.0-372.8]);infections (300.5 [268.9-335.9] vs 144.9 [109.2-192.3]);opportunistic infections (12.0 [7.4-19.6] vs 4.3 [1.4-13.3]);cardiac disorder TEAEs (22.8 [16.0-32.7] vs 4.2 [1.4-13.0]);and hepatic disorder TEAEs (77.0 [63.1-94.0] vs 15.1 [8.1-28.1]). The most common opportunistic infections in phase 3 trials and the OLE were oral herpes and herpes zoster (including varicella zoster virus). IRs remained relatively stable for serious TEAEs (31.2 [23.0-42.4] vs 30.5 [19.7-47.3]), malignancies (372.2 [120.8-868.5] vs 276.7 [33.5-999.6]/100,000 PY), confirmed macular edema (n/N, 1/882;0.7 [0.1-5.3] vs n/N, 1/687;1.4 [0.2-9.8]), and pulmonary TEAEs (11.3 [6.8-18.7] vs 0.0 [0.0-9.9]). The IR for serious infections remained relatively stable until OLE >36 months, at which time the IR increased (6.7 [3.5-12. 9] vs 9.8 [4.7-20.6]), which may be partially due to the COVID-19 pandemic. The most common serious infections were appendicitis (n/N, 3/882) and pyelonephritis acute (n/N, 1/882) (phase 3), and pneumonia (n/N, 4/762) and coronavirus infection (n/N, 3/762) (OLE). Most coronavirus infections were nonserious (31/34 [91.2%]). Conclusion(s): In this post hoc analysis, IRs of TEAEs in patients with RMS treated with continuous ozanimod 0.92 mg in phase 3 and OLE trials generally declined or remained stable over up to 5 years of observation time.
ABSTRACT
Background Multiple vaccines have been granted emergency use authorization by the Food and Drug Administration against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the currently available vaccines, none have been systematically studied for efficacy or toxicity in patients with immunodeficiency or with immunosuppressed states, such as B cell malignancy. The purpose of the study was to evaluate the immune response to currently available vaccines against COVID-19 in patients with hematologic and solid organ malignancies. Methods This prospective study enrolled 53 patients;12 with CLL, 10 with multiple myeloma (MM), 11 with non-Hodgkin's lymphoma (NHL) and 21 with a solid organ malignancy. Using a quantitative assay, IgG antibodies to SARS-CoV-2 Spike (S) protein, and nucleocapsid (N) protein by enzyme immunoassay were measured at baseline prior to vaccination and at 2 weeks after completion of vaccination. A fourfold increase in IgG was considered a positive response to vaccination. Through a predesigned survey, patients also self-reported side effects from each dose of vaccination. Results Seroconversion with vaccination was seen in 9/10 (90%) patients with MM, 5/12 (41.7%) patients with CLL, 6/11 (54.1%) patients with NHL, and 17/21 (80.9%) patients with solid organ malignancy. Per univariate analysis, CLL (OR 0.23, 95% CI 0.05-0.88;p= 0.033) was associated with lower odds of seroconversion while NHL (OR 0.48, 95% CI 0.12-1.8;p =0.291), MM (OR 5.33, 95% CI 0.61-46.08;p= 0.128) and solid organ malignancy (OR 2.90, 95% CI 0.79-10.64;p= 0.107) were not. Among patients with hematological malignancies, 5/13 (38.3%) patients treated with rituximab and 2/7 (28.5%) patients on immunoglobulin replacement (IgR) therapy responded to vaccination. This corresponded to reduced odds of seroconversion, 0.18 (95% CI 0.047-0.69;p = 0.013) in patients treated with rituximab and 0.14 (95% CI 0.024-0.826;p=0.030) in patients on IgR. Among patients with solid organ malignancies, treatment with chemotherapy (OR 2.05, 95% CI 0.48-8.61;p=0.320), immunotherapy (OR 4.57, 95% CI 0.52-39.9;p=0.169) or endocrine therapy (OR 1.0) did not lower odds of seroconversion with vaccination. Multivariate analysis revealed patients who received rituximab were less likely to respond to vaccination as compared to patients not previously treated with rituximab (OR 0.22, 95% CI 0.05-0.955;p=0.044). Injection site soreness was the most commonly reported side effect. The only severe side effect occurred in a patient with solid organ malignancy who developed Parsonage Turner syndrome. Conclusion Our study, to the best of our knowledge, is the first study comparing pre and post vaccination IgG titers against the SARS-CoV-2 S protein. Majority of patients with MM and solid organ malignancies, including those receiving active treatment, responded adequately to immunization. Patients with CLL appear less likely to respond to vaccination against COVID-19 as compared to patients with NHL, MM or solid organ malignancies. Previous treatment with rituximab was the most significant risk factor for suboptimal response to vaccination, regardless of underlying hematologic malignancy. These data highlight the importance of continuing risk mitigation strategies against COVID-19 in individuals with hematologic malignancy, particularly those with CLL or on treatment with rituximab. Future research is needed to investigate approaches to provide protective IgG against SARS-CoV-2 in this at-risk population. [Formula presented] Disclosures: Mustafa: Genentech: Speakers Bureau;GalaxoSmithKline: Speakers Bureau;CSL Behring: Speakers Bureau;Regeneron: Speakers Bureau;AstraZeneca: Speakers Bureau. Walsh: Janssen: Research Funding;Merck: Research Funding;Pfizer: Research Funding. Jamshed: Takeda: Honoraria.