Do Monoclonal Antibody Therapies Improve 'Real-World' Outcomes of COVID-19 in Patients with Lymphoid Malignancies? the UT Southwestern Experience

BACKGROUND: Patients with lymphoid malignancies are highly susceptible to COVID-19 infection with higher risk of complications and mortality. They have suboptimal humoral responses to vaccination underscoring the need for additional therapies, including pre- and post-exposure prophylaxis, to attenuate progression to severe COVID-19. The FDA has approved anti-SARS-CoV2-monoclonal antibodies (mAbs), casirivimab/imdevimab, bamlanivimab, sotrovimab, and bebtelovimab for treating mild/moderate COVID-19 infection and tixagevimab + cilgavimab (evusheld) for pre-exposure prophylaxis. The effectiveness of several mAbs has been compromised by the emergence of viral spike protein mutations and genetic variants. We aim to study the 'real-world' impact of mAbs on COVID-19-related outcomes among patients with lymphoid malignancies.

METHODS: In this IRB-approved study, we analyzed patients with lymphoid malignancies who received mAbs either for prophylaxis or treatment for COVID-19 at UT Southwestern Medical Center from December 2020 to July 2022. We gathered data on patient demographics, underlying malignancy, vaccination history, type of monoclonal antibody received, post mAb infusion adverse events, breakthrough infections and clinical outcomes related to COVID-19. We also studied the humoral responses in a subset of patients pre- and post-evusheld by measuring spike specific IgG (IgGSP) and IgG specific to nucleocapsid (IgGNC) levels in plasma samples. An IgGNC index value of 1.4 and above indicates recent infection or exposure. In the absence of IgGNC positivity, IgGSP arbitrary units ≥50 AU/ml indicates vaccine response or spike-specific mAb levels (Narasimhan M et al., J Clin Micro 2021).

RESULTS: Our cohort consisted of 226 patients with lymphoid malignancies who received mAbs as prophylaxis or treatment for COVID-19. Baseline characteristics of the study cohort are depicted in Table 1. Most patients were over 55 years (84%), 142 (62.8%) had received ≥ 3 doses of vaccinations and 83% had exposure to immunosuppressive therapy.

Evusheld was administered as primary prophylaxis in 193 (85.4%) patients. To treat mild/moderate COVID-19, 26 (11.5%) patients received bamlanivimab, 4 (1.8%) casirivimab/imdevimab, 1 (0.4%) sotrovimab and 2 (0.8%) who had previously received evusheld were treated with bebtelovimab. There were only 6 (2.7%) COVID-19-related hospitalizations post-mAb therapies in this cohort, 4 (15%) post-bamlanivimab and 2 post-evusheld. Post-Evusheld breakthrough infections were reported in 16 (8.3%) patients, of which one patient with refractory lymphoma died due to COVID-19-related acute respiratory distress syndrome. The median time to COVID-19 infection was 120 days post-evusheld. Of these patients, 6 underwent viral genetic testing, 4 (25%) were identified as BA.2 and 5 (31%) as BA.4/5 Omicron variants.

Of 36 patients analyzed for post-evusheld serologic responses, 30 had at least 1 pre-evusheld IgGSP measurement indicating a humoral response specific to COVID-19 vaccines. Seven of 30 patients had poor immunogenic response to vaccines (IgGSP <50 AU/ml) and 18 had IgGSP levels much below the effective viral neutralization titer (VNT, 4160 AU/ml). At a median of 4 months following evusheld, 35 out of 36 patients had IgGSP levels significantly above VNT (P < 0.01). One patient though having IgGSP level below VNT, still showed a 10-fold rise in level compared to vaccine response. No patient had IgGNC index value ≥ 1.4 or PCR positive indicating absence of COVID-19 exposure in these patients.

CONCLUSIONS: Our results show that mAbs are both safe and efficacious adjuncts to physical mitigation and vaccination strategies in protecting patients with lymphoid malignancies against severe COVID-19. All anti-SARS-CoV2 mAbs used for therapy cross react in current IgGSP assays, therefore it is difficult to tease out vaccine specific humoral responses when both are given. Whether antibody affinity could differentiate the two is an area of ongoing research. Evusheld in our cohort induced good serologic responses above VNT even after 3-4 months of treatment and can be effective against the ongoing Omicron variant surge. Waning immune responses post-mAb therapies call for boosters that cover emerging variants, whose timing and dosage may need to be personalized for patients with lymphoid malignancies.

Anderson:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Madanat:BluePrint Medicines, GERON, OncLiv: Consultancy, Honoraria; Sierra Oncology, Stemline Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees. Awan:Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Genentech: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Incyte: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Kite Pharma: Consultancy; Cellecter Bisosciences: Consultancy; Caribou Biosciences: Consultancy; Epizyme: Consultancy; ADCT Therapeutics: Consultancy; Cardinal Health: Consultancy; Merck: Consultancy; BMS: Consultancy; Dava Oncology: Consultancy; Johnson and Johnson: Consultancy; BeiGene: Consultancy. Ramakrishnan Geethakumari:Kite: Consultancy; BMS: Consultancy; Rafael Pharma: Consultancy; Pharmacyclics LLC: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Membership on an entity's Board of Directors or advisory committees.