ABSTRACT
Introduction Different vaccines have been recently approved by FDA and EMA for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating a protection rate ranging from 60% to almost 95% in phase II/III trials. Immunocompromised patients, including those undergoing allogeneic stem cell transplantation (allo-SCT), were excluded from vaccine trials. While EBMT recommended the vaccination for transplanted patients, data concerning efficacy and safety in this particular setting are scarce. Since infections represent a relevant cause of transplant-related mortality and the treatment and management of SARS-CoV-2 infection in allo-SCT patients proved to be challenging and complex, we prospectively evaluated the safety and the development of protective response against SARS-CoV-2 vaccines in our allogeneic transplanted patients. Materials and Methods Starting in March 2021, allogeneic stem cell transplanted patients with different hematological diseases underwent COVID-19 vaccination. Taking into account the EBMT recommendations, we considered patients suitable for vaccination when (1) they were at least 3-6 months after allo-SCT, (2) didn't have any graft versus host (GvHD) activity, and (3) received less than 0,5 mg/kg steroids as part of the immunosuppressive treatment. There was no recommendation for a specific type of vaccine, with the only exception for life-attenuated vaccines, which are mostly contraindicated in the post allo-SCT setting. Vaccinated patients were regularly monitored for the potential development of adverse events. The anti-SARS-CoV-2 Spike protein antibodies were measured in blood samples to assess the humoral response. In case of no response with undetectable anti-Spike antibodies 2 week after the second dose of vaccine, we repeated the measurements at regular intervals until week + 6-8 after the completion of vaccination. Patients with no measurable antibodies 8 weeks after completion of the vaccination were considered as no responders. Results Between 03/2021 and 06/2021 a total of 83 patients underwent COVID-19 vaccination (including first and second dose) during the post allo-SCT follow-up. Patients' characteristics are listed in Table 1. Most patients (77%) received BNT162b2, while only a small subgroup (8%) underwent a mixed vaccination after a first dose of ChAdOx1-S. We considered the mixed vaccination mostly to maximize the response. Overall, the two vaccine doses were well tolerated, with only 5% of patients developing a reactivation of GvHD. No relevant grade 3 or 4 organ toxicities were observed. Overall, 66% of patients in our cohort showed a humoral response. The incidence of positive serology was lower in patients who underwent the vaccination within the first 18 months after allo-SCT (29% vs 83% for patients >18 months after allo-SCT, p< 0.001). In multivariate analysis other risk factors that were associated with poor or no response were lack of immune reconstitution (p< 0.001) and ongoing immunosuppressive therapy (p= 0.009). The age of patients at the time of vaccination, sex, intensity of conditioning regimen and the use of ATG did not prove to have an influence for a humoral response during the post-transplant follow up. Discussion The achievement of a protective immunity against SARS-CoV-2 represents a crucial event for a frail population, like allogeneic stem cell transplanted patients. So far and to our knowledge little is known about the safety and efficacy of the COVID-19 vaccination in this particular setting. Here, we report one of the first series of patients undergoing COVID-19 vaccination after allo-SCT. We demonstrated that a humoral response can be achieved, especially for those patients who are in the long-term follow-up, underwent immune reconstitution and are free from immunosuppressive drugs. For the other patients, who represent the frailer subgroup, in the absence of a documented immune response after 2 doses of vaccine, the option of a third dose in order to increase the probability of response should be evaluated in prospective clinical trials. [Formula presented] Disclosures: Viardot: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roche Ltd: 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;University Hospital of Ulm: Current Employment;Amgen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Roche: Consultancy, Honoraria;Agios: Consultancy, Honoraria, Research Funding;Astellas: Consultancy, Honoraria, Research Funding;Jazz: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Ulm University Hospital: Current Employment;Abbvie: Consultancy, Honoraria, Research Funding;Oxford Biomedicals: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Astex: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;AstraZeneca: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding;Helsinn: Consultancy, Honoraria;Pfizer: Research Funding;Berlin-Chemie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;GEMoaB: Consultancy, Honoraria. Sala: Novartis: Consultancy, Honoraria;Celgene/BMS: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Jazz: Consultancy, Honoraria.
ABSTRACT
Background: Blinatumomab, a bispecific T-cell engager (BiTE ®) molecule that directs cytotoxic T-cells to lyse CD19-expressing B lineage cells, has been investigated in NHL (Goebeler JCO 2016, Viardot Blood 2016, Katz ASH 2019). Here, we evaluated subcutaneous (SC) blinatumomab, which may simplify administration, improve convenience, and potentially reduce adverse events (AEs). Methods: Patients (pts;≥18 y) had indolent NHL (follicular, marginal zone, lymphoplasmacytic, mantle cell, or small lymphocytic) that was primary refractory (1+ prior line), relapsed (within 1 y of first response), or that had responded to initial therapy for ≥1 y and relapsed after 2+ lines, including an anti-CD20 monoclonal antibody. Disease must not have been irradiated and was measurable (≥1.5 cm) on PET-CT or CT. Pts had a 3-wk continuous intravenous (cIV) run-in period followed by SC dosing in 5 cohorts, a further 2 wks of cIV dosing, and the option for a second cycle of cIV dosing (Figure). The primary objective was safety and tolerability of SC blinatumomab;secondary objectives included pharmacokinetics (PK), estimating the maximum tolerated dose (MTD), ie, the highest dose at which ≤1/6 pts had a dose-limiting toxicity (DLT), and efficacy (NCT 02961881). Results: Pts (n=29) had a median (range) age of 64 (42-75) y, 55% were male, 90% Caucasian, with follicular I-IIIA (76%), marginal zone (10%), mantle cell (10%) and lymphoplasmacytic lymphoma (3%) subtypes;no pts had prior allo-hematopoietic stem cell transplant (HSCT), 38% had prior auto-HSCT. Of the 29 pts, 5 discontinued (D/C) blinatumomab due to AEs (n=3;2 cIV, 1 SC), pt request (1), and disease progression (1);no pts D/C due to COVID-19 control measures;26 pts completed the study;pts received a median (range) of 5 (3-10) doses. AEs leading to D/C in SC treatment included neurologic events of aphasia and seizure. During SC dosing, 2 DLTs occurred (aphasia, n=1;seizure, n=1 ). MTD was not reached. Five pts had grade 3 (G3) AEs (thrombocytopenia, erosive esophagitis, asthenia, device-related infection, hyperglycemia, aphasia, seizure;pts may have had >1 G3 AE);there were no G4 AEs or fatal AEs. AEs of interest included neurologic events (all, n=15;G3, n=2), infection (2;1), and cytokine release syndrome (4;0). One pt had grade 1 injection site erythema. Anti-blinatumomab antibodies have not been detected to date. Preliminary PK results were consistent across the 5 SC cohorts and 3 different dosing regimens. Following the first dose, maximum concentrations (C max) were reached after ~5-12 hours and exposures (C max and area under concentration-time curve [AUC] from 0-12 hours) increased in a dose-related manner. At steady state, exposures (AUC over the dosing interval) increased in a dose-related manner for dosing intervals of once every 12, 24, and 48 hours across cohorts. Blinatumomab bioavailability and apparent terminal elimination half-life were favorable for extending the dosing interval to once every other day and potentially longer intervals. The steady-state concentrations during both cIV infusion periods were consistent with those previously reported in NHL pts. In all pts, the overall response rate (ORR, representative of cIV, 5 wks and SC, 1wk) per Cheson criteria was 69% (evaluable, n=23: complete response [CR], 21%;partial response [PR], 48%;cycle 1 [C1], n=22: ORR, 62%;CR, 14%;PR,48%;cycle 2 [C2], n=17: 45%;17%;28%;respectively);per Lugano criteria, the ORR was 52% (n=21: CR, 24%;PR, 28%;C1, n=18: 45%;17%;28%;C2, n=12: 31%;21%;10%);for follicular lymphoma, ORR was 77% per Cheson (n=19: CR, 23%;PR, 55%) and 55% per Lugano (n=15: CR, 23%;PR, 32%). Conclusions: In pts with R/R indolent NHL, SC blinatumomab had a favorable safety profile, with the caveat that pts who could not tolerate cIV blinatumomab did not advance to SC dosing. Efficacy was comparable with that seen for cIV dosing in prior blinatumomab NHL studies. In contrast to prior blinatumomab trials, no dose dependency in efficacy or toxicity was observed because SC dosi g was administered for only 1 wk, after 3 wks of cIV;pts not tolerating cIV did not receive SC dosing. Safety/tolerability of blinatumomab SC administration over the whole cycle is currently being evaluated in a phase 1 trial of pts with R/R acute lymphoblastic leukemia (NCT 04521231). SC blinatumomab PK, including bioavailability and half-life, showed promising features, warranting further investigation. [Formula presented] Disclosures: Rossi: Astellas: Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Alexion: Membership on an entity's Board of Directors or advisory committees;Sanofi: Honoraria;Takeda: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo: Consultancy, Honoraria;Janssen: Membership on an entity's Board of Directors or advisory committees;Jazz: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees. Prince: Takeda: Consultancy, Honoraria;Amgen: Honoraria, Research Funding;Novartis: Honoraria. Tam: Janssen: Consultancy, Honoraria, Research Funding;BeiGene: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria, Research Funding;Loxo: Consultancy;Roche: Consultancy, Honoraria;Novartis: Honoraria;Pharmacyclics: Honoraria. Ku: Roche: Consultancy;Genor Biopharma: Consultancy;Antegene: Consultancy. Thieblemont: Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Popplewell: Pfizer: Other: Travel;Hoffman La Roche: Other: Food;Novartis: Other: Travel. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Haioun: Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Janssen-Cilag: Consultancy;Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Novartis: Honoraria;Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Servier/Pfizer: Honoraria;Gilead Sciences: Consultancy, Honoraria;Takeda: Consultancy;Miltenyi Biotec: Consultancy. Viardot: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees;University Hospital of Ulm: Current Employment. Ferreri: Pfizer: Research Funding;x Incyte: Membership on an entity's Board of Directors or advisory committees;Amgen: Research Funding;Genmab: Research Funding;BMS: Research Funding;Hutchison Medipharma: Research Funding;PletixaPharm: Membership on an entity's Board of Directors or advisory committees;Adienne: Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics: Research Funding;Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding;Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding;Ospedale San Raffaele srl: Patents & Royalties;Beigene: Research Funding. Wong: Amgen: Current Employment;Amgen: Current equity holder in publicly-traded company. Kadu: IQVIA: Current Employment. Zugmaier: Amgen: Current Employment;Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed;receives royalties of family members of international applications published as WO2010/052014;WO2010/052013;WO2011/051307;WO2012/055961;WO 2012/062596;WO2014/122251;and WO2015/181683;Amgen: Current equity holder in publicly-traded company. Zeng: Amgen: Current Employment, Current equity holder in publicly-traded company. Rambaldi: Celgene: Other: Travel, Accommodations, Expenses;Jazz Pharmaceuticals: Consultancy;Astellas Pharma: Consultancy;Novartis: Consultancy;Omeros: Consultancy, Honoraria;Amgen: Consultancy, Honoraria. OffLabelDisclosure: Blinatumomab is approved in the United States for administration as a continuous intravenous infusion. It has not been approved for subcutaneous administration.