Response to BNT162b2 Sars-Cov-2 Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant

Recipients of allogeneic hematopoietic stem cell transplant (HSCT) have been excluded from clinical trials of SARS-CoV-2 messenger RNA (mRNA) vaccines;however, since these patients are at higher risk of severe complications following infection, they have been given high priority in vaccination campaigns worldwide. In this prospective observational study, we evaluated the immunogenicity of two BNT162b2 (Pfizer-BioNTech) vaccine doses in allogeneic HSCT recipients compared to healthy controls. IgG antibodies to the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 were analyzed by SARS-CoV-2 IgG II Quant (Abbott, Ireland). The cutoff value of the test used in this study is 7.1 BAU/mL (Binding Antibody Unit/mL) and the results greater than 7.1 indicate that seroconversion has occurred, as recommended by the manufacturer. Peripheral blood samples were collected for immunological analysis at three timepoints: pre-vaccine baseline (w0, before the first BNT162b2 dose), week 3 (w3, before the second vaccine dose) and week 5 (w5, 2 weeks following the second dose). Patients older than 18 years who received BNT162b2 vaccine following an HSCT at seven Italian centers were included in the study. Enrolled patients received two successive doses (at 3-week interval) at a median of 15 months (range 2-141) after HSCT. Twenty-nine age-matched health care workers who were vaccinated with BNT162b2 were recruited as the control group. Among the 34 patients evaluable for serological response, three patients were excluded from the analysis as the baseline serology demonstrated previous natural SARS-CoV-2 infection. On w3, after the first vaccine dose 7/31 (23%) patients developed anti-S IgG antibodies as compared to 28/29 (97%) controls (p<0.01). HSCT recipients showed lower antibody titers (median 1.8 BAU, range 0-481) as compared to healthy controls (median 118 BAU, range 6-1172, p<0.01). In univariate analysis, transplant-to-vaccination interval (>12 months, p<0.01), baseline CD4+ T cell count (>200/mm3, p=0.01), and CD4+CD45RA+ T naive cell count (>100/ mm3, p<0.01) were significantly associated with antibody response after the first vaccine dose. On w5, after the second vaccine dose, 24/31 (77%) of the patients showed antibody response, as compared to 99% of healthy controls (p<0.01);in fact, 71% of non-responders to the first dose developed IgG antibodies after vaccine boost (Figure 1). Median antibody titer after second dose was 350 BAU/ml (0-21.731). In univariate analysis, no significant association was found between patient characteristics and immunogenicity after vaccine boost. Adverse events were rare and modest. Nine percent of the patients reported mild local reactions after vaccine administration, including pain at the injection site and less commonly local erythema, local lymphadenopathy, or swelling;35% of patients reported systemic adverse events, and all were mild. The most frequently reported systemic reactions included weakness (15%), headache (9%), and diarrhea (3%). In conclusion, in recipients of HSCT, a single dose of the BNT162b2 SARS-CoV-2 vaccine yielded poor efficacy, while immunogenicity increased significantly after vaccine boost at day 21 after the first dose. Patients who received vaccines beyond one year after transplant were more likely to mount anti-S IgG antibodies, which could be due to a broader immune reconstitution, as we observed an enhanced response to single BNT162b2 vaccine dose in patients with higher CD4+ T cell and particularly CD4+CD45RA+ naïve T cell counts. [Formula presented] Disclosures: Kordasti: Alexion: Honoraria;Celgene: Research Funding;Beckman Coulter: Honoraria;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pane: AbbVie;Amgen;Novartis: Other: Travel, accommodation, expenses;AbbVie;Amgen;Novartis, GSK, Incyte: Speakers Bureau;Novartis Pharma SAS;: Research Funding;AbbVie;Amgen;Novartis, GSK, Incyte: Consultancy.

Efficacy and Safety of Front-Line Venetoclax and Rituximab (VenR) for the Treatment of Young Patients with Chronic Lymphocytic Leukemia and an Unfavorable Biologic Profile. Preliminary Results of the Gimema Study ‘Veritas‘

Fixed-duration treatment with venetoclax (Ven), a highly selective Bcl-2 inhibitor combined with an anti-CD20 monoclonal antibody, showed high efficacy inducing high rates of deep responses with undetectable minimal residual disease (uMRD) in patients with previously treated and untreated chronic lymphocytic leukemia (CLL). The efficacy and safety of the Ven and rituximab (VenR) combination have been investigated in a multicenter, prospective study of the GIMEMA group that included young patients with previously untreated CLL (LLC 1518, VERITAS, NCT03455517). The primary endpoint of this study was the CR rate assessed according to the iwCLL criteria. Inclusion criteria were: treatment requirement per iwCLL criteria, age ≤65 years, cumulative Illness rating scale score ≤6, creatinine clearance ≥30 mL/min, and an unfavorable biologic profile with IGHV unmutated and or TP53 disruption. Treatment consisted of the Ven dose ramp-up (from 20 to 400 mg daily, during 5-weeks) followed by Ven 400 mg daily, combined with R for six 28-day courses (375 mg/m2, course 1;500 mg/m2, courses 2-6). Patients continued with Ven single agent, 400 mg daily, until month 13. Tumor lysis syndrome (TLS) prophylaxis measures included hydration, allopurinol, or rasburicase. All patients received Pneumocystis Jirovecii prophylaxis. G-CSF was given in patients with recurrent and severe granulocytopenia. Adverse events (AEs) were graded according to the CTCAE criteria v.5, TLS events were classified according to Howard's criteria. Response was assessed at months 7 and 15 and included clinical examination, PB evaluation, BM aspirate, BM biopsy, and CT scan. MRD was checked centrally in the PB and BM by a 6/4-color flow-cytometry assay with a sensitivity of at least 10-4 according to the internationally standardized European Research Initiative on CLL. Quantitative MRD results assessed by flow-cytometry were categorized as uMRD (uMRD4;<10-4), intermediate MRD, or high MRD (≥10-2). MRD was further evaluated by allele-specific oligonucleotide PCR with a sensitivity up to 10-5 in the PB and BM of patients who showed uMRD4 by flow-cytometry. During the follow-up, MRD was monitored every 6 months. Between October 2018 and May 2020, 77 patients with CLL were included in this study. Two patients were off study before the start of treatment (withdrawal of consent, 1;Covid-19 infection, 1) and were not included in the analysis. The median age was 53.5 years (range 38-65). Binet stage B/C was present in 84% of patients, increased beta-2 microglobulin in 41%. Seventy-one (96%) of patients were IGHV unmutated, while 3 (4%) were IGHV mutated and showed TP53 mutation (Table 1). At the data cutoff of June 30, 2020, 65 (87%) patients completed the ramp-up phase. The planned 400 mg dose of Ven was reached within 5 weeks in 78.5% of patients. Response was assessed in 34 patients at the end of the VenR combination therapy. A response was achieved by 32 (94%) patients. Responses included 20 (59%) CRs, 1 CRi (3%) and 11 (32%) PRs due to residual enlarged nodes (median maximum size, 1.9 cm). Treatment failure due to toxicity was recorded in 2 (6%) patients. Overall, a response with uMRD4 by flow-cytometry in the PB was observed in 26 (76.5%) cases, and in the PB and BM, in 17 (50.0%). The rates of patients with CR and uMRD4 by flow-cytometry in the PB, and both in the PB and BM, were 44%, and 35%, respectively (Table 2). No detectable disease by PCR, both in the PB and BM, was observed in 4 (12%) patients. With a median follow-up of 4.5 months from the start of therapy, no patient has progressed or died. Fifty-three percent of patients were hospitalized during the first seven days of the Ven ramp-up phase. A transient laboratory TLS was observed in 3 patients. Treatment was discontinued after the first dose of Ven in 1 patient with evidence of laboratory TLS associated with severe neurologic toxicity due to the concomitant administration of fentanyl. Selected grade ≥3 AEs included neutropenia in 10 patients (ramp-up phase, 5) and neutropenic fever in 4. Gra e ≥3 infection was recorded in 3 patients and was the reason for treatment discontinuation in 1 who developed COVID-19 pneumonia. In conclusion, the preliminary results of this study demonstrate the high efficacy of the front-line VenR combination, which resulted in a high proportion of CRs and responses with uMRD4 in young patients with CLL and an unfavorable biologic profile. [Formula presented] Disclosures: Mauro: Astrazeneca: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Octopharma: Consultancy. Reda: Gilead: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees. Trentin: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Shire: Honoraria;Takeda: Membership on an entity's Board of Directors or advisory committees;Octapharma: Membership on an entity's Board of Directors or advisory committees. Coscia: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm Therapeutics: Research Funding;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sportoletti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Laurenti: Roche: Membership on an entity's Board of Directors or advisory committees;AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gaidano: Astrazeneca: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Sunesys: Membership on an entity's Board of Directors or advisory committees. Marasca: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Shire: Honoraria;Roche: Membership on an entity's Board of Directors or advisory committees. Murru: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rigolin: Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scarfo: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AstraZeneca: Honoraria;Gilead: Membership on an entity's Board of Directors or advisory committees. Marchetti: Pfizer: Membership on an entity's Board of Directors or advisor committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees. Levato: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galieni: Celgene: Honoraria;Takeda: Honoraria;AbbVie: Honoraria;Janssen: Honoraria. Liberati: Verastem: Research Funding;Onconova: Research Funding;Janssen: Honoraria, Research Funding;Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Honoraria, Research Funding;Pfizer: Research Funding;Karyopharm: Research Funding;Morphosys: Research Funding;Novartis: Research Funding;GSK: Research Funding;Incyte: Honoraria;Oncopeptides: Research Funding;Takeda: Research Funding. Molica: Roche: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Visentin: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees, SpeakersBureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale: Janssen: Honoraria. Del Giudice: Janssen: Other: grant for meeting participation;Tolero: Membership on an entity's Board of Directors or advisory committees;Roche: Other: grant for meeting partecipation;AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Cuneo: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astra Zeneca: Honoraria;Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Incyte: Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Membership on an entity's Board of Directors or advisory committees;Novartis: Speakers Bureau;Roche: Membership on an entity's Board of Directors or advisory committees.