Immunogenicity and clinical effectiveness of mRNA vaccine booster against SARS-CoV-2 Omicron in patients with haematological malignancies: A national prospective cohort study.

Information regarding the protective anti-SARS-CoV-2 antibody levels and the effectiveness of the mRNA vaccines against the Omicron variant in patients with haematological malignancies is limited. We prospectively followed two times BNT162b2 vaccinated oncohaematological patients (n = 1010) without prior COVID-19 for PCR-confirmed breakthrough infections during the Alpha/Delta and the Omicron phases of the pandemic. Anti-S1-IgG levels were longitudinally monitored in patients who had received the third (booster) vaccine dose. Patients with anti-S1-IgG levels <50 BAU/mL 1 month after the booster had a higher risk of Omicron infections (RR 1.91; 95% CI 1.39-2.63; p = 0.0001) and severe infections (RR 8.74; 95% CI 3.99-19.1; p < 0.0001). Conversely, the risk of severe COVID-19 was <1% with anti-S1-IgG levels >500 BAU/mL and neutralizing antibody concentrations >50 U/mL. The risks of breakthrough Omicron infections (HR 0.55; 95% CI 0.32-0.96; p = 0.034) and severe COVID-19 (HR 0.27; 95% 0.11-0.7; p = 0.0074) were lower among patients who had received the booster dose. In conclusion, low antibody levels are associated with significantly increased risk of both the breakthrough Omicron infections and severe COVID-19. The third mRNA vaccine dose improved the protection against the Omicron and reduced the risk of severe disease.

Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study.

BACKGROUND: Haematological malignancies and their treatments are likely to affect SARS-CoV-2 vaccine efficacy. We aimed to evaluate serological response to BNT162b2 vaccine in patients with haematological malignancies by type of treatment. METHODS: Our national prospective cohort study was done in Lithuania and assessed serological response to one and two BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine doses in healthy health-care workers and in patients with haematological malignancies. Eligible participants were aged 18 years or older, had received both vaccine doses, and had available biobanked blood samples from before vaccination and after the second dose. Biobanked samples and health data were obtained from Vilnius University Hospital Santaros Klinikos Biobank. Abbott Architect SARS-CoV-2 IgG Quant II chemiluminescent microparticle assay was used to quantify serum anti-SARS-CoV-2-S1 IgG antibody (anti-S1 IgG antibody) concentrations 0-10 days before the first BNT162b2 vaccine, on the day of second immunisation (around day 21), and 7 to 21 days after the second immunisation. Adverse events were assessed by a standardised questionnaire. Breakthrough infections were characterised clinically and by SARS-CoV-2 genotyping whenever possible. This study is registered with ClinicalTrials.gov, NCT04871165. FINDINGS: Between Jan 8 and April 21, 2021, 885 participants with haematological malignancies were included in the study. 857 patients were anti-S1 IgG seronegative at timepoint 0 and constituted the main analysis cohort. The age-matched comparison was made between 315 patients with haematological malignancies who were aged 18-60 years and 67 healthy health-care workers in the same age group. Patients aged 18-60 years with haematological malignancies had lower median anti-S1 IgG antibody responses after two BNT162b2 vaccine doses than did health-care workers of the same age group (median 6961 AU/mL [IQR 1292-20 672] vs 21 395 AU/mL [14 831-33 553]; p<0·0001). Compared with untreated patients with haematological malignancies (n=53; median 5761 AU/mL [629-16 141]), patients actively treated with Bruton tyrosine kinase inhibitors (BTKIs; n=44; 0 AU/mL [0-7]; p<0·0001), ruxolitinib (n=16; 10 AU/mL [0-45]; p<0·0001), venetoclax (n=10; 4 AU/mL [0-1218]; p=0·0005), or anti-CD20 antibody therapy (n=87; 17 AU/mL [1-2319]; p<0·0001) showed particularly poor anti-S1 IgG antibody responses following two BNT162b2 doses. Patients being treated with tyrosine kinase inhibitors (n=41; 10 537 AU/mL [IQR 2335-19 388]) or patients who received autologous haematopoietic stem-cell transplantation (HSCT; n=192; 6203 AU/mL [1451-16 834]) or allogeneic HSCT (n=122; 6304 AU/mL [1120-16 913]) were among the subgroups with the highest numerical responses. Nine SARS-CoV-2 infections and three COVID-19 deaths were observed among fully vaccinated patients with haematological malignancies. INTERPRETATION: Patients with haematological malignancies mount blunted and heterogeneous antibody responses to the full course of BNT162b2 mRNA vaccination. Patients who are actively treated with BTKIs, ruxolitinib, venetoclax, or anti-CD20 antibody therapies seem to be the most negatively affected and might be left unprotected from SARS-CoV-2 infection. Breakthrough severe SARS-CoV-2 infections in fully vaccinated patients with haematological malignancies emphasise the importance of ongoing strict adherence to non-pharmacological interventions and household vaccination while SARS-CoV-2 is circulating in the community. FUNDING: Vilnius University Hospital Santaros Klinikos. TRANSLATION: For the Lithuanian translation of the abstract see Supplementary Materials section.

Venetoclax-based salvage therapy followed by Venetoclax and DLI maintenance vs. FLAG-Ida for relapsed or refractory acute myeloid leukemia after allogeneic stem cell transplantation.

We retrospectively compared the outcomes of 20 patients receiving Venetoclax + low-dose Cytarabine + Actinomycin D (ACTIVE) with 29 patients receiving FLAG-Ida as salvage therapy for relapsed or refractory AML (R/R AML) after alloSCT. The groups were statistically balanced according to age, performance status, cytogenetics, and previous treatment. The overall response rate (CR + CRp + MLFS) of ACTIVE was 75% (15/20) in comparison to 66% (19/29) in the FLAG-Ida group (p = 0.542). The cumulative CR + CRp rate was significantly higher in the ACTIVE group compared to FLAG-Ida (70% (14/20) vs. 34% (10/29), respectively, p = 0.02). All three patients failing previous Venetoclax therapy and five out of seven patients with previous FLAG-Ida exposure achieved a CR/CRp after ACTIVE induction. ACTIVE patients survived longer compared to FLAG-Ida patients (13.1 vs. 5.1 months, respectively, p = 0.032). The treatment-related mortality was 0% in the ACTIVE group and 34% (10/29) in the FLAG-Ida patients (p = 0.003). The cumulative incidence of relapse did not differ between the two treatment groups. ACTIVE appears to have comparable antileukemic activity and lower toxicity compared to FLAG-Ida resulting in improved survival. Patients with Venetoclax or FLAG-Ida exposure responded to ACTIVE.

Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax-based salvage therapies.

OBJECTIVES AND METHODS: We conducted a retrospective analysis to evaluate the outcomes of 28 heavily pretreated (median 3 (2-6) treatment lines, sixteen (57%) allotransplanted) relapsed/refractory acute myeloid leukemia patients who had failed salvage venetoclax-based therapies. RESULTS: The median age was 59 years (20-80), 20 patients (71%) had ECOG 2-4 status, and 18 patients (64%) were stratified to European Leukemia Network 2017 adverse risk group. The most common mutations were ASXL1 (21%), RUNX1 (18%), FLT3 ITD/TKD (18%), PTPN11 (15%), NRAS/KRAS (15%), and WT1 (15%). Twenty-two patients (79%) received different post-venetoclax salvage therapies with the overall response rate of 23% (complete remission + morphological leukemia-free state). Three of six (50%) patients achieved complete remissions after therapy with venetoclax + actinomycin D ± low-dose cytarabine. The remaining 6 patients did not receive any further salvage treatment mainly due to poor general condition. The median overall survival was 3.9 months for all patients (4.3 for those receiving post-venetoclax salvage vs 1.3 months receiving palliative care alone, P < .001). CONCLUSIONS: Though the remission rate and survival of patients failing venetoclax are poor, a small proportion of these R/R AML patients may still respond to cautious intensification of chemotherapy with venetoclax.