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. ...

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Background Venetoclax based therapies have produced varying results in the relapsed or refractory acute myeloid leukemia (R/R AML) setting. Highest response rates were demonstrated after Venetoclax in combination with high dose chemotherapy. However, this approach is feasible mainly in fit, younger patients. Herein, we present a lower intensity combination therapy consisting of Venetoclax, low dose Cytarabine and Actinomycin D (ACTIVE) in patients with R/R AML administered in real-life clinical practice setting. Methods We performed an observational, retrospective, single centre study. The patients were at least 18 years of age and had R/R AML. All patients provided informed consent for treatment as well as data collection. Venetoclax ramp-up was administered over either 3 or 5 days until the daily dose of 600mg/d was reached. The ACTIVE regimen consisted of Venetoclax 600mg/d p/o on days 1-28, Cytarabine 20mg/m 2 s/c on days 1-10, Actinomycin D 12.5 µg/kg i/v on days 1, 2 and 3 (on days 1 and 2 for patients ≥65 years). Strong/moderate CYP3A inhibitors/inducers or Venetoclax dose reductions were not allowed. Indications for stopping Venetoclax before Day 28 were life threatening infectious complications or faster hematological recovery with the addition of G-CSF in responders. A second ACTIVE cycle was administered in non-responders without evidence of progressive disease after Cycle 1 or in responders with positive minimal residual disease (MRD). We evaluated baseline characteristics, composite CR (CRc = CR + CRi + CRp), overall response (ORR = CRc + MLFS), MRD negativity rates, overall survival (OS), relapse-free survival (RFS), event-free survival (EFS), Grade 3-5 non-hematological toxicities and Day 30 and Day 60 mortality rates. Results Fifty R/R AML patients were treated with ACTIVE and 56% (28/50) were male. The median age was 65 years (20-84). The median Eastern Cooperative Oncology Group (ECOG) status was 1 (0-3) and 40% (20/50) had ECOG status of 2 or 3. Secondary AML was confirmed in 48% (24/50) of cases. Adverse cytogenetics were identified in 28% (14/50) of patients whereas 60% (30/50) were stratified to adverse risk group in accordance with ELN 2017 guidelines. The most common gene mutations were IDH1/2 30% (15/50), FLT3 28% (14/50), ASXL1 22% (11/50), NPM1 14% (7/50), N/KRAS 12% (6/50) and RUNX1 12% (6/50). The median number of prior therapies was 2 (1-5). Intensive chemotherapy was administered in 80% (40/50) of whom 38% (15/40) had primary refractory disease and 48% (19/40) had previously received Fludarabine + Cytarabine + Idarubicin (FLAG-Ida) or Cytarabine + Mitoxantrone (HAM). Eight percent (4/50) had had prior Venetoclax exposure. Thirty-six percent (18/50) had relapsed after allogeneic stem cell transplantation (alloSCT) with a median time of 7.4 months (1.6-37.3) from transplant to relapse. One cycle of ACTIVE therapy was administered in 76% (38/50) of cases, whereas 24% (12/50) received 2 cycles. The median number of Venetoclax 600mg/d days per cycle was 18 (8-28). Additional FLT3/RAS/BCR-ABL1 inhibitors Gilteritinib, Trametinib or Dasatinib were administered in 12% (6/50). Forty-nine patients were evaluable for response and one patient died of sepsis before response evaluation (Table 1). The ORR was 73% (36/49) and the CRc rate was 67% (31/46). MRD negativity was confirmed in 61% (19/31) of CRc patients. Sixteen patients had undergone additional early bone marrow evaluations. Blast count reduction to &lt;5% was observed in 50% (8/16) after Venetoclax ramp-up and in 88% (14/16) on Day 4. Half of the ACTIVE responders (18/36) continued maintenance therapy with Venetoclax + low dose Cytarabine and optional DLI, whereas 36% (13/36) proceeded to either first or second alloSCT. After 16.4 months of median follow-up, the median OS, RFS and EFS were 13.1, 7.2 and 4.5 months, respectively (Figure 1A). Median OS was not reached in MRD negative patients (Figure 1B). In multivariable Cox regression analysis, adverse cytogenetics (HR 3.48, 95% CI 1.39 -8.55) and primary refractory disease (HR 2.54, 95% CI 1.05-6.12) were associated with worse OS. The most common grade 3-5 non-hematological adverse events were febrile neutropenia (54%, 27/50) and bacteremia/sepsis (34%, 17/50). Day 30 and Day 60 mortality rates were 8% (4/50) and 16% (8/50), respectively. Conclusions ACTIVE was effective and well tolerated in this unselected prognostically unfavourable older R/R AML patient population. Figure 1 Figure 1. Disclosures Zucenka: Jannsen: Honoraria, Other: Travel-expenses; Takeda: Other: Travel Expenses; Novartis: Honoraria, Other: Travel Expenses; Pfizer: Honoraria, Other: Travel Expenses; Astellas: Honoraria; Abbvie: Honoraria, Other: Travel Expenses. Maneikis: Abbvie: Honoraria. Pileckytė: Abbvie: Honoraria, Other: Travel Expenses. Griškevičius: Abbvie: Other: Travel Expenses. OffLabel Disclosure: Venetoclax has been used off-label for the treatment of R/R AML

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.