Treatment with obinutuzumab leads to worse outcomes in hematological patients diagnosed with Omicron variant COVID-19

Background: Hematological malignancies (HM) patients treated with anti-CD20s are at a higher risk for COVID-19 complications, however, little is known about the difference between these agents. Aim: To investigate the prognosis of HM COVID-19 pateints treated with obinutuzumab in comparison to rituximab. Methods: Single-center population-based cohort study including all HM patients treated with anti-CD20s from June 2021 to April 2022. Diagnosis of COVID-19 was based on positive SARS-CoV-2 PCR omicron variant. The Median follow-up was four months. Results: Among 143 HM patients, 47 were diagnosed with COVID- 19, 27 in the rituximab group and 20 in the obinutuzumab group. All obinutuzumab-treated patients had indolent HM, versus only 40.7% among the rituximab group (p <0.001). 13/20 of the obinutuzumab group (65.0%) received anti-CD20s as maintenance therapy, while most of the rituximab patients, 21/27 (77.8%) were on induction phase therapy (p = 0.003). COVID-19 prognosis was worse among obinutuzumab patients with higher admission rates (60.0% vs. 25.9%, p = 0.019), more patients with severe-critical disease (35.0% vs.7.4%, p = 0.017), and accounts for all mortality cases (3/20 vs. 0/27, p = 0.038). Conclusions: Omicron-variant COVID-19 disease outcome was worse among HM patients treated with obinutuzumab comparing to rituximab. As this treatment has not been shown to increase overall survival when given as maintenance, In our opinion, it may be prudent to delay treatment with obinutuzumab or replace it with a less potent anti-CD20 as long as the COVID-19 epidemic continues.

Real-World Efficacy of Venetoclax-Based Regimens in Patients with Chronic Lymphocytic Leukemia in Israel: A Multicenter Prospective Study

Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL). Method: A prospective observational nationwide multicenter study. Treatment-naïve (TN) and relapsed/refractory (R/R) CLL/SLL patients were enrolled in 13 medical centers in Israel. The primary endpoint was clinical response, per physician assessment 12-months after the initiation of venetoclax treatment. Key secondary endpoints included progression free survival (PFS), overall survival (OS) and uMRD as assessed at a central laboratory by 8-color flow-cytometry. Results: Between February 10, 2019, and Jun 17, 2021 (data cut), 199 CLL/SLL patients were enrolled from 13 medical centers in Israel to receive venetoclax based therapy. The study included 83 TN and 116 R/R evaluable CLL/SLL patients with a median age of 69 years (range, 34-85) and 70.5 years (range, 25-91), respectively (Table 1). R/R patients had received a median of one prior therapy with a range up to 8, of these patients 60 (51.7%) were previously treated with a B-cell receptor inhibitor (BCRi) including ibrutinib in 52 (44.8%) and idelalisib in combination with rituximab in 6 (5.2%). TN patients had been treated with venetoclax in combination with obinutuzumab (92.8%) or rituximab (4.8%) and R/R patients received either venetoclax with rituximab (60.3%) or obinutuzumab (9.5%), venetoclax monotherapy (25.8%) or triple therapy with venetoclax, rituximab and ibrutinib in 5 (4.3%). Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 80.7% (n=67) of TN and 81% (n=94) of R/R patients. The median duration of ramp-up was 38 and 42 days in TN and R\R patients, respectively. Prior to therapy, tumor lysis syndrome (TLS) risk was considered high in 12% and 29.3% of TN and R/R patients, respectively (Table 1). Laboratory TLS occurred in one TN patient and 4 R/R patients, whereas 3 of the R/R patients experienced clinical TLS. Nineteen TN and 75 R/R patients had a follow-up of at least 12 months or discontinued study prematurely. The 12-month overall response rate (ORR) for TN and R/R patients was 89.5% [complete response (CR) 13 (68.4%), partial response (PR) 4 (21.1%)] and 73.3% [CR 37 (49.3%), PR 18 (24%)], respectively. In the R/R cohort, the 12-month ORR among assessed patients was 67.6% (25/37) in BCRi-exposed versus 85.7% (30/35) in BCRi-naïve patients. At 12 months, peripheral blood uMRD (<0.01%) was achieved in 12 out of 14 (85.7%) TN and 26 out of 38 (68.4%) R/R evaluated patients. At a median follow-up of 5.1 months (range, 0.5-15.6) for TN and 10.1 months (range, 0-25.7) for R/R patients, the median PFS and OS, for both cohorts have not been reached. The estimated 12-month PFS was 90.9% for TN and 81.1% for R/R patients. For R/R patients with prior exposure to BCRi, the estimated 12-month PFS was 69.6% versus 94.8% in BCRi-naïve patients (figure 1). Grade ≥3 adverse events (AEs) were reported in 34.9% of TN patients and 43.9% R/R patients. The most frequent grade ≥3 AEs documented were neutropenia (TN: 19.2% and R/R 17.2%), infections (TN: 4.8% and R/R: 21.5%) and febrile neutropenia (TN: 2.4% and in R/R: 2.6%). COVID-19 occurred in 7 patients including one death. At the time of data cut, 10 deaths occurred, one TN and 9 R/R patients. Causes for death included infections (5 patients), disease progression (2 patients), acute myeloid leukemia/ myelodysplastic syndrome (2 patients) and a soft-tissue sarcoma (1 patient). Conclusions: This first interim analysis of our ongoing prospective real-world study of venetoclax-based treatment for TN and R/R CLL/SLL, demonstrates high efficacy together with a high proportion of undetectable MRD levels and a favorable toxicity profile. These efficacy results are comparable to those reported in previous Phase III clinical trials for CLL, with no new safety signals. [Formula presented] Disclosures: Herishanu: AbbVie: Consultancy, Honoraria, Research Funding;Janssen: Honoraria;Roche: Honoraria;AstraZeneca: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Itchaki: Janssen: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding. Levi: AbbVie: Consultancy, Research Funding. Aviv: AbbVie: Honoraria, Research Funding. Fineman: AbbVie: Research Funding. Dally: AbbVie: Honoraria, Research Funding. Tadmor: Janssen: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Abadi: AbbVie: Honoraria, Research Funding. Shvidel: AbbVie: Honoraria, Research Funding. Braester: AbbVie: Honoraria, Research Funding. Cohen: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Benjamini: Janssen: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding.

Five-month impact of tozinameran (BNT162b2) vaccine on kidney transplant and dialysis patients: Serology and clinical outcomes

Background: Dialysis-treated (DT) and kidney transplant (TX) patients face higher morbidly and mortality risks than the general population during COVID-19 pandemic. Determining humoral response and associated COVID-19 morbidity after vaccination will guide risk assessment and changes in vaccination policy in this vulnerable population. Methods: Prospective cohort study up to 5 months follow-up after Tozinameran or SARS-CoV-2 infection. Primary outcomes: qualitative and quantitative anti S1/ S2 antibody (ABs) and disease rates during follow up. Anti-SARS-2 IgG ABs were quantified using LIAISON SARS-CoV-2 S1/S2 IgG (DiaSorin) immunoassay in serum of TX, DT and treating team at our hospital. Demographics and clinical data were collected from participants files. Results: 174 DT patients (40% women, age 65±15 years) 253 TX patients (33%, 53±14 years) and 71 control participants (65%, 44±14 years) were recruited. 3 months or more after vaccination we detected anti S1/S2 ABs in 81% of DT (95%CI, 72-90%), 43% of TX (95%CI, 29-57%) and 100% of controls. After COVID-19 respective rates were 94% (95%CI, 83-100%), 75% (95%CI, 60-90%) and 100%. Quantitative titers were in line with qualitative ones. Predictors of negative serology were older age, diabetes, cancer history, lower lymphocyte count and lower vitamin D. Peritoneal dialysis predicted higher titers compared to hemodialysis. In TX, hypertension and higher levels of immnosupression predicated lower titers. Vaccination was associated with fewer subsequent COVID-19 infections (HR=0.23, 95% CI 0.05-0.99, p<0.05). Higher antibody titers associated with fewer events, HR 0.41/unit increase in log10 titer (p<0.05). Conclusions: Patients with ESRD, particularly TX, mounted delayed and diminished antibody response to vaccination, and lesser response was associated with more infections. Thus, measures to protect non-responsive patients are urgently required.

Covid-19 among patients with hematological malignancies: A national Israeli retrospective analysis

Background: The first COVID-19 patient was diagnosed in Israel in February 2020. It is of importance to evaluate outcomes across patients with hematological malignancies which are generally immunosuppressed and more susceptible to infectious complications. Aims: We aimed to characterize the clinical course of COVID-19 infection among patients with various lymphoid or myeloid malignancies and determine which of these patients were most at risk of severe infection or mortality. Methods: This was a national Israeli multicenter retrospective study. Patients with hematological malignancies who were diagnosed with COVID-19 from February 20, 2020 until January 31, 2021 were centrally reported and included in the retrospective analysis with no need for informed consent signing. Clinical and laboratory data regarding baseline characteristics, hematological management, and course and treatment of the COVID-19 disease were collected. Multivariate regression analyses were used to determine the variables associated with severe disease, hospitalization and mortality. Results: In total, 272 patients from 14 medical centers were included in the analysis. Among them, 140 (51.5%) were men, and the median age was 70yrs. The most frequent malignancies included lymphoma (44.5%), multiple myeloma (22.8%), and chronic lymphocytic leukemia (12.1%). 90 (33.1%) patients developed a severe or critical respiratory infection, and 58 (21.3%) died. According to multivariate regression analyses, both age > 70yrs (OR=2.26;95% CI: 1.04;4.95;p=0.041) and current steroid treatment (OR=3.23;95% CI: 1.06, 9.90;p=0.040) at time of COVID- 19 diagnosis were associated with severe to critical disease, while current treatment with monoclonal antibodies was associated with mild to moderate disease (OR=2.86;95% CI: 1.17, 6.99;p=0.022). Among the 159 hospitalized patients, the hospitalization was longer in patients with severe to critical respiratory infection (IRR=1.53;95% CI: 1.36, 1.72;p<0.001), or treated with dexamethasone (IRR=1.22;95% CI: 1.08, 1.38;p=0.002), with enoxaparin (IRR=1.18;95% CI: 1.06, 1.33;p=0.004) or convalescent plasma (IRR=1.17;95% CI: 1.04, 1.32, p=0.012);while the hospitalization was shorter in patients treated with remdesivir (IRR=0.78;95% CI: 0.69, 0.89;p<0.001). The mortality rate was higher in patients > 70yrs (OR=3.41;95% CI: 1.13, 10.34;p=0.030), with severe to critical infection (OR=27.27;95% CI: 7.40, 100.48, p<0.001), or in those treated with dexamethasone (OR=5.89;95% CI: 1.47, 23.63;p=0.012) for COVID-19 respiratory condition, and lower in patients treated with remdesivir (OR=0.19, 95% CI: 0.04, 0.82, p=0.026). Summary/Conclusion: Respiratory infection with COVID-19 seems to be particularly severe in patients with hematological malignancies. While steroids seem to increase both baseline severity of the infection and mortality, it seems that treatment with remdesivir was associated with reduced mortality and duration of hospitalization. These particularities of haemato-oncological patients may be explained by a remarkably severe COVID-19 viremia that might cause the high mortality rate, while the cytokine release syndrome which generally responds to steroid treatment may be milder in these patients. The management of hematological malignancies during acute COVID-19 infection should be individualized and further investigated.