ABSTRACT
B-cell chronic lymphocytic leukaemia (CLL) is associated with immune suppression and patients are at increased risk following SARS-CoV-2 infection. The Chronic Lymphocytic Leukaemia-Vaccine Response (CLL-VR) study was designed to assess immune responses following the introduction of Covid-19 vaccination in UK. Five hundred patients with CLL were recruited nationally through NHS and charity communications. Phlebotomy blood samples were taken from local patients ( n = 100) and dried blood spot samples were collected via post from participants across the UK ( n = 400). Ninety-six age-matched control subjects were also recruited locally. Samples were taken at 2-3 weeks following the first, second and third primary vaccine doses. Antibody and cellular responses against spike protein, and neutralising antibody titre to delta and omicron variant, were measured. Total serum immunoglobulin level was also determined. Responses were analysed according to clinical history, serum immunoglobulin level and vaccine type received. Donors with a clinical or serological history of prior natural infection were excluded from the analysis. Twenty percent (70/353) of participants developed a measurable antibody response after the first vaccination and this increased to 67% (323/486) following the second dose and 80% (202/254) after a third dose. The response rate in healthy controls plateaued at 100% after only two doses. The magnitude of the antibody response was also 3.7-fold lower following the second vaccine compared to controls ( n = 244;490 vs. 1821 U/ml, p < 0.0001) but increased markedly to 3114 U/ ml after third dose ( n = 51). No difference was observed in relation to the initial vaccine platform received. Multivariate analysis on 486 participants showed that BTKi therapy, history of recurrent infection and low serum antibody levels of IgA or IgM were independent prognostic markers for poor antibody response. Among participants with a detectable antibody response, a marked reduction in the ability to neutralise the delta and omicron variants of concern was noted compared to healthy controls following both the second and third dose of vaccine. Cellular responses were assessed following the second vaccine by IFN-g ELISPOT ( n = 91). Patients who had received the ChAdOx1 vaccine had similar levels to controls ( p = 0.39), while those who had received BNT162b2 had lower levels ( p < 0.0001). Five patients with poor spike-specific antibody responses to vaccination subsequently developed breakthrough infection with SARS-CoV-2 delta variant. Antibody responses and neutralisation remained poor following recovery from infection although T-cell responses were strong and only one patient required hospital admission. CLL-VR is the largest vaccine study conducted in patients with CLL and reveals diminished but comparable antibody responses to both the ChAdOx1 and BNT162b2 vaccines with some improvement following third primary dose of mRNA vaccine. In contrast T-cell responses following second dose are greater in those who received ChAdOx1 platform. Low neutralising activity against the delta and omicron variants highlights an ongoing risk for this vulnerable population despite repeated vaccination and reveals the need for alternative approaches to protection including prophylactic monoclonal antibody therapy..
ABSTRACT
Introduction: Daratumumab in combination with bortezomib and dexamethasone (DVd) demonstrated a superior overall response rates (ORR) and progression free survival (PFS) compared to Vd in the CASTOR phase 3 trial for patients with RRMM. On this basis, DVd was recommended in March 2019 for UK patients with RRMM that had 1 prior line (PL). Discrepancies in outcomes between patients treated in clinical trials compared to routine practice is well recognised due to a combination of patient, disease and treatment-related factors. In addition, bortezomib is often administered once-weekly in routine practice to minimise neuropathy, while CASTOR used bi-weekly bortezomib dosing. As a result, the real-world outcomes of patients treated with DVd are yet to be determined. The primary aims of this analysis was to assess the ORR and PFS for patients with RRMM with 1PL treated with DVd in routine practice. Secondary aims were to assess OS, time to next treatment (TTNT), and efficacy in different sub-groups (high risk cytogenetics, previous proteasome inhibitor (PI) exposure, refractoriness of prior therapies, bi-weekly vs weekly bortezomib schedule, and previous treatment free interval (TFI)). Methods: This was a retrospective analysis from 14 centres (academic and community hospitals;7 within the West Midlands Research Consortium (WMRC)) treated with DVd between March 2019 and June 2021. Patients received daratumumab (IV and then SC from June 2020) weekly in cycles 1-3, on day 1 of a 3-week cycle during cycles 4-8, and then monthly from cycle 9 to progression. SC Bortezomib was predominantly given weekly for cycles 1-8 although 5 centres used bi-weekly dosing for selected patients with aggressive disease. Adverse events were graded as per CTCAE criteria. Results: 288 patients were included, with a median age of 69 years (range 20-88) (Table 1). Patients received a median of 1 PL (range 1-2) with 93% (269) 1PL, 7% (18) 2 PL (due to COVID-19 measures). The majority had an ECOG performance status of 0-2 (98%) and most received weekly bortezomib (n=201). This population differed from those with 1PL treated on CASTOR in being older, more were ISS 3 (31% vs 19%, p=0.0145), and more had prior bortezomib exposure (71% vs 51%, p=0.0003), 4% were PI refractory, 9% had a GFR of <30ml/min (<20ml/min was an exclusion from CASTOR), and 2% had an ECOG performance status of ≥3. The ORR was 76%, with >VGPR in 54% (Table 2), with no significant difference in response between patients receiving biweekly vs weekly bortezomib (85% vs 83%;p=0.71). The median time to response was 1.6m. With a median follow up of 15m, the median PFS was 14m (95% CI 11.6-16). High cytogenetic risk patients had inferior outcomes: median PFS 10m (95% CI 6-14) for high risk vs not reached for standard risk (p=0.043);as did those with advanced ISS: median PFS was not reached, 15 and 12m for stage I, II and III respectively (p=0.05). For 15 patients with extramedullary disease (EMD), the median PFS was 3m (95% CI 1-5). Median PFS for patients who were PI refractory was shorter (10m vs 15m for PI sensitive patients (p=0.006)). There was no difference in median PFS for patients with prior PI exposure vs no prior PI (15 vs 13m;p=0.75), or according to weekly or bi-weekly bortezomib schedule (11 vs 15m;p=0.14). The median TTNT was 21m (95% CI 17-25). Overall, the median duration of treatment was 8m and 25 patients (9%) stopped treatment to receive a second autologous stem cell transplant. Those that had a prior TFI of >12m had a longer median PFS of 21m vs 10m (p=0.0004). The median OS has not been reached, with an estimated 2-year OS of 74%. For patients with high risk cytogenetics the median OS was 16m (95% CI 9-23;vs not reached for standard risk;p=0.0006), with estimated 2-year OS in the high risk group of 36%. There was no difference in OS for patients treated with biweekly vs weekly bortezomib (not reached for either;p=0.38). DVd was generally well tolerated with 6% stopping due to adverse events (CASTOR 9.5%). Grade 3 or 4 toxicity occurred in 62 (22%) most comm nly neutropenia and thrombocytopenia, with any grade infusion reactions reported in 27 (9%). Conclusions: These real-world data of DVd at 1 st relapse demonstrated good tolerability and high response rates with a weekly bortezomib schedule despite a more heterogenous population. However, high risk patients by cytogenetics, ISS or EMD had inferior outcomes as did those treated within 12 months from first line treatment. [Formula presented] Disclosures: Cook: Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria, Research Funding;Oncopeptides: Consultancy, Honoraria;Roche: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding. Pratt: Binding Site: Consultancy;BMS/Celgene: Consultancy;Gilead: Consultancy;Janssen: Consultancy;Takeda: Consultancy;Amgen: Consultancy. Kishore: Celgene: Other: Attending fees;Jannsen: Other: Attending fees;Sanofi: Other: Attending fees;Takeda: Other: Attending fees. Yong: Amgen: Honoraria;Autolus: Research Funding;BMS: Research Funding;Janssen: Honoraria, Research Funding;Sanofi: Honoraria, Research Funding;GSK: Honoraria;Takeda: Honoraria. Popat: Abbvie, Takeda, Janssen, and Celgene: Consultancy;Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;GlaxoSmithKline: Consultancy, Honoraria, Research Funding;AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria;Janssen and BMS: Other: travel expenses.
ABSTRACT
Background: Successful vaccination against SARS-CoV2 is highly effective in preventing serious COVID-19 illness and is particularly recommended for at risk populations including patients with multiple myeloma (MM). However, there is uncertainty to which extent modern intensified therapies targeting plasma cell features might attenuate vaccination responses;some early vaccination recommendations for MM have proposed extended treatment breaks of several weeks to maximise vaccination success. Such an approach can be challenging in UHiR MM and pPCL, where maintaining treatment intensity is hallmark for preventing rapid relapse of the aggressive tumor. To address this uncertainty, we measured post-vaccination serological responses in patients treated uniformly with intensified Dara-VR consolidation and Dara-R maintenance post-ASCT for UHiR NDMM or pPCL in the UK OPTIMUM/MUKnine trial (NCT03188172). Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM or pPCL were recruited to OPTIMUM and received intensified post-ASCT consolidation with Dara-VR(d) for 18 cycles followed by maintenance with Dara-R until progression. In an exploratory analysis, centrally stored serum samples available for patients with a completed and documented vaccination history of two doses of an anti-SARS-CoV2 vaccine were analyzed for serological vaccine responses Total IgG/IgA/IgM Anti-SARS-CoV-2 spike glycoprotein was measured by ELISA (MK654;The Binding Site). As per UK national guidance and local availability, patients received two vaccine doses 12 weeks apart of either tozinameran (Pfizer/Biontech) or vaxzevria (AstraZeneca);serum taken at least 3 weeks after patients received their second dose was analyzed. Results were correlated with baseline characteristics and annotated with treatment and response data. Patient with available matched serological and vaccination status data at time of data cut-off (09 JUL 2021) were included. Collection of vaccination status data is ongoing and updated results comprising additional patients enrolled in OPTIMUM, as well as antigen levels, will be presented. Data will also comprise longitudinal antibody level measurements for patient with available sequential material. Results: Serological vaccine response data was available for 40 OPTIMUM patients with documented completed double vaccination status. Median patient age was 58.5 years (range 39-70) and clinical and molecular tumor features were similar to the overall trial safety population. All patients had received their second dose before June 2021. Of the 40 patients, 42.5% had received tozinameran and 57.5% vaxzevria. Baseline characteristics of the two groups were comparable. At time of second vaccine dose, 55% of patients were receiving Dara-VR consolidation treatment and 45% Dara-R maintenance. There was no recommendation to pause trial treatment for purposes of vaccination and no extended times off treatment for this reason were reported. Overall, 72.5% of patients had a positive vaccine antibody level as per manufacturer cut-point for high specificity evidence of antigen exposure (infection or vaccine). The response rate was nominally higher for vaxzevria (91.3%) than for tozinameran (47.1%), a dysbalance that will be further investigated with ongoing extension of the cohort. Of note, 90% of patients analyzed had reached a complete response (CR) of their MM prior to being vaccinated, and the majority of patients not in CR had a positive vaccine response. Response rates were nominally slightly higher in patients in receipt of Dara-R maintenance at time of second dose with 77.8% compared to Dara-VR consolidation with 68.2%. Conclusions: These results show a high serological response rate to COVID-19 vaccination in UHiR MM patients receiving intensified post-ASCT consolidation and maintenance therapy in remission. Findings suggest that continuation of intensified post-ASCT therapy for patients with aggressive tumors and a high risk of relapse are compatible with serological responses to commonly used COVID-19 vaccines. Disclosures: Jen er: Janssen: Consultancy, Honoraria, Speakers Bureau;BMS/Celgene: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy;Pfizer: Consultancy. Hall: BMS/Celgene: Research Funding;Janssen: Research Funding. Garg: University Hospital Leicester: Current Employment;Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses;Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau;GSK: Consultancy, Honoraria, Speakers Bureau;takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau;amgen: Consultancy, Honoraria, Speakers Bureau;celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau;oncopeptides: Consultancy;Sanofi: Honoraria, Speakers Bureau. Pratt: Binding Site: Consultancy;BMS/Celgene: Consultancy;Gilead: Consultancy;Janssen: Consultancy;Takeda: Consultancy;Amgen: Consultancy. Cook: Karyopharm: Consultancy;Sanofi: Consultancy;Takeda: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;BMS/Celgene: Consultancy, Research Funding;Amgen: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding;Janssen: Consultancy, Other: Educational support, Research Funding;GSK: Consultancy;Karyopharm: Consultancy, Research Funding;Pfizer: Consultancy;Amgen: Honoraria;Seattle Genetics: Consultancy;Takeda: Consultancy, Other: Educational support;AbbVie: Consultancy.
ABSTRACT
B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.
Subject(s)
Antibodies, Viral , Antibody Formation/drug effects , COVID-19 Vaccines , COVID-19 , Immunization, Secondary , Leukemia, Lymphocytic, Chronic, B-Cell , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , Antibodies, Viral/immunology , BNT162 Vaccine , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Male , Middle AgedABSTRACT
We situate the contemporary crisis of COVID-19 deaths in seniors’ care facilities within the restructuring and privatisation of this sector. Through an ethnographic comparison in a for-profit and nonprofit facility, we explore what we identify as brutal and soft modes of privatisation within publicly subsidised long-term seniors’ care in Vancouver, British Columbia, and their influence on the material and relational conditions of work and care. Workers in both places are explicit that they deliver only bare-bones care to seniors with increasingly complex care needs, and we document the distinct forms and extent to which these precarious workers give gifts of their time, labour and other resources to compensate for the gaps in care that result from state withdrawal and the extraction of profits within the sector. We nonetheless locate more humane and hopeful processes in the nonprofit facility, where a history of cooperative relations between workers, management and families suggest the possibility of re-valuing the essential work of care. © 2021 The Authors. Antipode published by John Wiley & Sons Ltd on behalf of Antipode Foundation Ltd