Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
1.
British Journal of Haematology ; 197(SUPPL 1):3, 2022.
Article in English | EMBASE | ID: covidwho-1861225

ABSTRACT

Many patients with haematological cancers remain incompletely protected from SARS-CoV-2 following two doses of vaccine with Pfizer-BioNTech BNT162b2 nCoV-19 or ChAdOx1. Myelodysplastic syndrome (MDS) represents a spectrum of clonal bone marrow neoplasms. The response of patients with MDS to the COVID-19 vaccines remains unknown. Here, we report the humoral and T-cell responses of patients with low-and high-risk myelodysplastic syndrome (MDS), 2 weeks following completion of the second-dose schedules of ChAdOx1 or BNT162b2 nCoV-19 vaccines. Patients with MDS ( n = 38) followed up at Kings College Hospital, London were vaccinated with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccine. Written informed consent was provided. Eligibility criteria included the diagnosis of MDS as per the WHO classification and age ≥18 years. Healthy volunteers (HV;n = 30) served as a reference group. Blood samples were collected 2 weeks after the second vaccine dose. Plasma samples were tested for SARS-CoV-2-specific antibody aimed at the SARS-CoV-2 spike (S) protein receptor-binding domain and neutralisation assays against pseudotypes with SARS-CoV-2 Wuhan strain (WT), VOC.B.1.1.7 (alpha) or VOC.B.1.617.2 (delta) Spike. Cellular responses were assessed using IFNγ ELISPOT and flow cytometry (CD25 and CD69 expression) after 24 h peptide stimulation. IFNγ ELISpot analysis was performed ex vivo for assessment of T-cell response. 32% of the MDS patients received BNT162b2 and 58% received ChAdOx1 nCoV-19 vaccines. All HV received BNT162b2. Overall serological responses were as follows: HV BNT162b2 100% (26/26);MDS BNT162b2 100% (15/15) and MDS ChAdOx1 76.2% (16/21). Notably, the MDS ChAdOx1 cohort demonstrated significantly decreased serological titres to the MDS BNT162b2 cohort. The functional implications of seroconversion were assessed by neutralisation assays for SARS-CoV-2 WT and VOC alpha and delta. All but four MDS patients could neutralise all variant strains, but MDS cohorts showed significantly reduced median neutralisations for all three variant strains compared to HV. Five MDS ChAdOx1 patients who did not have a serological response were able to mount T-cell responses. Additionally, treatment with either azacytidine or calcineurin inhibitor cyclosporin did not impair appropriate T-cell responses. The numbers of individuals who were both serological and T-cell responders were as follows: HV 95% (20/21), MDS BNT162b2 71.4% (10/14) and MDS ChAdOx1 52.9% (9/17). Overall serological responses in the MDS cohorts were 100% for those who had completed the two-dose BNT162b2 vaccine schedule compared to 76.2% of patients vaccinated with the ChAdOx1 vaccine. It may be advisable that MDS patients are boosted with an mRNA-based vaccine to promote enhanced immunity in this specific population. We observed that neutralisation in seroconverted patients was significantly weaker for both the ChAdOx-1 and BNT162b2 MDS cohorts compared to HV. This highlights the continued need for a third primary dose for this clinically vulnerable patient group and our further work will analyse the cohort's response to this.

2.
British Journal of Haematology ; 197:3-3, 2022.
Article in English | Web of Science | ID: covidwho-1798114
3.
Blood ; 138:3696, 2021.
Article in English | EMBASE | ID: covidwho-1736305

ABSTRACT

Myelodysplastic syndromes (MDS) represent a spectrum of clonal bone marrow neoplasms from low risk disease through to those transforming into acute myeloid leukaemia. The COVID-19 pandemic has presented a great risk to those with hematological malignancies who are at higher risk of severe disease and death than the general population. Previous studies looking at the immune response to influenza vaccination in those with MDS had shown promising results, with immune responses not differing from those of healthy family members. Whilst some data exist to reassure the MDS community that majority of patients show seroconversion following Covid-19 vaccination, little data exists on their neutralizing capacity or post vaccination T-cell responses in this cohort. In addition, the majority of patients in these studies received BNT162b2 and there is little published data on vaccine response to the ChAdOx1 nCoV-19 vaccine. We have investigated the humoral and T-cell response of 39 patients with MDS two to four weeks following Covid-19 booster vaccination with BNT162b2 or ChAdOx1 nCoV-19 through the SOAP study (Sars-cov-2 fOr cAncer Patients, IRAS project ID:282337). Plasma and PBMCs from MDS cases and healthy controls have been collected, and are being assessed for both humoral and cellular responses to SARS_CoV_2, the alpha (B.1.1.7) and delta (B.1.617.2) variants. Humoral responses will be assessed using ELISA (peptide binding) and functional viral neutralization assays. Cellular responses will be assessed using IFNy ELISPOT and flow cytometry (CD25 and CD69 expression) after 24h peptide stimulation. All data at time point 1 (2 - 4 weeks following booster vaccination) have been collected and will subsequently be collected at 6 months and 12 months post-vaccination. We also report on the safety data for these vaccines within this patient population. Of this cohort 64% were male with a median age of 65 years (range 21-84). 54% received vaccination with ChAdOx1 nCoV-19 and 44% received BNT162b2 (2% unrecorded). The vaccines were well tolerated with no serious adverse events to date. The mean interval between doses was 70.7 days (range 50 - 90 days). 71% of the cohort were receiving no disease modifying therapy at the time of vaccination, half of whom were receiving supportive therapy and the other half no intervention for their MDS. Of those receiving disease modifying therapy;5 were receiving azacitidine, (1 in conjunction with low-dose cytarabine) and 3 ciclosporin. We will report the largest study of the humoral and T-cell mediated response to the Covid-19 vaccine in MDS patients to date. This will include cellular response to the delta variant and immunogenicity of both the BNT162b2 and ChAdOx1 nCoV-19 vaccines. Given the vulnerability of these patients to severe disease, investigating the immune response to the vaccines begins to build an evidence base for advising MDS patients on their ongoing risk of infection during the pandemic and going forward. The SOAP study will reassess the immune response at 6 and 12 months post-vaccination to continue to investigate post-vaccine immunity in this cohort. Disclosures: Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau;Apellis: Consultancy;Akari: Consultancy, Honoraria, Speakers Bureau;Biocryst: Consultancy, Honoraria, Speakers Bureau;Achilleon: Consultancy, Honoraria, Speakers Bureau;Alexion: Consultancy, Honoraria, Speakers Bureau;Ra Pharma: Consultancy, Honoraria, Speakers Bureau;Amgen: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau;Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Patten: JANSSEN: Honoraria;NOVARTIS: Honoraria;GILEAD SCIENCES: Honoraria, Research Funding;ROCHE: Research Funding;ASTRA ZENECA: Honoraria;ABBVIE: Honoraria.

4.
Blood ; 138:642, 2021.
Article in English | EMBASE | ID: covidwho-1582224

ABSTRACT

Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1;500 mg/m 2 on day 1 of cycles 2-6]) every 28-days or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival,;attainment of undetectable MRD;response to therapy;safety and toxicity;health-related quality of life and cost-effectiveness. A formal interim analysis was planned when 191 events were observed in both arms or 109 events in the FCR arm alone with a p-value of 0.005 leading to reporting of the trial. Here we report the results of this planned interim analysis. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK Centres between 9/19/2014 and 7/19/2018. The data was locked on 5/24/2021. 73.3% were male, median age was 62 years (33.6% >65yo) and 45.1% were Binet Stage C. IGHV data was available for 728 (94.4%) patients with 53.2% IGHV unmutated (≥98% homology to germline), 40.5% IGHV mutated and 6.3% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% 11q del, 12.3% trisomy 12, 29.7% normal and 35% 13q del;with 7.1% failed. The arms were well-balanced for disease variables with no significance differences. Median follow-up was 52.7 months. IR had a superior PFS compared to FCR (Median PFS not reached for IR versus 67 months for FCR;HR: 0.44;p<0.001;see Figure). The PFS was significantly better for IR in patients with IGHV unmutated CLL (HR: 0.41;p<0.001), but not for patients with IGHV mutated CLL at this follow-up (HR: 0.66;p=0.179). There was no difference in overall survival between the two arms (HR: 1.01;p=0.956) with a total of 29 deaths in FCR arm (including 4 from CLL, 3 Richter's [RT], 3 AML/MDS, 3 COVID-19 and 2 cardiac/sudden) and 30 in the IR arm (including 3 CLL, 1 RT, 0 AML/MDS, 3 COVID-19 and 8 cardiac/sudden). Second line treatment was initiated for 59 patients after FCR (including 38 BTKi, 7 venetoclax+R [venR], 4 BendamustineR [BR] and 3 CHOP-R [RT]) and 21 after IR (including 7 FCR, 5 venR, 1 BR, 1 CHOP-R [RT], 1 ABVD [Hodgkin's]). Overall, 88.1% of patients have received targeted therapies for CLL progression after FCR. The overall survival with FCR in FLAIR is significantly improved compared to FCR in previous NCRI trials (ADMIRE and ARCTIC) which had the same inclusion criteria, the same Centres and an identical FCR schedule, but were conducted prior to widespread availability of targeted therapies in the relapse (recruited between 2009 and 2012). The 4 year overall survival for FCR in FLAIR was 94.5% compared to 84.2% for FCR between 2009 and 2012. SAEs were reported in 53.7% of patients on FCR and 53.4% on IR. Notable differences for SAEs by organ class for FCR vs IR: infections in 33.6% of patients vs 27.1%;blood and lymphatic in 19.8% vs 10.7%;and cardiac in 1.1% vs 8.3%. With current follow-up, there were 10 sudden or cardiac deaths: 8 IR and 2 FCR. Further analysis indicated that 7 of the 8 cardiac or sudden deaths in the IR arm had a history of hypertension or cardiac disease (further detailed in additional ;Munir et al.). Neither of the sudden deaths in the FCR arm ad a prior cardiac or hypertensive history or were on cardiac or anti-hypertensive treatment. There were 6 cases of secondary MDS/AML in the FCR arm and 1 in the IR arm. Conclusion: Ibrutinib plus rituximab resulted in a superior PFS compared to FCR. There was no difference in overall survival, most likely due to effective second-line targeted therapy in patients progressing after FCR. [Formula presented] Disclosures: Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding;AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding;Pharmacyclics: Honoraria, Research Funding;Roche: Research Funding;Gilead: Research Funding;SOBI: Honoraria;BeiGene: Honoraria;AstraZeneca: Honoraria. Bloor: Novartis: Honoraria;Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria;AstraZeneca: Honoraria;Janssen-Cilag Ltd: Honoraria;Takeda UK Ltd: Honoraria;Celgene Ltd: Honoraria;Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Kite: Honoraria;Janssen: Honoraria;AbbVie;Takeda: Other: Conference support;Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Paneesha: Celgene: Honoraria;Roche: Honoraria;Janssen: Honoraria;Gilead: Honoraria;Bristol Myers Squibb: Honoraria;AbbVie: Honoraria. Howard: Roche: Current Employment. Cairns: Merck Sharpe and Dohme: Research Funding;Amgen: Research Funding;Takeda: Research Funding;Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria;ROCHE: Research Funding;JANSSEN: Honoraria;ASTRA ZENECA: Honoraria;ABBVIE: Honoraria;GILEAD SCIENCES: Honoraria, Research Funding. Munir: F. Hoffmann-La Roche: Consultancy;Alexion: Honoraria.

5.
Radiotherapy and Oncology ; 161:S241-S242, 2021.
Article in English | EMBASE | ID: covidwho-1492800

ABSTRACT

Purpose or Objective CD19 CAR-T therapy is the most effective salvage treatment for relapsed/refractory DLBCL. However the manufacture of CAR-T cells takes several weeks and patients (pts) are at risk of progression during this time and usually require some form of bridging therapy to contain their disease. Radiotherapy (RT) is an attractive bridging option, as the chance of response to further conventional cytotoxic therapy is low. RT is generally delivered in the window between apheresis and infusion and requires careful scheduling. The aim of this study is to evaluate the feasibility, toxicity and early outcome of bridging RT in a cohort of pts undergoing CAR-T therapy for DLBCL. Materials and Methods This was a prospective analysis of pts receiving bridging RT since the start of CAR-T programme at our institution. We collected data on pt demographics, disease and RT details, as well as outcomes including early response, relapse, survival and toxicity. Results (Table presented.) Between April 2019 & January 2021 a total of 27 pts have received bridging RT. Of these 23 have been infused (1 not infused due to COVID19, 1 due to cardiac function & 2 pending). The CAR-T therapy was delivered in 1 Haematology Institution, but bridging RT in 9 different referring centres. Pt and disease characteristics and RT details are shown in table 1. The median time from CT planning scan to start of RT was 10 days (4-42). The median time between apheresis and start of RT was 5 days (-37-21;3 patients received RT prior to apheresis at -37,-35 &-29 days) and median time between end of RT and CAR-T infusion was 19 days (10-116). No pts were delayed due to RT toxicity. Toxicity data was available for 22 pts. 10 (45.5%) reported no toxicity. Only 1 pt had grade 3 toxicity (vomiting & diarrhoea) and RT was stopped. The most common toxicities were skin reaction (n=5) & fatigue (n=4). 25/27 (92.6%) pts underwent a PET-CT between bridging RT & infusion. In 22 (88%) pts there was response in treatment field (CMR=2, PMR=20). In 13 (59.1%) of those pts there was evidence of progressive disease (PD) outside the field, but none were prevented from receiving CAR-T infusion due to PD. With median FU of 8.8 (0.6-20.6) months from date of CAR-T infusion, 12/ 23 (52.2%) infused pts have relapsed, (2 infield, 5 out of field, 5 in both) with a local control rate of 69.6%;CMR (12;52.2%) and PMR (4;17.4%). 7 pts have died since infusion, 6 due to PD and 1 due to sepsis. Median PFS was 5.1 months (95% CI 0.0-11.9 months) and median OS 17.8 months (95% CI 12.7-22.9 months). 1 pt had infusion delayed due to COVID19 infection and died of PD. Conclusion RT was a safe and effective bridging option in this cohort of DLBCL pts pre CAR-T therapy. With close collaboration between Haematologists and Radiation Oncologists, it is possible to deliver a course of radical dose RT in the narrow window between apheresis and infusion, even across a wide geographical network. Further work is required to determine which pts benefit most from bridging RT and the optimal dose and schedule.

6.
Roeker, L. E.; Scarfo, L.; Chatzikonstantinou, T.; Abrisqueta, P.; Eyre, T. A.; Cordoba, R.; Prat, A. M.; Villacampa, G.; Leslie, L. A.; Koropsak, M.; Quaresmini, G.; Allan, J. N.; Furman, R. R.; Bhavsar, E. B.; Pagel, J. M.; Hernandez-Rivas, J. A.; Patel, K.; Motta, M.; Bailey, N.; Miras, F.; Lamanna, N.; Alonso, R.; Osorio-Prendes, S.; Vitale, C.; Kamdar, M.; Baltasar, P.; Osterborg, A.; Hanson, L.; Baile, M.; Rodriguez-Hernandez, I.; Valenciano, S.; Popov, V. M.; Garcia, A. B.; Alfayate, A.; Oliveira, A. C.; Eichhorst, B.; Quaglia, F. M.; Reda, G.; Jimenez, J. L.; Varettoni, M.; Marchetti, M.; Romero, P.; Grau, R. R.; Munir, T.; Zabalza, A.; Janssens, A.; Niemann, C. U.; Perini, G. F.; Delgado, J.; San Segundo, L. Y.; Roncero, M. I. G.; Wilson, M.; Patten, P.; Marasca, R.; Iyengar, S.; Seddon, A.; Torres, A.; Ferrari, A.; Cuellar-Garcia, C.; Wojenski, D.; El-Sharkawi, D.; Itchaki, G.; Parry, H.; Mateos-Mazon, J. J.; Martinez-Calle, N.; Ma, S.; Naya, D.; Van der Spek, E.; Seymour, E. K.; Vazquez, E. G.; Rigolin, G. M.; Mauro, F. R.; Walter, H. S.; Labrador, J.; De Paoli, L.; Laurenti, L.; Ruiz, E.; Levin, M. D.; Simkovic, M.; Spacek, M.; Andreu, R.; Walewska, R.; Perez-Gonzalez, S.; Sundaram, S.; Wiestner, A.; Cuesta, A.; Broom, A.; Kater, A. P.; Muina, B.; Velasquez, C. A.; Ujjani, C. S.; Seri, C.; Antic, D.; Bron, D.; Vandenberghe, E.; Chong, E. A.; Lista, E.; Garcia, F. C.; Del Poeta, G.; Ahn, I.; Pu, J. J.; Brown, J. R.; Campos, J. A. S.; Malerba, L.; Trentin, L.; Orsucci, L.; Farina, L.; Villalon, L.; Vidal, M. J.; Sanchez, M. J.; Terol, M. J.; De Paolis, M. R.; Gentile, M.; Davids, M. S.; Shadman, M.; Yassin, M. A.; Foglietta, M.; Jaksic, O.; Sportoletti, P.; Barr, P. M.; Ramos, R.; Santiago, R.; Ruchlemer, R.; Kersting, S.; Huntington, S. F.; Herold, T.; Herishanu, Y.; Thompson, M. C.; Lebowitz, S.; Ryan, C.; Jacobs, R. W.; Portell, C. A.; Isaac, K.; Rambaldi, A.; Nabhan, C.; Brander, D. M.; Montserrat, E.; Rossi, G.; Garcia-Marco, J. A.; Coscia, M.; Malakhov, N.; Fernandez-Escalada, N.; Skanland, S. S.; Coombs, C. C.; Ghione, P.; Schuster, S. J.; Foa, R.; Cuneo, A.; Bosch, F.; Stamatopoulos, K.; Ghia, P.; Mato, A. R.; Patel, M..
Blood ; 136:14, 2020.
Article in English | Web of Science | ID: covidwho-1088505
SELECTION OF CITATIONS
SEARCH DETAIL