ABSTRACT
Introduction: Patients (pts) with hematological malignancies (HMs) are at increased risk for severe COVID19 infection and death (Grivas, 2021). Currently, vaccination represents the most effective prevention approach. HM pts have been shown to have lower immune responses to COVID19 vaccine, particularly those with lymphoid malignancies (LMs) (Herishanu, 2021;Thakkar 2021;Tzarfari 2021). We conducted an observational cohort study at Moffitt Cancer Center (MCC) to evaluate the immune response following one and two doses of the mRNA1273 (Moderna) vaccine in cancer pts. Here we report the results for pts with LMs and assessed associated factors. Methods: MCC pts who presented for the first mRNA-1273 vaccine dose from 1/12/2021-1/25/2021 and who provided consent were enrolled. Blood samples were collected prior to the 1 st and 2 nd doses (Days 1 and 29) and ~28 days after the 2 nd dose (Day 57). The IgG response against the SARS-CoV-2 spike (S) protein was measured using a two-step ELISA adapted from the Krammer (Icahn School of Medicine at Mount Sinai) protocol. The total 103 LM pts who received both vaccine doses and had samples at all time points were included in analyses. The 214 pts with solid tumors (ST) were included as comparison. Associations of seroconversion (SV) rates with pt characteristics were evaluated using the Fisher exact test or Chi-square test as appropriate. Associations of antibody (Ab) titers with pt characteristics were examined using Kruskal Wallis test. Factors independently associated with SV rates were evaluated using multivariable logistic regression. All analyses were performed using SAS 9.4 and R studio. Results: Baseline characteristics, cancer treatments and SV rates by these factors are listed in Tables 1 and 2. 55 pts had B-cell non-Hodgkin lymphoma (B-NHL), 23 had chronic lymphocytic leukemia (CLL), 15 had T- or NK-cell lymphoma (T/NK lymphoma) and 10 had Hodgkin lymphoma (HL). SV rates were significantly lower for LM pts compared to ST pts (49.5% vs 86.9% after the 1st dose and 68.9% vs 98.1% after the 2 nd dose, respectively, p<0.0001 for both doses). Pts with CLL and B-NHL had the lowest SV rates (21.7% and 43.6% after dose 1 and 65.2% and 58.2% after dose 2, respectively). None of the 11 pts on anti-CD20 monoclonal Ab (mAb) seroconverted after 2 doses. Pts on BTK inhibitors (BTKi) or PI3K inhibitors (PI3Ki) or venetoclax also had low SV rates [4/12 (33.3%) after 2 doses]. Only 1 out of the 8 pts post CAR-T seroconverted, despite the fact that 6 pts had CAR-T >12 months ago and 6 pts were in remission and have not received any cancer treatment after CAR-T. Pts with CLL and B-NHL but not on CD20 mAb/BTKi/PI3Ki/venetoclax or post CAR-T had much higher SV rates (31.3-60.5% after dose 1 and 79.0-81.3% after dose 2, Table 3). Other factors associated with lack of SV after 2 doses included: lymphocyte <1 x 10 9/L, low IgG level and on anticancer treatment within 3 months. Multivariate analyses showed that diagnosis of CLL or B-NHL compared to ST, CAR-T and CD20 mAb/BTKi/PI3Ki/venetoclax were independently associated with decreased SV after 2 doses (Table 4). In the univariate model, Ab titers after 1 and 2 doses were significantly lower in pts with diagnosis of CLL/B-NHL, low lymphocyte count, low IgG and on cancer treatment (Figures 1-3). HL and T/NK lymphoma had titers comparable to solid tumors (Figure 1). Conclusions: Pts with CLL and B-NHL had low SV rates and Ab titers after receiving the mRNA-1273 vaccine when compared with ST, HL and T/NK-lymphoma. Current or past treatments with CD20 mAb/BTKi/PI3Ki/venetoclax and CAR-T were associated with lower immune response, with pooled SV rates of 16.7% after 2 doses. In general, LM pts had lower SV rates and Ab titers after the 1 st dose vs ST, but responses improved after the 2 nd dose. Further studies are needed to improve immune responses to COVID19 vaccines in LM pts, including the potential role of a 3 rd booster dose. [Formula presented] Disclosures: Gaballa: Adaptive Biotechnologies: Research Funding;Epizyme: Consultancy, Resear h Funding;TG therapeutics: Consultancy, Speakers Bureau;Beigene: Consultancy;ADC Therapeutics: Consultancy. Saeed: Bristol-Myers Squibb Company: Consultancy;sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator;Celgene Corporation: Consultancy, Other: investigator;MEI Pharma Inc: Consultancy, Other: investigator;Kite Pharma: Consultancy, Other: investigator;Other-TG therapeutics: Consultancy, Other: investigator;Nektar Therapeutics: Consultancy, Other: research investigator;MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees;Other-Epizyme, Inc.: Consultancy;Other-Secura Bio, Inc.: Consultancy;Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shah: Pharmacyclics/Janssen: Honoraria, Other: Expenses;Pfizer: Consultancy, Other: Expenses;BeiGene: Consultancy, Honoraria;Servier Genetics: Other;Jazz Pharmaceuticals: Research Funding;Precision Biosciences: Consultancy;Amgen: Consultancy;Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding;Acrotech/Spectrum: Honoraria;Novartis: Consultancy, Other: Expenses;Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses;Adaptive Biotechnologies: Consultancy;Incyte: Research Funding. Locke: Janssen: Consultancy, Other: Scientific Advisory Role;BMS/Celgene: Consultancy, Other: Scientific Advisory Role;EcoR1: Consultancy;Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding;Calibr: Consultancy, Other: Scientific Advisory Role;Amgen: Consultancy, Other: Scientific Advisory Role;Bluebird Bio: Consultancy, Other: Scientific Advisory Role;Umoja: Consultancy, Other;Cowen: Consultancy;Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding;Emerging Therapy Solutions: Consultancy;Gerson Lehrman Group: Consultancy;Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy;Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role;GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role;Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role;Wugen: Consultancy, Other;Takeda: Consultancy, Other;Novartis: Consultancy, Other, Research Funding;Legend Biotech: Consultancy, Other. Chavez: Abbvie: Consultancy;AstraZeneca: Research Funding;Kite/Gilead: Consultancy;Karyopharm Therapeutics: Consultancy;MorphoSys: Speakers Bureau;Epizyme: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau;Merck: Research Funding;Adaptive: Research Funding;BeiGene: Speakers Bureau;Novartis: Consultancy;ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: AbbVie: Consultancy;ElevateBio Management: Consultancy;Daiichi Sankyo: Consultancy;Celgene/BMS: Consultancy;Millenium Pharma/Takeda: Consultancy;BerGenBio: Consultancy;Agios: Consultancy;Astellas: Consultancy;Jazz: Consultancy. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees;Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory;Sellas: Other: ), patents/royalties/other intellectual property;MEI, Sunesis: Research Funding;AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau. Giuliano: Merck & CO: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
ABSTRACT
Background: Patients (pts) with cancer are at higher risk for complications and mortality related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although mRNA vaccines have been granted Food and Drug Administration emergency use authorization (EUA) for prevention of COVID-19, the pivotal trials largely excluded pts with active cancer. Emerging data suggests suboptimal efficacy of these vaccines in pts with hematologic malignancies. There are also theoretical concerns that programmed cell death protein 1 inhibitors (PD-1i) could potentiate vaccine-related adverse events (AEs);conversely, these vaccines could activate the immune system, increasing the risk for immune-related reactions (IRRs) after PD-1i treatment. Pts with classic Hodgkin lymphoma (cHL) receiving PD-1i represent a unique cohort and should be investigated for safety and efficacy issues with SARS-CoV-2 vaccines. Methods: We conducted a retrospective analysis of pts with cHL who were treated with PD-1i within the past 12 months. Our primary objective was to determine the frequency of vaccine-related AEs and also subsequent IRRs to PD-1i after vaccination as reported in the medical records. Our secondary objective was to determine efficacy based on post-vaccine COVID-19 infection rates and by presence of adequate receptor binding domain (RBD) IgG antibody level to the SARS-CoV-2 spike protein. This assay was a clinically available institutional assay developed under EUA. While the level of antibody that is associated with immune protection has not yet been defined, we used RBD IgG > 0.700 AU as positive since it was previously correlated with virus neutralization titer in vitro. Results: From July 1, 2020 through June 31, 2021, we identified 27 pts who received PD-1i for cHL and were seen at the University of Pennsylvania. Seventeen (63%) pts received nivolumab and 10 (37%) received pembrolizumab. The median age was 42 years (23-86), median number of therapies was 4 (2-15), and 7 (26%) had prior history of COVID-19 infection (none required hospitalization). Twenty-three pts (85% of total) were vaccinated: 17 (74%) received Pfizer-BioNTech BNT162b2 and 6 (26%) had Moderna mRNA-1273 formulations. Of 19 (83%) pts who received at least one dose of PD-1i prior vaccine, the median time between last PD-1i infusion and first vaccine administration was 20 days (2-157). Of 19 (83%) pts who received any PD-1i after vaccine, the median time to infusion was 18 days (4-89). In pts who had prior COVID-19 infection, the median time between the prior infection and vaccine was 91 days (range 78-350). There were no unexpected toxicities noted and no severe adverse events or hospitalizations directly related to vaccination. No patient discontinued the vaccination series due to side effects. In 12 vaccinated pts who had vaccine-related AEs solicited by the medical provider, 7 (58%) developed injection site reaction/pain: grade 1 (6/12) and grade 2 (1/12). Six (50%) pts had systemic AEs: grade 1 fatigue (4/12), grade 2 fatigue (1/12), transient generalized lymphadenopathy (1/12), fever (1/12). No new IRRs occurred in pts receiving subsequent PD-1i after vaccination. Two weeks after second vaccination, 1 patient developed worsening cough with imaging suggestive of pneumonitis but improved with antibiotics. There were no post-vaccine COVID-19 infections noted. RBD IgG antibody levels were available in 12/23 (52%) of all vaccinated pts;11/12 (92%) pts had positive antibody titers. The only patient who did not mount positive RBD IgG antibody titers received brentuximab vedotin concurrently with PD-1i prior to vaccination. There were insufficient events to correlate pre-vaccine factors with AEs or efficacy. Conclusion: Pts with relapsed/refractory cHL on PD-1i who received SARS-CoV-2 vaccines had no unexpected toxicities and tolerated subsequent PD-1i without new IRRs. The efficacy based on post-vaccination COVID-19 rates and RBD IgG levels is encouraging in these heavily pretreated pts. We plan an additional prospective component of this study using atient reported outcomes and long-term safety and efficacy follow-up. Disclosures: Svoboda: Incyte: Research Funding;Genmab: Consultancy;Merck: Research Funding;Pharmacyclics: Consultancy, Research Funding;BMS: Consultancy, Research Funding;TG: Research Funding;Imbrium: Consultancy;Seattle Genetics: Consultancy, Research Funding;Astra Zeneca: Consultancy, Research Funding;Atara: Consultancy;Adaptive: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding;Merck: Other: Data safety monitoring board;Incyte: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Membership on an entity's Board of Directors or advisory committees;Pharmacyclics: Research Funding;ATARA: Research Funding;Millenium: Research Funding;Rafael: Research Funding;Debiopharm: Research Funding. Ruella: AbClon: Consultancy, Research Funding;BMS, BAYER, GSK: Consultancy;Novartis: Patents & Royalties;Tmunity: Patents & Royalties;viTToria biotherapeutics: Research Funding. Landsburg: Triphase: Research Funding;Takeda: Research Funding;Curis: Research Funding;ADCT: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member;Morphosys: Membership on an entity's Board of Directors or advisory committees. Barta: Seagen: Honoraria;Daiichi Sankyo: Honoraria;Acrotech: Honoraria;Kyowa Kirin: Honoraria. Gerson: TG Therapeutics: Consultancy;Kite: Consultancy;Abbvie: Consultancy;Pharmacyclics: Consultancy. Schuster: Loxo Oncology: Consultancy;Nordic Nanovector: Consultancy;Genentech/Roche: Consultancy, Research Funding;Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Acerta Pharma/AstraZeneca: Consultancy;BeiGene: Consultancy;Juno Theraputics: Consultancy, Research Funding;Tessa Theraputics: Consultancy;Pharmaclyclics: Research Funding;Abbvie: Consultancy, Research Funding;Alimera Sciences: Consultancy;Adaptive Biotechnologies: Research Funding;Merck: Research Funding;Incyte: Research Funding;TG Theraputics: Research Funding;DTRM: Research Funding.
ABSTRACT
Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is require to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. [Formula presented] Disclosures: Gerson: TG Therapeutics: Consultancy;Kite: Consultancy;Abbvie: Consultancy;Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding;Celgene/BMS: Research Funding;BeiGene: Research Funding;Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy;BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Takeda: Research Funding;Genentech: Consultancy;AstraZeneca: Speakers Bureau;Roche: Consultancy;Karyopharm: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding;AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharma: Consultancy, Honoraria;Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Honoraria, Speakers Bureau;TG Therapeutics: Consultancy, Honoraria, Research Funding;Incyte: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Genmab: Consultancy, Honoraria;Epizyme: Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau;Servier Pharmaceuticals: Consultancy;Seattle Genetics: Speakers Bureau;Sanofi: Speakers Bureau;Pharmacyclics: Consultancy;MorphoSys: Consultancy;Kite (Gilead): Speakers Bureau;KaryoPharm: Consultancy;CSL Therapeutics: Consultancy;Bristol-Myers Squibb: Speakers Bureau;Biogen: Consultancy;Beigene: Consultancy;AstraZeneca: Speakers Bureau;ADC Therapeutics: Consultancy;Adaptive Biotechnologies: Consultancy;AbbVie: Consultancy. Grover: Genentech: Research Funding;Novartis: Consultancy;ADC: Other: Advisory Board;Kite: Other: Advisory Board;Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months;BMS: Divested equity in a private or publicly-traded company in the past 24 months;Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months;Novatis: Divested equity in a private or publicly-traded company in the past 24 months;Janssen: Divested equity in a private or publicly-traded company in the past 24 months;Morphosys: Divested equity in a private or publicly-traded company in the past 24 months;ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months;Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months;Beigene: Divested equity in a private or publicly-traded company in the past 24 months;Merck: Divested equity in a private or publicly-traded company in the past 24 months;KITE: Divested equity in a private or publicly-traded company in the past 24 months;Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support;Humanigen: Consultancy, Honoraria, Other: Travel support;Celgene: Consultancy, Honoraria, Other: Travel support;Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding;Lonza: Consultancy, Honoraria, Other: Travel support;AbbVie: Consultancy, Honoraria;Precision Biosciences: Consultancy, Honoraria, Other: Travel support;Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support;Nkarta: Consultancy, Honoraria;Axis: Speakers Bureau;Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy;Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.