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Blood ; 138(SUPPL 1):316, 2021.
Article in English | EMBASE | ID: covidwho-1770200


The efficacy of COVID-19 vaccines in cancer populations remain unknown. Myeloproliferative neoplasms (MPNs), including chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) remain a vulnerable patient population and are immunocompromised due to impaired innate and adaptive immunity, heightened inflammation, and effects of ongoing treatment. We evaluate antibody and T-cell responses in MPN patients following completion of the BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccine series. Patients with a known diagnosis of MPN presenting at Massachusetts General Hospital and eligible for COVID-19 vaccination were recruited. All participants gave informed consent and the study protocol was approved by the Institutional Review Board. 33 MPN patients were enrolled and 23 patients completed vaccination. Baseline and post-vaccination peripheral blood samples were collected and peripheral blood mononuclear cells (PBMCs) isolated. 26 vaccinated participants with no history of malignancy were included as healthy controls (PMID 33972942). Baseline characteristics are tabled below. Qualitative ELISA for human IgG/A/M against SARS-CoV-2 spike protein using donor serum was performed per manufacturer instructions. Seroconversion occurred in 22/23 (96%) of MPN patients and 25/26 (96%) of healthy controls (Figure). To measure SARS-CoV-2 T-cell immunity, an IFNγ ELISpot assay previously developed in convalescent and vaccinated healthy individuals was used. Freshly isolated PBMCs from patients were stimulated with commercially available overlapping 15mer peptide pools spanning the SARS-CoV-2 spike and nucleocapsid proteins. Given its size, the spike protein was split into two pools (Spike A or B). IFNγ-producing T-cells were quantified by counting the median spot forming units (SFU) per 2.5x10 5 PBMCs from duplicate wells. A positive threshold was defined as >6 SFUs per 2.5x105 PBMCs to either Spike A or B after subtraction of background, based on prior receiver operator curve (ROC) analysis of ELISpot responses (sensitivity 90% specificity 92%). Post-vaccination ELISpot responses occurred in 21/23 (91%) of MPN patients and 26/26 (100%) of healthy controls (p=0.99) (Figure). The median SFU to total spike protein (Spike A+B) increased after vaccination in both MPN patients (0 to 38, p=0.02) and healthy controls (6 to 134, p=0.002). MPN patients had significantly lower median SFU's on post-vaccination ELISpot compared to healthy controls (38 vs 134, p=0.044), although this was not significant after adjusting for age in multivariable logistic regression. MF patients had the lowest seroconversion and ELISpot response rates, and lowest median post-vaccination SFUs, although this was not significant. There were no other differences in post-vaccination SFUs with regards to gender, vaccine type, number of days postvaccine, treatment, and absolute lymphocyte count. Whole-blood assay based on the in vitro diagnostic QuantiFERON TB Gold Plus assay was also used to assess T-cell response. Heparinized whole blood from donors was stimulated with S1 and S2 subdomains for the SARS-CoV-2 spike protein, with measurement of IFNγ released into plasma with the QuantiFERON ELISA. IFNγ release of >0.3 IU/mL was considered a positive threshold, based on prior ROC analysis (sensitivity and specificity 100%). MPN patients had significantly lower IFNγ response rates compared to healthy controls (57% versus 100%, p=0.003) (Figure). Our findings demonstrate robust antibody and T-cell responses to BNT162b2 and mRNA-1273 vaccination in MPN patients, with >90% serologic and ELISpot responder rates. We detected subtle differences in T-cell responses in MPN patients compared to healthy controls. MPN patients had lower median post-vaccination ELISpot SFUs and lower rates of T-cell responses on IFNγ-whole blood assay compared to healthy controls. As the whole blood assay uses whole protein antigen rather than peptide pools, differences from ELISpot testing may reflect deficiencies in antigen pr cessing and presentation. It is unclear whether these subtle differences translate into less clinical protection from COVID-19, or to what extent our results are confounded by the older age of MPN patients. Further evaluation of B and T-cell responses to COVID-19 vaccination in a larger sample size of MPN patients is warranted.

Blood ; 138:1508, 2021.
Article in English | EMBASE | ID: covidwho-1582236


[Formula presented] Background: Coronavirus disease-2019 (COVID-19) is an inflammatory, multisystem infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) and is associated with increased risk of thrombosis, particularly among critically ill patients. The myeloproliferative neoplasms (MPNs) include Philadelphia chromosome-negative (Ph-negative) MPNs polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), and Philadelphia-chromosome positive chronic myeloid leukemia (CML). Patients with MPNs, especially PH-negative, have increased risk of thrombotic complications. Given the increased propensity of thrombosis and prognostic significance of thrombosis in both COVID and MPNs, defining the risk of thrombotic complications in this patient population compared to the general population is important. Methods: Using an institutional database within the Mass General Brigham integrated health network, we retrospectively analyzed 63 consecutive patients with MPN who were ≥ 18 years old and tested positive for SARS-COV-2 infection based on polymerase chain reaction (PCR) testing from March 1, 2020 to January 1, 2021. We compared patients admitted to the hospital in our “MPN cohort” with patients admitted to the hospital from a separate COVID-19 (non-MPN cohort) Mass General Brigham registry of 1114 consecutive patients who tested positive for SARS-COV-2 infection based on PCR testing from March 13, 2020 to April 3, 2020. Care was taken to ensure the cohorts were mutually exclusive. The 90-day primary outcome for MPN cohort was a composite of all-cause death, any thrombosis (composite of arterial and venous thromboembolism [VTE]), International Society on Thrombosis and Haemostasis (ISTH) defined major and clinically relevant non-major bleeding. To identify risk factors for primary outcome in MPN cohort we used a multivariable logistic regression using age, sex, hospital admission status, MPN type, cytoreduction for MPN, hypertension, smoking status, baseline anticoagulation (AC), prior thrombosis (stroke, myocardial infarction or VTE) as co-variables. The 90-day outcomes of interest in our MPN vs non-MPN cohort analysis were any thrombosis, death, ISTH major and clinically relevant non-major bleeding and readmission for any reason. To assess impact of MPN status in hospitalized patients in our MPN vs non-MPN comparison, we used a multivariable logistic regression using age, sex, race, Hispanic ethnicity, ICU admission, treatment with steroids and/or Remdesivir, baseline AC and aspirin use, prior thrombosis (stroke, myocardial infarction or VTE), diabetes, heart failure, admission hematocrit, platelet count and D-dimer as co-variables. Continuous variables were compared using student t-test and categorical variables were compared using Fischer's Exact Test with a p value of < 0.05 considered significant. Results: Of the 63 patients with MPN (23 with PV, 17 ET, 4 PMF, 15 CML, 4 other), 27 (43%) were admitted to the hospital for COVID-19 and 5 (8%) required ICU admission. The mean age of all MPN patients was 66, 84% were White, 8% Black and 10% Hispanic. Primary 90-day outcome occurred in 12 (19%) of MPN patients. In multivariable analysis, only admission to hospital was associated with increased odds of composite (aOR 21.11, 95% CI 2.38 - 546.40), Figure 1A. In patients with (n = 27) and without MPN (n = 399) who were admitted to the hospital, patients with MPN were older (mean age 70 vs 61, p = 0.0076), more likely to be White (89% vs 54%, p = 0.0004) and less likely to be Hispanic (7% vs 29%, p = 0.0158), less likely to be admitted to the ICU (19% vs 43%, p = 0.0138), and more likely to be treated with corticosteroids (30% vs 14%, p = 0.025) or remdesivir (41% vs 13%, p < 0.0001). After multivariable logistic regression, diagnosis of MPN was significantly associated with increased odds of thrombosis (aOR 5.38, 95% CI 1.15-25.38) and readmission (aOR 6.28, 95% CI 1.60-24.88), but not bleeding (aOR 3.51, 95% CI 0.62-18.87) or death (aOR 4.29, 95% CI 0.95-18.9 ), Figure 1B. Conclusions: Thrombotic complications are common in patients with MPN and COVID-19, particularly if hospitalized for COVID-19. After multivariable analysis, MPN patients admitted for COVID-19 had a significantly increased risk of thrombotic complications compared with non-MPN patients. [Formula presented] Disclosures: Al-Samkari: Dova/Sobi: Consultancy, Research Funding;Novartis: Consultancy;Argenx: Consultancy;Rigel: Consultancy;Amgen: Research Funding;Agios: Consultancy, Research Funding;Moderna: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding;BMS: Consultancy, Research Funding;Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees;Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fathi: Agios/Servier: Consultancy, Other: Clinical Trial Support;BMS: Consultancy, Other: Clinical Trial Support;AbbVie: Consultancy, Other: Clinical Trial Support;Pfizer: Consultancy;Trillium: Consultancy;Kura: Consultancy;Blueprint Medicines Corporation: Consultancy;Genentech: Consultancy;Novartis: Consultancy;Trovagene: Consultancy;Daiichi Sankyo: Consultancy;Novartis: Consultancy;Morphosys: Consultancy;Kite: Consultancy;Foghorn: Consultancy;Takeda: Consultancy;Amgen: Consultancy;Seattle Genetics: Consultancy;NewLink Genetics: Consultancy;Forty Seven: Consultancy;Ipsen: Consultancy. Goldhaber: Bayer: Consultancy, Research Funding;Boehringer-Ingelheim: Consultancy, Research Funding;BMS: Research Funding;Boston Scientific BTG EKOS: Research Funding;Daiichi: Research Funding;Janssen: Research Funding;Pfizer: Consultancy, Research Funding;Agile: Consultancy. Piazza: Portola: Research Funding;Bayer: Research Funding;Amgen: Research Funding;BMS: Research Funding;Janssen: Research Funding;BSC: Research Funding. Hobbs: Celgene/Bristol Myers Squibb: Consultancy;Novartis: Consultancy;Merck: Research Funding;Constellation Pharmaceuticals: Consultancy, Research Funding;Bayer: Research Funding;Incyte Corporation: Research Funding;AbbVie.: Consultancy.

Blood ; 136:4-5, 2020.
Article in English | EMBASE | ID: covidwho-1344058


Characterization of molecular alterations in acute myeloid leukemia (AML) has led to development of targeted therapies, including FLT3 and IDH1/2 inhibitors. Maintenance therapy following hematopoietic cell transplantation (HCT) has shown substantial promise. Enasidenib (ENA), a selective IDH2 inhibitor, was associated with impressive rates of response in relapsed/refractory (R/R) AML and is now FDA-approved for this indication. We sought to assess the tolerability and define the maximum tolerated dose (MTD) of ENA as maintenance following HCT for IDH2-mutated myeloid malignancy. HCT-eligible patients (pts) ≥ 18 years with AML in remission, or myelodysplastic syndrome (MDS) with <5% marrow blasts, were enrolled. There were no restrictions on conditioning or donor type. A 2-step registration process was utilized;1 before HCT and 1 before ENA initiation. Before HCT, pts were required to have normal organ and recovered marrow function (neutrophils > 1000/µL and platelets > 50000/µL). Those with prior HCT, active disease, QTc ≥450ms, and active infections were excluded. ENA was initiated between day 30 and 90 after HCT, at which time the following were required: chimerism ≥70% of donor origin among blood/marrow cells, no acute graft versus host disease (aGVHD) requiring ≥0.5mg/kg/day prednisone or equivalent, and no relapse. ENA was taken orally (po) daily (qd) in 28-day cycles. The period for dose-limiting toxicity (DLT) evaluation was the first cycle, escalation to successive levels was guided by DLT incidence, and 2 levels (50mg,100mg) were studied. Following establishment of MTD or recommended phase 2 dose (RP2D), 10 pts would be enrolled in an expansion cohort. Pts were monitored for relapse and toxicity and continued until disease progression, intolerable toxicity, or receipt of 12 cycles. Nineteen pts have been registered prior to HCT at 3 sites, Massachusetts General Hospital, Dana Farber Cancer Institute, and Johns Hopkins Hospital. Three pts could not initiate ENA following HCT;2 due to logistic challenges of the COVID pandemic and 1 due to relapse. The remaining 16 pts initiated ENA treatment. The median age was 61 years (range 31-76);12 (75%) were male, and 13 (81%) were Caucasian. Fourteen (88%) had AML, of which 6 were AML with MDS related changes and 2 had antecedent myeloproliferative neoplasm. Two pts (13%) had MDS. Among these 16 pts, 9 (56%) had IDH2 R140, and 5 (25%) had IDH2 R172 mutations. IDH2 subtype data was unavailable for 2 pts. Of 15 pts with available data from time of diagnosis, 11 (73%) had intermediate-risk and 4 (27%) had adverse-risk cytogenetics. Among these 15 pts, common concurrent mutations were DNMT3A (47%), SRSF2 (33%), and RUNX1 (33%). Eleven AML pts (85%) received intensive versus non-intensive therapies (15%) prior to HCT, and among all pts, 7 (44%) had received ENA prior to HCT. HCT data was available for all 16 pts;4 pts (25%) received myeloablative, and 12 (75%) received reduced-intensity conditioning. Nine pts (56%) had a matched unrelated, 6 (38%) had haploidentical, and 1 (6%) had a matched related donor HCT. Three pts were enrolled at the 50mg dose level, 6 pts at 100mg, and after no DLTs were detected, the remaining were enrolled in an expansion cohort at 100mg qd. Median follow-up (F/U) for surviving patients is currently 11.7 months (range 1.5-18.9). 2 pts (13%) have relapsed during F/U, at 96 and 364 days post HCT. Additional ≥grade (G) 3 toxicities detected during treatment, possibly or probably related to ENA, included neutropenia, anemia, and bilirubinemia. Six pts (38%) required dose interruptions lasting a median 19 days (range 7-25), 4 required a dose reduction to 50mg, and 1 stopped treatment due to G3 bilirubinemia. In total, 3 pts (18%) discontinued study treatment, 1 for aforementioned G3 bilirubinemia, 1 to pursue a GVHD trial, and 1 for relapse. Six pts have completed the 12-month f/u without relapse, and 7 remain on study. 15 of 16 pts remain alive. Thus far, 3 pts have experienced ≥ G2 aGVHD, and 4 had moderate chronic GVHD. Serial me surement of 2HG is being conducted on samples, and these will be reported. Enasidenib is well-tolerated as post-HCT maintenance therapy for myeloid malignancy at the RP2D of 100mg qd. No DLTs have been detected, and a low rate of post-HCT relapse has been identified to date, although longer f/u is needed. Larger, randomized studies of ENA in the post-SCT setting would determine the true efficacy of this agent as maintenance therapy. Disclosures: Fathi: Blueprint: Consultancy;Jazz: Consultancy;Amgen: Consultancy;Newlink Genetics: Consultancy;Pfizer: Consultancy;Abbvie: Consultancy;Seattle Genetics: Consultancy, Research Funding;Agios: Consultancy, Research Funding;PTC Therapeutics: Consultancy;Takeda: Consultancy, Research Funding;Boston Biomedical: Consultancy;Amphivena: Consultancy;BMS/Celgene: Consultancy, Research Funding;Kite: Consultancy;Trovagene: Consultancy;Forty Seven: Consultancy;Novartis: Consultancy;Daiichi Sankyo: Consultancy;Astellas: Consultancy;Trillium: Consultancy;Kura Oncology: Consultancy. Soiffer: Gilead: Consultancy;Novartis: Consultancy;Juno: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;VOR Biopharma: Consultancy;alexion: Consultancy;Rheos Therapeutics: Consultancy;Cugene: Consultancy;Precision Bioscience: Consultancy;Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Kiadis: Membership on an entity's Board of Directors or advisory committees;Mana Therapeutics: Consultancy. Levis: Menarini: Honoraria;Amgen: Honoraria;FujiFilm: Honoraria, Research Funding;Astellas: Honoraria, Research Funding;Daiichi-Sankyo: Honoraria. Mims: Novartis: Speakers Bureau;Kura Oncology: Membership on an entity's Board of Directors or advisory committees;Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study;Agios: Consultancy;Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees;Jazz Pharmaceuticals: Other: Data Safety Monitoring Board;Abbvie: Membership on an entity's Board of Directors or advisory committees. Devine: Magenta Therapeutics: Consultancy. Defilipp: Incyte: Research Funding;Regimmune: Research Funding;Syndax Pharmaceuticals: Consultancy. Spitzer: Jazz Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees;Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Frigault: Celgene: Consultancy;Arcellx: Consultancy;Novartis: Consultancy, Research Funding;Gilead/Kite: Consultancy, Research Funding. Amrein: Amgen: Research Funding;AstraZeneca: Consultancy, Research Funding;Takeda: Research Funding. Hobbs: Incyte: Research Funding;Merck: Research Funding;Bayer: Research Funding;Constellation: Honoraria, Research Funding;Jazz: Honoraria;Celgene/BMS: Honoraria;Novartis: Honoraria. Brunner: Janssen: Research Funding;Acceleron Pharma Inc.: Consultancy;GSK: Research Funding;Xcenda: Consultancy;Takeda: Consultancy, Research Funding;Novartis: Consultancy, Research Funding;Jazz Pharma: Consultancy;Forty Seven, Inc: Consultancy;Celgene/BMS: Consultancy, Research Funding;Biogen: Consultancy;Astra Zeneca: Research Funding. Narayan: Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months;Takeda: Other: Prior Spouse employment within 24 months;Sanofi-Genzyme: Other: Current Spouse employment. Chen: AbbVie: Other: Data and Safety Monitoring Board Member;Incyte Corporation: Consultancy;Takeda: Consultancy;Actinium: Other: Data and Safety Monitoring Board Member;Equillium: Other: Data and Safety Monitoring Board Member;Magenta: Consultancy;Kiadis: Consultancy. OffLabel Disclosure: Enasidenib as post-transplant maintenance therapy