scholarly journals Factors Associated with Seroconversion after COVID-19 Vaccination in Patients with Hematologic Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3511-3511
Author(s):  
Thomas A. Ollila ◽  
Rebecca Masel ◽  
John L Reagan ◽  
Kimberly Paiva ◽  
Shaolei Lu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Plasma Cell ◽  
Lymphocyte Count ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Categorical Variables ◽  
B Cell Lymphomas ◽  
Cell Antibody ◽  
Active Disease

Abstract Background: Recent studies reported low rates of seroconversion response to COVID-19 vaccination in patients (pts) with hematologic malignancies (HMs). Vaccine choice among the 3 FDA-authorized products (BNT162b2/Pfizer-BioNTech, mRNA-1273/Moderna, or Ad26.COV2.S/J&J), prior therapy, and disease-specific factors may affect seroconversion. Addressing these factors may improve seroconversion rates and identify pts at risk of severe COVID-19 infection despite vaccination. Methods: We conducted a retrospective study of adults with HMs vaccinated in our center between 2/2021 and 7/2021, excluding pts with prior COVID-19 infection. Seroconversion was assessed by the qualitative SARS-CoV-2 Total Antibody Test (IgG/IgM against Receptor Binding Domain [RBD], Wondfo USA, Willowbrook, IL). A subset of samples was tested by the semi-quantitative Abbott AdviseDx SARS-CoV-2 IgG II assay (IgG against RBD). For univariate associations (UVA) we used Fisher's exact test for categorical variables, and fractional polynomial fits for continuous variables to examine non-linearity. Multivariable analysis (MVA) used a robust Poisson model reporting risk ratio (RR) with 95% confidence intervals (CI). Results: Among 239 eligible pts, median age was 70 (range, 28-94), and 112 (47%) were female. HMs included aggressive B-cell lymphomas (n=74, 31%), indolent B-cell lymphomas (n=52, 22%), chronic lymphocytic leukemia (CLL, n=30, 13%), other lymphomas (n-19, 8%), plasma cell neoplasms (n=43, 18%), and myeloid cancers (n=21, 9%); 140 pts (59%) received BNT162b2/Pfizer, 74 (31%) mRNA-1273/Moderna, and 23 (10%) Ad26.COV2.S/J&J vaccines (2 pts had undetermined vaccine type). HM was active in 100 pts (42%), whereas 108 (45%) pts were in remission after treatment, and 31 (13%) on watchful waiting (WW, never treated); 141 (59%) had a prior exposure to an anti-B-cell monoclonal antibody, and 22 (9%) prior stem cell transplantation. Overall, 99 pts (41%; binomial 95% CI, 35-48%) showed post-vaccination seroconversion upon testing at median 10 weeks from first vaccine. Seroconversion was significantly less frequent among pts with lymphomas compared with plasma cell or myeloid neoplasms (overall P=.020; Fig A). It was also less frequent after prior anti-B-cell antibody exposure (29% vs 59%, P<.0001; Fig. B), and in those with active disease (28%, vs 49% for remission [P=.0027], vs 58% for WW [P=.0045]; Fig. C). Furthermore, seroconversion was significantly more frequent after mRNA-1273/Moderna vaccine (57%) compared with BNT162b2/Pfizer (36%, P=.006) or Ad26.COV2.S/J&J (22%, P=.004; Fig. D). It was not associated with age (Fig. E), WBC (Fig. G), or time from vaccination (Fig. I), but was significantly higher with increased lymphocyte count (P<.0001; Fig F) and time elapsed from last chemotherapy (P=.0039; Fig. H). In a MVA (Fig. J), vaccination with mRNA-1273 remained significantly associated with higher rate of seroconversion compared with BNT162b2 (RR=0.59; 95%CI, 0.44-0.79) or Ad26.COV2.S (RR=0.35; 95%CI, 0.16-0.77). Higher seroconversion rate was also associated with remission (RR=1.98; 95%CI, 1.42-2.76) or WW status (RR=1.72; 95%CI 1.02-2.89) compared with active disease, and higher lymphocyte count. Exposure to anti-B-cell antibodies remained associated with lack of seroconversion (RR=0.66; 95%CI, 0.44-0.99). Seroconversion was borderline less frequent in CLL than lymphomas, and higher with plasma cell or myeloid disorders. Results were similar in the subset of pts (n=191) with prior treatment, adjusting for time from last chemotherapy(data not shown). The anti-COVID-19 IgG titers on semiquantitative test (n=47, all after mRNA-based vaccines) were also lower in pts with active disease compared with those in remission (P=.065) or under WW (P=.028), and in those with prior anti-B-cell antibody (P=.0095). Conclusions: Pts with HMs demonstrate overall low rates of seroconversion after vaccination against COVID-19, particularly when they have active disease or are on/after B-cell depleting monoclonal antibody therapy. The mRNA vaccines (particularly mRNA-1273) appear to have elicited superior responses compared with the adenovirus-based product. Pts with active HMs or those within 2 years of last therapy should be particularly aware of the risk of infection despite vaccines and should be considered for strategies to enhance anti-COVID-19 immunity regardless of age. Figure 1 Figure 1. Disclosures Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

scholarly journals Does Trauma Heighten the Risk of Hematologic Malignancies? a Retrospective Study of U.S. Combat Veterans

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4130-4130
Author(s):  
Christin Destefano ◽  
Krista Shaw ◽  
Ian Stewart ◽  
Eduard Poltavskiy ◽  
Kevin Chung ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Plasma Cell ◽  
Combat Veterans ◽  
Medical Center ◽  
Hematologic Malignancies ◽  
B Cell Lymphomas ◽  
Traumatic Injuries ◽  
Plasma Cell Dyscrasias

Introduction: Multiple case reports have described lymphomas and plasma cell neoplasms developing after trauma 1-4. It has been hypothesized that trauma-induced inflammation may contribute to the neoplasia, and that the site of trauma may serve as the nidus (locus minoris resistentiae) 1, 5. However, to our knowledge there are no studies demonstrating causality. Traumatic injuries sustained during combat have been linked with higher rates of hypertension, coronary artery disease, diabetes mellitus and chronic kidney disease 6. Whether severe injury also increases the risk of hematologic malignancies is unknown. We hypothesized that combat injured veterans have higher rates of lymphoma and plasma cell dyscrasias than un-injured combat veterans. Methods: This was a retrospective cohort study of US military personnel injured during combat operations in Iraq or Afghanistan from 2002-2015 extracted from the Department of Defense (DoD) Trauma Registry. Patients were excluded if they died in theater, had multiple battle injuries, had pre-existing cancer diagnoses or missing data. A comparator arm of deployed and un-injured Iraq and Afghanistan combat veterans was obtained from the Military Health System Data Repository (MDR) matched for year of birth, branch of service, and sex. Cancer diagnoses were defined using International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) Clinical Modification codes obtained from both the DoD and the Veterans Health Administration through the MDR and the Veterans Informatics and Computing Infrastructure, respectively. Malignancy classifications by ICD codes are demonstrated in Table 1 and broken down into aggressive B-cell lymphomas, indolent B-cell lymphomas, Hodgkin lymphoma, T-cell lymphomas and plasma cell dyscrasias. Statistical analyses were performed with the chi-square test and fisher's exact test. This study was approved by the IRB at David Grant USAF Medical Center. Results: There were 9,654 subjects each in the injured and un-injured cohorts. Baseline demographics are demonstrated in Table 2. The mean age was 26 and most patients were junior enlisted, members of the Army, males, and of non-Hispanic white ethnicity/race. The average post-trauma follow-up time was 5.3 years. Overall rates of aggressive B-cell lymphomas, indolent B-cell lymphomas, Hodgkin lymphoma, T-cell lymphomas and plasma cell dyscrasias were low, as demonstrated in Table 3, and there were no statistically significant differences in incidence rates between the two cohorts. Discussion: Traumatic injuries can activate innate immune responses involving inflammatory cytokines, complement, coagulation and dendritic cells, resulting in a pro-inflammatory state 7. Preclinical studies reveal that such inflammation may hamper T-cell immune-surveillance needed to eradicate malignancy 8. However, in our cohort of severely injured combat veterans, rates of lymphomas and plasma cell dyscrasias were not increased over un-injured combat veterans. Strengths of this study include a well-characterized cohort with a matched comparator arm enabling vigorous examination of the impacts of traumatic injuries on cancer. Limitations include retrospective design and relatively short follow up. It is possible that differences will emerge with longer follow up. Conclusions: Despite critical combat trauma injuries being associated with a heightened risk of multiple chronic comorbidities, they do not appear to heighten the risk of lymphoid or plasma cell neoplasms within the first 5-years. The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the U.S. Air Force, David Grant USAF Medical Center, the Uniformed Services University or the Department of Defense. References: 1. Kriwalsky MS, Oral Surg, 2010. 2. Huang J, Medicine, 2019. 3. Stemberga V, Hematol Oncol, 2003. 4. Erdogan B, Eur Spine J, 2005. 5. Lo Schiavo A, Clin Dermatol, 2014. 6. Stewart IJ, Circulation, 2015. 7. Huber-Lang M, Nature Immunology, 2018. 8. Krall J, Science, 2018. Disclosures No relevant conflicts of interest to declare.

scholarly journals Advances and Perspectives in the Treatment of B-Cell Malignancies

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2266
Author(s):  
Marta Cuenca ◽  
Victor Peperzak
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Plasma Cell ◽  
Heterogeneous Group ◽  
B Cell Differentiation ◽  
B Cell Lymphomas ◽  
B Cell Malignancies ◽  
Plasma Cell Dyscrasias

B-cell malignancies arise from different stages of B-cell differentiation and constitute a heterogeneous group of cancers including B-cell lymphomas, B-cell leukemias, and plasma cell dyscrasias [...]

scholarly journals Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas

Blood ◽  
1987 ◽  
Vol 69 (2) ◽  
pp. 584-591 ◽  
Author(s):  
OW Press ◽  
F Appelbaum ◽  
JA Ledbetter ◽  
PJ Martin ◽  
J Zarling ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Lymph Node ◽  
B Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
B Cell Lymphomas ◽  
Antigenic Modulation ◽  
Minor Response ◽  
High Doses ◽  
Anti Cd20

Abstract Four patients with refractory malignant B cell lymphomas were treated with continuous intravenous (IV) infusions of murine monoclonal antibody (MoAb) 1F5 (anti-CD20) over five to ten days. Dose-dependent levels of free serum 1F5 were detected in all patients. Two patients had circulating tumor cells and in both cases 90% of malignant cells were eliminated from the blood stream within four hours of initiation of serotherapy. Antigenic modulation did not occur, and sustained reduction of circulating tumor cells was observed throughout the duration of the infusions. Serial bone marrow aspirations and lymph node biopsies were examined by immunoperoxidase and immunofluorescence techniques to ascertain MoAb penetration into extravascular sites. High doses (100 to 800 mg/m2/d and high serum 1F5 levels (13 to 190 micrograms/mL) were required to coat tumor cells in these compartments in contrast to the low doses that were adequate for depletion of circulating cells. Clinical response appeared to correlate with dose of MoAb administered with progressive disease (52 mg), stable disease (104 mg), minor response (1,032 mg), and partial response (2,380 mg) observed in consecutive patients. The patient treated with the highest 1F5 dose achieved a 90% reduction in evaluable lymph node disease, but the duration of this remission was brief (six weeks). This study demonstrates that high doses of 1F5 can be administered to patients with negligible toxicity by continuous infusion and that clinical responses can be obtained in patients given greater than 1 g of unmodified antibody over a ten-day period.

scholarly journals Enhancer mutations of Akv murine leukemia virus inhibit the induction of mature B-cell lymphomas and shift disease specificity towards the more differentiated plasma cell stage

Virology ◽  
2007 ◽  
Vol 362 (1) ◽  
pp. 179-191 ◽  
Author(s):  
Karina Dalsgaard Sørensen ◽  
Sandra Kunder ◽  
Leticia Quintanilla-Martinez ◽  
Jonna Sørensen ◽  
Jörg Schmidt ◽  
...  
Keyword(s):  
B Cell ◽  
Plasma Cell ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
B Cell Lymphomas ◽  
Cell Stage ◽  
Disease Specificity ◽  
Murine Leukemia

scholarly journals Autoantibody Inhibitor Eradication In Acquired Hemophilia Associated with Cancer: a Retrospective Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1418-1418 ◽  
Author(s):  
Khendi T White ◽  
Anita Aggarwal ◽  
Marisanta Napolitano ◽  
Craig M. Kessler
Keyword(s):  
B Cell ◽  
Solid Tumor ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Acquired Hemophilia ◽  
Term Survival ◽  
Fviii Inhibitor ◽  
Underlying Malignancy ◽  
Fviii Activity

Abstract Abstract 1418 Introduction: Acquired hemophilia (AH), a rare autoimmune disorder primarily of adults, is typically characterized by the presence of IgG oligoclonal antibodies to the clotting factor VIII protein (FVIII). About 10–15% of patients with AH have an underlying malignancy, but the etiologic relationship of cancer to formation of FVIII inhibitor is yet to be determined. To date, there have been no published, comprehensive reviews on the efficacy of various treatments for AH in the context of either solid tumor or hematologic malignancies. Therefore, we have systematically reviewed 86 patients with cancer-associated AH from our own cancer center and from the published literature. Methods: The literature search for this systematic review was performed using PubMed MEDLINE, Ovid MEDLINE, CINAHL, SCOPUS, and Embase. The search terms included various combinations of “acquired”, “cancer”, “factor VIII”, “hemophilia A”, “autoantibodies”, and “treatment.” The major criterion for inclusion was a diagnosis of cancer before or within three months after appearance of acquired inhibitor. Both solid and hematologic malignancies were included. Any report that did not document a FVIII inhibitor titer and/or FVIII activity was excluded. Success in inhibitor eradication has been defined as undetectable inhibitor and normalization of FVIII activity. All articles with an abstract in English published in the period from January 1985 to July 2010 were considered. Results: 86 cases of AH were collected and analyzed according to classification of cancer and efficacy of treatments for inhibitor and malignancy. The mean age is 67.8 years. 74% of patients were of Caucasian or European background, 8% were of Asian descent, and 2% were of African descent. AH was associated with solid malignancy in 50 cases (58%) and hematologic malignancy in 36 cases (42%). Among all AH cases, 15% and 14% of patients had lymphoma and CLL, respectively. Of the solid tumors, lung and prostate carcinoma (each 12%) occurred with the greatest frequency followed by colorectal (9%) and bladder (5%). Not all patients had treatment for their underlying cancer, bleeding and/or inhibitor. Complete eradication (CE) of inhibitor was achieved in 48 patients (56%), no eradication (NE) in 22 (26%), and 16 (18%) had unknown status. Of the 73% of patients with CE, 22 were treated with chemotherapy, 10 were treated with surgery, and 1 with both (Table 1). In this series, there was a trend towards successful inhibitor eradication with treatment of B-cell lymphoproliferative malignancies as well as lung and prostate cancer. Long term survival was best achieved when successful CE and treatment of underlying malignancy occurred concurrently. Conclusions: This literature and case series suggests that AH is associated almost equally with hematological and solid tumor malignancies. These retrospective data suggest that treatment of the cancer with chemotherapy or surgery is very likely to induce eradication of the autoantibody inhibitor. There is a trend for increased success in CE in B-cell lymphoproliferative malignancies and selected solid tumors. Long term survival appears dependent on concurrent CE and treatment of the cancer. Disclosures: Kessler: Grifols S.A.: Research Funding; Baxter-Immuno: Research Funding; NovoNordisk: Research Funding.

scholarly journals A Prospective Study and Identification of Genomewide Association Markers of Familial Predisposition to Plasma Cell Dyscrasias

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Adam S Sperling ◽  
Rebecca Georgakopoulou ◽  
Mehmet Kemal Samur ◽  
Christine Ivy Liacos ◽  
Brittany E Sandoval ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
B Cell ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Advisory Committees ◽  
Familial Predisposition ◽  
Plasma Cell Dyscrasias ◽  
Second Degree

Introduction: An increased inherited risk for the development of plasma cell dyscrasias (PCDs) has long been suspected, however to date, only a limited number of potential genomic risk loci have been described. To characterize the inherited risk and facilitate identification of additional risk loci it is important to combine detailed pedigrees with extensive genetic analysis. To identify familial PCDs we initiated a prospective study with active recruitment of a large cohort of patients with PCDs and active screening of their relatives combined with tissue banking and subsequent genetic analysis. Methods: All patients in the Department of Clinical Therapeutics diagnosed with PCDs between January 2017 and January 2019, were offered enrollment in the study. Following informed consent, 1st and 2nd degree relatives over the age of 30 were eligible for screening. A detailed family pedigree was created for each index case with special focus on family history of PCDs, B-cell lymphomas, or other hematologic or solid malignancies. As a control, subjects' spouses were also screened. Screening included serum protein electrophoresis with immunofixation. In families where an additional member was identified with a PCD or B-cell malignancy, peripheral blood was collected from consenting family members over the age of 18 for further genetic analysis. Samples from affected individuals were profiled using whole genome sequencing (WGS) and unaffected individuals were genotyped using Axiom Arrays. Data were analyzed using Axion Array Suite and plink and GATK toolkit with BWA. Results: Of 1,084 patients screened for participation in the study; 752 had multiple myeloma (MM), 77 had smoldering MM, 81 a monoclonal gammopathy of undetermined significance, 93 Waldenström's Macroglobulinemia and 81 had AL amyloidosis. 176 (16.2%) patients refused to participate in the study, while 44 (4.1%) patients were ineligible for further screening due to the absence of a living first- or second-degree relative. The median number of screened first or second-degree relatives per index patient was 3 (range 1 to 10). The median age of index cases was 65 years, offspring was 37 years, second-degree relatives was 65 years, and spouses was 65 years. The incidence of a PCD among second-degree relatives was 4.5%, while it was 0.6% among offspring. As a control group, the incidence of PCDs among spouses was 2.6%. Overall at least one additional member (beyond the index patient) with a monoclonal gammopathy was detected in 98 families (11.3%). In 57 families (6.6%) there was a positive history of at least one additional first- or second-degree relative with a PCD or B-cell malignancy. In addition, 41 new cases of monoclonal gammopathy (4.7%) were identified through the screening process associated with this study. To identify genetic loci that could be associated with a predisposition to development of PCDs, genetic analysis was performed on the most heavily affected 18 families, those with at least three affected members or with early onset disease (i.e. PCD diagnosed before age 50). We have evaluated 838,750 SNPs from 103 samples from 18 families. 30 samples were from affected members and 73 from unaffected members. We found eight SNPs (rs13233413, rs11648113, rs59444635, rs148480125, rs113556240, rs11547122, rs671880, rs4726610) that are significantly enriched in affected members with a p-value below the suggestive cut-off of <1e-5. The top candidate was in the untranslated region (UTR) of TSPAN33, a marker of activated and malignant B-cells. We did not detect any significant enrichment in germline mutations in previously reported genes associated with familial PCD risk such as KDM1a, KRAS or DIS3. Functional annotation of the 8 SNPs identified here showed that rs148480125, located in the promoter region of the apoptosis regulator SIVA1, is predicted to impact the allele specific expression level. Further validation work is ongoing. Conclusions: Our active prospective screening approach to identify familial predisposition to PCDs revealed that 11.3% of patients had families with at least one additional affected member and some families had a substantially higher incidence of PCDs with earlier onset. Study of these high-risk families have identified genomewide association markers which in future may help us define familial predisposition to plasma cell dyscrasias. Disclosures Gavriatopoulou: Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria. Munshi:Janssen: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; C4: Current equity holder in private company; Adaptive: Consultancy. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

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