Humoral and cellular immunogenicity of SARS-CoV-2 vaccines in chronic lymphocytic leukemia: a prospective cohort study.

Chronic lymphocytic leukemia (CLL), the most common leukemia worldwide, is associated with increased COVID-19 mortality. Previous studies suggest only a portion of vaccinated CLL patients develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies. Whether the elicited antibodies are functional and/or accompanied by functional T-cell responses is unknown. This prospective cohort study included patients with CLL who received SARS-CoV-2 and PCV13 vaccines (not concurrently). The primary cohort included adults with CLL off therapy. Coprimary outcomes were serologic response to SARS-CoV-2 (receptor binding domain [RBD] immunoassay) and PCV13 vaccines (23-serotype IgG assay). Characterization of SARS-CoV-2 antibodies and their functional activity and assessment of functional T-cell responses was performed. Sixty percent (18/30) of patients demonstrated serologic responses to SARS-CoV-2 vaccination, appearing more frequent among treatment-naïve patients (72%). Among treatment-naïve patients, an absolute lymphocyte count ≤24 000/µL was associated with serologic response (94% vs 14%; P < .001). On interferon-γ release assays, 80% (16/20) of patients had functional spike-specific T-cell responses, including 78% (7/9) with a negative RBD immunoassay, a group enriched for prior B-cell-depleting therapies. A bead-based multiplex immunoassay identified antibodies against wild-type and variant SARS-CoV-2 (α, ß, γ, and δ) in all tested patients and confirmed Fc-receptor binding and effector functions of these antibodies. Of 11 patients with negative RBD immunoassay after vaccination, 6 (55%) responded to an additional mRNA-based vaccine dose. The PCV13 serologic response rate was 29% (8/28). Our data demonstrate that SARS-CoV-2 vaccination induces functional T-cell and antibody responses in patients with CLL and provides the framework for investigating the molecular mechanisms and clinical benefit of these responses. This trial was registered at www.clinicaltrials.gov as #NCT05007860.

Association of Thrombosis With Hypereosinophilic Syndrome in Patients With Genetic Alterations.

Importance: Hypereosinophilic syndromes (HESs) are a rare group of disorders that result in overproduction of eosinophils, leading to tissue damage. Thrombotic complications in HES and associated risk factors in this patient population have not been extensively studied. Objective: To investigate the rates of and risk factors associated with thrombotic events in patients with HES, including markers of clonal hematopoiesis as evidenced by molecular aberrations on next-generation sequencing. Design, Setting, and Participants: This retrospective cohort study evaluated patients seen at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, from January 1, 2015, to January 1, 2020. Patients who had hypereosinophilia with an absolute eosinophil count of 1500 cells/µL or greater on 2 separate occasions at least 1 month apart and who underwent genetic or molecular testing as part of their work-up were included. Patients with secondary eosinophilia were excluded. Main Outcomes and Measures: Symptomatic and asymptomatic arterial and venous thrombotic events after the diagnosis of HES and all-cause death. Results: A total of 71 patients (median age, 58 years [interquartile range (IQR), 43-67 years]; 36 women [51%]; 57 White patients [80%]) were included. Patients had a median follow-up time of 29 months (IQR, 19-49 months). Seventeen patients (24%) had 1 or more thrombotic events, including 11 venous thromboembolic events and 11 arterial thrombotic events (8 patients had ≥1 event and 3 patients had recurrent events). Patients with 1 or more thrombotic events had a higher median Eastern Cooperative Oncology Group performance status (median, 1 [IQR, 1-2] vs 0 [IQR, 0-1]; P = .002), had more frequent cardiac involvement (7 of 17 events [41%] vs 6 of 54 events [11%]; P = .01), more frequently received treatment (17 of 17 events [100%] vs 40 of 54 events [74%]; P = .02), and had more molecular aberrations on next-generation sequencing (12 of 17 [71%] vs 12 of 54 [26%]; P = .003) vs patients without thrombosis. After multivariable analysis, the presence of molecular aberration was associated with increased odds of thrombosis (adjusted odds ratio, 5.4; 95% CI, 1.1-27.7). Death occurred more frequently in patients with thrombotic events compared with those without (6 of 17 [35%] vs 2 of 54 [4%]; P = .002) and in patients with molecular aberrations compared with those without (6 of 24 [25%] vs 1 of 40 [3%]; P = .009), although only thrombotic events were significantly associated with increased odds of death after multivariable analysis. Conclusions and Relevance: In this cohort study, thrombosis was common in patients with HES and was significantly associated with increased risk of death.

A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies.

Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy delays, dose reductions, and discontinuation. There is no FDA-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romiplostim treatment pathways at 4 U.S. centers. The primary outcome was achievement of a romiplostim response [median on-romiplostim platelet count (Plt) ≥75x109/L and ≥30x109/L above baseline]. Secondary outcomes included time to Plt≥100x109/L and rates of the following: Plt<100x109/L, Plt<75x109/L, Plt<50x109/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare weekly dosing with intracycle/intermittent dosing. 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of 4 (range, 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays and 89% avoided platelet transfusions. Median per-patient Plt on romiplostim was significantly higher than baseline (116x109/L vs. 60x109/L, P<0.001). Bone marrow tumor invasion, prior pelvic irradiation, and prior temozolomide predicted romiplostim non-response. Bleeding rates were lower than historical CIT cohorts and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose reductions/treatment delays (IRR 3.00, 95% CI 1.30-6.91, P=0.010) or bleeding (IRR 4.84, 95% CI 1.18-19.89, P=0.029). Blunted response (10% response rate) was seen in non-myeloid hematologic malignancy patients with bone marrow involvement. In conclusion, romiplostim was safe and effective for CIT in most solid tumor patients.

A Clinical Prediction Model to Assess Risk for Chemotherapy-Related Hospitalization in Patients Initiating Palliative Chemotherapy.

IMPORTANCE: Chemotherapy-related hospitalizations in patients with advanced cancer are common, distressing, and costly. Methods to identify patients at high risk of chemotherapy toxic effects will permit development of targeted strategies to prevent chemotherapy-related hospitalizations. OBJECTIVE: To demonstrate the feasibility of using readily available clinical data to assess patient-specific risk of chemotherapy-related hospitalization. DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study conducted from January 2003 through December 2011 at the Mass General/North Shore Cancer Center, a community-based cancer center in northeastern Massachusetts. The parent cohort included 1579 consecutive patients with advanced solid-tumor cancer receiving palliative-intent chemotherapy. Case patients (n = 146) included all patients from the parent cohort who experienced a chemotherapy-related hospitalization. Controls (n = 292) were randomly selected from 1433 patients who did not experience a chemotherapy-related hospitalization. EXPOSURES: Putative risk factors for chemotherapy-related hospitalization-including patient characteristics, treatment characteristics, and pretreatment laboratory values-were abstracted from medical records. Multivariable logistic regression was used to model the patient-specific risk of chemotherapy-related hospitalization. MAIN OUTCOMES AND MEASURES: Chemotherapy-related hospitalization, as adjudicated by the oncology clinical care team within a systematic quality-assessment program. RESULTS: A total of 146 (9.2%) of 1579 patients from the parent cohort experienced a chemotherapy-related hospitalization. In multivariate regression, 7 variables were significantly associated with chemotherapy-related hospitalization: age, Charlson comorbidity score, creatinine clearance, calcium level, below-normal white blood cell and/or platelet count, polychemotherapy (vs monotherapy), and receipt of camptothecin chemotherapy. The median predicted risk of chemotherapy-related hospitalization was 6.0% (interquartile range [IQR], 3.6%-11.4%) in control patients and 14.7% (IQR, 6.8%-22.5%) in case patients. The bootstrap-adjusted C statistic was 0.71 (95% CI, 0.66-0.75). At a risk threshold of 15%, the model exhibited a sensitivity of 49% (95% CI, 41%-57%) and a specificity of 85% (95% CI, 81%-89%) for predicting chemotherapy-related hospitalization. CONCLUSIONS AND RELEVANCE: In patients initiating palliative chemotherapy for cancer, readily available clinical data were associated with the patient-specific risk of chemotherapy-related hospitalization. External validation and evaluation in the context of a clinical decision support tool are warranted.

Dabigatran: a review of clinical and pharmacoeconomic evidence.

Dabigatran etexilate is the first commercially available oral direct thrombin inhibitor. A single trial has studied patients at risk for stroke associated with nonvalvular atrial fibrillation; in this trial, dabigatran 150 mg twice a day met the criteria for superiority over warfarin in preventing stroke and systemic embolism while reducing the rate of hemorrhagic stroke with a similar risk of major bleeding. For the treatment of venous thromboembolism, dabigatran 150 mg twice a day had comparable efficacy and safety versus warfarin. In contrast, dabigatran was less effective than enoxaparin 30 mg twice a day in venous thromboembolism prevention in orthopedic surgery. Advantages of dabigatran over warfarin include its lack of need for routine laboratory monitoring, a fixed-dose regimen, and potentially fewer clinically important drug interactions. Concerns include higher incidences of dyspepsia and gastrointestinal bleeding, twice-daily dosing, and lack of effective antidote. Additional drawbacks include higher drug cost versus warfarin, accumulation in case of renal impairment, higher discontinuation rates due to adverse events, and limited long-term safety and trial data. From a payer perspective, overall costs will be higher with dabigatran compared with warfarin, but dabigatran does meet the threshold to be considered a cost-effective therapy. In addition, the lack of need for regular laboratory monitoring is a quality of life advantage for patients on dabigatran. These observations suggest that dabigatran is a valuable addition to the therapeutic armamentarium for stroke prevention in selected patients with atrial fibrillation although caution should be exercised given the limited data on this agent and higher cost.

Variable contribution of monoclonal antibodies to ADCC in patients with chronic lymphocytic leukemia.

Monoclonal antibodies (mAbs) are increasingly used in treatment protocols for chronic lymphocytic leukemia (CLL). Here we determined (i) the extent of antibody-dependent cellular cytotoxicity (ADCC) of four different mAbs against primary CLL cells, (ii) whether ADCC correlates with antigen density on CLL cells, and (iii) whether allogeneic natural killer (NK) cells display superior ADCC than autologous. Effector cells for ADCC were (i) NK-92 cells not expressing FcR, (ii) NK-92 cells transfected with a high-affinity Fc receptor, (iii) autologous NK cells from patients with CLL, (iv) allogeneic NK cells. Results suggest that ADCC contributes to killing of CLL cells by anti-CD20 antibodies (rituximab and veltuzumab), whereas mAbs against CD22 (epratuzumab) and CD23 (lumiliximab) showed minimal ADCC. The magnitude of anti-CD20 mediated ADCC did not correlate with antigen density of CD20. ADCC was not influenced by the FcR genotype expressed by autologous NK cells. Allogeneic NK cells were superior to autologous NK cells in killing primary CLL cells.

Electronic medical devices: a primer for pathologists.

CONTEXT: Electronic medical devices (EMDs) with downloadable memories, such as implantable cardiac pacemakers, defibrillators, drug pumps, insulin pumps, and glucose monitors, are now an integral part of routine medical practice in the United States, and functional organ replacements, such as the artificial heart, pancreas, and retina, will most likely become commonplace in the near future. Often, EMDs end up in the hands of the pathologist as a surgical specimen or at autopsy. No established guidelines for systematic examination and reporting or comprehensive reviews of EMDs currently exist for the pathologist. OBJECTIVE: To provide pathologists with a general overview of EMDs, including a brief history; epidemiology; essential technical aspects, indications, contraindications, and complications of selected devices; potential applications in pathology; relevant government regulations; and suggested examination and reporting guidelines. DATA SOURCES: Articles indexed on PubMed of the National Library of Medicine, various medical and history of medicine textbooks, US Food and Drug Administration publications and product information, and specifications provided by device manufacturers. STUDY SELECTION: Studies were selected on the basis of relevance to the study objectives. DATA EXTRACTION: Descriptive data were selected by the author. DATA SYNTHESIS: Suggested examination and reporting guidelines for EMDs received as surgical specimens and retrieved at autopsy. CONCLUSIONS: Electronic medical devices received as surgical specimens and retrieved at autopsy are increasing in number and level of sophistication. They should be systematically examined and reported, should have electronic memories downloaded when indicated, will help pathologists answer more questions with greater certainty, and should become an integral part of the formal knowledge base, research focus, training, and practice of pathology.