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Multiple asparaginase products have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of acute lymphoblastic leukemia in pediatric and adult patients. Hepatic veno-occlusive disease (VOD) is a potentially life-threatening disorder resulting from damage to the liver sinusoidal endothelial cells. To evaluate this safety concern with asparaginase (i.e. Asparlas, Oncaspar, Rylaze, and Erwinaze) use, we performed a postmarketing review of hepatic VOD reports retrieved from the FDA Adverse Event Reporting System database and literature with these four products. We identified 55 cases of hepatic VOD following exposure to asparaginase products. The median time to onset of hepatic VOD from the first dose of asparaginase was 18 days (interquartile range 13-24 days). Notably, 80% (44/55) of cases reported grades 3-5 VOD per the Common Terminology Criteria for Adverse Events. Although patients received asparaginase with standard chemotherapeutic agents known to induce VOD, case-level data indicates that asparaginase products may have contributed to hepatic VOD. Asparaginase products are associated with hepatotoxicity and thrombosis, suggesting a plausible mechanism for asparaginase-induced hepatic VOD. Based on the totality of data, including temporality and biologic plausibility, we determined hepatic VOD to be a class effect with asparaginase products. These data contributed to the addition of hepatic VOD to the hepatoxicity warning in the US Prescribing Information for asparaginase class products.
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Imunoterapia Adotiva , Linfoma de Células T , Segunda Neoplasia Primária , Humanos , Linfócitos B/imunologia , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células B/epidemiologia , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfoma de Células T/epidemiologia , Linfoma de Células T/imunologia , Incidência , Fatores de Risco , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/imunologiaRESUMO
BACKGROUND: Current hemovigilance methods generally rely on survey data or administrative claims data utilizing billing and revenue codes, each of which has limitations. We used electronic health records (EHR) linked to blood bank data to comprehensively characterize red blood cell (RBC) utilization patterns and trends in three healthcare systems participating in the U.S. Food and Drug Administration Center for Biologics Evaluation and Research Biologics Effectiveness and Safety (BEST) initiative. METHODS: We used Information Standard for Blood and Transplant (ISBT) 128 codes linked to EHR from three healthcare systems data sources to identify and quantify RBC-transfused individuals, RBC transfusion episodes, transfused RBC units, and processing methods per year during 2012-2018. RESULTS: There were 577,822 RBC units transfused among 112,705 patients comprising 345,373 transfusion episodes between 2012 and 2018. Utilization in terms of RBC units and patients increased slightly in one and decreased slightly in the other two healthcare facilities. About 90% of RBC-transfused patients had 1 (~46%) or 2-5 (~42%)transfusion episodes in 2018. Among the small proportion of patients with ≥12 transfusion episodes per year, approximately 60% of episodes included only one RBC unit. All facilities used leukocyte-reduced RBCs during the study period whereas irradiated RBC utilization patterns differed across facilities. DISCUSSION: ISBT 128 codes and EHRs were used to observe patterns of RBC transfusion and modification methods at the unit level and patient level in three healthcare systems participating in the BEST initiative. This study shows that the ISBT 128 coding system in an EHR environment provides a feasible source for hemovigilance activities.
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Registros Eletrônicos de Saúde , Transfusão de Eritrócitos , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Estados Unidos , Eritrócitos , Idoso , Produtos Biológicos/uso terapêutico , Bancos de Sangue/normas , Bancos de Sangue/estatística & dados numéricos , AdolescenteRESUMO
Background: Population-based survival studies of adult acute myeloid leukemia (AML) have not simultaneously evaluated age at diagnosis, race and ethnicity, sex, calendar period or AML subtypes/subgroups among chemotherapy-treated patients. Methods: For 28,473 chemotherapy-treated AML patients diagnosed at ages ≥20 years in population-based cancer registry areas of the Surveillance, Epidemiology, and End Results Program (2001-2018, followed through 2019), we evaluated 1-month through 5-year relative survival (RS) and 95% confidence intervals (95% CI) using the actuarial method in the SEER∗Stat Survival Session and overall survival (OS) using multivariable Cox regression to estimate proportional hazard ratios (HR) and 95% CI. Findings: RS decreased with increasing age (20-39, 40-59, 60-74, 75-84, ≥85 years) at AML diagnosis. RS declined substantially within the first month and, except for acute promyelocytic leukemia, decreasing patterns continued thereafter for core binding factor AML, AML with antecedent condition/therapy, and all other AML. For all ages, acute promyelocytic leukemia RS stabilized after the first year. For total AML the hazard of death was significantly increased for non-Hispanic (NH)-Black (HR = 1.18, 95% CI = 1.12-1.24) and NH-Pacific Islander patients (HR = 1.31, 95% CI = 1.11-1.55) compared with NH-White patients. In contrast, NH-Asian and Hispanic patients had similar OS to NH-White patients across all ages and most AML subgroups. Males had significantly inferior survival to females with some exceptions. Compared to 2001-2006, in 2013-2018 OS improved for all age and AML subgroups. Interpretation: Chemotherapy-treated U.S. adults with AML have notable differences in survival by age, race and ethnicity, sex, calendar-year period, and AML subgroup. Despite survival gains over time, our findings highlight the need for improving early outcomes across all AML subgroups, older ages, and Black and Pacific Islander patients and long-term outcomes among most treated groups. Funding: Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology.
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Isatuximab is a CD38-directed antibody indicated for the treatment of relapsed or refractory multiple myeloma. The Division of Pharmacovigilance at the U.S. Food and Drug Administration (FDA) reviewed case reports from postmarketing sources, including the FDA Adverse Event Reporting System (FAERS), PubMed, and Embase, to investigate a potential association between isatuximab and the risk of varicella zoster virus (VZV) reactivation. We identified 20 reports of which 15 met our case definition and causality criteria. All 15 patients (80% male, median age = 60 years) received isatuximab for a hematologic neoplasm; eight (53%) for previously untreated multiple myeloma. All cases described additional risk factors for VZV reactivation, including concomitant proteasome inhibitor and/or immunomodulatory drug (n = 10, 67%) use. Based on this postmarket analysis, the U.S. Prescribing Information for isatuximab was updated to include this new safety information, including recommendations for antiviral prophylaxis.
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Herpes Zoster , Mieloma Múltiplo , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Herpesvirus Humano 3 , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Herpes Zoster/induzido quimicamente , Herpes Zoster/tratamento farmacológicoRESUMO
Efforts to reduce global cancer disparities begin with an understanding of geographic patterns in cancer incidence, mortality, and prevalence. Using the GLOBOCAN (2002) and Cancer Incidence in Five Continents databases, we describe overall cancer incidence, mortality, and prevalence, age-adjusted temporal trends, and age-specific incidence patterns in selected geographic regions of the world. For the eight most common malignancies-cancers of lung, breast, colon and rectum, stomach, prostate, liver, cervix, and esophagus-the most important risk factors, cancer prevention and control measures are briefly reviewed.In 2002, an estimated 11 million new cancer cases and 7 million cancer deaths were reported worldwide; nearly 25 million persons were living with cancer. Among the eight most common cancers, global disparities in cancer incidence, mortality, and prevalence are evident, likely due to complex interactions of nonmodifiable (ie, genetic susceptibility and aging) and modifiable risk factors (ie, tobacco, infectious agents, diet, and physical activity). Indeed, when risk factors among populations are intertwined with differences in individual behaviors, cultural beliefs and practices, socioeconomic conditions, and health care systems, global cancer disparities are inevitable. For the eight most common cancers, priorities for reducing cancer disparities are discussed.
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Background: Historically, survivors of common lymphoid neoplasms (LNs) had increased risks for therapy-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML). Despite major treatment advances in the treatment of LNs over the last two decades, a comprehensive evaluation of tMDS/AML trends following both common and rare LNs treated in this contemporary period is lacking. Methods: In US cancer registries during 2000-2018, we identified 1496 tMDS/AML cases among 186,503 adults who were treated with initial chemo/immunotherapy for first primary LN and survived ≥1 year. We quantified tMDS/AML standardized incidence ratios (SIRs), excess absolute risks (EARs, per 10,000 person-years), and cumulative incidence. Findings: The highest tMDS/AML risks occurred after precursor leukemia/lymphoma (SIR = 39, EAR = 30), Burkitt leukemia/lymphoma (SIR = 20, EAR = 24), peripheral T-cell lymphoma (SIR = 12, EAR = 23), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; SIR = 9.0, EAR = 27), and mantle cell lymphoma (SIR = 8.5, EAR = 25). Elevated risks (SIRs = 4.2-6.9, EARs = 4.9-15) also were observed after all other LN subtypes except hairy cell leukemia and mycosis fungoides/Sézary syndrome. Among patients treated more recently, tMDS/AML risks were significantly higher after CLL/SLL (SIR2000-2005 = 4.8, SIR2012-2017 = 10, Ptrend = 0.0043), significantly lower after Hodgkin (SIR2000-2005 = 15, SIR2012-2017 = 6.3, Ptrend = 0.024) and marginal zone (SIR2000-2005 = 7.5, SIR2012-2017 = 2.3, Ptrend = 0.015) lymphomas, and non-significantly lower after mantle cell lymphoma (SIR2000-2005 = 10, SIR2012-2017 = 3.2, Ptrend = 0.054), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (SIR2000-2005 = 6.9, SIR2012-2017 = 1.0, Ptrend = 0.067), and plasma cell neoplasms (SIR2000-2005 = 5.4, SIR2012-2017 = 3.1, Ptrend = 0.051). EAR and cumulative incidence trends generally were similar to SIR trends. Median survival after tMDS/AML was 8.0 months (interquartile range, 3.0-22.0). Interpretation: Although tMDS/AML risks are significantly elevated after initial chemo/immunotherapy for most LNs, patients treated more recently have lower tMDS/AML risks, except after CLL/SLL. Though rare, the poor prognosis following tMDS/AML emphasizes the importance of continued efforts to reduce treatment-associated toxicity. Funding: This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. LMM, GMD, REC, and CBS verified the data, and all authors had access to the data and made the decision to submit for publication.
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BACKGROUND: Longitudinal patterns of immune globulins (IG) use have not been described in large populations. Understanding IG usage is important given potential supply limitations impacting individuals for whom IG is the sole life-saving/health-preserving therapy. The study describes US IG utilization patterns from 2009 to 2019. STUDY DESIGN AND METHODS: Using IBM MarketScan commercial and Medicare claims data, we examined four metrics overall and by condition-specific categories during 2009-2019: (1) IG administrations per 100,000 person-years, (2) IG recipients per 100,000 enrollees, (3) average annual administrations per recipient, and (4) average annual dose per recipient. RESULTS: In the commercial and Medicare populations respectively: IG administrations per 100,000 person-years increased by 120% (213-470) and 144% (692-1693); IG recipients per 100,000 enrollees grew by 71% (24-42) and 102% (89-179); average annual administrations per recipient rose by 28% (8-10) and 19% (8-9); and average annual dose (grams) per recipient increased by 29% (384-497) and 34% (317-426). IG administrations associated with immunodeficiency (per 100,000 person-years) increased by 154% (from 127 to 321) and 176% (from 365 to 1007). Autoimmune and neurologic conditions were associated with higher annual average administrations and dose than other conditions. DISCUSSION: IG use increased, coinciding with a growth in the IG recipient population in the United States. Several conditions contributed to the trend, with the largest increase observed among immunodeficient individuals. Future investigations should assess changes in the demand for IVIG by disease state or indication and consider treatment effectiveness.
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Imunoglobulina G , Medicare , Idoso , Humanos , Estados Unidos , Estudos RetrospectivosRESUMO
INTRODUCTION: Detection of adverse reactions to drugs and biologic agents is an important component of regulatory approval and post-market safety evaluation. Real-world data, including insurance claims and electronic health records data, are increasingly used for the evaluation of potential safety outcomes; however, there are different types of data elements available within these data resources, impacting the development and performance of computable phenotypes for the identification of adverse events (AEs) associated with a given therapy. OBJECTIVE: To evaluate the utility of different types of data elements to the performance of computable phenotypes for AEs. METHODS: We used intravenous immunoglobulin (IVIG) as a model therapeutic agent and conducted a single-center, retrospective study of 3897 individuals who had at least one IVIG administration between 1 January 2014 and 31 December 2019. We identified the potential occurrence of four different AEs, including two proximal AEs (anaphylaxis and heart rate alterations) and two distal AEs (thrombosis and hemolysis). We considered three different computable phenotypes: (1) an International Classification of Disease (ICD)-based phenotype; (2) a phenotype-based on EHR-derived contextual information based on structured data elements, including laboratory values, medication administrations, or vital signs; and (3) a compound phenotype that required both an ICD code for the AE in combination with additional EHR-derived structured data elements. We evaluated the performance of each of these computable phenotypes compared with chart review-based identification of AEs, assessing the positive predictive value (PPV), specificity, and estimated sensitivity of each computable phenotype method. RESULTS: Compound computable phenotypes had a high positive predictive value for acute AEs such as anaphylaxis and bradycardia or tachycardia; however, few patients had both ICD codes and the relevant contextual data, which decreased the sensitivity of these computable phenotypes. In contrast, computable phenotypes for distal AEs (i.e., thrombotic events or hemolysis) frequently had ICD codes for these conditions in the absence of an AE due to a prior history of such events, suggesting that patient medical history of AEs negatively impacted the PPV of computable phenotypes based on ICD codes. CONCLUSIONS: These data provide evidence for the utility of different structured data elements in computable phenotypes for AEs. Such computable phenotypes can be used across different data sources for the detection of infusion-related adverse events.
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Anafilaxia , Imunoglobulinas Intravenosas , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Estudos Retrospectivos , Registros Eletrônicos de Saúde , Hemólise , Fenótipo , AlgoritmosRESUMO
This case series investigates reports of 20 patients with colitis temporally associated with alpelisib use.
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Colite , Tiazóis , Humanos , Estados Unidos/epidemiologia , United States Food and Drug Administration , Protocolos de Quimioterapia Combinada Antineoplásica , Colite/induzido quimicamenteRESUMO
Importance: Immune checkpoint inhibitors (ICIs) have improved survival in patients with advanced melanoma but can be associated with a spectrum of immune-related adverse events (AEs), including both autoimmune-related AEs and other immune-related inflammatory AEs. These associations have primarily been evaluated in clinical trials that include highly selected patients, with older adults often underrepresented. Objective: To evaluate the association between use of ICIs and immune-related AEs (autoimmune and other immune related) among older patients with cutaneous melanoma. Design, Setting, and Participants: A population-based cohort study was conducted from January 1, 2011, to December 31, 2015. Data were analyzed from January 31 to May 31, 2021. With use of a linked database of Medicare claims and Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries, patients of White race diagnosed with stages II-IV or unknown (American Joint Committee on Cancer, AJCC Cancer Staging Manual 6th edition) first primary cutaneous melanoma during 2011-2015, as reported to SEER, and followed up through December 31, 2015, were identified. Exposures: Immune checkpoint inhibitors for treatment of melanoma. Main Outcomes and Measures: The association between ICIs and immune-related AEs ascertained from Medicare claims data was estimated using multivariable Cox regression with hazard ratios (HRs) and 95% CIs and with cumulative incidence accounting for competing risk of death. Results: The study included 4489 patients of White race with first primary melanoma (3002 men [66.9%]; median age, 74.9 [range, 66.0-84.9] years). During follow-up (median, 1.4 [range, 0-5.0] years), 1576 patients (35.1%) had an immune-related AE on a Medicare claim. Use of ICIs (reported for 418 patients) was associated with autoimmune-related AEs (HR, 2.5; 95% CI, 1.6-4.0), including primary adrenal insufficiency (HR, 9.9; 95% CI, 4.5-21.5) and ulcerative colitis (HR, 8.6; 95% CI, 2.8-26.3). Immune checkpoint inhibitors also were associated with other immune-related AEs (HR, 2.2; 95% CI, 1.7-2.8), including Cushing syndrome (HR, 11.8; 95% CI, 1.4-97.2), hyperthyroidism (HR, 6.3; 95% CI, 2.0-19.5), hypothyroidism (HR, 3.8; 95% CI, 2.4-6.1), hypopituitarism (HR, 19.8; 95% CI, 5.4-72.9), other pituitary gland disorders (HR, 6.0; 95% CI, 1.2-30.2), diarrhea (HR, 3.5; 95% CI, 2.5-4.9), and sepsis or septicemia (HR, 2.2; 95% CI, 1.4-3.3). Most associations were pronounced within 6 months following the first ICI claim and comparable with or without a baseline history of autoimmune disease. The cumulative incidence at 6 months following the first ICI claim was 13.7% (95% CI, 9.7%-18.3%) for autoimmune-related AEs and 46.8% (95% CI, 40.7%-52.7%) for other immune-related AEs. Conclusions and Relevance: In this cohort study of older adults with melanoma, ICIs were associated with autoimmune-related AEs and other immune-related AEs. Although some findings were consistent with clinical trials of ICIs, others warrant further investigation. As ICI use continues to expand rapidly, ongoing investigation of the spectrum of immune-related AEs may optimize management of disease in patients.
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Melanoma , Neoplasias Cutâneas , Idoso , Estudos de Coortes , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Medicare , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Estados Unidos/epidemiologia , Melanoma Maligno CutâneoRESUMO
OBJECTIVES: Benzene is a known haematoxin and leukemogen that can cause benzene poisoning (BP), that is, a persistent reduction in white cell counts that is strongly associated with increased risk of lymphohaematopoietic malignancies. Data are needed on the exposure-response, particularly at low doses and susceptible populations for clinical and regulatory purposes. METHODS: In a case-cohort study among 110 631 Chinese workers first employed 1949-1987 and followed up during 1972-1999, we evaluated BP risk according to benzene exposure level and investigated risk modification by subject (sex, attained age) and exposure-related factors (latency, exposure windows, age at first benzene exposure, coexposure to toluene) using excess relative risk and excess absolute risk models. RESULTS: There were 538 BP cases and 909 benzene-exposed referents. The exposure metric with best model fit was cumulative benzene exposure during a 5-year risk window, followed by a 9-month lag period before BP diagnosis. Estimated excess absolute risk of BP at age 60 increased from 0.5% for subjects in the lowest benzene exposure category (>0 to 10 ppm-years) to 5.0% for those in the highest category (>100 ppm-years) compared with unexposed subjects. Increased risks were apparent at low cumulative exposure levels and for workers who were first exposed at <30 years of age. CONCLUSIONS: Our data show a clear association between benzene exposure and BP, beginning at low cumulative benzene exposure levels with no threshold, and with higher risks for workers exposed at younger ages. These findings are important because BP has been linked to a strongly increased development of lymphohaematopoietic malignancies.
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BACKGROUND: Bexsero® (GlaxoSmithKline) is a four-component Neisseria meningitidis serogroup B vaccine (MenB-4C). It was licensed in the United States in 2015 for use among individuals ages 10-25 years. We aimed to assess the post-licensure safety profile of MenB-4C by examining reports received in the Vaccine Adverse Event Reporting System (VAERS). METHODS: VAERS is a national passive surveillance system for adverse events (AEs) following immunization that uses the Medical Dictionary for Regulatory Activities to code reported AEs and the Code of Federal Regulations to classify reports by seriousness. In this case series, we analyzed U.S. reports involving MenB-4C received between January 23, 2015 through December 31, 2018. We used Empirical Bayesian data mining to identify MenB-4C/AE combinations reported at least twice as often as expected. RESULTS: VAERS received 1,867 reports following MenB-4C administration, representing 332 reports per million doses distributed. Most reports were for females (59%), with a median age of 17 years (interquartile range: 16-18 years); 40% of reports described simultaneous administration of other vaccines. The majority of reports were classified as non-serious (96%). The most commonly reported AEs were injection site pain (22%), pyrexia (16%), and headache (16%). Data mining identified disproportionate reporting for "injected limb mobility decreased" secondary to injection site reactions, including extensive swelling of the vaccinated limb and injection site pain. CONCLUSIONS: Analysis of passive surveillance data from over 5.6 million doses of MenB-4C distributed in the United States did not reveal new safety concerns. The large majority of reports were classified as non-serious and the reported AEs were generally consistent with the safety experience described in clinical studies and the product's package insert. While our results are reassuring, continued post-marketing surveillance is warranted.