Background Beta‐lactam antibiotics are a relatively common cause of immune thrombocytopenia. Because the many beta‐lactam drugs now in clinical use have structural similarities, when a patient experiences this complication the question of whether an alternative member of this drug family can safely be used often arises but there are little data available to guide this decision. Study Design and Methods Drug‐dependent, platelet‐reactive antibodies from 32 patients who experienced thrombocytopenia while being treated with a beta‐lactam drug of the penam (piperacillin, etc.) or cephem (ceftriaxone etc.) groups were studied for serologic cross‐reactivity with other drugs from these families using flow cytometry. Cross‐reactions observed were analyzed for correlations with structural features of the drugs tested. Results Among 14 antibodies specific for penam drugs, five “strong” cross‐reactions with other penam drugs were found. Among 18 antibodies specific for cephem drugs, 8 “strong cross‐reactions were identified. Antibodies induced by penam drugs did not cross‐react strongly with cephem drugs and vice versa. A strong correlation between cross‐reactions and similar or identical R1 side groups of the beta‐lactams studied was observed. Discussion The findings suggest that patients who experience immune thrombocytopenia while being treated with a beta‐lactam of the penam group can safely be treated with a cephem drug and vice versa. If a patient is to be switched to another beta lactam within the same group, the likelihood of serologic cross‐reactivity can be minimized by choosing an agent with a distinctly different R1 side group.
More than 50 beta lactam (BL) antibiotics are now in active use for treatment of a wide range of bacterial infections. BL antibiotics are among the most common drugs capable of inducing antibodies (DDAbs) that cause drug-induced immune thrombocytopenia (DITP). Most DDAbs are highly specific for the sensitizing drug but beta lactams all have a common core structure and many similarities among side groups that are added to augment potency and modify specificity, raising the possibility that a DDAb specific for one BL may cross-react with another. We studied DDAbs from 33 patients with DITP induced by 9 commonly used BL drugs to determine whether patterns of cross-reactivity exist that might influence the choice of an alternative antibiotic in a patient with BL-induced DITP. DDAbs were demonstrated in a flow cytometric assay considered to be "positive" when immunoglobulins in patient serum but not normal serum react with normal platelets in the presence, but not in the absence of drug (Blood 2018;131:1486). DDAbs detected in the 33 patients were specific for 9 different BL drugs that were divided into two groups, "penicillins" (Group 1) and cephalosporins (Group 2) on the basis of structural similarities (Figure 1). In Group 1 were 19 DDAbs specific for amoxicillin (2), nafcillin (4) and piperacillin (13). Structurally similar ampicillin and penicillin were also tested with these abs. In Group 2 were 14 DDAbs specific for cefadroxil (1), cefepime (2), ceftazidime (2), ceftizoxime (1), ceftriaxone (7) and cephalexin 1). Cross-reactions identified within these groups of DDAbs are shown in Tables 1 and 2. Cross-reactions, many quite strong (S) were observed among DDAbs specific for drugs in both structural groups (Tables 1 and 2). Particularly noteworthy were cross-reactions of the 19 Group 1 DDAbs with ampicillin (6) and penicillin (6) (Table 1) and of the 14 Group 2 DDAbs with cefepime (6), ceftizoxazole (6) and ceftriaxone (3) (Table 2). The findings show that platelet-specific DDAbs induced by beta lactam antibiotics, in contrast with those induced by medications like quinine, sulfamethoxazole and vancomycin, commonly cross-react with other antibiotics of this class. In patients with immune thrombocytopenia induced by a beta lactam antibiotic, it may be prudent to avoid switching to another beta lactam or, if this is necessary, to monitor platelet counts carefully. Disclosures No relevant conflicts of interest to declare.
Background Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have dramatically improved outcomes for a range of solid malignancies. irAEs from CPIs affect a wide range of tissues, vary in severity, and are difficult to predict. Multiple studies have reported on incidence of irAEs by immunotherapy type, but few have examined the association of irAEs with tumor histology or with sites of metastasis. This study aims to investigate the association between type and incidence of irAEs with type of solid tumor histology, as well as with sites of cancer metastasis. Methods We performed a retrospective analysis of all patients with genitourinary (GU), melanoma, gastrointestinal (GI), and lung malignancies treated with CPI monotherapy at the University of California, Irvine using an outpatient oncology pharmacy database. Data was collected from 1/1/2020 to 6/30/ 2021. Patients were aged 18 years and older. Patients must have received at least one dose of a CPI agent. Patients who received CPI-containing combination therapy with chemotherapy or targeted therapy were excluded. Results Of 423 patients on unique treatment lines in our data set, 268 patients received CPI monotherapy. irAEs were documented in 133 patients (49.6%). 71 patients (62.8%) required treatment with oral or intravenous steroids, and 42 patients (37.2%) received treatment with other supportive therapy. The incidence of irAEs based on tumor type is listed in table 1. Most common irAEs per tumor type were rash in GU malignancies (26.0%), colitis in melanoma (25.4%), rash in GI malignancies (29.3%), and pneumonitis in lung malignancies (60.0%). In patients with irAEs, 102 (76.7%) had metastatic disease and of those, 18 (17.6%) had an irAE involving a metastatic site (p<0.0001). In patients with irAEs involving the primary site of malignancy, 2 patients (4.7%) with renal cell carcinoma had nephritis, 12 patients (37.5%) with melanoma had dermatitis, and 2 patients (50%) with a lung malignancy had pneumonitis. Conclusions This study examines the differences in type and incidence of irAEs across GU, melanoma, GI, and lung cancers treated with CPI monotherapy. We found differences in the incidence of irAEs as relavant to tumor histology. Further, there was a statistically significant increased incidence of irAEs involving a metastatic site. Additional studies are needed, including those with a larger sample, combination immunotherapy and chemotherapy, as well as with additional tumor histologies. Ethics Approval Application #16536 for HS #2021-6843 titled, "Primary Cancer Histology and Sites of Metastatic Disease Correlate with Tissues Affected by Immune-Related Adverse Events" obtained approval by the University of California, Irvine Institutional Review Board. A waiver of consent was obtained as this study involved no more than minimal risk as it was a retrospective chart review.
480 Background: Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized management of GU malignancies. These agents are associated with a unique subset of toxicities that are immune-mediated, with a broad clinical spectrum that may affect any organ. Patients can also experience ³1 irAE involving multiple organ systems. Individual patient susceptibilities and type of CPI used may influence the incidence and type of irAEs that may develop. Wehypothesize that there are also differences in irAEs based on the histologic malignancy subtype. Methods: We performed a retrospective analysis of all patients with GU malignancies who received CPIs at the University of California Irvine using an outpatient oncology pharmacy database. Data was collected from 1/1/2020 to 6/30/2021. Patients were aged ³18 years and had a diagnosis of urothelial carcinoma (UC), renal cell carcinoma (RCC), prostate adenocarcinoma, or penile squamous cell carcinoma. Patients must have received ³1 dose of a CPI agent including ipilimumab (I), nivolumab (N), pembrolizumab (P), atezolizumab (At), avelumab (Av), durvalumab (D), and cemiplimab (C). Results: A total of 128 patients who received 141 unique CPI regimens were included. Documented irAEs were noted in 50.0% of patients and 18.4% had ³1 irAE. A total of 99 unique irAEs were recorded. In those who experienced irAEs, 92.2% of patients received CPIs in the metastatic setting and 7.8% in the adjuvant setting. In those who experienced irAEs, 12.5% of patients received combination CPIs with I+N, while 87.5% received single-agent CPI. In those who experienced irAEs, 46.8% of patients had UC, 50.0% had RCC, 1.6% had prostate cancer, and 1.6% had penile cancer. In those who experienced irAEs, 24.2% had skin rash or pruritis, 23.2% had endocrinopathies, 14.1% had colitis, 13.1% had other toxicity including arthritis, 12.0% had hepatitis, 3.9% had myositis, 2.9% had pneumonitis, 1.9% had neurologic toxicity including myasthenia gravis and encephalitis, 1.9% had carpal tunnel syndrome, 1.9% had nephritis, and 0.9% had autoimmune thrombocytopenia. Various irAEs for UC and RCC are summarized in Table. Conclusions: In this dataset, there were differences in type and incidence of irAEs in patients with UC and RCC, while the sample size was too small to draw conclusions about patients with prostate and penile cancer. Further investigation is needed involving other solid tumor types, including non-GU malignancies, to definitively answer this question.[Table: see text]
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