Reynolds, Kerry L.

Background Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. Methods We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29–84 days). Results Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). Conclusion A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

Background Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Abstract The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Expanding use of immune‐checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune‐related adverse events (irAE‐N). We evaluate the real‐world frequency, phenotypes, co‐occurring immune‐related adverse events (irAEs), and long‐term outcomes of severe, grade III to V irAE‐N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE‐N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE‐N reporting are outlined. ANN NEUROL 2020;87:659–669

Significance Statement Kidney toxicity from use of immune checkpoint inhibitors is being recognized as an increasingly frequent complication of treatment. However, existing data on immune checkpoint inhibitor–associated AKI have been limited to small, mostly single-center studies. In this multicenter study of 138 patients with immune checkpoint inhibitor–associated AKI and 276 controls, the authors characterize the clinical features of this complication and identify risk factors associated with its development, clinicopathologic features, and determinants of kidney recovery after an episode. Failure to achieve kidney recovery was associated with worse overall survival, and a minority (23%) of patients who were retreated with immune checkpoint inhibitors had a recurrence of AKI. The study provides insights into immune checkpoint inhibitor–associated AKI, although further study is needed to inform the care of affected patients. Background Despite increasing recognition of the importance of immune checkpoint inhibitor–associated AKI, data on this complication of immunotherapy are sparse. Methods We conducted a multicenter study of 138 patients with immune checkpoint inhibitor–associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. Results Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor–associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6–37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis–causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis–causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor–associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. Conclusions This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor–associated AKI.

Abstract Introduction: The development of immune checkpoint inhibitors (ICPis) has ushered in a new paradigm for the treatment of both solid and liquid malignancies. However, these therapies, which promote an activated T cell phenotype, can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (IRAEs), which can affect a variety of organ systems. Autoimmune hemolytic anemia (AIHA) has been described as a rare complication of ICPis, but existing data are mostly limited to isolated case reports. Further, guidelines for the diagnosis and treatment of these patients are lacking. We describe the clinical and laboratory features of 14 patients who developed ICPi-associated AIHA. Methods: We contacted hematology departments at 18 academic medical centers across the U.S. to inquire about potential cases of ICPi-associated AIHA. Nine centers contributed a total of 14 cases to the current series. We defined AIHA as an abrupt decrease in hemoglobin ≥2g/dL, the presence of at least two laboratory features of hemolysis (elevated serum lactate dehydrogenase [LDH], elevated reticulocyte percentage, low or absent serum haptoglobin, and spherocytes), and the exclusion of other causes of anemia. We collected data on demographics and comorbidities, features of AIHA, and response to treatment. We defined complete recovery (CR) and partial recovery (PR) of hemoglobin as an increase from the nadir hemoglobin to within 1 and 2 g/dL of the baseline value, respectively, in the absence of recent transfusion. Results: The clinical features of the 14 patients in our cohort with ICPi-associated AIHA are summarized in the Figure (panel A). Underlying malignancies included melanoma (n = 9), non-small cell lung cancer (n = 3), colorectal cancer (n = 1), and acute myelogenous leukemia (n = 1). Four patients had a pre-existing diagnosis of a lymphoproliferative disorder, and two of these patients were known to have a positive direct antiglobulin test (DAT) prior to initiation of ICPi. ICPis used included ipilimumab, nivolumab, a combination of ipilimumab and nivolumab, and pembrolizumab. Representative hemoglobin and LDH trends are shown in the Figure (panels B and C). The median (interquartile range [IQR]) interval from initiation of ICPis to AIHA was 55 (22-110) days. Eight patients (57%) were DAT positive: 3 were positive for both IgG and C3; 3 were positive for IgG alone; 2 were positive for C3 alone; and 1 was weakly positive on polyspecific testing. Five patients (36%) were DAT negative, and in one patient a DAT was not performed. The median (IQR) hemoglobin nadir was 6.3 (6.1-8.0) g/dL,and 11 patients (79%) required red blood cell transfusion. All patients were treated with glucocorticoids, with 3 requiring additional immunosuppressive therapy. All patients achieved a CR or PR of hemoglobin in response to treatment (CR, n = 11; PR, n =3). The median (IQR) time from the hemoglobin nadir to CR or PR was 47 (30-62) days. Seven patients (50%) experienced at least one other IRAE. Seven patients (50%) were re-challenged with ICPis, and one patient developed recurrent AIHA with re-challenge. Conclusion: ICPi-associated AIHA is a recently-described phenomenon, which will be encountered more frequently with the widespread use of ICPis. ICPi-associated AIHA shares many clinical features with other forms of AIHA; however, a unique aspect of ICPi-associated AIHA appears to be a relatively high incidence of DAT negativity (36% in our series, compared with 3-11% in other forms of AIHA). It is possible that more advanced DAT testing - i.e., "super-Coombs" - which was not performed in any of the patients in this series, would have yielded different results. Glucocorticoids appear to be an effective first-line regimen in most patients with ICPi-associated AIHA. Furthermore, we found that AIHA does not necessarily recur with ICPi re-challenge. Additional studies are needed to better understand the mechanisms underlying ICPi-associated AIHA and optimal treatment strategies. Disclosures Anagnostou: ASH Research Training Award for Fellows 2018: Research Funding; Mayo Clinic SPORE: Research Funding; Mayo Clinic Immune Monitoring Core: Research Funding; Mayo Clinic Hematology Research Division: Research Funding. Salama:BMS: Research Funding; Celldex: Research Funding; Dynavax: Research Funding; Genentech: Research Funding; Merck: Research Funding; Reata: Research Funding; Incyte: Research Funding; Immunocore: Research Funding; Array: Consultancy; Merck: Consultancy; Biocryst: Consultancy; BMS: Speakers Bureau.