Corticosteroids for the management of immune-related adverse events in patients receiving checkpoint inhibitors

2017 ◽  
Vol 25 (3) ◽  
pp. 544-550 ◽  
Author(s):  
Kiersten J Williams ◽  
Dennis W Grauer ◽  
David W Henry ◽  
Michelle L Rockey

Introduction Due to enhanced T-cell activity, immune checkpoint inhibitors cause immune-related adverse effects. Corticosteroids are the mainstay of immune-related adverse effect management but the optimal strategy has not been determined, putting patients at risk for steroid-related adverse effects and potentially decreased efficacy of immunotherapy. This study aims to characterize the use of corticosteroids for the management of immune-related adverse effect. Methods and materials A retrospective, single-center evaluation of patients receiving checkpoint inhibitors was conducted. The primary objective was to evaluate corticosteroid use for immune-related adverse effects, including starting dose, taper strategy, total duration, and resumption of immunotherapy. Secondary objective was to describe the incidence and significance of hyperglycemia. Results One hundred and three patients met inclusion criteria and experienced 123 immune-related adverse effects. Prednisone was used most commonly (67%) at an average starting dose of 0.88 mg/kg (range 0.07–17.0). On average, steroid tapers began 9.2 days after initiation (range 0–89) and were continued for a total of 84.2 days (range 3–693). In 21.1% of cases, checkpoint inhibitor therapy was not delayed and 68.6% resumed checkpoint inhibitors, while the patient was taking steroids (30.4 mg prednisone on average, range 5–80). On average, checkpoint inhibitor therapy was resumed 18.6 days after detection of immune-related adverse effect (range 0–150). Clinically relevant hyperglycemia occurred in 8.9%. Conclusion Utilization of steroids for immune-related adverse effect at our institution is highly variable. The majority of patients received prolonged courses of steroids and resumed checkpoint inhibitor therapy with concomitant steroids above recommended doses. Additional monitoring for hyperglycemia and other steroid associated adverse effects should be considered.

2018 ◽  
Vol 7 (7) ◽  
pp. G1-G7 ◽  
Author(s):  
C E Higham ◽  
A Olsson-Brown ◽  
P Carroll ◽  
T Cooksley ◽  
J Larkin ◽  
...  

Immunotherapy treatment with checkpoint inhibitors (CPI) (CTLA-4 and PD-1 inhibitors) significantly improves survival in a number of cancers. Treatment can be limited by immune-mediated adverse effects including endocrinopathies such as hypophysitis, adrenalitis, thyroiditis and diabetes mellitus. If endocrinopathies (particularly hypocortisolemia) are not recognized early, they can be fatal. The diagnosis and management of endocrinopathies can be complicated by simultaneous multi-organ immune adverse effects. Here, we present Endocrine Emergency Guidance for the acute management of the endocrine complications of checkpoint inhibitor therapy, the first specialty-specific guidance with Endocrinology, Oncology and Acute Medicine input and endorsed by the Society for Endocrinology Clinical Committee. We present algorithms for management: endocrine assessment and management of patients in the first 24 hours who present life-threateningly unwell (CTCAE grade 3–4) and the appropriate management of mild-moderately unwell patients (CTCAE grade 1–2) presenting with features compatible with an endocrinopathy. Other important considerations in relation to hypohysitis and the maintenance of glucocorticoid therapy are discussed.


2018 ◽  
Vol 38 (04) ◽  
pp. 366-378 ◽  
Author(s):  
Brian Nadeau ◽  
Leslie Fecher ◽  
Scott Owens ◽  
Nataliya Razumilava

AbstractImmune checkpoint inhibition targeted against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality. Hepatotoxicity from checkpoint inhibitors is a less common irAE and often mild, while its incidence and severity vary based on the class and dose of checkpoint inhibitor, monotherapy versus combination therapy, and the type of cancer. Histological assessment of suspected irAEs is nonspecific and can show a variety of features. Hepatic irAEs can require discontinuation of checkpoint inhibitor therapy and treatment with immunosuppressive agents.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4571-4571 ◽  
Author(s):  
Laura K Schoch ◽  
Ivan Borrello ◽  
Ephraim J. Fuchs ◽  
Javier Bolanos-Meade ◽  
Jeffrey Sean Huo ◽  
...  

Abstract Background: Concerns have been raised whether immune checkpoint inhibitor therapy in the alloBMT setting will result in graft versus host disease (GvHD) and transplant related mortality (TRM). We report our experience with a variety of checkpoint inhibitors used before or after allogeneic bone marrow transplantation (alloBMT). Our series comprises patients who received T cell-replete hematopoietic stem cells from HLA-haploidentical or -matched donors and is limited to those treated with post-transplant cyclophosphamide (PTCy) as primary GvHD prophylaxis. Patient selection: We retrospectively reviewed the records of alloBMT recipients who received PTCy and received checkpoint inhibitor therapy before or after alloBMT. GvHD was assessed using the CIBMTR GVHD index. Results: Eleven patients received checkpoint inhibitor therapy prior to alloBMT: anti-PD-1: Nivolumab n=6, anti-CTLA4: Ipilimumab n=8 (3 patients received both nivolumab and ipilimumab). These patients received a median of 4 (range 1 - 18) cycles of therapy. The median interval from last checkpoint inhibitor treatment to day of transplant was 43 (range 18-302) days. All patients received nonmyeloablative conditioning; 6 received partially mismatched allografts (5 were HLA haploidentical). Four patients developed Grade II aGvHD: Three patients who had received partially mismatched allografts (haplo-2, 9/10 unrelated-1) experienced stage 3 cutaneous GvHD only; one patient who received a 10/10 unrelated donor allograft developed stage 3 cutaneous GvHD with stage 1 liver involvement. Three patients were on immunosuppression when GvHD developed, the fourth patient with cutaneous and liver GvHD had been taken off tacrolimus on day 68 due to concerns of graft failure. GvHD resolved with treatment in each case. None of these patients developed chronic GvHD and none have died [median follow-up of 0.66 (range 0.91 - 2.0) years post alloBMT]. Nine patients received checkpoint therapy following alloBMT: anti-PD-1: Pembrolizumab n = 1, Nivolumab n= 6, anti-CTLA4: Ipilimumab n= 3 (one patient received nivolumab and ipilimumab). Eight patients had received nonmyeloablative conditioning; 5 received haploidentical allografts. Six received treatment for relapse of their hematologic malignancy, 1 for relapsed pediatric sarcoma, and 2 for newly diagnosed lung cancer. The median time to initiation of checkpoint inhibitor therapy was 1.2 (range: 0.8 - 5.8) years post alloBMT. Patients received a median of 5 (range 1 - 24) cycles of therapy. There was 1 case of Grade II aGvHD; stage 3 cutaneous GvHD when DLI from a 10/10 matched unrelated donor was given for relapsed disease after ipilimumab. This resulted in GvHD which was not accompanied by the desired graft-vs-leukemia effect. There were no other cases of acute or chronic GvHD in this group. There were 4 tumor-related deaths: pediatric sarcoma (1), lung cancer (1), and AML (2). The median follow-up for this group is 2 years (range 0.85 - 8.0) post alloBMT. Conclusions: In this small series, the incidence and severity of GvHD seen in patients who received checkpoint inhibitors was similar to that seen in patients treated with PTCy as GvHD prophylaxis without checkpoint inhibitors. GvHD was seen in patients treated with checkpoint inhibitors prior to alloBMT, but was generally mild and readily controlled and there were no associated deaths. In patients treated with checkpoint inhibitors after alloBMT, the only case of GvHD occurred after the patient received DLI. We caution that use of checkpoint inhibitors in closer temporal proximity to transplant might well be associated with increased risk of GvHD or severity of GvHD. Disclosures Borrello: WindMIL Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding. Wagner-Johnston:Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Other: member of DSMB.


2021 ◽  
Vol 14 (1) ◽  
pp. e238235
Author(s):  
Kwang Kiat Sim ◽  
Katie Connell ◽  
Mayank Bhandari ◽  
David Paton

Peritoneal melanosis is an uncommon benign condition, the pathophysiology of which is unclear. Macroscopically, it appears as diffuse dark brown or black pigmentation within the peritoneum, mimicking more sinister conditions such as metastatic melanoma. It has been described in a variety of contexts, but only exceedingly rarely in association with metastatic melanoma, with only two previous published case reports. We present a case of peritoneal melanosis associated with metastatic melanoma involving the spleen, previously treated with targeted and immune checkpoint inhibitor therapy. With increasing reports of melanoma regression manifesting as cutaneous tumorous melanosis in patients treated with immune checkpoint inhibitors, we postulate that, similarly, immunotherapy and tumour regression might have a role to play in the pathogenesis of the peritoneal pigmentation in this case.


2020 ◽  
Vol 38 (6) ◽  
pp. 576-583 ◽  
Author(s):  
Hamzah Abu-Sbeih ◽  
David M. Faleck ◽  
Biagio Ricciuti ◽  
Robin B. Mendelsohn ◽  
Abdul R. Naqash ◽  
...  

PURPOSE The risk of immune checkpoint inhibitor therapy–related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors. PATIENTS AND METHODS We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events. RESULTS Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn’s disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event–related deaths were recorded. Anti–cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively). CONCLUSION Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.


2019 ◽  
Vol 14 (12) ◽  
pp. 1692-1700 ◽  
Author(s):  
Harish Seethapathy ◽  
Sophia Zhao ◽  
Donald F. Chute ◽  
Leyre Zubiri ◽  
Yaa Oppong ◽  
...  

Background and objectivesImmune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint inhibitors.Design, setting, participants, & measurementsWe included all patients who received checkpoint inhibitor therapy from May 2011 to December 2016 at Massachusetts General Hospital. Baseline serum creatinine, averaged 6 months before checkpoint inhibitor start date, was compared with all subsequent creatinine values within 12 months of starting therapy. AKI was defined by Kidney Disease: Improving Global Outcomes criteria for fold changes in creatinine from baseline. Sustained AKI events lasted at least 3 days and was our primary outcome. The cause of sustained AKI was determined by chart review. Cumulative incidence and subdistribution hazard models were used to assess the relationship between baseline demographics, comorbidities, and medications, and sustained AKI and potential checkpoint inhibitor–related AKI.ResultsWe included 1016 patients in the analysis. Average age was 63 (SD 13) years, 61% were men, and 91% were white. Mean baseline creatinine was 0.9 mg/dl (SD 0.4 mg/dl), and 169 (17%) had CKD (eGFR<60 ml/min per 1.73 m2) at baseline. A total of 169 patients (17%) experienced AKI, defined by an increase in creatinine at least 1.5 times the baseline within 12 months; 82 patients (8%) experienced sustained AKI and 30 patients (3%) had potential checkpoint inhibitor–related AKI. The first episode of sustained AKI occurred, on average, 106 days (SD 85) after checkpoint inhibitor initiation. Sixteen (2%) patients experienced stage 3 sustained AKI and four patients required dialysis. Proton pump inhibitor use at baseline was associated with sustained AKI.ConclusionsAKI is common in patients receiving checkpoint inhibitor therapy. The causes of sustained AKI in this population are heterogenous and merit thorough evaluation. The role of PPI and other nephritis-inducing drugs in the development of sustained AKI needs to be better defined.


2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 131-131 ◽  
Author(s):  
Lia Head ◽  
Nicholas Gorden ◽  
Robert Van Gulick ◽  
Carol M. Amato ◽  
Ashley Frazer-Abel ◽  
...  

131 Background: Immune-related adverse events (IRAE) occur commonly with immune checkpoint inhibitor therapy for the treatment of cancer, although the specific event and severity can vary widely. Little is known regarding factors that may predict which patients will develop an IRAE. The goal of this study is to identify blood biomarkers predictive of IRAE associated with immune checkpoint inhibitor therapy. Methods: Blood samples collected from patients with melanoma prior to receiving therapy with immune checkpoint inhibitors were obtained from the University of Colorado Skin Cancer Biorepository. Testing for a panel of autoantibodies and cytokines (ANA, CCP 3.1, IL-1 beta, IL-2, IL-6, IL-10, IL-12, IP-10, MCP-1, TNF alpha, IFN alpha 2, IFN gamma) in serum samples from patients who had at least one documented IRAE was performed by Exsera BioLabs. Descriptive statistics were used to evaluate biomarker levels in relation to type, grade, and number of adverse events. Results: Pre-treatment samples from 45 patients were evaluated. Median age was 55; 26 were male and 19 were female. The most common IRAEs were colitis (n = 22), thyroid dysfunction (n = 21), and dermatitis (n = 20). Most IRAEs were grade 2 in severity, and the majority of patients (n = 36) experienced more than 1 IRAE. TNF alpha was elevated in 60% of patient samples, while IFN alpha 2 was elevated in 44%. Borderline ANA was detected in 27% of samples and ANA was positive in 11%. No samples had elevation of IL-2. Between 9% and 18% of samples had elevation of the other immune markers tested (IFN gamma, IL-1 beta, IL-6, IL-10, IL-12, and CCP 3.1). Elevation of TNF alpha and IFN alpha 2 were associated with higher grades of IRAEs. No associations between immune markers and the number or type of adverse events in an individual patient were noted. Results from 15 patients who did not have a documented IRAE on immune checkpoint inhibitor therapy are currently pending to confirm these findings are unique to patients developing IRAE. Conclusions: This preliminary data suggests that baseline elevations of TNF alpha and IFN alpha 2 may predict development of IRAEs with immune checkpoint inhibitor therapy. Results from samples from patients who did not develop an IRAE on therapy will be reported at the meeting.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A169-A170
Author(s):  
Domenic Disanti ◽  
Alissa Marr ◽  
Whitney Sears Goldner

Abstract Background: Drug induced sarcoid like reactions (DISR) have recently been described as a potential consequence of immune checkpoint inhibitor therapy. However, hypercalcemia associated with DISR has not been reported. Clinical Case: A 72 year old male presented with metastatic melanoma. He initiated therapy with Ipilimumab/Nivolumab (Ipi/Nivo). Three weeks after his first cycle he developed symptomatic hypercalcemia (calcium 14.4 mg/dL), and acute kidney injury (creatinine 3.45mg/dL), PTH 12 pg/mL, 25OHD 51, and PTHrp 0.5. He received IV fluids and IV bisphosphonates and calcium normalized to 9.1 mg/dL and creatinine 1.85 mg/dL. His Ipi/Nivo were stopped due to concern for neurotoxicity. He subsequently switched to Q3week Pembrolizumab (Pembro) and after 2 infusions, he again developed hypercalcemia (calcium 11.8 mg/dL). FDG PET demonstrated a complete radiographic response. Labs showed a 1,25OH2D of 103 pg/mL (reference range 19.9–79.3 pg/mL), PTH of 4 pg/mL and calcium of 11.4 mg/dL. He was treated with prednisone 20 mg QD. After 9 days on prednisone, 1,25OH2D was 26 pg/mL and calcium 9.4 mg/dL. He took prednisone for 3 weeks total. Repeat labs off prednisone for one week were 1,25OH2D of 38 pg/mL and calcium 9.1 mg/dL. He continued on Pembro. After being off steroids for 5 weeks, he developed body aches and swelling of the hands. 1,25OH2D increased to 100 pg/mL and calcium to 10 mg/dL. He restarted prednisone and stopped Pembro. Labs one month later showed a 1,25OH2D of 45 pg/dL while still on prednisone 10 mg qd and a normal calcium in the mid 9’s. Follow up FDG PET showed hypermetabolic bilateral hilar and mediastinal lymphadenopathy not seen on previous imaging. Ultrasound-guided lymph node biopsy revealed granulomatous lymphadenitis. He was diagnosed with DISR, secondary to immunotherapy with checkpoint inhibitors. He continues on prednisone 10 mg per day and calcium and 1,25OH2D levels have remained normal. Conclusion: This is the first case of 1,25OH2D mediated hypercalcemia as a consequence of DISR induced by immune checkpoint inhibitor therapy. Hypercalcemia in the setting of malignancy is more commonly due to humoral hypercalcemia of malignancy from PTHrp or bone metastasis, but DISR needs to be a consideration in persons with hypercalcemia on immune checkpoint inhibitor therapy, with elevated 1,25OH2D levels and low PTH and PTHrp levels.


2021 ◽  
Author(s):  
Joseph D Butner ◽  
Geoffrey V Martin ◽  
Zhihui Wang ◽  
Bruna Corradetti ◽  
Mauro Ferrari ◽  
...  

Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. Here we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (μ). The model was validated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. The derived parameters Λ and μ were both significantly different between responding versus non-responding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within two months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology, demonstrating reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these results suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis.


Sign in / Sign up

Export Citation Format

Share Document