Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials

Kanjanapan, Yada; Day, Daphne; Butler, Marcus O.; Wang, L.; Joshua, Anthony M.; Hogg, David; Leighl, Natasha B.; Razak, Albiruni R. Abdul; Hansen, Aaron R.; Boujos, S.; Chappell, Mary Anne; Chow, K.; Sherwin, Barbara B.; Stayner, Lee Anne; Soultani, L.; Zambrana, Ana I.; Siu, Lillian L.; Bedard, Philippe L.; Spreafico, Anna

doi:10.1016/j.ejca.2018.10.017

Cited by 50 publications

(35 citation statements)

References 23 publications

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“…13 The OR for irAEs occurrence within the first month compared with after 1 month was 3.13 (95% CI: 1.95 to 5.02) and decreased over time, being 2.80 (95% CI: 1.76 to 4.44) at 3 months. 13 Clinical trials typically include a summary table of adverse events incidence irrespective of when the patient experienced the event. This method of reporting toxicities is suboptimal for capturing the impact of time on therapy free from toxicities, especially when that toxicity can be an important cause of treatment discontinuation in patients receiving ICIs.…”

Section: Characteristics Of Iraes Conditioned As a Function Of Timementioning

confidence: 92%

“…10 In a retrospective review including 352 patients enrolled in 21 early phase clinical trials of ICI, 260 (74%) patients experienced irAEs. 13 In this case, the risk of developing irAEs was studied using the OR model for irAEs occurrence at various time points. 13 The OR for irAEs occurrence within the first month compared with after 1 month was 3.13 (95% CI: 1.95 to 5.02) and decreased over time, being 2.80 (95% CI: 1.76 to 4.44) at 3 months.…”

Section: Characteristics Of Iraes Conditioned As a Function Of Timementioning

confidence: 99%

“…13 In this case, the risk of developing irAEs was studied using the OR model for irAEs occurrence at various time points. 13 The OR for irAEs occurrence within the first month compared with after 1 month was 3.13 (95% CI: 1.95 to 5.02) and decreased over time, being 2.80 (95% CI: 1.76 to 4.44) at 3 months. 13 Clinical trials typically include a summary table of adverse events incidence irrespective of when the patient experienced the event.…”

Section: Characteristics Of Iraes Conditioned As a Function Of Timementioning

confidence: 99%

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Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors

Nuzzo

Pond

Alaiwi

et al. 2020

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs.MethodsWe identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method.ResultsA total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p<0.001), first-line ICI therapy (p=0.011), and PD-1 inhibitor therapy (p=0.007) were all significantly associated with irAE development.ConclusionsThis study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted.

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Section: Characteristics Of Iraes Conditioned As a Function Of Timementioning

confidence: 92%

Section: Characteristics Of Iraes Conditioned As a Function Of Timementioning

confidence: 99%

Section: Characteristics Of Iraes Conditioned As a Function Of Timementioning

confidence: 99%

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Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors

Nuzzo

Pond

Alaiwi

et al. 2020

J Immunother Cancer

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“…Antibody or cell-based immunotherapeutics for cancer carry inherent risks of bystander immune activation, in addition to the effects of treating the intended tumor target [1][2][3][4][5]. The most severe of these immune-related adverse events (irAEs) are cytokine release syndrome (CRS) and neurotoxicity, most prominently described in patients treated with CAR-T-cells [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Immune checkpoint blockade induces irAEs during short-term follow-up of some patients with cancer, though robust immune biomarkers correlating with adverse effects of therapy are still being investigated [1,4,7,[20][21][22][23][24][25]. For long-term survivors who received immunotherapy or following CRS, immune monitoring is not yet standard of care, despite evidence that such patients may continue to experience secondary effects of treatment and irAEs [1,3].…”

Section: Introductionmentioning

confidence: 99%

Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm

Panoskaltsis

McCarthy

Stagg

et al. 2020

Cancer Immunol Immunother

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Cytokine storm can result from cancer immunotherapy or certain infections, including COVID-19. Though short-term immune-related adverse events are routinely described, longer-term immune consequences and sequential immune monitoring are not as well defined. In 2006, six healthy volunteers received TGN1412, a CD28 superagonist antibody, in a first-in-man clinical trial and suffered from cytokine storm. After the initial cytokine release, antibody effect-specific immune monitoring started on Day + 10 and consisted mainly of evaluation of dendritic cell and T-cell subsets and 15 serum cytokines at 21 time-points over 2 years. All patients developed problems with concentration and memory; three patients were diagnosed with mild-to-moderate depression. Mild neutropenia and autoantibody production was observed intermittently. One patient suffered from peripheral dry gangrene, required amputations, and had persistent Raynaud's phenomenon. Gastrointestinal irritability was noted in three patients and coincided with elevated γδT-cells. One had pruritus associated with elevated IgE levels, also found in three other asymptomatic patients. Dendritic cells, initially undetectable, rose to normal within a month. Naïve CD8 + T-cells were maintained at high levels, whereas naïve CD4 + and memory CD4 + and CD8 + T-cells started high but declined over 2 years. T-regulatory cells cycled circannually and were normal in number. Cytokine dysregulation was especially noted in one patient with systemic symptoms. Over a 2-year follow-up, cognitive deficits were observed in all patients following TGN1412 infusion. Some also had signs or symptoms of psychological, mucosal or immune dysregulation. These observations may discern immunopathology, treatment targets, and long-term monitoring strategies for other patients undergoing immunotherapy or with cytokine storm.

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Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors

Aldrich

Pundole

Tummala

et al. 2021

Arthritis & Rheumatology

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Objective. To estimate the incidence of immune checkpoint inhibitor-related myositis (ICI-myositis) in cancer patients receiving ICIs, and to report associated clinical manifestations, patterns of care, and outcomes.Methods. We identified a retrospective cohort of patients receiving ICIs between 2016 and 2019 seen at the University of Texas MD Anderson Cancer Center. Cases of ICI-myositis were identified using International Classification of Disease codes and confirmed by reviewing medical records and pathology, as available.Results. A total of 9,088 patients received an ICI. Thirty-six patients (0.40%) were identified as having ICI-myositis: 17 patients (47%) with ICI-myositis alone and 19 (53%) with overlap manifestations (5 patients with myocarditis, 5 with myasthenia gravis, and 9 with both). The incidence of ICI-myositis was 0.31% in those receiving ICI monotherapy and 0.94% in those receiving combination ICI therapy (relative risk 3.1 [95% confidence interval 1.5-6.1]). Twenty-five patients (69%) received ≥1 treatment in addition to glucocorticoids: plasmapheresis in 17 patients (47%), intravenous immunoglobulin in 12 (33%), and biologics in 11 (31%). Patients with overlap conditions had worse outcomes than those with myositis alone, and 79% of them developed respiratory failure. Eight patients died as a result of ICImyositis, and all had overlap syndrome with myasthenia gravis or myocarditis (P < 0.05); 75% of these patients had a concomitant infection.Conclusion. ICI-myositis is a rare but severe adverse event. More than half of the patients presented with overlap manifestations and had deleterious outcomes, including respiratory failure and death. None of the patients with ICI-myositis alone died as a result of adverse events. Optimal treatment strategies have yet to be determined. PATIENTS AND METHODSPatients. We conducted a retrospective cohort study of patients seen at our institution between March 2016 and September 2019 who had received ≥1 of the following ICIs:

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Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials

Cited by 50 publications

References 23 publications

Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors

Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors

Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm

Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors

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