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Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life

Published:October 02, 2022DOI:https://doi.org/10.1016/j.ejca.2022.08.029

      Highlights

      • Up to 35.5% of patients with cancer have chronic immune-related adverse events (irAEs) ≥1 year since immune checkpoint inhibitor cessation.
      • Chronic irAEs drastically reduce health-related quality of life (HRQoL) after immune checkpoint inhibitor cessation.
      • Cancer patients without chronic irAEs show similar HRQoL to the normal population.
      • Chronic irAEs have similar impacts on HRQoL as non-exacerbated autoimmune diseases.
      • Patients with chronic irAEs felt inadequately informed about long-term sequelae.

      Abstract

      Background

      Immune checkpoint inhibitors (ICIs) may induce persistent immune-related adverse events (irAEs). We investigated persistent irAEs and implications on patients' lives compared to non-ICI-induced autoimmune diseases (AIs).

      Methods

      The multicentre, cross-sectional study comprised 200 patients with cancer ≥12 weeks after ICI cessation (ICI-patients) and 2705 patients with AIs (AI-patients), recruited in German outpatient clinics and support groups. The prevalence of persistent irAEs subdivided in long-term (12 weeks to <12 months) and chronic irAEs (≥12 months) since ICI discontinuation, health-related quality of life (HRQoL) using the EuroQol 5D-5L (EQ-Index/VAS score), and burden of autoimmune symptoms and respective therapies were assessed.

      Results

      Long-term/chronic irAEs occurred in 51.9%/35.5% of outpatient ICI-patients, including arthralgia (16.7%/16.1%), myalgia (13.0%/14.0%), hypothyroidism (11.1%/10.8%), xerostomia (7.4%/8.6%), vitiligo (13.0%/7.5%) and hypophysitis (9.3%/7.5%). ICI-patients with long-term/chronic irAEs reported clinically significantly reduced HRQoL compared to ICI-patients without long-term/chronic irAEs (EQ-Index score: 0.767/0.752 versus 0.920/0.923, p < 0.001/0.001; EQ-VAS score: 52.2/52.0 versus 63.6/74.7, p =/< 0.040/0.001). Multiple linear regression analyses confirmed clinically significant reductions in HRQoL scores by chronic irAEs (EQ-Index/VAS score: −0.163/−23.4, p < 0.001/0.001). HRQoL, burden of autoimmune symptoms and burden of respective therapies in ICI-patients with chronic irAEs were similar to AI-patients with non-exacerbated AIs. Patients with chronic irAEs felt inadequately informed about side-effects compared to patients without chronic irAEs (p < 0.001).

      Conclusion

      Persistent irAEs impose a significant burden on patients after ICI cessation. Especially in early tumour stages, risk-benefit ratios must be carefully evaluated, and patients need to be informed about potential long-term sequelae.

      Graphical abstract

      Keywords

      1. Introduction

      Since Food and Drug Administration approval of ipilimumab as a first immune checkpoint inhibitor (ICI) in 2011, there has been a remarkable increase in the number of ICIs, approved indications [
      • Hargadon K.M.
      • Johnson C.E.
      • Williams C.J.
      Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors.
      ] and trials addressing earlier stages of cancer [
      • Luke J.J.
      • Rutkowski P.
      • Queirolo P.
      • Del Vecchio M.
      • Mackiewicz J.
      • Chiarion-Sileni V.
      • et al.
      Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.
      ]. Encouragingly, the effectiveness of ICIs is leading to a steadily growing group of long-term survivors [
      • Robert C.
      • Thomas L.
      • Bondarenko I.
      • O'Day S.
      • Weber J.
      • Garbe C.
      • et al.
      Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
      ,
      • Weber J.S.
      • D'Angelo S.P.
      • Minor D.
      • Hodi F.S.
      • Gutzmer R.
      • Neyns B.
      • et al.
      Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
      ]. The downside of immunotherapies are their immune-related adverse events (irAEs), which often occur within the first three months of therapy and are usually reversible when ICI therapy is paused and/or immunomodulatory medications are administered [
      • Brahmer J.R.
      • Lacchetti C.
      • Schneider B.J.
      • Atkins M.B.
      • Brassil K.J.
      • Caterino J.M.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.
      ,
      • Weber J.S.
      • Hodi F.S.
      • Wolchok J.D.
      • Topalian S.L.
      • Schadendorf D.
      • Larkin J.
      • et al.
      Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.
      ]. However, ICIs also cause long-term sequelae–commonly affecting endocrine, exocrine, musculoskeletal or neurologic systems [
      • Hofmann L.
      • Forschner A.
      • Loquai C.
      • Goldinger S.M.
      • Zimmer L.
      • Ugurel S.
      • et al.
      Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.
      ,
      • Moreira A.
      • Loquai C.
      • Pföhler C.
      • Kähler K.C.
      • Knauss S.
      • Heppt M.V.
      • et al.
      Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.
      ,
      • Plaçais L.
      • Michot J.-M.
      • Champiat S.
      • Romano-Martin P.
      • Baldini C.
      • Joao M.S.
      • et al.
      Neurological complications induced by immune checkpoint inhibitors: a comprehensive descriptive case-series unravelling high risk of long-term sequelae.
      ]–and these appear to be systematically underreported in registration trials [
      • Ghisoni E.
      • Wicky A.
      • Bouchaab H.
      • Imbimbo M.
      • Delyon J.
      • Moura B.G.
      • et al.
      Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: an overlooked aspect in immunotherapy.
      ]. Indeed, a retrospective multicentre cohort study of anti-PD-1/L1-treated patients recently revealed a remarkably high incidence of so-called chronic irAEs (defined as irAEs that persisted for ≥12 weeks since ICI discontinuation) reaching 43.2%, of which only 14.4% resolved during a median follow-up of 529 days [
      • Patrinely J.R.
      • Johnson R.
      • Lawless A.R.
      • Bhave P.
      • Sawyers A.
      • Dimitrova M.
      • et al.
      Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma.
      ].
      Besides the frequency of persistent irAEs, their impact on patients' lives is crucial. Several studies examined health-related quality of life (HRQoL) in ICI-treated cancer survivors, with results ranging from significant limitations [
      • Boekhout A.H.
      • Rogiers A.
      • Jozwiak K.
      • Boers-Sonderen M.J.
      • van den Eertwegh A.J.
      • Hospers G.A.
      • et al.
      Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls.
      ,
      • Lai-Kwon J.
      • Khoo C.
      • Lo S.
      • Milne D.
      • Mohamed M.
      • Raleigh J.
      • et al.
      The survivorship experience for patients with metastatic melanoma on immune checkpoint and BRAF-MEK inhibitors.
      ,
      • O'Reilly A.
      • Hughes P.
      • Mann J.
      • Lai Z.
      • Teh J.J.
      • Mclean E.
      • et al.
      An immunotherapy survivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune checkpoint inhibitors.
      ,
      • Rogiers A.
      • Leys C.
      • De Cremer J.
      • Awada G.
      • Schembri A.
      • Theuns P.
      • et al.
      Health-related quality of life, emotional burden, and neurocognitive function in the first generation of metastatic melanoma survivors treated with pembrolizumab: a longitudinal pilot study.
      ] to good overall HRQoL [
      • Mamoor M.
      • Postow M.A.
      • Lavery J.A.
      • Baxi S.S.
      • Khan N.
      • Mao J.J.
      • et al.
      Quality of life in long-term survivors of advanced melanoma treated with checkpoint inhibitors.
      ]. However, the extent to which persistent irAEs impose a burden on cancer survivors has been examined in only one study, with no differences found from patients without irAEs [
      • Patrinely Jr., J.R.
      • Young A.C.
      • Quach H.
      • Williams G.R.
      • Ye F.
      • Fan R.
      • et al.
      Survivorship in immune therapy: assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand.
      ].
      In this study, we investigated the prevalence of persistent irAEs and their impact on HRQoL in patients with cancer as well as the burden of autoimmunity in terms of symptoms and therapies compared to patients with corresponding non-ICI-induced autoimmune diseases (AIs). Furthermore, patients' retrospective evaluation of ICI patient education was examined.

      2. Material and methods

      2.1 Patients

      After obtaining institutional review board approval (21-0499 KB, LMU Munich), this multicentre cross-sectional study was conducted from April to October 2021 including two patient cohorts:
      • (1)
        ICI-cohort: Eligible ICI-patients had a diagnosis of cancer (irrespective of cancer type or cancer stage), had received at least one dose of ICI (anti-PD-1/L1 and/or anti-CTLA-4) with last ICI administration ≥12 weeks ago and were ≥18 years of age. ICI-patients with prior or subsequent administration of other anti-cancer therapies were included. ICI-patients were identified by weekly review in three outpatient clinics (LMU Klinikum, Munich; University Hospital Schleswig-Holstein, Kiel; Hospital Bremerhaven Reinkenheide, Bremerhaven) to obtain an approximately representative sample of German skin cancer centres' outpatients. Additionally, patients were addressed online via support groups.
      • (2)
        AI-cohort: Eligible AI-patients had a diagnosis of at least one AI and were ≥18 years of age. AI-patients who had received any kind of ICI therapy were excluded. AI-patients were recruited through an outpatient clinic for internal medicine (LMU Klinikum, Munich) and reached online via support groups.

      2.2 Study design

      Each patient cohort was surveyed with a specific and pretested ICI-/AI-questionnaire (Supplementary Material 1 and 2). Both questionnaires collected data on patient demographics, persistent autoimmunity (persistent irAEs/AIs), burden of persistent autoimmune symptoms on a visual analogue scale (VAS), therapies for persistent autoimmunity and burden of these therapies on a VAS. Persistent irAEs that existed 12 weeks to <12 months since ICI discontinuation were defined as long-term irAEs, and those ≥12 months since ICI discontinuation were defined as chronic irAEs. To assess HRQoL, the standardised patient-reported outcome measure EuroQol 5D-5L (EQ-5D-5L) was applied, which comprises five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) evaluated by five ordinal levels (no, slight, moderate, severe or extreme problems), whereby 55 = 3125 different numerical health states are expressible [
      • Herdman M.
      • Gudex C.
      • Lloyd A.
      • Janssen M.
      • Kind P.
      • Parkin D.
      • et al.
      Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).
      ]. Based on these health states and using a value set for the German population, the metric EQ-Index score with a scale ranging from −0.661 (extreme problems in all five dimensions) to 1 (no problems in any dimension) was calculated for each patient [
      • Ludwig K.
      • von der Schulenburg J.-M.G.
      • Greiner W.
      German value set for the EQ-5D-5L.
      ]. In addition, the EQ-5D-5L includes a VAS that indicates HRQoL on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) as the metric EQ-VAS score [
      • Rabin R.
      • de Charro F.
      EQ-5D: a measure of health status from the EuroQol Group.
      ]. Determined EQ-Index scores rank HRQoL according to the preferences of the German population, while EQ-VAS scores express overall health states by individual assessments [
      • Whynes D.K.
      TOMBOLA Group
      Correspondence between EQ-5D health state classifications and EQ VAS scores.
      ]. Differences ≥0.08 for EQ-Index scores and differences ≥7 for EQ-VAS scores indicate clinically significant changes, described as minimally important differences [
      • Pickard A.S.
      • Neary M.P.
      • Cella D.
      Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer.
      ].
      ICI-questionnaires recorded additional data on type of cancer, stage of cancer, metastatic status, previous/current drug-based anti-cancer therapies, reversible irAEs, type of ICIs, date of last ICI administration and evaluation of ICI therapy on a VAS. AI-questionnaires specifically captured the presence of acute exacerbations of AIs.

      2.3 Statistical analysis

      Only entirely completed surveys were evaluated. Nominal, ordinal and metric variables were summarised by means, medians and/or percentages. Chi-square tests and Fisher's exact tests were used to compare nominal variables or ≤2 ordinal variables between two unpaired groups. Mann–Whitney tests were applied to compare >2 ordinal variables or non-normally distributed, metric variables between two unpaired groups. Unpaired t-tests were used to compare normally distributed, metric variables between two unpaired groups. Binomial logistic regression analysis was performed to examine predictor variables for the occurrence of chronic irAEs and multiple linear regression analyses were conducted to investigate predictor variables for the EQ-Index/VAS. All regression analyses included the type of recruitment cohort (0 = outpatient clinics, 1 = support groups) to control potential confounding due to different survey distribution channels [
      • McNamee R.
      Regression modelling and other methods to control confounding.
      ]. A two-sided p-value <0.05 was considered statistically significant. Statistical analyses were conducted using SPSS Statistics (IBM®, version 28.0).

      3. Results

      3.1 Patients

      Out of 3408 participants, 200 of 258 ICI-patients (77.5%) and 2705 of 3150 AI-patients (85.9%) had submitted entirely completed questionnaires and met inclusion criteria. ICI-patients were more frequently male (51.0% versus 11.6%, p < 0.001) and older (mean: 60 versus 47 years, p < 0.001) than AI-patients (Table 1).
      • (1)
        In the ICI-cohort, 104 ICI-patients (52.0%) had experienced reversible irAEs in the past, and 100 ICI-patients (50.0%) reported at least one persistent irAE existing at the time of survey completion with a mean of 2.4 persistent irAEs per affected patient. Most ICI-patients were diagnosed with melanoma (96.5%), had local (45.0%) or distant metastases (53.0%) and reported a complete response (67.5%). Progressive disease was reported by 8.5% of ICI-patients. Most frequently received ICI regimens were pembrolizumab (41.0%), nivolumab (39.5%) and ipilimumab plus nivolumab (29.5%) with a median time of 16 months (range: 2.8–102.0 months) since the last ICI administration. Only 14.5% of ICI-patients were currently receiving other drug-based anti-cancer therapies (Supplementary Table 1).
      • (2)
        In the AI-cohort, AI-patients indicated a mean of 1.6 AIs per patient, with autoimmune hypothyroidism (16.5%), Sjogren's syndrome (13.6%), vitiligo (10.3%), sarcoidosis (10.0%) and psoriatic arthritis (9.6%) most frequently cited. Among AI-patients, 67.9% reported non-exacerbated AIs, whereas 32.1% stated acute exacerbations at the time of survey completion (Supplementary Table 2).
      Table 1ICI-cohort and AI-cohort: patient demographics and recruitment cohorts.
      ICI-cohort

      n = 200 (6.9%)
      AI-cohort
      Patients had at least one of the following autoimmune diseases: Addison's disease, ankylosing spondylitis, autoimmune gastritis, autoimmune haematological disorder, autoimmune hepatitis, autoimmune hyperthyroidism, autoimmune hypothyroidism, bullous pemphigoid, Crohn's disease, dermatomyositis, diabetes mellitus type 1, giant cell arteritis, hypophysitis, idiopathic pulmonary fibrosis, lichen ruber, lichen sclerosus, multiple sclerosis, myasthenia gravis, myositis, neurodermatitis, pemphigus vulgaris, polymyalgia rheumatica, polymyositis, polyneuropathy (chronic inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome), primary biliary/sclerosing cholangitis, psoriasis vulgaris, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, Sjogren's syndrome, systemic sclerosis, systemic lupus erythematosus, ulcerative colitis and/or vitiligo.


      n = 2705 (93.1%)
      P-valueTotal

      n = 2905 (100.0%)
      Gender, n (%)
       Female98 (49.0)2391 (88.4)<0.001
      Chi-square test was used.
      2489 (85.7)
       Male102 (51.0)314 (11.6)416 (14.3)
      Age at time of survey, years
       Mean (SD)60 (14.6)47 (11.6)<0.001
      Unpaired t-test was used.
      48 (0.2)
       Median (range)60 (23.0–91.0)48 (18.0–84.0)49 (18.0–91.0)
      Marital status, n (%)
       Partnered152 (76.0)1989 (73.6)0.444
      Chi-square test was used.
      2141 (73.7)
       Not partnered48 (24.0)716 (26.5)764 (26.3)
      Education, n (%)
       Low qualification46 (23.0)303 (11.2)<0.001
      Mann–Whitney test was used.
      349 (12.0)
       Middle qualification76 (38.0)1134 (41.9)1210 (41.7)
       High qualification78 (39.0)1268 (46.9)1346 (46.3)
      Recruitment cohort, n (%)
       Outpatient clinics147 (73.5)9 (0.3)<0.001
      Unpaired t-test was used.
      156 (5.4)
       Support groups53 (26.5)2696 (99.7)2749 (94.6)
      ICI, immune checkpoint inhibitor; AI, non-ICI-induced autoimmune disease; SD, standard deviation.
      a Patients had at least one of the following autoimmune diseases: Addison's disease, ankylosing spondylitis, autoimmune gastritis, autoimmune haematological disorder, autoimmune hepatitis, autoimmune hyperthyroidism, autoimmune hypothyroidism, bullous pemphigoid, Crohn's disease, dermatomyositis, diabetes mellitus type 1, giant cell arteritis, hypophysitis, idiopathic pulmonary fibrosis, lichen ruber, lichen sclerosus, multiple sclerosis, myasthenia gravis, myositis, neurodermatitis, pemphigus vulgaris, polymyalgia rheumatica, polymyositis, polyneuropathy (chronic inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome), primary biliary/sclerosing cholangitis, psoriasis vulgaris, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, Sjogren's syndrome, systemic sclerosis, systemic lupus erythematosus, ulcerative colitis and/or vitiligo.
      b Chi-square test was used.
      c Unpaired t-test was used.
      d Mann–Whitney test was used.

      3.2 Prevalence of persistent irAEs

      Divided by recruitment type, the prevalence of persistent irAEs was lower in ICI-patients from outpatient clinics than in ICI-patients from support groups (41.5% versus 73.6%, p < 0.001). The outpatient ICI-cohort (n = 147), as an approximately representative sample for outpatients of German skin cancer centres, revealed long-term/chronic irAEs in 51.9%/35.5% of patients with arthralgia (16.7%/16.1%), myalgia (13.0%/14.0%), hypothyroidism (11.1%/10.8%), xerostomia (7.4%/8.6%), vitiligo (13.0%/7.5%) and hypophysitis (9.3%/7.5%) most frequently reported (Fig. 1 and Supplementary Table 3). When prevalence was further subdivided by time since ICI discontinuation, 54.2% (13 of 24) of patients with 12 weeks to <6 months, 50.0% (15 of 30) of patients with 6 to <12 months, 31.5% (17 of 54) of patients with 12 to <30 months and 41.0% (16 of 39) of patients with ≥30 months since ICI cessation reported persistent irAEs.
      Fig. 1
      Fig. 1Outpatient ICI-cohort (n = 147): Prevalence of persistent irAEs (a) by time since last ICI administration and (b) by type and time since last ICI administration with proportions and numbers of affected patients to all patients in the respective time periods. IrAE, immune-related adverse event; CN, cranial nerve; ICI, immune checkpoint inhibitor.
      Among ICI-patients with ≥12 months since ICI cessation (n = 122), a binomial logistic regression analysis was performed to investigate the occurrence of chronic irAEs: exposure to ipilimumab increased the risk of chronic irAEs (odds ratio: 4.6, p = 0.005), whereas gender, age, time since ICI cessation, number of ICIs and reversible irAEs showed no influence. The recruitment cohort was controlled as confounder with a higher probability of chronic irAEs in patients from support groups (odds ratio: 3.1, p = 0.032) (Supplementary Table 4).

      3.3 HRQoL in patients with versus without persistent irAEs

      In the total ICI-cohort, ICI-patients with long-term/chronic irAEs showed lower HRQoL than ICI-patients without long-term/chronic irAEs (EQ-Index score: 0.767/0.752 versus 0.920/0.923, p < 0.001/0.001; EQ-VAS score: 52.2/52.0 versus 63.6/74.7, p =/< 0.040/0.001), with differences exceeding minimally important differences (EQ-Index/VAS scores ≥0.08/≥7), indicating clinically significant changes. The same applies to the breakdown by time since ICI cessation, with the exception of EQ-VAS scores in ICI-patients <6 months after therapy (Fig. 2). Moreover, ICI-patients with chronic irAEs reported clinically relevantly lower EQ-5D-5L scores than representative values of the German population [
      • Grochtdreis T.
      • Dams J.
      • König H.-H.
      • Konnopka A.
      Health-related quality of life measured with the EQ-5D-5L: estimation of normative index values based on a representative German population sample and value set.
      ], whereas ICI-patients without chronic irAEs indicated approximately similar or even higher EQ-5D-5L scores (Fig. 2 and Supplemental Table 5).
      Fig. 2
      Fig. 2ICI-cohort (n = 200): EQ-5D-5L scores. (a) EQ-Index scores and (b) EQ-VAS scores in patients with versus without chronic irAEs and a representative value set for the German population [
      • Grochtdreis T.
      • Dams J.
      • König H.-H.
      • Konnopka A.
      Health-related quality of life measured with the EQ-5D-5L: estimation of normative index values based on a representative German population sample and value set.
      ]. MIDs indicate clinically significant changes based on differences in HRQoL scores (≥0.08 for EQ-Index scores and ≥7 for EQ-VAS scores). (c) EQ-Index scores and (d) EQ-VAS scores in patients with versus without persistent irAEs by time since last ICI administration. Asterisks indicate clinically significant changes (p < 0.05) with differences exceeding respective MIDs. Higher EQ-5D-5L scores correspond to higher HRQoL and vice versa. HRQoL, health-related quality of life; MID, minimally important difference; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; VAS, visual analogue scale.
      Multiple linear regression analyses among ICI-patients with ≥12 months since ICI cessation (n = 122) confirmed clinically significant reductions in EQ-5D-5L scores by chronic irAEs (EQ-Index/VAS score: −0.163/−23.4, p < 0.001/0.001) and in EQ-VAS scores by current drug-based anti-cancer therapies (−13.4, p = 0.016). Gender, age, time since ICI discontinuation, number of ICIs, exposure to ipilimumab and reversible irAEs showed no significant effects. As confounder, recruitment type influenced EQ-Index scores with reduced values in ICI-patients from support groups (−0.099, p = 0.023) (Supplementary Tables 6 and 7).
      Analysing the EQ-5D-5L dimensions over time since ICI cessation to obtain deeper insight into health profiles, ICI-patients with persistent irAEs indicated worse health states, particularly for mobility, usual activities and pain/discomfort, compared to ICI-patients without persistent irAEs (Fig. 3).
      Fig. 3
      Fig. 3ICI-cohort (n = 200): EQ-5D-5L dimensions. (a) Mobility, (b) self-care, (c) usual activities, (d) pain/discomfort and (e) anxiety/depression in patients with versus without persistent irAEs by time since last ICI administration. ICI, immune checkpoint inhibitor; irAE, immune-related adverse event.
      Additionally, EQ-5D-5L dimensions were assessed for most frequently reported persistent irAEs. Moderate to extreme problems in the dimensions of mobility, usual activities and pain/discomfort appeared not only with comparatively higher proportions in arthralgias and myalgias but also in the dimension of mobility in hypophysitis (Fig. 4).
      Fig. 4
      Fig. 4Patients with persistent irAEs (n = 100): EQ-5D-5L dimensions of specific chronic irAEs. Shown are EQ-5D-5L's five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) rated by five levels of severity (no, slight, moderate, severe or extreme problems) for the most frequently reported persistent irAEs. Patients may have other additional persistent irAEs. irAE, immune-related adverse event.

      3.4 HRQoL, burden of symptoms and burden of therapy in patients with chronic irAEs versus with AIs

      As irAEs imitate spontaneous AIs [
      • Johnson D.B.
      • Nebhan C.A.
      • Moslehi J.J.
      • Balko J.M.
      Immune-checkpoint inhibitors: long-term implications of toxicity.
      ], the consequences of autoimmunity were compared between ICI-patients with chronic irAEs and AI-patients (in total and by symptom-specific subgroups) with respect to EQ-Index/VAS scores, burden of autoimmune symptoms and burden of related therapies.
      Among symptom-specific subgroups, ICI-patients with chronic irAEs showed significantly higher EQ-Index/VAS scores or lower symptom burdens than AI-patients with exacerbated AIs in 11 of 40 comparisons. Compared to AI-patients with non-exacerbated AIs, ICI-patients with chronic irAEs differed significantly in 4 of 40 comparisons: outpatient ICI-patients with arthralgia/hypothyroidism indicated lower symptom burden than AI-patients with rheumatoid arthritis/hypothyroidism, whereas ICI-patients with vitiligo showed lower EQ-Index scores than AI-patients with vitiligo (Fig. 5).
      Fig. 5
      Fig. 5HRQoL (EQ-Index score, EQ-VAS score), burden of autoimmune symptoms and burden of related therapies in ICI-patients with chronic irAEs (n = 52) versus AI-patients (n = 2705). Besides all patients, subgroups with specific ICI-induced/non-ICI-induced symptom complexes were examined (with a minimum of n = 10 per symptom-specific subgroup). Analyses were divided by recruitment type of ICI-patients (outpatient ICI-cohort, support group ICI-cohort) and symptom conditions of AI-patients (non-exacerbated AI-cohort, exacerbated AI-cohort). Bold numbers indicate lower EQ-Index/VAS scores (corresponding to lower HRQoL and vice versa) and higher burden of symptoms/therapies in ICI-patients than AI-patients. Significant differences (p < 0.05) are coloured. (a) Patients may have other additional chronic irAEs/AIs. (b) Mann–Whitney test was used. (c) Unpaired t-test was used. (d) To assess burden of therapy, patients who reported selected chronic irAEs/AIs and who reported therapy for that or other chronic irAEs/AIs were evaluated. AI, autoimmune disease; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; SD, standard deviation.

      3.5 Therapy of chronic irAEs versus AIs

      To investigate therapy of autoimmunity, the number of therapeutic agents per autoimmune symptom was determined for each patient. ICI-patients with chronic irAEs reported a significantly lower number of medications per autoimmune symptom than AI-patients (0.61 versus 1.07, p < 0.001).

      3.6 Evaluation of ICI therapy and patient education

      Retrospective evaluations of ICI therapy and patient education revealed that ICI-patients with chronic irAEs felt less adequately informed about side-effects of immunotherapy than ICI-patients without chronic irAEs (difference in agreements: −15.4%, p < 0.001) (Supplementary Table 8).

      4. Discussion

      This study investigated the prevalence and impact of persistent irAEs ≥12 weeks since ICI cessation by evaluating HRQoL, burden of symptoms and associated therapies compared to that of AIs. HRQoL in patients with cancer and with persistent irAEs was clinically significantly reduced compared to those without persistent irAEs and the latter's HRQoL was comparable to that of the general population.
      The prevalence of persistent irAEs was 41.5% among all patients in our trial. Although this might include late-onset irAEs, these would only account for 1.4–4.7%
      The incidence of late-onset irAEs (onset >12 months after ICI initiation) was reported to be 5.3%, of which 24% occurred after ICI cessation. Thus, the incidence of late-onset irAEs after ICI cessation was 5.3% × 26.0% = 1.4% [
      • Owen C.
      • Bai X.
      • Quah T.
      • Lo S.
      • Allayous C.
      • Callaghan S.
      • et al.
      Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.
      ].
      ,
      Out of 387 patients, 33 (8.5%) patients developed late-onset irAEs within the first 12 weeks after ICI cessation. These late-onset irAEs persisted beyond 12 weeks after ICI cessation with a probability of 55.7% (= 167/300 patients). Thus, the incidence of late-onset irAEs after ICI cessation was 8.5% × 55.7% = 4.7% [
      • Patrinely J.R.
      • Johnson R.
      • Lawless A.R.
      • Bhave P.
      • Sawyers A.
      • Dimitrova M.
      • et al.
      Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma.
      ].
      [
      • Patrinely J.R.
      • Johnson R.
      • Lawless A.R.
      • Bhave P.
      • Sawyers A.
      • Dimitrova M.
      • et al.
      Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma.
      ,
      • Owen C.
      • Bai X.
      • Quah T.
      • Lo S.
      • Allayous C.
      • Callaghan S.
      • et al.
      Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.
      ]. Our results are similar to data from a retrospective multicentre study of 387 patients with melanoma after anti-PD-1 therapy reporting 43.2% [
      • Patrinely J.R.
      • Johnson R.
      • Lawless A.R.
      • Bhave P.
      • Sawyers A.
      • Dimitrova M.
      • et al.
      Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma.
      ]. The frequencies of specific persistent irAEs differed, especially with a higher prevalence of arthralgia (16.3% versus 5.7%) and myalgia (13.6% versus 0.3%) in our study, whereas a cross-sectional survey study among 90 melanoma survivors after ICI therapy observed nearly equal proportions of aching joints (17%) and aching muscles (12%) [
      • Mamoor M.
      • Postow M.A.
      • Lavery J.A.
      • Baxi S.S.
      • Khan N.
      • Mao J.J.
      • et al.
      Quality of life in long-term survivors of advanced melanoma treated with checkpoint inhibitors.
      ]. Survey-based studies might better detect persisting symptoms which are not raised by patients and subsequently not noted in medical records. As persistent toxicities are underreported in registration trials [
      • Ghisoni E.
      • Wicky A.
      • Bouchaab H.
      • Imbimbo M.
      • Delyon J.
      • Moura B.G.
      • et al.
      Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: an overlooked aspect in immunotherapy.
      ], there is a need for improved reporting in the era of immunotherapy [
      • Heinzerling L.
      • Ascierto P.A.
      • Dummer R.
      • Gogas H.
      • Grob J.-J.
      • Lebbe C.
      • et al.
      Adverse events 2.0—let us get SERIOs: new reporting for adverse event outcomes needed in the era of immunooncology.
      ]. Furthermore, consistent with previous studies patients recruited from support groups were more likely to be female, younger and more highly educated, potentially with a different reporting behaviour or even different symptom profiles [
      • Grande G.E.
      • Myers L.B.
      • Sutton S.R.
      How do patients who participate in cancer support groups differ from those who do not?.
      ,
      • Steginga S.K.
      • Campbell A.
      • Ferguson M.
      • Beeden A.
      • Walls M.
      • Cairns W.
      • et al.
      Socio-demographic, psychosocial and attitudinal predictors of help seeking after cancer diagnosis.
      ].
      Interestingly, survivors with ≥30 months after ICI discontinuation had a higher prevalence of chronic irAEs (41.0%) than patients with 12 to <30 months after therapy cessation (31.5%). This finding might be explainable by higher ICI activity in patients with persistent irAEs leading to better outcomes. An improved recurrence-free survival (RFS) for patients with persistent irAEs ≥12 weeks since ICI cessation has been described [
      • Patrinely J.R.
      • Johnson R.
      • Lawless A.R.
      • Bhave P.
      • Sawyers A.
      • Dimitrova M.
      • et al.
      Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma.
      ] and would be consistent with the association between acute irAEs and prolonged RFS [
      • Eggermont A.M.M.
      • Kicinski M.
      • Blank C.U.
      • Mandala M.
      • Long G.V.
      • Atkinson V.
      • et al.
      Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial.
      ].
      In accordance to our findings, the increased risks of chronic irAEs due to exposure to ipilimumab was also observed in a study examining toxicities after ICI cessation in 217 patients with melanoma, renal cell carcinoma or non-small cell lung cancer [
      • Patrinely Jr., J.R.
      • Young A.C.
      • Quach H.
      • Williams G.R.
      • Ye F.
      • Fan R.
      • et al.
      Survivorship in immune therapy: assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand.
      ]. To our knowledge, the aforementioned study is the only investigation that has specifically examined effects of persistent irAEs after ICI cessation on HRQoL. Using two cancer-specific tools (National Comprehensive Cancer Network Distress Thermometer; Functional Assessment of Cancer Therapy – General) and a post-traumatic instrument (Impact of Event Scale – Revised), no differences were found [
      • Patrinely Jr., J.R.
      • Young A.C.
      • Quach H.
      • Williams G.R.
      • Ye F.
      • Fan R.
      • et al.
      Survivorship in immune therapy: assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand.
      ]. In our study, the non-cancer-specific EQ-5D-5L was applied, which is a responsive instrument to symptoms and severities [
      • Whynes D.K.
      TOMBOLA Group
      Correspondence between EQ-5D health state classifications and EQ VAS scores.
      ]. For both EQ-5D-5L scores, significant and clinically relevant limitations in HRQoL were detected in patients with persistent irAEs compared to patients without persistent irAEs and to German population [
      • Grochtdreis T.
      • Dams J.
      • König H.-H.
      • Konnopka A.
      Health-related quality of life measured with the EQ-5D-5L: estimation of normative index values based on a representative German population sample and value set.
      ]. In contrast, patients without persistent irAEs and ≥12 months since ICI discontinuation reported similar or even higher HRQoL than the German population, which might be explained by response-shifts. Response-shifts describe changes in internal perceptions that lead to more positive survey-based assessments of HRQoL after serious life events [
      • Breetvelt I.
      • Van Dam F.
      Underreporting by cancer patients: the case of response-shift.
      ].
      Furthermore, the impact of chronic irAEs was similar to that of non-exacerbated AIs when assessed using HRQoL, burden of symptoms and burden of therapies, which is consistent with the observation that persistent irAEs are usually (96.4%) low grade [
      • Patrinely J.R.
      • Johnson R.
      • Lawless A.R.
      • Bhave P.
      • Sawyers A.
      • Dimitrova M.
      • et al.
      Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma.
      ].
      ICIs in adjuvant settings for patients with cancer and with a low risk of recurrence are increasingly being studied and have shown to significantly improve RFS [
      • Luke J.J.
      • Rutkowski P.
      • Queirolo P.
      • Del Vecchio M.
      • Mackiewicz J.
      • Chiarion-Sileni V.
      • et al.
      Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.
      ,
      • Choueiri T.K.
      • Tomczak P.
      • Park S.H.
      • Venugopal B.
      • Ferguson T.
      • Chang Y.H.
      • et al.
      Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma.
      ]. Nevertheless, the potential impact of chronic toxicities and associated limitations in HRQoL need to be carefully balanced against the achievable reduction of absolute risk of recurrence [
      • Higham C.E.
      • Chatzimavridou-Grigoriadou V.
      • Fitzgerald C.T.
      • Trainer P.J.
      • Eggermont A.M.M.
      • Lorigan P.
      Adjuvant immunotherapy: the sting in the tail.
      ].
      As acute irAEs need to be reported early and treated promptly to ensure adequate management, and since data from registration trials are mainly available for acute irAEs, ICI patient education [
      • Wood L.S.
      • Moldawer N.P.
      • Lewis C.
      Immune checkpoint inhibitor therapy.
      ] and treatment guidelines [
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • Lacchetti C.
      • Adkins S.
      • Anadkat M.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update.
      ] predominantly focus on acute irAEs, resulting in a void of patient education and treatment guidelines for chronic irAEs. Accordingly, patients with chronic irAEs reported inadequate patient education and comparatively received fewer treatments for their autoimmune conditions than patients with AIs, potentially indicating under-diagnosis and/or under-treatment.

      5. Conclusion

      Persistent irAEs lead to considerable impairments in HRQoL and substantial disease burden. Increased attention needs to be dedicated to this issue, including longitudinal data collection and more comprehensive patient education. Balanced risk-benefit analyses need to be conducted, especially for adjuvant ICI therapy in patients with low risk of recurrence.

      Ethics approval

      The Ethics Committee at the Medical Faculty of LMU Munich approved the clinical study as anonymized collection and analysis of patient data (21-0499 KB).

      Author contributions

      All authors contributed to this publication according to the ICMJE criteria for authorship. T. U. Schulz: Conceptualisation, Methodology, Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing. S. Zierold: Conceptualisation, Investigation, Writing - Review & Editing. M. M. Sachse: Investigation, Writing - Review & Editing. G. Pesch: Investigation, Writing - Review & Editing. D. Tomsitz: Investigation, Writing - Review & Editing. K. Schilbach: Investigation, Writing - Review & Editing. K. C. Kähler: Investigation, Writing - Review & Editing. L. E. French: Investigation, Writing - Review & Editing, Supervision. L. Heinzerling: Conceptualisation, Methodology, Investigation, Writing - Review & Editing, Supervision.

      Funding

      This study was funded by the German Federal Ministry of Education and Research (BMBF) as part of the project MelAutim ( 01ZX1905A ), which aims a systems medicine investigation of melanoma and autoimmunity in the context of immune therapies. The funding source had no influence on the design, conduct, analysis and/or report of this research.

      Data availability

      Data are available from the corresponding author on reasonable request.

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
      S. Zierold has received speaker fees and/or travel grants from BMS , Sun Pharma and MSD . M. M. Sachse reports speaker honoraria from Novartis and advisory board honoraria from Sanofi Genzyme. D. Tomsitz reports consultancy, speaker fees and/or travel grants from BMS, Roche , Novartis , Sanofi , Recordati , Kyowa Kirin and Sun Pharma. K. Schilbach has served as consultant and/or has received honoraria from Recordati rare diseases, Pfizer, Ipsen, Sandoz and Consilient Health. There are no conflicts of interest concerning the present study. K. C. Kähler has served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis; travel support from Amgen , Merck Sharp and Dohme , Bristol Myers Squibb , Amgen, Pierre Fabre , Medac and Novartis. L. E. French has served as paid consultant and/or speaker for Galderma, Janssen, Leo Pharma, Eli Lilly, Almirall, Union Therapeutics, Regeneron, Novartis, Amgen, Abbvie, UCB, Biotest, AC-Immune and InflaRx. None of these activities pertain to cancer immunotherapy and ICIs however. L. Heinzerling reports consultancy, speaker fees, travel grants and/or research funding: BMS, MSD, Merck, Roche, Amgen, Curevac , Novartis, Sanofi and Pierre Fabre; clinical studies: BMS, MSD, Merck, Roche, Amgen, GSK, Curevac and Novartis. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      The authors would like to thank the patients for participating in this study.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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