Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: Abu-Sbeih H, Tang T, Ali FS, Johnson DH, Qiao W, Diab A, Wang Y. The Impact of Immune Checkpoint Inhibitor-Related Adverse Events and Their Immunosuppressive Treatment on Patients’ Outcomes. ACTA ACUST UNITED AC 2020. [DOI: 10.4103/jipo.jipo_12_18] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]

For:	Abu-Sbeih H, Tang T, Ali FS, Johnson DH, Qiao W, Diab A, Wang Y. The Impact of Immune Checkpoint Inhibitor-Related Adverse Events and Their Immunosuppressive Treatment on Patients’ Outcomes. ACTA ACUST UNITED AC 2020. [DOI: 10.4103/jipo.jipo_12_18] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]

Number

Cited by Other Article(s)

Suzuki K, Yasui Y, Tsuchiya K, Matsumoto H, Yamazaki Y, Uchihara N, Tanaka Y, Miyamoto H, Yamada-Shimizu M, Keitoku T, Okada R, Higuchi M, Takaura K, Tanaka S, Maeyashiki C, Tamaki N, Nakanishi H, Takahashi Y, Asahina Y, Okamoto R, Kurosaki M, Izumi N. Impact of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab. J Gastroenterol Hepatol 2024;39:1183-1189. [PMID: 38494668 DOI: 10.1111/jgh.16532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/04/2024] [Accepted: 02/21/2024] [Indexed: 03/19/2024]

Affiliation(s)

Keito Suzuki Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Yutaka Yasui Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Kaoru Tsuchiya Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Hiroaki Matsumoto Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Yudai Yamazaki Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Naoki Uchihara Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Yuki Tanaka Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Haruka Miyamoto Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Michiko Yamada-Shimizu Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Taisei Keitoku Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Risa Okada Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Mayu Higuchi Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Kenta Takaura Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Shohei Tanaka Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Chiaki Maeyashiki Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Nobuharu Tamaki Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Hiroyuki Nakanishi Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Yuka Takahashi Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Yasuhiro Asahina Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, Tokyo, Japan
Ryuichi Okamoto Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, Tokyo, Japan
Masayuki Kurosaki Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Namiki Izumi Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

Collapse

Suijkerbuijk KPM, van Eijs MJM, van Wijk F, Eggermont AMM. Clinical and translational attributes of immune-related adverse events. NATURE CANCER 2024;5:557-571. [PMID: 38360861 DOI: 10.1038/s43018-024-00730-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/12/2024] [Indexed: 02/17/2024]

Gallo C, Dispinzieri G, Zucchini N, Invernizzi P, Massironi S. Autoimmune pancreatitis: Cornerstones and future perspectives. World J Gastroenterol 2024;30:817-832. [PMID: 38516247 PMCID: PMC10950636 DOI: 10.3748/wjg.v30.i8.817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/18/2023] [Accepted: 01/25/2024] [Indexed: 02/26/2024] Open

Van Buren I, Madison C, Kohn A, Berry E, Kulkarni RP, Thompson RF. Survival Among Veterans Receiving Steroids for Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy. JAMA Netw Open 2023;6:e2340695. [PMID: 37906189 PMCID: PMC10618850 DOI: 10.1001/jamanetworkopen.2023.40695] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/19/2023] [Indexed: 11/02/2023] Open

Abstract

Importance

Systemic steroids are commonly used to manage immune-related adverse events (irAEs), but it remains unclear whether they may undermine immune checkpoint inhibitor (ICI) therapy outcomes. Few studies have assessed the impact of steroid timing and its association with continuation or cessation of ICI therapy.

Objective

To characterize how systemic steroids and steroid timing for irAEs are associated with survival in patients receiving ICI therapy.

Design, Setting, and Participants

This multicenter retrospective cohort study encompassed veterans receiving ICI for cancer between January 1, 2010, and December 31, 2021. Data analysis was conducted September 8, 2023.

Exposures

Identifiable primary diagnosis of cancer. Patients were categorized into 3 cohorts: those receiving no steroids, systemic steroids for irAEs, and steroids for non-irAE-associated reasons. All eligible patients received 1 or more doses of an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab). Eligible patients in the steroid group received at least 1 dose (intravenous, intramuscular, or oral) of dexamethasone, hydrocortisone, methylprednisolone, prednisone, or prednisolone. Steroid use at baseline for palliation or infusion prophylaxis or delivered as a single dose was deemed to be non-irAE associated. All other patterns of steroid use were assumed to be for irAEs.

Main Outcomes and Measures

The primary outcome was overall survival, with a 5-year follow-up after ICI initiation. Kaplan-Meier survival analyses were performed with pairwise log-rank tests to determine significance. Risk was modeled with Cox proportional hazard regression.

Results

The cohort consisted of 20 163 veterans receiving ICI therapy including 12 221 patients (mean [SD] age, 69.5 [8.0] years; 11 830 male patients [96.8%]; 9394 White patients [76.9%]) who received systemic steroids during ICI treatment and 7942 patients (mean [SD] age, 70.3 [8.5] years; 7747 male patients [97.5%]; 6085 White patients [76.6%]) who did not. Patients with an irAE diagnosis had significantly improved overall survival (OS) compared with those without (median [IQR] OS, 17.4 [6.6 to 48.5] months vs 10.5 [3.5 to 36.8] months; adjusted hazard ratio, 0.84; 95% CI, 0.81-0.84; P < .001). For patients with irAEs, systemic steroids for irAEs were associated with significantly improved survival compared with those who received steroids for non-irAE-related reasons or no steroid treatment (median [IQR] OS, 21.3 [9.3 to 58.2] months vs 13.6 [5.5 to 33.7] months vs 15.8 [4.9 to not reached] months; P <.001). However, among those who received steroids for irAEs, early steroid use (<2 months after ICI initiation) was associated with reduced relative survival benefit vs later steroid use, regardless of ICI continuation or cessation following steroid initiation (median [IQR] OS after ICI cessation 4.4 [1.9 to 19.5] months vs 16.0 [8.0 to 42.2] months; median [IQR] OS after ICI continuation, 16.0 [7.1 to not reached] months vs 29.2 [16.5 to 53.5] months; P <.001).

Conclusions and Relevance

This study suggests that steroids for irAE management may not abrogate irAE-associated survival benefits. However, early steroid administration within 2 months of ICI initiation is associated with shorter survival despite continuation of ICI therapy.

Collapse

Shatila M, Ma W, Cui Y, Naz S, S Thomas A, N De Toni E, Török HP, Khaled NB, Altan M, Schneider B, Wang Y. Effects of immunosuppressive treatment on patient outcomes after immune checkpoint inhibitor-related gastrointestinal toxicity. J Cancer Res Clin Oncol 2023;149:7793-7803. [PMID: 37029815 DOI: 10.1007/s00432-023-04736-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/31/2023] [Indexed: 04/09/2023]

Abstract

PURPOSE

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of certain cancers but cause immune-related adverse events (irAEs). Gastrointestinal irAEs may necessitate extended periods of steroid use and the initiation of selective immunosuppressive therapy (SIT) which could theoretically counteract the effect of ICIs. In this study, we aim to explore the impact of immunosuppression use and duration on cancer progression and progression-free survival (PFS).

METHODS

This is a single-center retrospective review exploring cancer outcomes in patients taking ICIs who developed gastrointestinal irAEs within 1 year of ICI initiation. Cancer outcome and progression free survival (PFS) were measured and compared by using IBM SPSS Statistics 26.

RESULTS

Of the 116 patients included in this study, 69 received immunosuppression to treat irAEs. The occurrence of colitis and use of immunosuppression for colitis were associated with less cancer progression by later assessment (p < 0.05). Shorter durations of steroids with or without SIT for colitis were associated with less cancer progression within the study window than no immunosuppression (p < 0.05). Immunosuppression has no effect on PFS (p < 0.05).

CONCLUSION

Our study reported shorter duration of steroid treatment for colitis may be associated with less cancer progression. Though the use of immunosuppression was not found to impact PFS, this may be confounded by the presence of colitis, which is known to improve cancer outcomes and could mask any negative impact of immunosuppression on survival. It may be preferable to limit long-term immunosuppression in the treatment of immune-mediated colitis to minimize potential complications. Prospective studies are needed to clarify this relationship, and treatments that abrogate the need for immunosuppression in these patients such as fecal microbiota transplantation.

Collapse

Affiliation(s)

Malek Shatila Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
Weijie Ma Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
Yantong Cui Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA Bachelor of Science in Biological Sciences, Cornell University, Ithaca, NY, USA
Sidra Naz Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
Anusha S Thomas Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA
Enrico N De Toni Department of Medicine II, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
Helga-Paula Török Department of Medicine II, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
Najib Ben Khaled Department of Medicine II, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
Mehmet Altan Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Bryan Schneider Department of Thoracic Medical Oncology, The University of Michigan, Ann Harbor, MI, USA
Yinghong Wang Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030, USA.

Collapse

Faucheux A, Olson E, Lantz J, Roberts N, Aggarwal V, Newman I, Ponnatapura J, Lycan T. A Novel Workflow to Create a Checkpoint Inhibitor Pneumonitis Patient Registry. Cureus 2023;15:e34683. [PMID: 36909081 PMCID: PMC9994379 DOI: 10.7759/cureus.34683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2023] [Indexed: 02/09/2023] Open

Abstract

Background Despite being a groundbreaking cancer therapy, immune checkpoint inhibitors (ICI) can lead to potentially life-threatening toxicity with checkpoint inhibitor pneumonitis (CIP). While treatable, it is easy for clinicians to miss the symptoms of CIP, which can lead to a delay in diagnosis and worsening respiratory function. There is no consensus approach to systematically identifying patients at risk of developing CIP. Thus, we sought to create a workflow that could inform patient selection for ICI therapy based on previously reported risk factors for CIP development. Materials and methods We retrospectively identified 250 patients with lung cancer treated with at least one dose of an ICI over 20 months. Data were collected on comorbidities, cancer type and stage, performance status, ICI cycles, biomarkers, prior curative treatment, diagnostic evaluation, antibiotics, steroids, progression, and survival. A single-blinded radiologist characterized radiographic patterns of suspected CIP cases. Results Among 97 patients who received steroids while admitted to the hospital, 12 (6%) had at least one sign or symptom suggestive of CIP. Chronic obstructive pulmonary disease and non-small cell lung cancer subtypes correlated with suspicion of having CIP. CIP was confirmed in five patients (42%) and ruled out (mimics) in seven (58%). Median times until symptoms were 17 months and one month for confirmed and mimic cases, respectively. The median time to confirm or exclude CIP was 5 ± 4 days. Most suspected cases underwent thoracic imaging, blood cultures, and empiric antibiotics. Radiographic patterns in suspected cases included ground glass opacities, organizing pneumonia, acute interstitial pneumonia/acute respiratory distress syndrome, bronchiolitis, radiation recall pneumonitis, hypersensitivity pneumonitis, and post-radiation fibrotic changes. Conclusions CIP mimics are common in clinical practice; therefore, it is reasonable to empirically treat suspected cases with shorter courses of steroids until diagnostic clarity is achieved. This proof-of-concept study demonstrates that this novel workflow can identify the true incidence of CIP, inform treatment decisions, and lead to the development of implementation studies to improve patient care directly.

Collapse

Liu Z, Zhu Y, Xie H, Zou Z. Immune-mediated hepatitis induced by immune checkpoint inhibitors: Current updates and future perspectives. Front Pharmacol 2023;13:1077468. [PMID: 36699050 PMCID: PMC9868416 DOI: 10.3389/fphar.2022.1077468] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open

Mesalamine and cholestyramine for immune checkpoint inhibitor-mediated diarrhea and colitis. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04116-9. [PMID: 35972690 DOI: 10.1007/s00432-022-04116-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/06/2022] [Indexed: 10/15/2022]

Kfoury M, Najean M, Lappara A, Voisin AL, Champiat S, Michot JM, Laghouati S, Robert C, Besse B, Soria JC, Lambotte O, Massard C, Marabelle A, Texier M. Analysis of the association between prospectively collected immune-related adverse events and survival in patients with solid tumor treated with immune-checkpoint blockers, taking into account immortal-time bias. Cancer Treat Rev 2022;110:102452. [PMID: 35998515 DOI: 10.1016/j.ctrv.2022.102452] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 11/02/2022]

Abstract

BACKGROUND

Numerous retrospective studies and reviews have reported a positive association between immune-related adverse events (irAEs) and survival in non-small cell lung cancer (NSCLC) and melanoma patients treated with immune checkpoint blockers (ICBs). However, some results are controversial and the studies, whose results converge, should be interpreted cautiously because most of them do not deal appropriately with the immortal-time bias. Here, we report an observational real-life study of the association between prospectively collected irAEs and survival of patients treated with ICBs while dealing with the immortal-time bias.

METHODS

Data from patients treated at Gustave Roussy from June 2014 to October 2017 with anti-PD-(L)1 antibodies for a melanoma or NSCLC have been prospectively collected in the REISAMIC database, a pharmacovigilance registry dedicated to irAEs. Adverse events of grade 2 and higher were collected prospectively. To study the association between the occurrence of irAEs and survival, we used both a landmark analysis and a Cox regression model with time-dependent covariate.

RESULTS

577 patients were treated with anti-PD-(L)1 antibodies for melanoma (60.3 %) or NSCLC (39.7 %). The occurrence of an irAE was significantly associated with improved overall survival (OS): HR 0.56, 95 % CI [0.41; 0.75], p = 0.0001 and progression-free survival (PFS): HR 0.63, 95 % CI [0.47; 0.83], p = 0.001 using a Cox regression model with time-dependent covariate. In a 12-week landmark analysis, median OS was 21.2 months (95 % CI, 12.2 to 35.7) and 16.4 months (95 % CI, 12.4 to 21.3) p = 0.26 and median PFS was 14.3 months (95 % CI, 9.5 to 24.6) and 13.4 months (95 % CI, 10.2 to 18.3) p = 0.66, for patients with and without irAEs, respectively.

CONCLUSIONS

In our real-life study of patients with melanoma and NSCLC treated with anti-PD-(L)1 antibodies, we confirm that irAEs are associated with improved survival using a time-varying Cox regression model. Analysis with a landmark method showed no difference in OS or PFS between patients who experienced irAE during the first 12 weeks of treatment and those who did not. Retrospective analysis and reviews including studies that do not deal with the immortal-time bias and studies insufficiently powered for a landmark analysis should be interpreted with caution.

Collapse

Affiliation(s)

Maria Kfoury Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France; Département d'Oncologie Médicale, Gustave Roussy, Villejuif, France.
Marie Najean Département d'Epidémiologie et de Biostatistiques, Gustave Roussy, Villejuif, France
Ariane Lappara Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France; Département interdisciplinaire du parcours patient (DIOPP), Gustave Roussy, Villejuif, France
Anne-Laure Voisin Unité de Pharmacovigilance, Gustave Roussy, Villejuif, France
Stéphane Champiat Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
Jean-Marie Michot Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
Salim Laghouati Unité de Pharmacovigilance, Gustave Roussy, Villejuif, France
Caroline Robert Département d'Oncologie Médicale, Gustave Roussy, Villejuif, France; Université Paris Saclay, F-94276 Le Kremlin Bicêtre, France
Benjamin Besse Département d'Oncologie Médicale, Gustave Roussy, Villejuif, France; Université Paris Saclay, F-94276 Le Kremlin Bicêtre, France
Jean-Charles Soria Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France; Université Paris Saclay, F-94276 Le Kremlin Bicêtre, France
Olivier Lambotte Département de Médecine Interne et Immunologie clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France; INSERM U1184, Immunologie des infections virales et maladies auto-immunes, F-94276 Le Kremlin Bicêtre, France; CEA, DSV/iMETI, IDMIT, F-92265 Fontenay-aux-Roses, France
Christophe Massard Université Paris Saclay, F-94276 Le Kremlin Bicêtre, France; Département d'Oncologie Médicale, Centre Eugène Marquis, Rennes, France
Aurélien Marabelle Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France; Département de Médecine Interne et Immunologie clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France; INSERM U1015 & CIC1428, Villejuif, France
Matthieu Texier Département d'Epidémiologie et de Biostatistiques, Gustave Roussy, Villejuif, France

Collapse

Duong SL, Prüss H. Paraneoplastic Autoimmune Neurological Syndromes and the Role of Immune Checkpoint Inhibitors. Neurotherapeutics 2022;19:848-863. [PMID: 35043373 PMCID: PMC9294109 DOI: 10.1007/s13311-022-01184-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2022] [Indexed: 12/14/2022] Open

Ghosh N, Bass AR. Checkpoint Inhibitor-Associated Autoimmunity: What a Rheumatologist Needs to Know. J Clin Rheumatol 2022;28:e659-e666. [PMID: 31743272 DOI: 10.1097/rhu.0000000000001209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]

Arai K, Matsuda M, Nakayasu H, Meguro S, Kurokami T, Kubota A, Iwasaki T, Suzuki M, Kawaguchi S, Iwashita T. Nivolumab-induced liver injury with a steroid-refractory increase in biliary enzymes, in a patient with malignant mesothelioma: An autopsy case report. Clin Case Rep 2021;9:e05174. [PMID: 34987810 PMCID: PMC8697699 DOI: 10.1002/ccr3.5174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/29/2021] [Accepted: 11/07/2021] [Indexed: 12/19/2022] Open

Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, Atkins MB, Brassil KJ, Caterino JM, Chau I, Davies MJ, Ernstoff MS, Fecher L, Ghosh M, Jaiyesimi I, Mammen JS, Naing A, Nastoupil LJ, Phillips T, Porter LD, Reichner CA, Seigel C, Song JM, Spira A, Suarez-Almazor M, Swami U, Thompson JA, Vikas P, Wang Y, Weber JS, Funchain P, Bollin K. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol 2021;39:4073-4126. [PMID: 34724392 DOI: 10.1200/jco.21.01440] [Citation(s) in RCA: 901] [Impact Index Per Article: 225.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open

Abstract

PURPOSE

To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy.

METHODS

A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021.

RESULTS

A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus.

RECOMMENDATIONS

Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.

Collapse

Affiliation(s)

Bryan J Schneider University of Michigan Health System, Ann Arbor, MI
Jarushka Naidoo Beaumont Hospital, Dublin, Ireland.,Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Bianca D Santomasso Memorial Sloan Kettering Cancer Center, New York, NY
Christina Lacchetti American Society of Clinical Oncology, Alexandria, VA
Sherry Adkins MD Anderson Cancer Center, Houston, TX
Milan Anadkat Washington University, St Louis, MO
Michael B Atkins Georgetown Lombardi Comprehensive Cancer Center, Washington, DC
Kelly J Brassil MD Anderson Cancer Center, Houston, TX
Jeffrey M Caterino The Ohio State University Wexner Medical Center, Columbus, OH
Ian Chau Royal Marsden Hospital and Institute of Cancer Research, London & Surrey, Sutton, UK
Marianne J Davies Smilow Cancer Hospital and Yale School of Nursing; New Haven, CT
Marc S Ernstoff National Cancer Institute, Bethesda, MD
Leslie Fecher University of Michigan Health System, Ann Arbor, MI
Monalisa Ghosh University of Michigan, Ann Arbor, MI
Ishmael Jaiyesimi Cancer Care Associates PC, Royal Oak, MI
Jennifer S Mammen Johns Hopkins University, Baltimore, MD
Aung Naing MD Anderson Cancer Center, Houston, TX
Loretta J Nastoupil MD Anderson Cancer Center, Houston, TX
Tanyanika Phillips City of Hope, Duarte, CA
Laura D Porter Patient Advocate, Colon Cancer Alliance, Washington, DC
Cristina A Reichner Georgetown University, Washington, DC
Carole Seigel Patient Advocate, MGH Cancer Center, Boston, MA
Jung-Min Song Cleveland Clinic, Cleveland, OH
Alexander Spira Virginia Cancer Specialists and US Oncology, Fairfax, VA
Maria Suarez-Almazor MD Anderson Cancer Center, Houston, TX
Umang Swami Huntsman Cancer Institute-University of Utah, Salt Lake City, UT
John A Thompson Seattle Cancer Care Alliance, University of Washington/Fred Hutchinson, Seattle, WA
Praveen Vikas University of Iowa, Iowa City, IA
Yinghong Wang MD Anderson Cancer Center, Houston, TX
Jeffrey S Weber NYU Langone Medical Center, New York, NY
Pauline Funchain Cleveland Clinic, Cleveland, OH
Kathryn Bollin Scripps MD Anderson Cancer Center, San Diego, CA

Collapse

Zou F, Faleck D, Thomas A, Harris J, Satish D, Wang X, Charabaty A, Ernstoff MS, Glitza Oliva IC, Hanauer S, McQuade J, Obeid M, Shah A, Richards DM, Sharon E, Wolchok J, Thompson J, Wang Y. Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: a two-center observational study. J Immunother Cancer 2021;9:e003277. [PMID: 34789551 PMCID: PMC8601082 DOI: 10.1136/jitc-2021-003277] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open

Affiliation(s)

Fangwen Zou Department of Oncology, Second Xiangya Hospital, Changsha, Hunan, China Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
David Faleck Department of Gastroenterology, Hepatology and Nutrition, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Anusha Thomas Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Jessica Harris Department of Gastroenterology, Hepatology and Nutrition, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Deepika Satish Department of Gastroenterology, Hepatology and Nutrition, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Xuemei Wang Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Aline Charabaty Department of Gastroenterology, Johns Hopkins University, Washington, DC, USA
Marc S Ernstoff Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA
Isabella C Glitza Oliva Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Stephen Hanauer Department of Medicine, Northwestern University, Chicago, Illinois, USA
Jennifer McQuade Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Michel Obeid Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Amishi Shah Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
David M Richards Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Elad Sharon Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA
Jedd Wolchok Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
John Thompson University of Washington, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
Yinghong Wang Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Collapse

Jacob JS, Dutra BE, Garcia-Rodriguez V, Panneerselvam K, Abraham FO, Zou F, Ma W, Grivas P, Thompson JA, Altan M, Oliva ICG, Zhang HC, Thomas AS, Wang Y. Clinical Characteristics and Outcomes of Oral Mucositis Associated With Immune Checkpoint Inhibitors in Patients With Cancer. J Natl Compr Canc Netw 2021;19:1415-1424. [PMID: 34348238 DOI: 10.6004/jnccn.2020.7697] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/07/2020] [Indexed: 11/17/2022]

Abstract

BACKGROUND

Immune checkpoint inhibitor (ICI) therapy predisposes patients to immune-related adverse events (irAEs). Data are limited regarding the incidence, management, and outcomes of one such irAE: mucositis. In this study, we evaluated the clinical characteristics, disease course, treatment, and outcomes of ICI-mediated mucositis.

METHODS

This was a retrospective, single-center study of patients who received ICI therapy and developed oral mucositis at The University of Texas MD Anderson Cancer Center from January 2009 to September 2019. Inclusion criteria included age ≥18 years, a diagnosis of oral mucositis and/or stomatitis based on ICD-9 and ICD-10 codes, and therapy using CTLA-4 or PD-1/L1 inhibitors alone or combined with other agents.

RESULTS

We identified 152 patients with a mean age of 60 years, 51% of whom were men. Of the sample patients, 73% had stage IV cancer, with melanoma the most common (28%). Median time from ICI initiation to mucositis was 91 days. The most common clinical presentation of mucositis was odynophagia and/or oral pain (89%), 91% developed CTCAE grade 1-2 mucositis, and 78% received anti-PD-1/L1 monotherapy. Compared with anti-PD-1/L1-based therapy, anti-CTLA-4-based therapy was more frequently associated with earlier onset of mucositis (73 vs 96 days; P=.077) and a lower rate of symptom resolution (76% vs 92%; P=.029); 24% of patients required immunosuppressive therapy, which was associated with longer symptom duration (84 vs 34 days; P=.002) and higher mucositis recurrence rate (61% vs 32%; P=.006). ICI interruption was associated with worse survival (P=.037). Mucositis recurrence, immunosuppressant use, and presence of other irAEs did not affect survival.

CONCLUSIONS

For ICI-mediated mucositis, a diagnosis of exclusion has not been well recognized and is understudied. Although the clinical symptoms of mucositis are mostly mild, approximately 25% of patients require immunosuppression. Mucositis recurrence can occur in approximately 39% patients. Our results showed that ICI interruption compromises overall survival.

Collapse

Affiliation(s)

Jake S Jacob 1Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
Barbara E Dutra 2Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
Victor Garcia-Rodriguez 2Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
Kavea Panneerselvam 1Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
Fiyinfoluwa O Abraham 2Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
Fangwen Zou 3Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.,4Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
Weijie Ma 3Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.,5Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
Petros Grivas 6Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, Washington; and
John A Thompson 6Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, Washington; and
Mehmet Altan 7Department of Thoracic/Head & Neck Medical Oncology, and
Isabella C Glitza Oliva 8Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Hao Chi Zhang 3Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
Anusha S Thomas 3Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
Yinghong Wang 3Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas

Collapse

Wagner-Johnston ND, Sharman J, Furman RR, Salles G, Brown JR, Robak T, Gu L, Xing G, Chan RJ, Rajakumaraswamy N, Gopal AK. Idelalisib immune-related toxicity is associated with improved treatment response. Leuk Lymphoma 2021;62:2915-2920. [PMID: 34319205 DOI: 10.1080/10428194.2021.1948038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]

Sullivan RJ, Weber JS. Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies. Nat Rev Drug Discov 2021;21:495-508. [PMID: 34316029 DOI: 10.1038/s41573-021-00259-5] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2021] [Indexed: 02/07/2023]

Thompson LL, Yoon J, Krasnow NA, Chang MS, Li EB, McMahon DE, Chen ST. Association Between Systemic Corticosteroid Treatment for Cutaneous Immune-Related Adverse Events and Survival Outcomes in Patients With Advanced Cancer. JAMA Dermatol 2021;157:2778391. [PMID: 33851976 PMCID: PMC8047752 DOI: 10.1001/jamadermatol.2021.0727] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/21/2021] [Indexed: 12/19/2022]

Balducci D, Quatraccioni C, Benedetti A, Marzioni M, Maroni L. Gastrointestinal disorders as immune-related adverse events. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021;2:174-186. [PMID: 36046145 PMCID: PMC9400751 DOI: 10.37349/etat.2021.00039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 02/23/2021] [Indexed: 11/19/2022] Open

Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not? Cancers (Basel) 2021;13:cancers13050989. [PMID: 33673446 PMCID: PMC7956829 DOI: 10.3390/cancers13050989] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/31/2022] Open

Abstract

Simple Summary

This study examined the real-world experience and occurrence of immune-related adverse events (irAEs) under cancer checkpoint immunotherapy, and the relationship between its treatment rechallenge status and their impact on clinical outcomes. The current study demonstrates that immune checkpoint inhibitors (ICI) reinitiation after an irAE-related interruption in the setting of cancer immunotherapy was not associated with significantly improved survival outcome when compared with those without ICI treatment reinitiation after irAE-related therapy interruption.

Abstract

Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

Collapse

Duong SL, Barbiero FJ, Nowak RJ, Baehring JM. Neurotoxicities associated with immune checkpoint inhibitor therapy. J Neurooncol 2021;152:265-277. [PMID: 33454891 DOI: 10.1007/s11060-021-03695-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022]

Abstract

INTRODUCTION

Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities.

METHODS

Patients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded.

RESULTS

We identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5 weeks (range 1-72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3-4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3-4 severity negatively impacted overall survival (OS) (p = 0.046).

CONCLUSIONS

ICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.

Collapse

Kelly K, Manitz J, Patel MR, D'Angelo SP, Apolo AB, Rajan A, Kasturi V, Speit I, Bajars M, Warth J, Gulley JL. Efficacy and immune-related adverse event associations in avelumab-treated patients. J Immunother Cancer 2020;8:e001427. [PMID: 33219092 PMCID: PMC7682456 DOI: 10.1136/jitc-2020-001427] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2020] [Indexed: 11/11/2022] Open

Romanski NA, Holmstroem RB, Ellebaek E, Svane IM. Characterization of risk factors and efficacy of medical management of immune-related hepatotoxicity in real-world patients with metastatic melanoma treated with immune checkpoint inhibitors. Eur J Cancer 2020;130:211-218. [PMID: 32229418 DOI: 10.1016/j.ejca.2020.02.041] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 02/01/2020] [Accepted: 02/13/2020] [Indexed: 12/31/2022]

Abstract

INTRODUCTION

Immune-related hepatitis (ir-hepatitis) is a common side-effect of checkpoint inhibitors (CPIs). Here, we characterise ir-hepatitis in a large cohort of patients with metastatic melanoma (MM) treated with CPIs and describe potential risk factors and efficacy of medical management.

METHODS

The retrospective study included a large cohort of patients with MM treated with CPIs between 2010 and 2019. Patients were retrieved from the national Danish Metastatic Melanoma Database.

RESULTS

Five hundred twenty one patients were included. Ir-hepatitis was found in 6.8% of patients. Combination therapy was associated with a significantly greater risk than monotherapy. Of all patients, 34.9% with hepatitis had a different hepatitis grading, when based on either alanine transaminase (ALT) or aspartate transaminase (AST) levels. Of all patients, 72.1% with hepatitis received steroid treatment, and two patients received additional second-line immunosuppressants. Of all patients, 35.5% experienced hepatitis relapse during steroid tapering. Of all patients, 18.6% and 25% of patients with grade ≥2 and ≥ III3, respectively, developed hepatitis within 7 days after finishing an antibiotic treatment for infection. Patients (62.5%) who received a cumulative dose of >4000 mg steroid experienced cancer progression, compared with 22.7% of patients treated with <4000 mg.

CONCLUSION

Several observations of clinical importance were made. Infection and antibiotic treatment during CPIs could be a possible risk factor for developing ir-hepatitis. Severity of ir-hepatitis is potentially underestimated in a significant number of patients, if only one liver enzyme is measured. The role of second-line immunosuppressants needs to be further investigated because of the high risk of hepatitis relapse during steroid tapering and the potential negative impact of cumulative steroid dose on response to CPIs.

Collapse

Abu-Sbeih H, Tang T, Ali FS, Luo W, Neelapu SS, Westin JR, Okhuysen PC, Foo WC, Curry JL, Richards DM, Ge PS, Wang Y. Gastrointestinal Adverse Events Observed After Chimeric Antigen Receptor T-Cell Therapy. Am J Clin Oncol 2020;42:789-796. [PMID: 31478934 DOI: 10.1097/coc.0000000000000596] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]

Abstract

BACKGROUND

Chimeric antigen receptor T-cell (CART) therapy can significantly improve outcomes for patients with certain hematologic malignancies. The most notable drawbacks of CART are cytokine release syndrome and CART-related encephalopathy syndrome. Gastrointestinal adverse events (GI-AEs) have not yet been reported in association with CART. Herein, we describe the incidence and clinical features of GI-AEs observed after CART.

MATERIALS AND METHODS

We report a case series of patients with hematologic malignancies who received CART, in a clinical trial or as the standard of care, and subsequently suffered from GI-AEs between 2012 and 2018.

RESULTS

In our cohort, 37 of 132 (28%) patients experienced GI-AEs. All 37 experienced diarrhea with a median onset of 7 days (interquartile range, 4 to 25 d) after CART infusion. The median age of these patients was 58 years. Most had diffuse large B-cell lymphoma (51%). Seventeen patients experienced cytokine release syndrome, and 9 experienced CART-related encephalopathy syndrome. The interleukin-6 antagonist was required in 15 patients. Overall, 49% of patients had grade 1 diarrhea, 32% had grade 2, and 15% had grade 3. Other gastrointestinal symptoms in these patients were abdominal pain (41%), nausea and vomiting (49%), fever (8%), bloody stools (3%), and abdominal distension (5%). The median duration of symptoms was 6 days (interquartile range, 3 to 9 d). In 32 patients who underwent imaging, 8 (25%) had findings suggestive of gastrointestinal tract inflammation. Nine (24%) patients experienced GI-AE recurrence after initial improvement. The symptoms were attributed to an alternative cause in 17 (13%) cases and to CART in 20 (15%) cases. One patient developed CART-related refractory colitis that eventually responded to antibiotics for pneumonia.

CONCLUSION

CART-related GI-AEs occur in 15% of patients treated with CART. These symptoms are typically mild and self-limiting, requiring only symptomatic treatment. Nevertheless, CART may, in rare cases, lead to refractory colitis.

Collapse

Menon T, Afzali A. Immune-Mediated Colitis. ACTA ACUST UNITED AC 2019;17:506-523. [PMID: 31741212 DOI: 10.1007/s11938-019-00263-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]

Meyerson C, Naini BV. Something old, something new: liver injury associated with total parenteral nutrition therapy and immune checkpoint inhibitors. Hum Pathol 2019;96:39-47. [PMID: 31669893 DOI: 10.1016/j.humpath.2019.10.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/09/2019] [Indexed: 02/06/2023]

Anderson R, Theron AJ, Rapoport BL. Immunopathogenesis of Immune Checkpoint Inhibitor-Related Adverse Events: Roles of the Intestinal Microbiome and Th17 Cells. Front Immunol 2019;10:2254. [PMID: 31616428 PMCID: PMC6775220 DOI: 10.3389/fimmu.2019.02254] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/06/2019] [Indexed: 12/18/2022] Open

Abstract

The advent of novel, innovative, and effective anti-cancer immunotherapies has engendered an era of renewed optimism among cancer specialists and their patients. Foremost among these successful immunotherapies are monoclonal antibodies (MAbs) which target immune checkpoint inhibitor (ICI) molecules, most prominently cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed cell death protein-1 (PD-1) and its major ligand, PD-L1. These immunotherapeutic agents are, however, often associated with the occurrence of immune-mediated toxicities known as immune-related adverse events (IRAEs). The incidence of severe toxicities increases substantially when these agents are used together, particularly with CTLA-4 in combination with PD-1 or PD-L1 antagonists. Accordingly, dissociating the beneficial anti-tumor therapeutic activity of these agents from the emergence of IRAEs represents a significant challenge to attaining the optimum efficacy of ICI-targeted immunotherapy of cancer. This situation is compounded by an increasing awareness, possibly unsurprising, that both the beneficial and harmful effects of ICI-targeted therapies appear to result from an over-reactive immune system. Nevertheless, this challenge may not be insurmountable. This contention is based on acquisition of recent insights into the role of the gut microbiome and its products as determinants of the efficacy of ICI-targeted immunotherapy, as well as an increasing realization of the enigmatic involvement of Th17 cells in both anti-tumor activity and the pathogenesis of some types of IRAEs. Evidence linking the beneficial and harmful activities of ICI-targeted immunotherapy, recent mechanistic insights focusing on the gut microbiome and Th17 cells, as well as strategies to attenuate IRAEs in the setting of retention of therapeutic activity, therefore represent the major thrusts of this review.

Collapse

Sears CR, Peikert T, Possick JD, Naidoo J, Nishino M, Patel SP, Camus P, Gaga M, Garon EB, Gould MK, Limper AH, Montgrain PR, Travis WD, Rivera MP. Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor-related Pneumonitis. An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med 2019;200:e31-e43. [PMID: 31518182 PMCID: PMC6775885 DOI: 10.1164/rccm.201906-1202st] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open

Abu-Sbeih H, Ali FS, Naqash AR, Owen DH, Patel S, Otterson GA, Kendra K, Ricciuti B, Chiari R, De Giglio A, Sleiman J, Funchain P, Wills B, Zhang J, Naidoo J, Philpott J, Gao J, Subudhi SK, Wang Y. Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis. J Clin Oncol 2019;37:2738-2745. [PMID: 31163011 PMCID: PMC6800279 DOI: 10.1200/jco.19.00320] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open

Abstract

PURPOSE

Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption.

METHODS

This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence.

RESULTS

Of the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019).

CONCLUSION

One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-4.

Collapse

Tang T, Abu-Sbeih H, Luo W, Lum P, Qiao W, Bresalier RS, Richards DM, Wang Y. Upper gastrointestinal symptoms and associated endoscopic and histological features in patients receiving immune checkpoint inhibitors. Scand J Gastroenterol 2019;54:538-545. [PMID: 31079556 DOI: 10.1080/00365521.2019.1594356] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]

Abu-Sbeih H, Ali FS, Wang X, Mallepally N, Chen E, Altan M, Bresalier RS, Charabaty A, Dadu R, Jazaeri A, Lashner B, Wang Y. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis. J Immunother Cancer 2019;7:93. [PMID: 30940209 PMCID: PMC6444537 DOI: 10.1186/s40425-019-0577-1] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 03/22/2019] [Indexed: 02/07/2023] Open

Abstract

BACKGROUND

Current treatment guidelines for immune-mediated colitis (IMC) recommend 4 to 6 weeks of steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) in patients who do not respond to steroids. We assessed the effect of early SIT introduction and number of SIT infusions on clinical outcomes.

METHODS

We performed a retrospective review of patients with IMC who received SIT at The University of Texas MD Anderson Cancer Center between January and December 2018. Logistic regression analyses were used to assess associations between clinical outcomes and features of IMC.

RESULTS

Of the 1459 patients who received immune checkpoint inhibitors, 179 developed IMC of any grade; 84 of these 179 patients received SIT. Of the 84 patients who received SIT, 79% were males, and the mean age was 60 years (standard deviation, 14). Compared with patients who received SIT > 10 days after IMC onset, patients who received early SIT (≤10 days) required fewer hospitalizations (P = 0.03), experienced steroid taper failure less frequently (P = 0.03), had fewer steroid tapering attempts (P < 0.01), had a shorter course of steroid treatment (P = 0.09), and had a shorter duration of symptoms (P < 0.01). Patients who received one or two infusions of SIT achieved histologic remission less frequently (P = 0.09) and had higher fecal calprotectin levels after SIT (P = 0.01) compared with patients who received three or more infusions. Risk factors for IMC recurrence after weaning off steroids included: 1) needing multiple hospitalizations, 2) experiencing steroid taper failure after SIT, 3) receiving infliximab rather than vedolizumab, 4) receiving fewer than three infusions of SIT, 5) having higher fecal calprotectin levels after SIT, and 6) receiving a longer course of steroids, hospitalization and IMC symptoms. Unsuccessful weaning from steroids after SIT was associated with high IMC grades; multiple hospitalizations; steroid-resistant IMC; long interval from IMC to SIT initiation; and long duration of steroids, IMC symptoms, and hospitalization.

CONCLUSION

SIT should be introduced early in the disease course of IMC instead of waiting until failure of steroid therapy or steroid taper. Patients who received three or more infusions of SIT had more favorable clinical outcomes.

Collapse

Jennings JJ, Mandaliya R, Nakshabandi A, Lewis JH. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol 2019;15:231-244. [PMID: 30677306 DOI: 10.1080/17425255.2019.1574744] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]