A Wolf in Sheep's Clothing: Systemic Immune Activation Post Immunotherapy

ABSTRACT Introduction Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH). Methods All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection. Results Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH. Conclusion SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

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032 Neurological sequelae of immune checkpoint inhibitors: a case series

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.31 ◽

2018 ◽

Vol 89 (6) ◽

pp. A13.3-A14 ◽

Cited By ~ 1

Author(s):

Matthew Silsby ◽

Stephen R Duma ◽

Neil Mahant ◽

Steve Vucic ◽

Andrew Henderson

Keyword(s):

T Cells ◽

Checkpoint Inhibitors ◽

Early Recognition ◽

Case Series ◽

Tumour Response ◽

Stage Iv ◽

High Dose ◽

Solid Organ ◽

Fisher Syndrome ◽

Neurological Sequelae

IntroductionMonoclonal antibodies directed against co-stimulatory molecules on T cells (checkpoint inhibitors, CIs) are used to treat solid organ malignancies. Neurological complications are an increasingly recognised consequence of their use. We present three patients referred to the Neurology service at Westmead Hospital in 2017 with new neurological complaints following CI therapy.CasesPatient 1, a 54 year old woman with stage IV non-small cell lung cancer treated with pembrolizumab (anti-PD-1), presented with cerebral vasculitis causing bilateral ACA territory cerebral infarction. Patient 2, a 59 year old woman with metastatic melanoma treated with ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1), presented with ataxia, diplopia and ptosis consistent with Miller Fisher syndrome. Patient 3, a 77 year old woman with metastatic colorectal adenocarcinoma treated with nivolumab (anti-PD-1), presented with ocular myasthenia manifesting as fatigable ptosis and complex ophthalmoplegia.The diagnoses were made by clinical assessment with imaging and neurophysiological investigations where possible. Antibodies relevant to the neurological condition were negative, in keeping with previous reports. CIs were discontinued in all patients. Treatment included intravenous pulsed methylprednisolone followed by high dose oral taper in all patients. Additionally, Patient 1 was treated with infliximab and rituximab; Patients 2 and 3 received intravenous immunoglobulin followed by monthly maintenance therapy; Patient 2 underwent plasma exchange. Patients 1 and 2 recovered independent ambulation. Patient 3 died two months after presentation due to underlying malignancy.ConclusionCheckpoint inhibitors block co-stimulatory molecules on T-cells, allowing the immune system to mount an anti-tumour response. The resulting immune dysregulation can also lead to organ-specific inflammatory and immune complications, of which neurological sequelae are increasingly recognised. The three reported patients highlight the spectrum of disease that can arise. Their occurrence within one year suggests an increasing incidence, and a need for increased vigilance. Early recognition is paramount as treatment with high dose corticosteroids, even in conditions that would not normally respond, is recommended.

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Management Of Immunotherapy Adverse Events In Oncological Patients: Anti-Ctla-4, Anti-Pd-1/Pd-L1

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200622161418 ◽

2020 ◽

Vol 15 ◽

Author(s):

Mattia Brigida ◽

Alessia Perricelli ◽

Fausto Sposato ◽

Maria Giovanna Spadafora ◽

Angelo Pomillo ◽

...

Keyword(s):

Adverse Events ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Corticosteroid Treatment ◽

High Dose ◽

Emergency Setting ◽

Serious Adverse Events ◽

Oncological Patients ◽

Grade Ii ◽

Dose Corticosteroid

Background: The widespread use of immunotherapy drugs in the oncological field has led to the spread of new toxicities compared to the more common chemotherapy treatments. This is because immunotherapy with anti-CTLA-4 (Cytotoxic T Lymphocytes-Associated Antigen 4), anti-PD-1 and anti-PD-L1 monoclonal antibodies has become the standard-of-care in a growing number of indications. Any organ or tissue can be involved, but more commonly side effects are reported regarding skin, colon, endocrine glands, liver, lung and kidney. Other less frequent, but more serious, adverse events are neurological and myocarditis. Methods: We performed an electronic search on PUBMED of the literature concerning immunotherapy-related toxicities and their management in oncological patients from 2007 to 2020, with particular attention to the most recent publications. Aim: To summarize the different types of immunotherapy-related toxicities, together with their incidence and diagnosis, and to simplify their management, especially in the emergency setting. Conclusion: Usually, for grade I toxicities it is not recommended to stop immunotherapy; for most of grade II toxicities, immunotherapy should be postponed to when toxicity will have regressed to grade I, considering the possibility of a corticosteroid treatment for most of toxicities. The majority of grade III and IV require administration of high-dose corticosteroid intravenous therapy and suspension of immunotherapy. Mortality related to immune checkpoint inhibitors’ toxicity, occurring at a rate of 0.3-1.3%, is well below fatality rates due to other oncologic interventions and should not discourage the promising results so far reached by immunotherapy.

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Acute colonic pseudo-obstruction following nivolumab and ipilimumab combination therapy for metastatic melanoma

Trends in Immunotherapy ◽

10.24294/ti.v5.i2.1297 ◽

2021 ◽

Vol 5 (2) ◽

Author(s):

Mami Ishibashi ◽

Yoshihiro Ishida ◽

Atsushi Otsuka ◽

Shuji Yamamoto ◽

Kenji Kabashima

Keyword(s):

Combination Therapy ◽

Adverse Events ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Early Recognition ◽

High Dose ◽

Prompt Treatment ◽

Prompt Diagnosis

Immune-related adverse events (irAEs) are commonly observed in patients treated with immune checkpoint inhibitors (ICI), and prompt diagnosis and treatment of irAEs is of utmost importance. Gastrointestinal (GI) events are among the most frequent irAEs and the hallmark symptom is diarrhea. Intestinal hypomotility as irAEs is exceedingly rare, and needs wider recognition given that the presentation is insidious.Here, we report a case of 79-year-old woman with metastatic melanoma under nivolumab and ipilimumab combination therapy. She developed ileus symptom, and was diagnosed with acute colonic pseudo-obstruction. The symptom relieved soon after administering high-dose prednisolone five days after the onset. ICI therapy was discontinued.Intestinal hypomotility as GI irAEs is exceedingly rare and there have been five reported cases to our knowledge. In reviewing past cases, we speculate that the prompt initiation of corticosteroids resulted in a favorable outcome. Our case illustrates that early recognition of these rare irAEs is essential in order to ensure prompt treatment.

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P08.01 Immune-Related Acute Motor Axonal Neuropathy: A Small Case Series and Review of the Literature

Neuro-Oncology ◽

10.1093/neuonc/noab180.088 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii26-ii26

Author(s):

Y Pina ◽

N Tran ◽

P Forsyth ◽

S Mokhtari ◽

E Peguero

Keyword(s):

Checkpoint Inhibitors ◽

Axonal Neuropathy ◽

Case Series ◽

Standard Of Care ◽

Cancer Center ◽

High Dose ◽

Acute Motor Axonal Neuropathy ◽

First Case ◽

Oncological Patients ◽

Solid Malignancies

Abstract BACKGROUND Immunotherapy have revolutionized cancer treatment in the past decade, with a significant increased survival in patients with solid tumors. However, the use of immune checkpoint inhibitors (ICIs) has been associated with a growing number of neurotoxicities, some of which can be fatal if not recognized and treated promptly. Some of these neurotoxicities include very uncommon syndromes like Acute Motor Axonal Neuropathy (AMAN). Herein we present four oncological cases of patients who underwent immunotherapy and developed AMAN. METHODS Four patients were diagnosed with immune-related AMAN between 2017 and 2000 at H. Lee Moffitt Cancer Center. The patients were treated with standard of care and currently follow up in clinic. RESULTS We describe four oncological patients who developed a motor axonal neuropathy (i.e., AMAN) confirmed on nerve conduction studies following 2 cycles of immunotherapy, including a 28 year old woman with melanoma brain metastasis and a 50 year old woman with renal cell carcinoma both treated with ipilimumab and nivolumab, a 32 year old man with Hodgkin lymphoma who was treated with nivolumab and brentuximab, and a 77 year old woman with renal urothelial cancer who was treated with pembrolizumab and cabozantinib. All four patients were promptly recognized as having immune-related neurotoxicity (irNs), were promptly treated (i.e., high dose steroids +/- IVIG +/- other immunomodulators), and significantly improved and have remained stable. CONCLUSION This is the first case series of patients with AMAN following two cycles of immunotherapy, who were successfully treated. It is crucial to develop a better understanding of the irNs associated with ICIs, including those rare conditions that are difficult to diagnose and treat, as the utilization of these immunomodulating therapies continues to increase and expand to include other solid malignancies. Neurologists should be involved early on in any case of suspected irN to assist in the management of these complicated patients and a swift work up should be initiated for timely diagnosis and treatment.

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NCMP-21. IMMUNE-RELATED ACUTE MOTOR AXONAL NEUROPATHY: A SMALL CASE SERIES AND REVIEW OF THE LITERATURE

Neuro-Oncology ◽

10.1093/neuonc/noab196.592 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi151-vi151

Author(s):

Yolanda Pina ◽

Nam Tran ◽

Neha Verma ◽

Michael Vogelbaum ◽

Peter Forsyth ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Axonal Neuropathy ◽

Case Series ◽

Standard Of Care ◽

Cancer Center ◽

High Dose ◽

Acute Motor Axonal Neuropathy ◽

First Case ◽

Oncological Patients ◽

Solid Malignancies

Abstract BACKGROUND Immunotherapy revolutionized cancer treatment in the past decade, with a significant increased survival in patients with solid tumors. However, immune checkpoint inhibitors (ICIs) have been associated with a growing number of neurotoxicities, some of which can be fatal if not recognized and treated promptly. Some of these neurotoxicities include very uncommon syndromes like Acute Motor Axonal Neuropathy (AMAN). Herein we present four oncological cases of patients who underwent immunotherapy and developed AMAN. METHODS Four patients were diagnosed with immune-related AMAN between 2017 and 2000 at H. Lee Moffitt Cancer Center. Patients were treated with standard of care. RESULTS We describe four oncological patients who developed a motor axonal neuropathy (i.e., AMAN) confirmed on nerve conduction studies following 2 cycles of immunotherapy, including a 28 year old woman with melanoma brain metastasis and a 50 year old woman with renal cell carcinoma both treated with ipilimumab and nivolumab, a 32 year old man with Hodgkin lymphoma who was treated with nivolumab and brentuximab, and a 77 year old woman with renal urothelial cancer who was treated with pembrolizumab and cabozantinib. All four patients were promptly recognized as having immune-related neurotoxicity (irNs), were promptly treated (i.e., high dose steroids +/- IVIG +/- other immunomodulators), and significantly improved and have remained stable. CONCLUSION This is the first case series of patients with AMAN following two cycles of immunotherapy, who were successfully treated. It is crucial to develop a better understanding of irNs, including those rare conditions that are difficult to diagnose and treat, as the utilization of these immunomodulating therapies continues to expand to include other solid malignancies. Neurologists should be involved early on in any case of suspected irN to assist in the management of these complicated patients and a swift work up should be initiated for timely diagnosis and treatment.

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OR32-06 Opportunistic Assessment of Pituitary Gland with Routine MRI and PET/CT Can Guide in Earlier and Increased Identification of Hypophysitis in Patients Treated with Combination Checkpoint Inhibitors

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1494 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Anna Galligan ◽

Amir Iravani ◽

Arian Lasocki ◽

Roslyn Wallace ◽

Alison Weppler ◽

...

Keyword(s):

Adverse Events ◽

Functional Neuroimaging ◽

Checkpoint Inhibitors ◽

Early Recognition ◽

Tumour Response ◽

Standardized Uptake Value ◽

Clinical Syndrome ◽

Whole Body ◽

Specific Reference ◽

High Dose

Abstract Background: Hypophysitis is one of the commonly reported adverse events related to immune checkpoint inhibitors (ICI), and the incidence is expected to rise with increased use of combined programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated protein 4 (CTLA4) blockade. The clinical diagnosis can be delayed due to non-specific symptoms. At our centre, subjects undergo periodic imaging to assess tumour response to ICI. We reviewed whether neuroimaging studies can guide us in the diagnosis of hypophysitis and whether early changes can be detected before the onset of the clinical syndrome. Methods: We retrospectively reviewed the medical charts, biochemistry, structural brain imaging and whole-body positron emission tomography (PET) with specific reference to hypophysitis in 162 patients treated with combination ICI at a tertiary melanoma referral centre. Suspected cases were identified based on meeting one or more of the following criteria: 1) A documented diagnosis of hypophysitis or pituitary dysfunction found on chart review, 2) A relative change in pituitary size or appearance from baseline on neuroimaging studies, or 3) An increase in pituitary maximum standardized uptake value (SUVmax) greater than 25% from baseline on 18F-FDG PET. Results: 58/162 patients (36%) met criteria for suspected hypophysitis. Only 4 patients were identified on routine screening of early morning cortisol. 14 patients presented with symptoms leading to biochemical work up. A further 40 patients were found to have suspicious imaging changes, 13 of which went on to receive a formal diagnosis of hypophysitis. Of the remaining 27 patients, 23 were receiving high dose glucocorticoids for concomitant immune related adverse events at the time of the abnormal imaging study.Conclusion: We report the highest incidence to date of suspected hypophysitis in cohort of patients treated with combination ICI. This study highlights the important role of structural and functional neuroimaging in the early recognition of hypophysitis. Imaging may also play a role when the clinical syndrome is masked by concurrent glucocorticoid use.

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Diagnosis and Management of Checkpoint Inhibitor Side Effects in Patients with Bladder Cancer: the Urologist’s Perspective

Bladder Cancer ◽

10.3233/blc-200362 ◽

2020 ◽

Vol 6 (4) ◽

pp. 425-433

Author(s):

Neal Shore

Keyword(s):

Bladder Cancer ◽

Side Effects ◽

Corticosteroid Therapy ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Early Recognition ◽

Cytotoxic T Cell ◽

High Dose ◽

Cell Mediated Immunity ◽

Multiple Cancer

From 2016 through the present day, we have witnessed extraordinarily rapid advances and regulatory approvals of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway, which has significantly improved survival among patients with advanced and metastatic urothelial carcinoma (mUC). Although these agents usually are well tolerated, their unique mechanism of action may enhance cytotoxic T-cell mediated immunity, evoking unique side effects that differ from conventional chemotherapy or molecularly targeted agents. The most common immune-related adverse events (irAEs) are dermatitis, colitis, pneumonitis, thyroid dysfunction, and transaminitis, but any organ system permeated by the lymphatic vasculature can be affected; also, neuropathies and arthralgias may occur. Immune-mediated events of any grade require prompt recognition and appropriate management to mitigate the risk of irAE exacerbation. Most patients with mild (grade 1) irAEs may continue checkpoint inhibitor treatment with careful monitoring. For grade 2 irAEs, it is appropriate to suspend treatment, initiate corticosteroid therapy, and only resume treatment if the irAE resolves to < grade 1. Events classified as > grade 3 may require permanent treatment cessation and high-dose corticosteroid therapy. In clinical trials of PD-1/PD-L1 inhibitors across multiple cancer types, approximately 15% of patients with mUC developed irAEs requiring corticosteroid therapy. Training physicians and nurse providers and counseling patients regarding the early recognition of irAEs are mandatory to ensure timely irAE detection and optimized patient management. Hence, operationalizing an advanced bladder cancer clinic requires collaboration and coordination amongst urologists, medical and radiation oncologists, and other medical specialists who participate in the increasingly multimodal and multidisciplinary care of patients with bladder cancer.

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High-dose interleukin-2 (HD IL-2) for metastatic renal Cell carcinoma (mRCC): Contemporary utilization trends in the United States.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.449 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 449-449

Author(s):

Christopher B. Allard ◽

Francisco Gelpi-Hammerschmidt ◽

Lauren Christine Harshman ◽

Izak Faiena ◽

Parth K Modi ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Lung Metastases ◽

Interleukin 2 ◽

Standard Of Care ◽

Good Health ◽

The United States ◽

High Dose ◽

Study Cohort ◽

Severe Hypotension ◽

Nationally Representative

449 Background: Targeted therapies (TT) have revolutionized treatment of mRCC with broad based efficacy and tolerability but ultimately all patients progress. While HD IL-2, the prior standard of care treatment, is associated with significant toxicities, it remains the only agent proven to elicit durable complete responses albeit rarely. This study evaluated trends in HD IL-2 use for patients with mRCC during the TT era. Methods: Our study cohort was comprised of a weighted sample of 2,351 patients with mRCC undergoing HDIL-2 treatment from 2004-2012, from the Premier Hospital Database (Premier Inc., Charlotte, NC), a nationally representative hospital discharge database. We employed descriptive statistics and fitted multivariable regression models, accounting for clustering and weighting, to identify predictors of treatment toxicity and tolerability. Results: We found a progressive decrease in the use of HD IL-2 from 2004 to 2008 with a general upward trend thereafter. HD IL-2 was increasingly concentrated at academic centers representing the site of treatment for 24% of patients in 2004 versus 90% of patients in 2012. Most patients were men (75.3%), Caucasian (70.7%) and aged <60 (59.6%) with lung metastases (60.9%) and otherwise healthy (64.72%, Charlson comorbidity index=0). Our adjusted analysis showed that severe hypotension was associated with patients <50 years (odds ratio [OR]: 1.35, p=0.045), while the likelihood of receiving ≥2 cycles of HDIL-2 was associated with good health (CCI=0, OR: 1.72, p=0.004) and having >1 metastatic site (OR: 4.32, p<0.001). Conclusions: Over the past decade, the use of HD IL-2 initially diminished coinciding with the widespread availability of TT but has remerged potentially due to renewed enthusiasm for immunotherapies showing promising efficacy with novel immune checkpoint inhibitors in mRCC. HD IL-2 has increasingly been limited to academic centers and our analysis suggests a strong selection bias for younger, healthier patients who can better tolerate the toxicities and those with a greater burden of metastatic disease. Future studies are warranted to determine the optimal role of HDIL-2 in the contemporary treatment of mRCC.

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