Abstract
Background
Hyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined ...the risk and predictors of hyponatremia and other electrolyte abnormalities in a ‘real-world’ sample of patients receiving ICIs to treat advanced malignancies.
Methods
This was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018. Patients were followed for 12 months after initiation of ICIs or until death. Common Terminology for Cancer Adverse Events version 5.0 criteria were used to grade the severity of hyponatremia and other electrolyte abnormalities. The predictors of severe (Grade 3 or 4) hyponatremia were determined using a multivariable logistic regression model. The etiology of Grade 3 or 4 hyponatremia was determined by chart review.
Results
A total of 2458 patients were included. Their average age was 64 years standard deviation (SD) 13, 58% were male and 90% were white. In the first year after starting ICIs, 62% experienced hyponatremia (sodium <134 mEq/L) and 136 (6%) experienced severe hyponatremia (<124 mEq/L). Severe hyponatremia occurred on average 164 days (SD 100) after drug initiation. Only nine cases of severe hyponatremia were due to endocrinopathies (0.3% overall incidence). Risk factors for severe hyponatremia included ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) use, diuretic use and non-White race. Other severe electrolyte abnormalities were also commonly observed: severe hypokalemia (potassium <3.0 mEq/L) occurred in 6%, severe hyperkalemia (potassium ≥6.1 mEq/L) occurred in 0.6%, severe hypophosphatemia (phosphorus <2 mg/dL) occurred in 17% and severe hypocalcemia (corrected calcium <7.0 mg/dL) occurred in 0.2%.
Conclusions
Hyponatremia is common in cancer patients receiving ICIs. However, endocrinopathies are an uncommon cause of severe hyponatremia.
Immune checkpoint inhibitors (ICI) can induce a durable response against a wide range of malignancies but cause immune related adverse events. The purpose of this study was to evaluate whether the ...pattern of inflammation in a liver biopsy in patients on ICIs is likely to be related to ICIs or other causes, and whether the pattern correlates with LFT abnormalities, imaging findings, and responsiveness to steroids. Cancer patients on ICIs who underwent liver biopsy were identified. Clinical data were obtained from electronic records. Liver biopsies were recorded as hepatitic, cholangitic, mixed, steatotic, or as mild nonspecific changes. In total, 28 liver biopsies had a predominantly hepatitic pattern of inflammation, including 11 biopsies with granulomas and 10 with endothelialitis. Eight biopsies had a mixed hepatocytic and cholangitic pattern of injury, including 6 with granulomas and 4 with endothelialitis. Sixteen patients had a predominantly cholangitic pattern, with portal-based inflammation. Three patients had a pattern resembling fatty liver, and five had mild nonspecific changes. The three most common histologic patterns correlated with the pattern of LFT abnormalities. The majority of patients with a cholangitic pattern had competing causes for elevated LFTs, including disease progression or concomitant chemotherapy. The cholangitic pattern was more likely to have bile duct dilatation or narrowing on liver imaging. The pattern of inflammation, degree of lobular injury, or presence of granulomas or endothelialitis did not predict response to steroids or the need for secondary immunosuppression. In this retrospective study, the pattern of inflammation did not predict the need for steroids, the length of time that steroids is required, or the need for secondary immunosuppression. A cholangitic pattern was seen when the pattern of LFTs was cholestatic, and was associated with imaging abnormalities of the bile duct, but a similar pattern was seen in bile duct obstruction and other drug reactions.
IMPORTANCE: There is limited information on immune checkpoint inhibitor–induced bullous pemphigoid (ICI-BP) in patients with cancer, with most existing studies being case reports or small case series ...from a single institution. Prior review attempts have not approached the literature in a systematic manner and have focused only on ICI-BP secondary to anti–programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) therapy. The current knowledge base of all aspects of ICI-BP is limited. OBJECTIVE: To characterize the risk factors, clinical presentation, diagnostic findings, treatments, and outcomes of ICI-BP in patients with cancer as reported in the current literature. EVIDENCE REVIEW: A systematic review was performed using PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Articles reporting data on individual patients who met preestablished inclusion criteria were selected, and a predefined set of data was abstracted. When possible, study results were quantitatively combined. FINDINGS: In total, 70 studies reporting data on 127 individual patients undergoing ICI therapy for cancer (median IQR age, 71 64-77 years; 27 women 21.3%) were included. In pooled analyses, patients ranged in age from 35 to 90 years. Immune checkpoint inhibitor–induced bullous pemphigoid often occurred during the course of anti-PD-1, PD-L1, or cytotoxic T lymphocyte–associated antigen 4 therapy but was also found to develop up to several months after treatment cessation. Prodromal symptoms, such as pruritus or nonspecific skin eruptions, were found in approximately half of the patient population. Histopathologic or serologic testing, when undertaken, was a helpful adjunct in establishing diagnosis. Treatment with immunotherapy was discontinued after ICI-BP development in most patients. The most common treatments were systemic and topical corticosteroids. Steroid-sparing therapies, such as antibiotics and other systemic immunomodulators, were also used as adjuvant treatment modalities. Biologic and targeted agents, used predominantly in cases refractory to treatment with corticosteroids, were associated with marked symptomatic improvement in most patients. CONCLUSIONS AND RELEVANCE: The results of this systematic review suggest that ICI-BP often poses a therapeutic challenge for patients with cancer who are receiving immunotherapy. Further research on the early recognition, diagnosis, and use of targeted treatment modalities will be essential in developing more personalized treatment options for affected patients while minimizing morbidity and mortality.
Immune checkpoint inhibitors (ICIs) have now been approved in numerous and diverse cancer types and combination regimens. Effective recognition and treatment of ICI toxicities, which might occur ...acutely, affect any organ system, and produce many distinct clinical syndromes, have emerged as essential goals of ICI management. Thus, developing robust diagnostic and management approaches for ICI toxicity across the health-care system is an urgent and unmet clinical need. In this Personal View, we describe barriers to high-quality care that have constrained the most effective management of patients with cancer receiving ICI treatment. We review education initiatives to enhance patient and physician awareness, which is necessary given the broad spectrum of ICI toxicities often experienced by patients, and assess various systems-based approaches that maximise the chances of appropriate management. In addition, we describe research pipelines that broaden evidence-based approaches and the pathobiology of these novel events. Developing effective, systematic approaches for the recognition and treatment of ICI toxicities will continue to grow in importance as these agents proliferate in cancer care.
There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker ...of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.
This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.
This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.
Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).
GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
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OBJECTIVETo describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs).
METHODSPatients with ICI-related neuropathy (irNeuropathy) were ...identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents.
RESULTSWe identified 19 patients with irNeuropathies. ICIs included anti-programmed death–1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy.
CONCLUSIONNeuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.
Cytokine release syndrome is a well-known complication of chimeric antigen receptor T-cell (CAR-T) therapy and can lead to multiorgan dysfunction. However, the nephrotoxicity of CAR-T therapy is ...unknown. We aimed to characterize the occurrence, cause, and outcomes of acute kidney injury (AKI), along with the occurrence of electrolyte abnormalities, among adults with diffuse large B-cell lymphoma receiving CAR-T therapy.
Case series.
We reviewed the course of 78 adults receiving CAR-T therapy with axicabtagene ciloleucel or tisagenlecleucel at 2 major cancer centers between October 2017 and February 2019. Baseline demographics, comorbid conditions, medications, and laboratory values were obtained from electronic health records. AKI was defined using KDIGO (Kidney Disease: Improving Global Outcomes) criteria. The cause, clinical course, and outcome of AKI events and electrolyte abnormalities in the first 30 days after CAR-T infusion were characterized using data contained in electronic health records.
Among 78 patients receiving CAR-T therapy, cytokine release syndrome occurred in 85%, of whom 62% were treated with tocilizumab. AKI occurred in 15 patients (19%): 8 had decreased kidney perfusion, 6 developed acute tubular necrosis, and 1 patient had urinary obstruction related to disease progression. Those with acute tubular necrosis and obstruction had the longest lengths of stay and highest 60-day mortality. Electrolyte abnormalities were common; hypophosphatemia, hypokalemia, and hyponatremia occurred in 75%, 56%, and 51% of patients, respectively.
Small sample size; AKI adjudicated by retrospective chart review; lack of biopsy data.
In this case series of patients with diffuse large B-cell lymphoma receiving CAR-T therapy, AKI and electrolyte abnormalities occurred commonly in the context of cytokine release syndrome.
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IMPORTANCE: Despite the efficacy of immune checkpoint inhibitors (ICIs), cutaneous immune-related adverse events (cirAEs) occur in 20% to 40% of all treated patients. To our knowledge, little is ...known about the predictive value of these cutaneous eruptions and their subtypes regarding cancer survival. OBJECTIVE: To determine the association of developing cirAEs following treatment with anti–programmed cell death 1 (PD-1) or anti–programmed cell death ligand 1 (PD-L1) therapy with patient survival. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from the TriNetX Diamond Network, a database of health records and claims data from more than 200 million US and European patients, to conduct a population-level cohort analysis. The study included 7008 eligible patients who developed cirAEs after treatment with anti–PD-1 or anti–PD-L1 therapy for malignant neoplasms of digestive organs, bronchus or lung, melanoma of skin, and urinary tract who were identified through the TriNetX Diamond Network along with 7008 matched controls. EXPOSURES: Development of cirAEs within 6 months following anti–PD-1 or anti–PD-L1 therapy. MAIN OUTCOMES AND MEASURES: A 6-month analysis using a Cox proportional hazards model was performed to determine the association of cirAEs with overall survival after adjusting for demographic characteristics, cancer type, and cancer stage. RESULTS: A total of 7008 patients (3036 women 43.3%; mean SD age, 68.2 11.2 years) were matched to 7008 (3044 women 43.4%; mean SD age, 68.3 11.1 years) controls. Pruritus (hazard ratio HR, 0.695; 95% CI, 0.602-0.803; P < .001), drug eruption (HR, 0.755; 95% CI, 0.635-0.897; P = .001), xerosis (HR, 0.626; 95% CI, 0.469-0.834; P = .001), nonspecific rashes (HR, 0.704; 95% CI, 0.634-0.781; P < .001), and appearance of any cirAE (HR, 0.778; 95% CI, 0.726-0.834; P < .001) were significantly protective of mortality using a Benjamini-Hochberg correction with a significance level of .05. Additionally, psoriasis (HR, 0.703; 95% CI, 0.497-0.994; P = .045) and lichen planus/lichenoid dermatitis (HR, 0.511; 95% CI, 0.279-0.939; P = .03) were significant. Eczematous dermatitis (HR, 0.612; 95% CI, 0.314-1.195), vitiligo (HR, 0.534; 95% CI, 0.254-1.123), bullous pemphigoid (HR, 0.524; 95% CI, 0.140-1.956), and Grover disease (HR, 0.468; 95% CI, 0.115-1.898) were all associated with strong protective clinical effects. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that the development of cirAEs is strongly associated with response to ICI therapy and patient survival.
Estrogen receptor-positive (ER+) tumors of the breast are generally highly responsive to endocrine treatment. Although endocrine therapy is the mainstay of adjuvant treatment for ER+ breast cancer, ...the role of endocrine therapy in the neoadjuvant setting is unclear.
To evaluate the effect of neoadjuvant endocrine therapy (NET) on the response rate and the rate of breast conservation surgery (BCS) for ER+ breast cancer.
Based on PRISMA guidelines, a librarian-led search of PubMed and Ovid MEDLINE was performed to identify eligible trials published from inception to May 15, 2015. The search was performed in May 2015.
Inclusion criteria were prospective, randomized, neoadjuvant clinical trials that reported response rates with at least 1 arm incorporating NET (n = 20). Two authors independently analyzed the studies for inclusion.
Pooled odds ratios (ORs), 95% CIs, and P values were estimated for end points using the fixed- and random-effects statistical model.
The analysis included 20 studies with 3490 unique patients. Compared with combination chemotherapy, NET as monotherapy with aromatase inhibitors had a similar clinical response rate (OR, 1.08; 95% CI, 0.50-2.35; P = .85; n = 378), radiological response rate (OR, 1.38; 95% CI, 0.92-2.07; P = .12; n = 378), and BCS rate (OR, 0.65; 95% CI, 0.41-1.03; P = .07; n = 334) but with lower toxicity. Aromatase inhibitors were associated with a significantly higher clinical response rate (OR, 1.69; 95% CI, 1.36-2.10; P < .001; n = 1352), radiological response rate (OR, 1.49; 95% CI, 1.18-1.89; P < .001; n = 1418), and BCS rate (OR, 1.62; 95% CI, 1.24-2.12; P < .001; n = 918) compared with tamoxifen. Dual combination therapy with growth factor pathway inhibitors was associated with a higher radiological response rate (OR, 1.59; 95% CI, 1.04-2.43; P = .03; n = 355), but not clinical response rate (OR, 0.76; 95% CI, 0.54-1.07; P = .11; n = 537), compared with endocrine monotherapy. The incidence of pathologic complete response was low (<10%).
Neoadjuvant endocrine therapy, even as monotherapy, is associated with similar response rates as neoadjuvant combination chemotherapy but with significantly lower toxicity, suggesting that NET needs to be reconsidered as a potential option in the appropriate setting. Additional research is needed to develop rational NET combinations and predictive biomarkers to personalize the optimal neoadjuvant strategy for ER+ breast cancer.
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