Abstract
BackgroundIpilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected. The use of ipilimumab is associated with a typical but unpredictable pattern of side effects. The purpose of this study was to identify clinical features and blood biomarkers capable of predicting ipilimumab related toxicity.MethodsWe performed a prospective study aimed at analyzing potential clinical and biological markers associated with immune-related toxicity in patients treated with ipilimumab (3 mg/kg, q3w). We enrolled 140 consecutive melanoma patients treated with ipilimumab for metastatic disease. The following prospectively collected data were utilized: patient characteristics, previous therapies, level of circulating biomarkers associated with tumour burden or immune-inflammation status (lactic dehydrogenase, C-reactive protein, β2-microglobulin, vascular endothelial growth factor, interleukin-2, interleukin-6, S-100, alkaline phosphatase, transaminases) and blood cells subsets (leukocyte and lymphocyte subpopulations). Logistic regression was used for multivariate analysis of data.ResultsOut of 140 patients, 36 (26%) experienced a severe adverse event, 33 (24%) discontinued treatment for severe toxicity. Among the immune-profile biomarkers analyzed, only interleukin-6 was associated with the risk of toxicity. Female patients had a further increase of immune-related adverse events. Low baseline interleukin-6 serum levels (OR = 2.84, 95% CI 1.34–6.03, P = 0.007) and sex female (OR = 1.5, 95% CI 1.06–2.16 P = 0.022) and were significant and independent risk factors for immune related adverse events.ConclusionsBaseline IL6 serum levels and female sex were significantly and independently associated with higher risk of severe toxicity and could be exploited in clinical practice to personalize toxicity surveillance in patients treated with ipilimumab.
Highlights
Ipilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected
LDH was measured by means of the kinetic method optimized according to the German Society of Clinical Chemistry (Roche Cobas 8000 c720, Cobas Core and ISE 1800), CRP was measured with nephelometric method (Siemens Vista), beta2-microglobulin was measured with immunonephelometric method (Siemens Vista), VEGF was measured with immunoenzymatic method (Thermo Scientific), IL2 was measured with immunoenzymatic method (Thermo Scientific), IL6 was measured with chemoluminescent immunoenzymatic method (Beckman Coulter DXI 800), S-100 was measured with chemoluminescent immunodosing (Diasorin Liaison XL LAS)
With the advent of second generation anti-immune checkpoint monoclonal antibodies, ipilimumab is no more the standard first line immunotherapy for metastatic melanoma patients; it is approved in the adjuvant setting and is still a second line option for patients progressing after anti-PD1 inhibitors and is administered as first line treatment in combination with nivolumab
Summary
Ipilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected. Melanoma is a highly immunogenic tumor, as a consequence of the high somatic mutation rate and expression of neoantigens characterizing this malignancy [1, 2]. Immunotherapy treatments, such as active specific immunization (i.e., vaccines) and immuno stimulating cytokines (e.g., interferon alpha and interleukin-2) basically failed to significantly improve patient survival [3, 4]. Patients treated with ipilimumab at the registered dose of 3 mg/kg q21 days for 4 cycles experienced grade (G) 3 (not life-threatening) or G4 (life-threatening) adverse events (AEs) in up to 19.1 and 3.8% of patients, respectively, due to the development of autoimmunity effects. The identification of patients who have a higher likelihood to develop severe AEs could help personalize the safety survey, for example by means of telephonic interviews between visits or biochemical monitoring (e.g., hypophysis hormone levels) after treatment conclusion
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