+ Toxicities of immunotherapy – A case study Maria KFOURY Intern Medical Oncology
+ Ms L, 46 yo � Medical history � Excision of 5 benign nevus (2011) � Family history � Father: Head and neck cancer � Social History � No alcohol or tobacco consumption � Saleswoman
+ History of present illness Biopsy Melanoma metastasis, NRAS mutation BRAF WT October 2015 December 2015 January 2016 Discovery of CAP CT left axillary lymphadenopathy Head MRI : No lesions
CAP CT 04/01/16 � Left axillary lymphadenopathy 10 x 5,2 cm � No pulmonary, visceral or bone lesions
+ Multi-disciplinary Consultation Meeting 12/01/16 � Aggressive melanoma stage III C � No surgery : � Inflammatory skin � Fast growing � PS 0 � Systemic therapy � Nivolumab + Ipilimumab
+ History of present illness Impaired vision Headache Vitiligo 18 Jan 16 8 Feb 16 15 Feb 16 29 Fev 16 C1 C2 C3 : no injection Nivolumab 3 mg/ kg Ipilimumab 1 mg / kg Head CT well tolerated
Head CT 29/02/16 � Enlargement of the pituitary gland volume measured at 9 mm (versus 6 mm) : evocative of hypophysitis � No brain or meningeal lesion
+ Assessment of hypophysitis � Hormonal tests � TSH, T3, T4 normal � Cortisol normal � FSH, LH normal � Endocrinologist’s advice : � Intravenous corticosteroids bolus of 1 mg / kg / day for 3 days � Followed by oral corticosteroids 1 mg / kg / day : 100 mg/ day
+ History of present illness � Improvement of impaired vision and headaches � C3 21/03/2016: Nivolumab 3 mg/ kg + Ipilimumab 1 mg / kg � Discovery of a hepatitis : � Grade 4 � Cytolysis: ALAT 100 N, ASAT 50 N � Cholestasis : GGT 3 N, Bilirubine N � Grade 3 � TP 82%, Factor V normal
+ Assessment of Hepatitis � No new medications � Liver US 25/03/16 : � Homogenous hepatomegaly, no focal lesion, bile duct dilatation, vesicular microlithiasis � Auto-immune assessment � Bacterial analysis Negative � Viral serology: HIV , HAV , HBV , HCV � PCR CMV , EBV , HSV
+ Assessment of Hepatitis � Immune-mediated hepatitis under corticosteroids � No sign of hepatic failure � Hepatologist’s advice : � Maintain of corticosteroids � Monitoring of liver function tests and hemostasis � No hepatotoxic medications � If increase in cytolysis: liver biopsy
+ Immune-related adverse effects : Ipilimumab Weber J et al, JCO 2012
+ History of present illness C3 Nivolumab Ipilimumab 21 Mar 16 11 Apr 16 M4 Assessment No blurry vision Improvement of hepatitis CAP CT Head MRI
CAP CT 11/04/16 � Decrease of left axillary lymphadenopathy by 54%
Head MRI 11/04/16 � Enlargement of the pituitary gland measured at 7 mm, no bulging into the sellar diaphragm
+ History of present illness C3 Left axillary Nivolumab lymphadenectomy Ipilimumab M4 Assessment 1N+/7N of 4 cm 21 Mar 16 11 Apr 16 17 May 16 Multi-disciplinary consultation meeting : Cessation of immunotherapy (cytolysis grade 4). Continuation of corticosteroids
+ History of present illness C3 Left axillary Nivolumab lymphadenectomy Ipilimumab 21 Mar 16 17 May 16 18 Jul 16 M7 assessment Clinical exam : normal Biological tests: normal CAP CT : no lesions Head MRI : Decrease of the pituitary gland’s volume
+ History of present illness External radiation therapy C3 axillary area Left axillary Nivolumab lymphadenectom 50 Gy in 25 fractions Ipilimumab y 21 Mar 16 17 May 16 Sept – Nov 16 M11 assessment Clinical exam : normal Biological tests: normal CAP CT, Head MRI : stable
CAP CT 07/11/16 � No suspicious lesion
+ Conclusion Persistance of a complete response 9 month after the 3 rd and last injection of Nivolumab and Ipilimumab for a stage III melanoma
I mmune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center Restrospective study 103 patients (35%) required corticosteroid 2011-2013 29 (10%) required anti-TNF α therapy 298 patients with melanoma included Ipililumab 3 mg/ kg Horvat T et al, JCO 2015
+ Thank you for your attention
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