The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Ipilimumab-induced cutaneous reactions.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p>d<p>MelanA-specific vaccination.</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; TKI, tyrosine kinase inhibitor; PR, partial response; SD, stable disease; PD, progressive disease; MR, mixed response; CR, complete response; MAH, melanoma-associated hypopigmentation.</p

Ipilimumab-induced ischemic gastritis.

<p>Hematoxillin eosin staining showed edematous hypervascularized lamina propria mucosae, foveolar hyperplasia and regenerative basal crypts at 10× magnification (A) and 50× magnification (B). Endoscopic narrow band imaging (NBI) showed signs of reactive chronic inflammation of the gastric corpus mucosa with prominent vascular pattern consistent with an ischemic gastritis (C). Positron emission tomography (PET) scan illustrated high level tracer uptake in the gastric wall consistent with inflammation (D) and its spontaneous resolution after four months with a remaining thickening of the gastric wall (E).</p

Ipilimumab-induced miscellaneous reactions.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor-free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab melanoma.</p>c<p>stage IV metastatic disease (AJCC 2009).</p>d<p>sinusitis.</p>e<p>VZV-infection.</p>f<p>limb perfusion with melphalan.</p>g<p>MAGE-A3 vaccination by GSK; NCT 00796445.</p>h<p>PRAME; vaccination with GSK2302025A.</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; VZV, varicella-zoster virus; SD, stable disease; MR, mixed response; PD, progression of disease.</p

Ipilimumab-induced myocardial fibrosis in conjunction with hepatotoxicity.

<p>Hematoxillin eosin staining at 50× magnification (A), 200× magnification (B) and 400× magnification (C) and chloracetate esterase staining at 50× magnification (D), 200× magnification (E) and 400× magnification (F) revealed neutrophilic granulocytes (black arrow) mostly around the central vein (asterisk). Portal fields were almost normal (white arrows). Some necrotic hepatocytes (black arrow heads panel C) and cholestasis of hepatocytes (white arrow heads panel C) indicating liver insufficiency, were detected pericentrally. Slightly elevated myocardial fibrosis (white arrow heads panel F) surrounded by structural changes of cardiomyocytes were detected (black arrow heads panel F).</p

Ipilimumab-induced skin reactions and nephritis.

<p>Melanoma-associated hypopigmentation (MAH) in a patient exhibiting a partial clinical response (A). Masson’s trichome staining showed lymphocytic nephritis in a patient with an ipilimumab-induced drug rash with eosinophilia and systemic symptoms (DRESS) (B). Skin toxicity with the formation of blisters upon induction of treatment with ipilimumab in an area that had been radiated, five weeks earlier, in a patient with previous resection of the distal part of digit II due to an acrolentiginous melanoma (C).</p

Ipilimumab-induced gastrointestinal, pancreatic and hepatic reactions.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p><p>M indicates male; F, female; TVP, polychemotherapy with temozolomide+vinblastin+carboplatin; TKI, tyrosine kinase inhibitor RAF265; ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma-glutamyl transferase; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; PR, partial response; SD, stable disease; PD, progressive disease.</p

Ipilimumab-induced reactions of the respiratory tract and renal system.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor-free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p>d<p>PRAME study; vaccination with GSK2302025A.</p>e<p>atypical pneumonia.</p>f<p>acute renal failure.</p>g<p>renal failure/atypical pneumonia.</p>h<p>iridocyclitis/keratitis, deafness.</p>I<p>renal failure/atypical pneumonia/iridocyclitis/keratitis.</p>j<p>deafness.</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; DVP; polychemotherapy with dacarbazine/vindesine/paclitaxel; GIT, gastrointestinal tract; PR, partial response; SD, stable disease; MR, mixed response; PD, progressive disease.</p

Ipilimumab-induced side effects of the endrocrine system.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor-free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p>d<p>limb perfusion with melphalan.</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; GIT, gastrointestinal tract; IGF-1, insulin-like growth factor-1; TSH, thyroid-stimulating hormone; PR, partial response; SD, stable disease; PD, progressive disease; MR, mixed response.</p