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Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis.

Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T - BMC Med (2015)

Bottom Line: Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies.A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.

View Article: PubMed Central - PubMed

Affiliation: Département de Rhumatologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France. anne.bertrand87@gmail.com.

ABSTRACT

Background: Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab).

Methods: A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R(©), package meta.

Results: Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65-79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18-30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56-66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69-89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6-12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.

Conclusion: The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.

No MeSH data available.


Related in: MedlinePlus

Risk ratio of developing an irAE with ipilimumab at 10 mg/kg compared with 3 mg/kg for global irAEs all grade (a) and high grade (b)
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Fig4: Risk ratio of developing an irAE with ipilimumab at 10 mg/kg compared with 3 mg/kg for global irAEs all grade (a) and high grade (b)

Mentions: The incidence of all-grade irAEs varied according to the dosage of the drug, from 61 % (95 % CI, 56–66; I2, 0) in patients receiving ipilimumab at 3 mg/kg to 79 % (95 % CI, 69–89; I2, 85) in patients treated with ipilimumab 10 mg/kg. This dose effect was corroborated in high-grade irAEs, evaluated to 17 % (95 % CI, 10–23; I2, 71, 85) with ipilimumab 3 mg/kg and 31 % (95 % CI, 22–39; I2, 62) with ipilimumab 10 mg/kg (Figures S5, S6 and S7 in Additional file 1). To perform a statistical comparison between the two main doses (3 mg/kg and 10 mg/kg) we made a subgroup analysis within the three studies comparing the two doses [17, 19, 30]. The risk ratio (RR) of developing an irAE with ipilimumab at 10 mg/kg compared with 3 mg/kg was 3.10 (1.59–6.03; P=0.0008) for the overall incidence level of irAEs for high grade. RR of overall incidence level of irAEs for all grade did not reach a statistically significant difference (RR, 1.16 (0.97–1.38); P=0.10; Fig. 4a,b).Fig. 4


Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis.

Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T - BMC Med (2015)

Risk ratio of developing an irAE with ipilimumab at 10 mg/kg compared with 3 mg/kg for global irAEs all grade (a) and high grade (b)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559965&req=5

Fig4: Risk ratio of developing an irAE with ipilimumab at 10 mg/kg compared with 3 mg/kg for global irAEs all grade (a) and high grade (b)
Mentions: The incidence of all-grade irAEs varied according to the dosage of the drug, from 61 % (95 % CI, 56–66; I2, 0) in patients receiving ipilimumab at 3 mg/kg to 79 % (95 % CI, 69–89; I2, 85) in patients treated with ipilimumab 10 mg/kg. This dose effect was corroborated in high-grade irAEs, evaluated to 17 % (95 % CI, 10–23; I2, 71, 85) with ipilimumab 3 mg/kg and 31 % (95 % CI, 22–39; I2, 62) with ipilimumab 10 mg/kg (Figures S5, S6 and S7 in Additional file 1). To perform a statistical comparison between the two main doses (3 mg/kg and 10 mg/kg) we made a subgroup analysis within the three studies comparing the two doses [17, 19, 30]. The risk ratio (RR) of developing an irAE with ipilimumab at 10 mg/kg compared with 3 mg/kg was 3.10 (1.59–6.03; P=0.0008) for the overall incidence level of irAEs for high grade. RR of overall incidence level of irAEs for all grade did not reach a statistically significant difference (RR, 1.16 (0.97–1.38); P=0.10; Fig. 4a,b).Fig. 4

Bottom Line: Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies.A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.

View Article: PubMed Central - PubMed

Affiliation: Département de Rhumatologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France. anne.bertrand87@gmail.com.

ABSTRACT

Background: Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab).

Methods: A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R(©), package meta.

Results: Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65-79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18-30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56-66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69-89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6-12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.

Conclusion: The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.

No MeSH data available.


Related in: MedlinePlus