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Valpione, Sara (2017) Biomarkers of prognosis and toxicity for metastatic melanoma patients treated with ipilimumab. [Ph.D. thesis]

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Abstract (english)

Background
Metastatic melanoma has a dismal prognosis, as a consequence of its intrinsic aggressiveness and the lack of effective treatment options: in fact, until recently, systemic therapies were numbered. Ipilimumab is a fully humanized monoclonal anti-Cytotoxic T-Lymphocyte Antigen 4 antibody that demonstrated a significant improvement of metastatic melanoma patient survival, however toxicity may be severe and life threatening. Clinicians lack reliable prognostic factors for prognosis and toxicity and this makes treatment decisions difficult.
Methods
An observational prospective study was performed at the Veneto Institute of Oncology (IOV), the main inclusion criteria being the administration of ipilimumab 3mg/kg every 3 weeks for metastatic melanoma. A total of 140 patients were included, clinical features and circulating biomarkers were evaluated for an association with prognosis or adverse events. Out of 140 patients, 113 were evaluated for prognostic factors, and the full cohort was included in a toxicity study. A prognostic model was derived and data from 97 patients from two other Italian Institutes were used to validate this prognostic model.
Results
Baseline serum lactic dehydrogenase (LDH) concentration and neutrophil count were significantly associated with prognosis. In particular, patients with higher circulating levels of LDH and higher neutrophils before treatment had a shorter survival and increased HR of death (HR=1.36, 95% CI 1.16-1.58, P<.001 and HR=1.76, 95% CI 1.41-2.10, P<.001, respectively). Data were validated on the external cohort and the prognostic model was confirmed.
Female patients and patients with lower baseline serum levels of interleukin-6 (IL6) had a higher risk of developing severe toxicity (OR=1.5, 95% CI 1.06-2.16 and OR=2.84 for 1ng/L variation, 95% CI 1.34-6.03, respectively).
Conclusions
We demonstrated that baseline levels of neutrophils and serum LDH could help clinicians to predict the outcome of melanoma patients treated with ipilimumab and that ipilimumab may not be the best treatment in patients with higher neutrophil count and LDH. Only comparative and translational studies could define if patients with high LDH and neutrophil are refractory to immunotherapy or have a more aggressive variant of melanoma independent from the treatment. Serum baseline IL6 could help in identifying patients with a greater risk of toxicity from ipilimumab and in planning a more specific monitoring during and after the treatment, with the purpose of increasing its safety. In particular, females with low IL6 serum levels should be carefully monitored for AEs.

Abstract (italian)

Background
Metastatic melanoma has a dismal prognosis, as a consequence of its intrinsic aggressiveness and the lack of effective treatment options: in fact, until recently, systemic therapies were numbered. Ipilimumab is a fully humanized monoclonal anti-Cytotoxic T-Lymphocyte Antigen 4 antibody that demonstrated a significant improvement of metastatic melanoma patient survival, however toxicity may be severe and life threatening. Clinicians lack reliable prognostic factors for prognosis and toxicity and this makes treatment decisions difficult.
Methods
An observational prospective study was performed at the Veneto Institute of Oncology (IOV), the main inclusion criteria being the administration of ipilimumab 3mg/kg every 3 weeks for metastatic melanoma. A total of 140 patients were included, clinical features and circulating biomarkers were evaluated for an association with prognosis or adverse events. Out of 140 patients, 113 were evaluated for prognostic factors, and the full cohort was included in a toxicity study. A prognostic model was derived and data from 97 patients from two other Italian Institutes were used to validate this prognostic model.
Results
Baseline serum lactic dehydrogenase (LDH) concentration and neutrophil count were significantly associated with prognosis. In particular, patients with higher circulating levels of LDH and higher neutrophils before treatment had a shorter survival and increased HR of death (HR=1.36, 95% CI 1.16-1.58, P<.001 and HR=1.76, 95% CI 1.41-2.10, P<.001, respectively). Data were validated on the external cohort and the prognostic model was confirmed.
Female patients and patients with lower baseline serum levels of interleukin-6 (IL6) had a higher risk of developing severe toxicity (OR=1.5, 95% CI 1.06-2.16 and OR=2.84 for 1ng/L variation, 95% CI 1.34-6.03, respectively).
Conclusions
We demonstrated that baseline levels of neutrophils and serum LDH could help clinicians to predict the outcome of melanoma patients treated with ipilimumab and that ipilimumab may not be the best treatment in patients with higher neutrophil count and LDH. Only comparative and translational studies could define if patients with high LDH and neutrophil are refractory to immunotherapy or have a more aggressive variant of melanoma independent from the treatment. Serum baseline IL6 could help in identifying patients with a greater risk of toxicity from ipilimumab and in planning a more specific monitoring during and after the treatment, with the purpose of increasing its safety. In particular, females with low IL6 serum levels should be carefully monitored for AEs.

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EPrint type:Ph.D. thesis
Tutor:Chiarion-Sileni, Vanna
Ph.D. course:Ciclo 29 > Corsi 29 > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:03 February 2017
Anno di Pubblicazione:2017
Key Words:immunotherapy, melanoma, biomarkers, ipilimumab, toxicity
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:10363
Depositato il:02 Nov 2017 16:26
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