Skip to main content

Advertisement

SpringerLink
Log in

Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Ipilimumab was the first immunotherapy approved for metastatic melanoma in decades and is currently registered as a second-line treatment. However, new immunotherapies, in combination with ipilimumab, offer even better clinical outcomes for patients compared with single-agent treatments, at the expense of improved toxicity. The aim of this study was to evaluate the feasibility of ipilimumab outside the clinical trials and to identify survival predictors for treatment benefit. Data were collected on 47 advanced melanoma patients treated with ipilimumab between 2010 and 2015 at a single center. Association of clinical characteristics (including primary tumor characteristics), serum lactate dehydrogenase (LDH), erythrocyte sedimentation rate, absolute eosinophil, lymphocyte, and neutrophil count, neutrophil/lymphocyte and eosinophil/lymphocyte ratio with toxicity and clinical outcome were assessed using univariate and multivariate analysis. Median progression-free survival at a median follow-up of 10 months was 2.7 months and median overall survival was 9.8 months. Objective response was observed in 17% of patients and the disease control rate at week 24 was 40%. The 1- and 2-year survival rates documented were 40 and 28%, respectively. Significant association between high LDH level (>1.5× upper limit of normal) and decreased overall survival was demonstrated in uni- and multivariate analysis (hazard ratio [HR]: 3.554, 95% CI: 1.225–10.306, p = 0.019). Neither biomarkers nor clinical outcome were associated with toxicity. Using baseline serum LDH to identify patients most likely to benefit from ipilimumab therapy could serve as a simple and inexpensive biomarker of clinical outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Tsao H, Atkins MB, Sober AJ (2004) Management of cutaneous melanoma. N Engl J Med 351:998–1012

    Article  CAS  PubMed  Google Scholar 

  2. Agarwala SS (2009) Current systemic therapy for metastatic melanoma. Expert Rev Anticancer Ther 9:587–595

    Article  CAS  PubMed  Google Scholar 

  3. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33:1889–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Postow MA, Chesney J, Pavlik AC et al (2015) Nivolumab and ipilimumab versus ipiliumab in untreated melanoma. N Engl J Med 372:2006–2017

    Article  PubMed  PubMed Central  Google Scholar 

  6. Eggermont AM, Chiarion-Sileni V, Grob JJ et al (2015) Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16:522–530

    Article  CAS  PubMed  Google Scholar 

  7. Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, Chapman PB, Schwartz GK, Allison JP, Wolchok JD (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116:1767–1775

    Article  CAS  PubMed  Google Scholar 

  8. Di Giacomo AM, Danielli R, Calabro L, Bertocci E, Nannicini C, Giannarelli D et al (2011) Ipilimumab experience in heavily pre-treated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy). Cancer Immunol Immunother 60:467–477

    Article  PubMed  CAS  Google Scholar 

  9. Di Giacomo AM, Calabro L, Danielli R et al (2013) Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother 62:1021–1028

    Article  PubMed  CAS  Google Scholar 

  10. Delyon J, Mateus C, Lefeuvre D, Lanoy E, Zitvogel L, Chaput N, Roy S, Eggermont AM, Routier E, Robert C (2013) Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol 24:1697–1703

    Article  CAS  PubMed  Google Scholar 

  11. Wilgenhof S, Du Four S, Vandenbroucke F, Everaert H, Salmon I, Liénard D, Marmol VD, Neyns B (2013) Single-center experience with ipilimumab in an expanded access program for patients with pre-treated advanced melanoma. J Immunother 36:215–222

    Article  CAS  PubMed  Google Scholar 

  12. Kelderman S, Heemskerk B, van Tinteren H, van den Brom R, Hospers GA, van den Eertwegh A, Kapiteijn EW, de Groot JW, Soetekouw P, Jansen RL, Fiets E, Furness AJ, Renn A, Krzystanek M, Szallasi Z, Lorigan P, Gore ME, Schumacher TN, Haanen JB, Larkin JM, Blank CU (2014) Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 63:449–458

    CAS  PubMed  Google Scholar 

  13. Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caracò C, Curvietto M, Esposito A, Paone M, Palla M, Cavalcanti E, Sandomenico F, Petrillo A, Botti G, Fulciniti F, Palmieri G, Queirolo P, Marchetti P, Ferraresi V, Rinaldi G, Pistillo MP, Ciliberto G, Mozzillo N, Ascierto PA (2014) Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 63:675–683

    Article  CAS  PubMed  Google Scholar 

  14. Berrocal A, Arance A, Lopez Martin JA, Soriano V, Muñoz E, Alonso L, Espinosa E, Lopez Criado P, Valdivia J, Martin Algarra S, Spanish Melanoma Group (2014) Ipilimumab for advanced melanoma: experience from the Spanish Expanded Access Program. Melanoma Res 24:577–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Diem S, Kasenda B, Martin-Liberal J, Lee A, Chauhan D, Gore M, Larkin J (2015) Prognostic score for patients with advanced melanoma treated with ipilimumab. Eur J Cancer 51:2785–2791

    Article  CAS  PubMed  Google Scholar 

  16. Ferrucci PF, Gandini S, Battaglia A, Alfieri S, di Giacomo AM, Giannarelli D, Cappellini GCA, de Galitiis F, Marchetti P, Amato G, Lazzeri A, Pala L, Cocorocchio E, Martinoli C (2015) Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br J Cancer 112:1904–1910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, Tarnanidis K, Holland-Letz T, Umansky L, Beckhove P, Sucker A, Schadendorf D, Utikal J, Umansky V (2015) Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin Cancer Res 21:5453–5459

    Article  CAS  PubMed  Google Scholar 

  18. Hannani D, Vetizou M, Enot D et al (2015) Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res 25:208–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Valpione S, Martinoli C, Fava P, Mocellin S, Campana LG, Quaglino P, Ferrucci PF, Pigozzo J, Astrua C, Testori A, Chiarion-Sileni V (2015) Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab. Eur J Cancer 51:2086–2094

    Article  CAS  PubMed  Google Scholar 

  20. Khoja L, Atenafu EG, Templeton A, Qye Y, Chappell MA, Saibil S, Hogg D, Butler MO, Joshua AM (2016) The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated cutaneous metastatic melanoma. Cancer Med 5:2792–2799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Martens A, Wistuba-Hamprecht K, Geukes Foppen M et al (2016) Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 22:2908–2918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zaragoza J, Caille A, Beneton N, Bens G, Christiann F, Maillard H, Machet L (2016) High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol 174:146–151

    Article  CAS  PubMed  Google Scholar 

  23. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Restifo NP, Haworth LR, Levy C, Mavroukakis SA, Nichol G, Yellin MJ, Rosenberg SA (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043–6053

    Article  CAS  PubMed  Google Scholar 

  24. Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, Kammula US, Hughes MS, Allen TE, Levy CL, Yellin M, Nichol G, White DE, Steinberg SM, Rosenberg SA (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13:6681–6688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  CAS  PubMed  Google Scholar 

  26. Platz A, Egyhazi S, Ringborg U, Hansson J (2008) Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenic subclass and body site. Mol Oncol 1:394–405

    Article  Google Scholar 

  27. Johnson DB, Lovly CM, Flavin M, Panageas KS, Ayers GD, Zhao Z, Iams WT, Colgan M, DeNoble S, Terry CR, Berry EG, Iafrate AJ, Sullivan RJ, Carvajal RD, Sosman JA (2015) Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. Cancer Immunol Res 3:288–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ascierto PA, Simeone E, Sileni VC, Pigozzo J, Maio M, Altomonte M, del Vecchio M, di Guardo L, Marchetti P, Ridolfi R, Cognetti F, Testori A, Bernengo M, Guida M, Marconcini R, Mandalà M, Cimminiello C, Rinaldi G, Aglietta M, Queirolo P (2014) Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort. J Transl Med 12:116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bonsack O, Nichol G, Humphrey R, Hodi FS (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420

    Article  CAS  PubMed  Google Scholar 

  30. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13:459–465

    Article  CAS  PubMed  Google Scholar 

  31. Queirolo P, Spagnolo F, Ascierto PA, Simeone E, Marchetti P, Scoppola A, del Vecchio M, di Guardo L, Maio M, di Giacomo AM, Antonuzzo A, Cognetti F, Ferraresi V, Ridolfi L, Guidoboni M, Guida M, Pigozzo J, Chiarion Sileni V (2014) Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neuro-Oncol 118:109–116

    Article  CAS  Google Scholar 

  32. Ugurel S, Thirumaran RK, Bloethner S, Gast A, Sucker A et al (2007) B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One 2(2):e236

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jakob JA, Basset RL, Cs N, Curry JL, Joseph RW et al (2012) NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118(16):4014–4023

    Article  CAS  PubMed  Google Scholar 

  34. Devitt B, Liu W, Salemi R, Wolfe R, Kelly J et al (2011) Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res 24(4):666–672

    Article  CAS  PubMed  Google Scholar 

  35. Carlino MS, Haydu LE, Kakavand H, Menzies AM, Hamilton AL, Yu B, Ng CC, Cooper WA, Thompson JF, Kefford RF, O'Toole SA, Scolyer RA, Long GV (2014) Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma. Br J Cancer 111(2):292–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ellehorst JA, Greene VR, Ekmekcioglu S, Warneke CL, Johnson MM et al (2011) Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res 17(2):229–235

    Article  CAS  Google Scholar 

  37. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  38. Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ (2013) The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol 88:218–230

    Article  PubMed  Google Scholar 

  39. Templeton AJ, McNamara MG, Šeruga B et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 106:dju124

    Article  PubMed  CAS  Google Scholar 

  40. Petrulio CA, Kim-Schulze S, Kaufman HL (2006) The tumor microenvironment and implications for cancer immunotherapy. Expert Opin Biol Ther 6:671–684

    Article  CAS  PubMed  Google Scholar 

  41. Vasievich EA, Huang L (2011) The suppressive tumor microenvironment: a challenge in cancer immunotherapy. Mol Pharm 8:635–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schmidt H, Bastholt L, Geertsen P, Christensen IJ, Larsen S, Gehl J, von der Maase H (2005) Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. Br J Cancer 93:273–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW (2011) The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 105:93–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ladányi A (2015) Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res 28:490–500

    Article  PubMed  Google Scholar 

  45. Simson L, Ellyard JI, Dent LA, Matthaei KI, Rothenberg ME, Foster PS, Smyth MJ, Parish CR (2007) Regulation of carcinogenesis by IL-5 and CCL11: a potential role for eosinophils in tumor immune surveillance. J Immunol 178:4222–4229

    Article  CAS  PubMed  Google Scholar 

  46. Carretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hämmerling GJ (2015) Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8+ T cells. Nat Immunol 16:609–617

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the National Research, Development and Innovation Office grant NKFI K105132.

Author information

Authors and Affiliations

  1. Department of Oncodermatology, National Institute of Oncology, 7-9. Ráth Gy. u., Budapest, H-1122, Hungary

    Tímea Balatoni, Kata Czirbesz, Péter Kovács, Gitta Pánczél & Gabriella Liszkay

  2. Department of Surgical and Molecular Pathology, National Institute of Oncology, Budapest, Hungary

    Andrea Ladányi, Eszter Bence & Vanda Plótár

  3. Center of Radiotherapy, National Institute of Oncology, Budapest, Hungary

    Georgina Fröhlich

Authors
  1. Tímea Balatoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Ladányi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georgina Fröhlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kata Czirbesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Péter Kovács
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gitta Pánczél
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eszter Bence
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vanda Plótár
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gabriella Liszkay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tímea Balatoni.

Ethics declarations

Conflicts of Interest

Tímea Balatoni has received speaker honoraria and financial support for attending symposia from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD), Novartis, and Roche. Gabriella Liszkay is on the advisory board and has received honoraria for speaking at conferences as well as financial support for educational programs from Bristol-Myers Squibb, GlaxoSmithKline, MSD, Novartis, and Roche. Gitta Pánczél and Kata Czirbesz has received speaker honoraria from Bristol-Myers Squibb, MSD, Novartis, and Roche. All other authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Balatoni, T., Ladányi, A., Fröhlich, G. et al. Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab. Pathol. Oncol. Res. 26, 317–325 (2020). https://doi.org/10.1007/s12253-018-0466-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-018-0466-9

Keywords

Search

Navigation