Kronik Lenfositik Lösemide PD-1/PD-L1 Ekspresyon Düzeyleri ve Prognostik Önemi

Ayfer Gedük; Özgür Mehtap; Elif Birtaş Ateşoğlu; Pinar Tarkun; Esra Terzi Demirsoy; Meral Uluköylü Mengüç; Serkan Ünal; Sinan Mersin; Abdullah Hacıhanefioğlu; Tülin Burhanoğlu; Gülçin Gacar

doi:10.31067/acusaglik.850893

Research Article

Kronik Lenfositik Lösemide PD-1/PD-L1 Ekspresyon Düzeyleri ve Prognostik Önemi

Year 2021, Volume: 12 Issue: 2, 197 - 203, 01.04.2021

Ayfer Gedük Özgür Mehtap , Elif Birtaş Ateşoğlu Pinar Tarkun , Esra Terzi Demirsoy , Meral Uluköylü Mengüç Serkan Ünal , Sinan Mersin Abdullah Hacıhanefioğlu Tülin Burhanoğlu Gülçin Gacar

https://doi.org/10.31067/acusaglik.850893

Abstract

Amaç:Çalışmamızda, kronik lenfositik lösemide (KLL) programlı hücre ölümü 1 (PD-1) ve programlı hücre ölümü ligandı 1 (PD-L1) ekspresyon düzeylerinin belirlenmesi ve prognoz üzerine etkilerinin değerlendirilmesi amaçlandı.
Hastalar ve Yöntem:Kliniğimizde takip edilmiş ve tanı anında periferik kandan akım sitometrisi çalışılmış 92 hasta bu çalışmaya dahil edildi. Lenfositlerde %20 ve üzeri hücrede PD-1/PD-L1 boyanma varlığı pozitif olarak kabul edildi
Bulgular:Hastaların ortanca takip süresi 31 (1-114) aydı. PD-1 pozitifliği hastaların 44’ünde (%47.8), PD-L1 pozitifliği ise 8’inde (%8.7) tespit edildi. Tüm kohortta ortalama PD-1 düzeyi %22.13±15.39, PD-L1 düzeyi ise %8.4±13.12 olarak saptandı. Ortanca genel sağkalıma ulaşılamamış olmakla birlikte 60. ayda PD-1 pozitif hastaların %69.1’i hayattayken, PD-1 negatif grupta bu oran %79’du (p=0.723). Yine 60. ayda PD-L1 pozitif hastaların %75’i hayattayken, PD-L1 negatif grupta bu oran %73.6’ydı (p=0.849). PD-1 negatif grupta ilk dizi tedavi sonrası kısmi yanıt ve üstü 18 (%85.7) hastada mevcutken, PD-1 pozitif grupta 10 (%71.4) hastada mevcuttu (p=0.401). Ortanca progresyonsuz sağkalım, PD-1 pozitif grupta 16 ay [ %95 GA,10.68-21.31] iken PD-1 negatif grupta 18 ay [%95 GA, 5.23-30.76] olarak tespit edildi (p=0.432). PD-1 pozitif hastalarda ikinci dizi tedaviye geçiş süresi 2 (0-25) ay iken, PD-1 negatif hastalarda 7 (0-80) ay olarak tespit edildi (p=0.372).
Sonuç:KLL’de periferik kanda lenfositler üzerinde PD-1 ekspresyonu tespit edilmiş olup PD-L1 ekspresyon düzeyi oldukça düşük düzeyde saptandı. PD-1 ve PD-L1 pozitifliğinin prognoz üzerinde net bir etkisi gözlemlenmedi

Keywords

programlı hücre ölümü 1, programlı hücre ölümü ligandı 1, kronik lenfositik lösemi

References

1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804-15.
2. Milne K, Sturrock B, Chevassut T. Chronic Lymphocytic Leukaemia in 2020: the Future Has Arrived. Curr Oncol Rep. 2020;22:36.
3. Rawstron AC, Kreuzer KA, Soosapilla A, Spacek M, Stehlikova O, Gambell P, et al. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project. Cytometry B Clin Cytom. 2018;94:121-8.
4. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 ;12:252-64.
5. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-9.
6. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027-34.
7. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-8.
8. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.
9. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007 Jul;19(7):813-24.
10. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44.
11. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF,et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54.
12. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-35.
13. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC,Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-9.
14. Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129:3419-27.
15. Brusa D, Serra S, Coscia M, Rossi D, D'Arena G, Laurenti L, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013;98:953-63.
16. Rusak M, Eljaszewicz A, Bołkun Ł, Łuksza E, Łapuć I, Piszcz J, et al. Prognostic significance of PD-1 expression on peripheral blood CD4+ T cells in patients with newly diagnosed chronic lymphocytic leukemia. Pol Arch Med Wewn. 2015;125:553-9.
17. Xerri L,Chetaille B, Serriari N, Attias C, Guillaume Y, Arnoulet C, et al. Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Hum Pathol. 2008 ;39:1050-8.
18. Grzywnowicz M, Zaleska J, Mertens D, Tomczak W, Wlasiuk P, Kosior K, et al. Programmed death-1 and its ligand are novel immunotolerant molecules expressed on leukemic B cells in chronic lymphocytic leukemia. PLoS One. 2012;7(4):e35178.
19. Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012;12:1412-21.
20. Menter T, Bodmer-Haecki A, Dirnhofer S, Tzankov A. Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas. Hum Pathol. 2016;54:17-24.
21. Panjwani PK, Charu V, DeLisser M, Molina-Kirsch H, Natkunam Y, Zhao S.Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum Pathol. 2018 ;71:91-9.
22. Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126:2193-201.
23. Zhang W, Bai JF, Zuo MX, Cao XX, Chen M, Zhang Y, et al.PD-1 expression on the surface of peripheral blood CD4(+) T cell and its association with the prognosis of patients with diffuse large B-cell lymphoma. Cancer Med. 2016;5:3077-84.
24. Keane C, Vari F, Hertzberg M, Cao KA, Green MR, Han E, et al. Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: a population-based study. Lancet Haematol. 2015;2:e445-55.
25. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomark Res. 2017;5:12.
26. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064-74.
27. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563-7.
28. Daud AI, Wolchok JD, Robert C, Hwu WJ, Weber JS, Ribas A, et al. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. J Clin Oncol. 2016;34:4102-9.
29. Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, et al. Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia. Asian Pac J Cancer Prev. 2017;18:2269-74.
30. Novák M, Procházka V, Turcsányi P, Papajík T. Numbers of CD8+PD-1+ and CD4+PD-1+ Cells in Peripheral Blood of Patients with Chronic Lymphocytic Leukemia Are Independent of Binet Stage and Are Significantly Higher Compared to Healthy Volunteers. Acta Haematol. 2015;134:208-14.
31. Grzywnowicz M, Karczmarczyk A, Skorka K, Zajac M, Zaleska J, Chocholska S, et al. Expression of Programmed Death 1 Ligand in Different Compartments of Chronic Lymphocytic Leukemia. Acta Haematol. 2015;134:255-62.
32. Grzywnowicz M, Karabon L, Karczmarczyk A, Zajac M, Skorka K, Zaleska J, et al. The function of a novel immunophenotype candidate molecule PD-1 in chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56:2908-13.
33. Korkmaz S, Erdem S, Akay E, Taşdemir EA, Karaman H, Keklik M. Do PD-1 and PD-L2 expressions have prognostic impact in hematologic malignancies? Turk J Med Sci. 2019;49:265-271.

PD-1/PD-L1 Expression Levels and Prognostic Significance in Chronic Lymphocytic Leukemia

Year 2021, Volume: 12 Issue: 2, 197 - 203, 01.04.2021

https://doi.org/10.31067/acusaglik.850893

Abstract

Purpose:In this study, we aimed to evaluate expression levels of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) and the effects on prognosis in chronic lymphocytic leukemia (CLL).
Patients and Methods:92 patients who had flow cytometry from peripheral blood at the time of diagnosis were included in this study. The presence of PD-1/PD-L1 staining in 20% and above in lymphocytes was considered positive.
Results:Median follow-up was 31 (1-114) months. PD-1 positivity was detected in 44 (47.8%), and PD-L1 positivity in 8 (8.7%) patients. The mean PD-1 level was 22.13% ± 15.39, and PD-L1 level was 8.4% ± 13.12 in all cohort. Overall survival rates were 69.1% in PD-1+ vs 79% in PD-1- groups and 75% in PD-L1+ vs 73.6% in the PD-L1- group in the 60th month (p=0.723, p=0.849 respectively). After first line treatment, partial response or better was observed in 18 (85.7%) patients in the PD-1- group and in 10 (71.4%) patients in the PD-1+ group (p=0.401). Median progression-free survival was 16 months [95% CI, 10.68-21.31] in the PD-1+ group, and 18 months [95% CI, 5.23-30.76] in the PD-1- group (p=0.432). In PD-1+ patients, time to next treatment was 2 (0-25) months, while in PD-1- patients it was determined as 7 (0-80) months (p=0.372).
Conclusion:PD-1 expression was detected on lymphocytes in peripheral blood in CLL, however PD-L1 expression level was quite low. There was no clear effect of PD-1 and PD-L1 positivity on prognosis

Keywords

programmed cell death 1, programmed cell death ligand 1, chronic lymphocytic leukemia

References

1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804-15.
2. Milne K, Sturrock B, Chevassut T. Chronic Lymphocytic Leukaemia in 2020: the Future Has Arrived. Curr Oncol Rep. 2020;22:36.
3. Rawstron AC, Kreuzer KA, Soosapilla A, Spacek M, Stehlikova O, Gambell P, et al. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project. Cytometry B Clin Cytom. 2018;94:121-8.
4. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 ;12:252-64.
5. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-9.
6. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027-34.
7. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-8.
8. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.
9. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007 Jul;19(7):813-24.
10. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44.
11. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF,et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54.
12. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-35.
13. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC,Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-9.
14. Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129:3419-27.
15. Brusa D, Serra S, Coscia M, Rossi D, D'Arena G, Laurenti L, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013;98:953-63.
16. Rusak M, Eljaszewicz A, Bołkun Ł, Łuksza E, Łapuć I, Piszcz J, et al. Prognostic significance of PD-1 expression on peripheral blood CD4+ T cells in patients with newly diagnosed chronic lymphocytic leukemia. Pol Arch Med Wewn. 2015;125:553-9.
17. Xerri L,Chetaille B, Serriari N, Attias C, Guillaume Y, Arnoulet C, et al. Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Hum Pathol. 2008 ;39:1050-8.
18. Grzywnowicz M, Zaleska J, Mertens D, Tomczak W, Wlasiuk P, Kosior K, et al. Programmed death-1 and its ligand are novel immunotolerant molecules expressed on leukemic B cells in chronic lymphocytic leukemia. PLoS One. 2012;7(4):e35178.
19. Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012;12:1412-21.
20. Menter T, Bodmer-Haecki A, Dirnhofer S, Tzankov A. Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas. Hum Pathol. 2016;54:17-24.
21. Panjwani PK, Charu V, DeLisser M, Molina-Kirsch H, Natkunam Y, Zhao S.Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum Pathol. 2018 ;71:91-9.
22. Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126:2193-201.
23. Zhang W, Bai JF, Zuo MX, Cao XX, Chen M, Zhang Y, et al.PD-1 expression on the surface of peripheral blood CD4(+) T cell and its association with the prognosis of patients with diffuse large B-cell lymphoma. Cancer Med. 2016;5:3077-84.
24. Keane C, Vari F, Hertzberg M, Cao KA, Green MR, Han E, et al. Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: a population-based study. Lancet Haematol. 2015;2:e445-55.
25. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomark Res. 2017;5:12.
26. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064-74.
27. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563-7.
28. Daud AI, Wolchok JD, Robert C, Hwu WJ, Weber JS, Ribas A, et al. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. J Clin Oncol. 2016;34:4102-9.
29. Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, et al. Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia. Asian Pac J Cancer Prev. 2017;18:2269-74.
30. Novák M, Procházka V, Turcsányi P, Papajík T. Numbers of CD8+PD-1+ and CD4+PD-1+ Cells in Peripheral Blood of Patients with Chronic Lymphocytic Leukemia Are Independent of Binet Stage and Are Significantly Higher Compared to Healthy Volunteers. Acta Haematol. 2015;134:208-14.
31. Grzywnowicz M, Karczmarczyk A, Skorka K, Zajac M, Zaleska J, Chocholska S, et al. Expression of Programmed Death 1 Ligand in Different Compartments of Chronic Lymphocytic Leukemia. Acta Haematol. 2015;134:255-62.
32. Grzywnowicz M, Karabon L, Karczmarczyk A, Zajac M, Skorka K, Zaleska J, et al. The function of a novel immunophenotype candidate molecule PD-1 in chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56:2908-13.
33. Korkmaz S, Erdem S, Akay E, Taşdemir EA, Karaman H, Keklik M. Do PD-1 and PD-L2 expressions have prognostic impact in hematologic malignancies? Turk J Med Sci. 2019;49:265-271.

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Details

Primary Language	Turkish
Subjects	Internal Diseases
Journal Section	Research Articles
Authors	Ayfer Gedük Özgür Mehtap Elif Birtaş Ateşoğlu Pinar Tarkun Esra Terzi Demirsoy Meral Uluköylü Mengüç Serkan Ünal Sinan Mersin Abdullah Hacıhanefioğlu Tülin Burhanoğlu Gülçin Gacar
Publication Date	April 1, 2021
Submission Date	April 17, 2020
Published in Issue	Year 2021Volume: 12 Issue: 2

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EndNote	Gedük A, Mehtap Ö, Ateşoğlu EB, Tarkun P, Terzi Demirsoy E, Uluköylü Mengüç M, Ünal S, Mersin S, Hacıhanefioğlu A, Burhanoğlu T, Gacar G (April 1, 2021) Kronik Lenfositik Lösemide PD-1/PD-L1 Ekspresyon Düzeyleri ve Prognostik Önemi. Acıbadem Üniversitesi Sağlık Bilimleri Dergisi 12 2 197–203.

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