Muhlis Cem AR, Teoman SOYSAL, Ayşe SALİHOĞLU, Hafize UZUN, Zafer BAŞLAR, Tuğrul ELVERDİ, Ahmet Emre EŞKAZAN, Şeniz ÖNGÖREN, Sinem Nihal ESATOĞLU, Dilek KESKİN, Yıldız AYDIN

The prognostic value of serum levels of a proliferation-inducing ligand (APRIL) in treatment-naïve patients with chronic lymphocytic leukemia

Background/aim: A proliferation-inducing ligand (APRIL) has been investigated as a prognostic marker in chronic lymphocytic leukemia (CLL) patients. However, there is no cut-off level for serum APRIL (sAPRIL) levels that predict time to treatment in CLL patients. Materials and methods: Between May and December 2012, 94 consecutive CLL patients and 25 healthy controls were assessed. sAPRIL levels were measured by ELISA. Demographic data and prognostic markers were obtained from the patients’ files. Treatment-naïve patients were followed up for 6.5 years for any treatment need. Results: Patients were divided into 3 groups: Treatment-naïve (n = 47), chemotherapy receiving (n = 25), and those who had received chemotherapy previously (n = 22). There was no difference in median sAPRIL levels of patients who were receiving chemotherapy at the sampling time and the healthy controls, which indicates that sAPRIL levels might be influenced by treatment. For treatment-naïve patients, the best cut-off in predicting time to treatment was found at the sAPRIL level of 2.04 ng/mL, with 78% sensitivity and 63% specificity. Time to treatment was significantly earlier in the APRIL high group (n = 27) than in the APRIL low group (n = 20) (P = 0.010, log-rank test). Conclusion: sAPRIL, a simple, promising blood test which can be measured by ELISA, will likely obtain a place in the wide range of prognostic markers in CLL. Prospective large-scale studies are required to validate and confirm the feasibility of the proposed cut-off level of 2.04 ng/mL as a predictor of time to treatment in treatment-naïve CLL patients.Key words: Chronic lymphocytic leukemia, treatment, survival, prognosis, chemotherapy

PDF

___

1. Hodgson K, Ferrer G, Montserrat E, Moreno C. Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica 2011; 96 (5): 752-761. doi:10.3324/ haematol.2010.036152
2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111 (12): 5446-5456. doi: 10.1182/ blood-2007-06-093906
3. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46 (2): 219-234. doi: 10.1182/blood.V46.2.219.219
4. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48 (1): 198-206. doi: 10.1002/1097-0142(19810701)48:1<198::aidcncr2820480131>3.0.co;2-v
5. Parikh SA, Shanafelt TD. Prognostic factors and risk stratification in chronic lymphocytic leukemia. Seminars in Oncology 2016; 43 (2): 233-240. doi: 10.1053/j. seminoncol.2016.02.009
6. Rossi D, Gerber B, Stussi G. Predictive and prognostic biomarkers in the era of new targeted therapies for chronic lymphocytic leukemia. Leukemia&Lymphoma 2017; 58 (7): 1548-1560. doi: 10.1080/10428194.2016.1250264
7. Hahne M, Kataoka T, Schroter M, Hofmann K, Irmler M et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. Journal of Experimental Medicine 1998; 188 (6): 1185-1190. doi: 10.1084/jem.188.6.1185
8. Nishio M, Endo T, Tsukada N, Ohata J, Kitada S et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha. Blood 2005; 106 (3): 1012- 1020. doi: 10.1182/blood-2004-03-0889
9. Planelles L, Carvalho-Pinto CE, Hardenberg G, Smaniotto S, Savino W et al. APRIL promotes B-1 cell-associated neoplasm. Cancer Cell 2004; 6 (4): 399-408. doi: 10.1016/j.ccr.2004.08.033
10. Tecchio C, Nichele I, Mosna F, Zampieri F, Leso A et al. A proliferation-inducing ligand (APRIL) serum levels predict time to first treatment in patients affected by B-cell chronic lymphocytic leukemia. European Journal of Haematology 2011; 87 (3): 228-234. doi: 10.1111/j.1600-0609.2011.01650.x
11. Ferrer G, Hodgson K, Pereira A, Juan M, Elena M et al. Combined analysis of levels of serum B-cell activating factor and a proliferation-inducing ligand as predictor of disease progression in patients with chronic lymphocytic leukemia. Leukemia&Lymphoma 2011; 52 (11): 2064-2068. doi: 10.3109/10428194.2011.591008
12. Planelles L, Castillo-Gutierrez S, Medema JP, Morales-Luque A, Merle-Beral H et al. APRIL but not BLyS serum levels are increased in chronic lymphocytic leukemia: prognostic relevance of APRIL for survival. Haematologica 2007; 92 (9): 1284-1285. doi: 10.3324/haematol.10317
13. Bojarska-Junak A, Hus I, Chocholska S, Wasik-Szczepanek E, Sieklucka M et al. BAFF and APRIL expression in B-cell chronic lymphocytic leukemia: correlation with biological and clinical features. Leukemia Research 2009; 33 (10): 1319-1327. doi: 10.1016/j.leukres.2009.03.030
14. Hallek M. Prognostic factors in chronic lymphocytic leukemia. Annals of Oncology 2008; 19 (Supplement 4): 51-53. doi: 10.1093/annonc/mdn196