Arbil AÇIKALIN, Emine KILIÇ BAĞIR, Semra PAYDAŞ, Perihan ALSANCAK, Melek ERGİN

Multiple myelomda kromozomal aberasyonlar: klinik sonuçlar ve bortezomib’ e yanıt

Amaç:Multiple myelom heterojen bir hastalık olup, en etkin tedavinin planlanlanabilmesi için kromozomal aberasyonların prognostic ve prediktif değerlerinin anlaşılması önemlidir. Bu çalışmada kurumumuzda tanı almış hastaların kromozomal aberasyonlarının sıklığını ve tedavi seçenekleri ile arasındaki ilişkiyi araştırmayı amaçladık. Gereç ve Yöntem:Ocak 2010 ve Aralık 2015 tarihleri arasında kurumumuzda tanı almış multiple myelomlu hastalarda, interfaz-floresan in situ hibridizasyon yöntemi ile del(17p13), del(13q14), t(11;14), and t(4;14) kromozomal aberasyonlarının sıklığını araştırdık. Bu sonuçların, konvansiyonel kemoterapi alan hastalar ile bortezomib tabanlı kemoterapi alan hastalardaki yanıtlarını karşılaştırdık. Bulgular:Seksen hastada (%72.7) en az bir adet kromozomal aberasyon saptandı. En sık saptanan aberasyon del(17p13) (%48.2) idi. Bunu sırasıyla del(13q14) (%40.9), t(11;14) (%16.4), ve t(4;14) (%11.8) takip etmekteydi. Klinik bulgularına ulaşılabilen 67 hastalık grupta, Bortezomib tabanlı kemoterapi alan 36 hastanın tedaviye yanıt oranı (%55.6) konvansiyonel kemoterapi alan gruba oranla (%48.4) daha yüksek idi. Kromozomal aberasyonlar ile karşılaştırıldığında; del (17p13) saptanan hastaların Bortezomib tabanlı kemoterapiye yanıtları (%63.2), konvansiyonel kemoterapi alanlardan (%50) daha yüksek saptandı. Benzer şonuç; del (13q14) saptanan hastalarda da gözlendi (Bortezomib alanlarda %61.5, konvansiyonel kemoterapi alanlarda %50). Sonuç: Bortezomib içeren tedaviler özellikle del (17p13) ve del (13q14) aberayonu saptanan hastalarda daha iyi sonuç vermektedir.

Anahtar Kelimeler:

bortezomib, kromozomal aberasyon, multiple myeloma

Chromosomal aberrations in multiple myeloma: clinical outcome and response to bortezomib.

Purpose: Multiple myeloma is a heterogeneous disease, for which an understanding of the prognostic and predictive value of chromosomal aberrations is necessary to prescribe the most appropriate therapy. We aimed to document the frequencies of chromosomal aberrations in our institute and searched the relationships between therapy regimens and chromosomal aberrations. Materials and methods: We analyzed the frequency of del(17p13), del(13q14), t(11;14), and t(4;14) in patients with MM by interphase-fluorescent in situ hybridization who were diagnosed between January 2010 and December 2015 in our institute. We researched the relationship between response to conventional chemotherapy and Bortezomib based chemotherapy.Results: Eighty patients (72.7%) had at least one chromosomal aberration. The most frequently observed aberration was del(17p13) (48.2%), followed by del(13q14) (40.9%), t(11;14) (16.4%), and t(4;14) (11.8%). In clinically analyzed subgroup (n=67), 36 patients who received Bortezomib based chemotherapy showed a higher response rate (55.6%) than conventional chemotherapy group (48.4%). With respect to chromosomal aberrations, response rates were higher in Bortezomib based therapy group (63.2%) than conventional chemotherapy group (50%) in del (17p13) positive patients as well as in del (13q14) positive patients (61.5% in Bortezomib based, 50% in conventional chemotherapy group). Conclusion: Bortezomib-containing regimens may have beneficial effects on the clinical outcome of patients with del (17p13) and del (13q14).

Keywords:

bortezomib, chromosomal aberration, multiple myeloma,

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Referans1. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H et al. WHO classification of tumours of haematopoietic and lymphoid tissues. France: IARC press; 2008.Referans2. Gmidene A, Avet-Loiseau H, Sennana H, Ben Abdallah I, Khlif A, Meddeb B, Elloumi M, et al. Molecular cytogenetic aberrations in Tunisian patients with multiple myeloma identified by cIg-FISH in fixed bone marrow cells. Cytogenet Genome Res 2012, 136:44-49.Referans3. Gao X, Li C, Zhang R, Yang R, Qu X, Qiu H, et al. Fluorescence in situ hybridization analysis of chromosome aberrations in 60 Chinese patients with multiple myeloma. Med Oncol 2012, 29:2200-2206.Referans4. Seidl S, Kaufmann H, Drach J: New insights into the pathophysiology of multiple myeloma. Lancet Oncology 2003, 4:557-564.Referans5. Avet-Loiseau H, Malard F, Campion L, Magrangeas F, Sebban C, Lioure B, et al. Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor? Blood 2011, 117:2009-2011.Referans6. Soverini S, Cavo M, Cellini C, Terragna C, Zamagni E, Ruggeri D, et al. Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation. Blood 2003, 102:1588-1594.Referans7. Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ, et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 2005, 106:2837-2840.Referans8. Segges P, Braggio E: Genetic markers used for risk stratification in multiple myeloma. Genet Res Int 2011, 2011:798089.Referans9. Terpos E, Eleutherakis-Papaiakovou V, Dimopoulos MA: Clinical implications of chromosomal abnormalities in multiple myeloma. Leukemia & Lymphoma 2006, 47:803-814.Referans10. Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL, et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 2002, 100:1579-1583.Referans11. Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ, et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 2003, 101:1520-1529.Referans12. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009, 23:2210-2221.Referans13. Hu Y, Chen L, Sun CY, She XM, Ai LS, Qin Y: Clinical significance of chromosomal abnormalities detected by interphase fluorescence in situ hybridization in newly diagnosed multiple myeloma patients. Chin Med J (Engl) 2011, 124:2981-2985.Referans14. He J, Yang L, Meng X, Wei G, Wu W, Han X, et al. A retrospective analysis of cytogenetic and clinical characteristics in patients with multiple myeloma. Am J Med Sci 2013, 345:88-93.Referans15. Durak BA, Akay OM, Sungar G, Bademci G, Aslan V, Caferler J, et al. Conventional and molecular cytogenetic analyses in Turkish patients with multiple myeloma. Turk J Haematol 2012, 29:135-142.Referans16. Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 2010, 28:4630-4634.Referans17. Chang H, Yeung J, Qi C, Xu W: Aberrant nuclear p53 protein expression detected by immunohistochemistry is associated with hemizygous P53 deletion and poor survival for multiple myeloma. Br J Haematol 2007, 138:324-329.Referans18. Yuregir OO, Sahin FI, Yilmaz Z, Kizilkilic E, Karakus S, Ozdogu H: Fluorescent in situ hybridization studies in multiple myeloma. Hematology 2009, 14:90-94.Referans19. Zojer N, Konigsberg R, Ackermann J, Fritz E, Dallinger S, Kromer E, et al. Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 2000, 95:1925-1930.Referans20. Kroger N, Schilling G, Einsele H, Liebisch P, Shimoni A, Nagler A, et al. Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation. Blood 2004, 103:4056-4061.Referans21. Shaughnessy J, Jr., Tian E, Sawyer J, McCoy J, Tricot G, Jacobson J, et al. Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol 2003, 120:44-52.Referans22. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008, 359:906-917.Referans23. Romano A, Conticello C, Di Raimondo F: Bortezomib for the treatment of previously untreated multiple myeloma. Immunotherapy 2013, 5:327-352.Referans24. Sonneveld P, Goldschmidt H, Rosinol L, Blade J, Lahuerta JJ, Cavo M, et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol 2013, 31:3279-3287.Referans25. Yang G, Chen W, Wu Y: Bortezomib, dexamethasone plus thalidomide for treatment of newly diagnosed multiple myeloma patients with or without renal impairment. Chin J Cancer Res 2013, 25:155-160.Referans26. Zeng Z, Lin J, Chen J: Bortezomib for patients with previously untreated multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. Ann Hematol 2013, 92:935-943.Referans27. Zou Y, Lin M, Sheng Z, Niu S: Bortezomib and lenalidomide as front-line therapy for multiple myeloma. Leuk Lymphoma 2013.Referans28. Jiang A, Reece D, Chang H: Genomic stratification of multiple myeloma treated with novel agents. Leuk Lymphoma 2012, 53:202-207.Referans29. Richardson PG, Xie WL, Mitsiades C, Chanan-Khan AA, Lonial S, Hassoun H, et al. Single-Agent Bortezomib in Previously Untreated Multiple Myeloma: Efficacy, Characterization of Peripheral Neuropathy, and Molecular Correlations With Response and Neuropathy. Journal of Clinical Oncology 2009, 27:3518-3525.Referans30. Shaughnessy JD, Zhou YM, Haessler J, van Rhee F, Anaissie E, Nair B, et al. TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3. British Journal of Haematology 2009, 147:347-351.