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Клинические особенности и терапия double-hit и double-expressor лимфом
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Baryakh E.A., Misyurina A.E., Kovriginab A.M. et al. Clinical features and therapy of double-hit and double-expressor lymphomas. Journal of Modern Oncology. 2017; 19 (5): 22–30.
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Материалы и методы. В анализ включены 85 больных: 45 мужчин и 40 женщин, с медианой возраста 46,6 (15–73) года. Всего 62 пациента с диффузной В-крупноклеточной лимфомой (ДВККЛ) и 23 – с В-клеточной лимфомой неклассифицируемой (ВЛН), получавших терапию по протоколам ЛБ-М-04/m-NHL-BFM-90 в ФГБУ ГНЦ и ГБУЗ ГКБ №52 с 2001 по 2015 г.
Результаты. I стадия диагностирована у 5 (6%) пациентов, II – у 13 (15%), III – у 7 (8%), IV – у 60 (71%). Double-hit лимфома диагностирована у 6 (7%) больных (5 MYC+/BCL2+, 1 MYC+/BCL6+), single-hit лимфома выявлена в 6 случаях. В 5/12 случаях выявлена транслокация t(8;14)(q24;q32), в 1/12 – t(2;8)(p21;q24), в 2/12 – t(8;22)(q24;q11) – выявлены перестройки локусов генов c-MYC и IGL, в 3/12 – перестройка с-MYC с не-IG-партнером [отсутствовала транслокация t(8;14)(q24;q32) и перестройки локусов генов IGK и IGL], в 1 случае транслокации с участием гена c-MYC партнер не уточнен [выявлена перестройка гена c-MYC при отсутствии транслокации t(8;14(q24;q32)]. Прогностическую значимость в отношении общей выживаемости имели 8 факторов: нозология – ВЛН vs ДВККЛ (р=0,007; относительный риск – ОР 4,5), поражение костного мозга (р=0,0004; ОР 7,9), наличие В-симптомов (р=0,0002; ОР 8,4), экспрессия BCL2 (р=0,01; ОР 4,4), коэкспрессия MYC/BCL2 (р=0,017; ОР 0,08), наличие double-hit или double-expressor лимфомы (р=0,009; ОР 15,1), отсутствие в терапии ритуксимаба (р=0,03; ОР 0,3), невыполнение аутологичной трансплантации гемопоэтических стволовых клеток – аутоТГСК (р=0,003; ОР 0,06). В отношении вероятности развития рецидива/прогрессирования значимыми оказались 2 фактора: double-hit или double-expressor лимфома (р=0,0005; ОР 4,0) и международный прогностический индекс (р=0,03; ОР 4,9).
Выводы. Таким образом, комплексная диагностика, включающая, помимо стандартно рекомендуемой иммуногистохимической панели для агрессивных В-клеточных лимфом, антитела к BCL2 (клон 124, Dako) и MYC (клон Y69, Epitomics), выполнение стандартного цитогенетического исследования и FISH для выявления перестроек генов MYC, BCL2 и BCL6, позволяет не только установить правильный диагноз (ДВККЛ, ВЛН или лимфома Беркитта), но и выделить double-hit и double-expressor лимфомы, требующие проведения интенсивной индукции с включением ритуксимаба и высокодозной консолидации с аутоТГСК в первой ремиссии.
Ключевые слова: диффузная B-крупноклеточная лимфома, double-hit лимфома, double-expresser лимфома, В-клеточная лимфома неклассифицируемая, занимающая промежуточное положение между диффузной В-крупноклеточной лимфомой и лимфомой Беркитта, взрослые, лечение, факторы прогноза.
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Purpose. The identifying of the clinical, morphological, immunophenotypic and cytogenetic features of double-hit and double-expressor lymphomas as well as the development of optimal tactics of treatment and evaluation of efficiency of the ASCT were the main purposes of the study.
Material and methods. The study included 85 patients: 45 males and 40 females, the median was 46,6 years (15–73). 62 patients with DLBCL and 23 with BCLu were given BL-М-04/ m-NHL-BFM-90 regimes in Hematological Scientific Center and Municipal Clinical Hospital №52, 2001–2015.
Results. Stage I was diagnosed in 5 (6%) patients, II – in 13 (15%) patients, III – in 7 (8%) patients, IV – in 60 (71%) patients. Double-hit lymphoma was diagnosed in 6 (7%) patients (5 MYC+/BCL2+, 1 MYC+/BCL6+), single-hit lymphoma was diagnosed in 6 patients. The translocation was detected in 5 of 12 cases t(8;14)(q24;q32), in 1 case of 12 – t(2;8)(p21;q24), in 2 cases of 12 – t(8;22)(q24;q11) (restructuring c-MYC and IGL gene loci have been identified), in 3 cases of 12 – restructuring of с-MYC with non-IG partner [translocation was absent t(8;14)(q24;q32) and restructuring IGK and IGL gene loci], the partner was not identified in one case of translocation with c-MYC gene [restructuring c-MYC gene loci was identified and translocation was absent t(8;14(q24;q32)]. 8 factors had prognostic significance in relation to OS: nosology – BCLu vs DLBCL (р=0.007; RR=4.5), bone marrow lesion (р=0.0004; RR=7.9), B-symptoms (р=0.0002; RR=8.4), BCL2 ex * pression (I=0.01; RR=4.4), MYC/BCL2 coex * pression (р=0.017; RR=0.08), double-hit or double-expressor lymphomas (р=0.009; RR=15.1), the absence of rituximab in therapy (р=0.03; RR=0.3), unfulfillment of ASCT (р=0.003; RR=0.06). Two factors were significant in relation to probability of development of recurrence/progression: double-hit or double-expressor lymphomas (р=0.0005; RR=4.0) and IPI (р=0.03; RR=4.9).
Conclusions. Thus, complex diagnostic includes the antibody to the BCL2 (clone 124, Dako) and MYC (clone Y69, Epitomics), and the conduct of standard cytogenetic analysis (SCA) and FISH to detect rearrangements of MYC, BCL2, and BCL6 genes in addition to standard immunohistochemical panel for aggressive B-cell lymphomas. It allows not only to establish the correct diagnosis (DLBCL, BCLu or LB), but also to detect the double-hit and double-expressor lymphomas, which require intensive induction with rituximab and high-consolidation ASCT in first remission.
Key words: diffuse large B-cell lymphoma, double-hit lymphoma, double-expresser-lymphoma, B-cell lymphoma unclassified, lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, adults, treatment, prognostic factors.
2. Subar M, Neri A, Inghirami G et al. Frequent c-myc oncogne activation and infrequent presense of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood 1988; 72: 667–71.
3. Johnson NA, Savage KJ, Ludkovski O et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009; 114: 2273–9.
4. Le Gouill S, Talmant P, Touzeau C et al. The clinical presentation and prognosis of diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC rearrangement. Haematologica 2007; 92: 1335–42.
5. Petrich AM, Gandhi M, Jovanovic B et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood 2014; 124 (15): 2354–61.
6. Greenwood M, Armytage T, Fay K. Outcomes of allogeneic stem cell transplantation for non-Hodgkin lymphoma with concurrent MYC and BCL2 translocations: a single center retrospective analysis. Hematol Oncol 2013; 3 (Suppl. 1): 103.
7. Kanungo A, Medeiros LJ, Abruzzo LV, Lin P. Lymphoid neoplasms associated with concurrent t(14;18) and 8q24/c-MYC translocation generally have a poor prognosis. Modern Pathology 2006; 19: 25–33.
8. Tomita N, Tokunaka M, Nakamura N et al. Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations. Haematologica 2009; 94 (7): 935–43.
9. Li S, Lin P, Fayad LE et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol 2012; 25 (1): 145–56.
10. Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations. Leukemia 2009; 23: 777–83.
11. Snuderl M, Kolman OK, Chen YB et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol 2010; 34 (3): 327–40.
12. Oki Y, Noorani M, Davis RE et al. Double hit lymphoma: M.D.Anderson Experince. Blood 2013; 122 (21): 1776.
13. Sun H, Savage K, Karsan A. Outcome of patients wits double-hit lymphomas treated with CODOX-M/IVAC + R followed by hematopoietic stem cell transplantation in British Columbia. Blood 2013; 122 (21): 1788.
14. Leucci E, Cocco M, Onnis A et al. MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation J Pathol 2008; 216 (4): 440–50.
15. Onnis A, De Falco G, Antonicelli G et al. Аlteration of microRNAs regulated by c-MYC in Burkitt lymphoma. PLoS One 2010; 5 (9): pii: e12960.
16. Tzankov A, Xu-Monette ZY, Gerhard MV et al. Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Mod Pathol 2014; 27 (7): 958–71.
17. Valera A, López-Guillermo A, Cardesa-Salzmann T et al. Grup per l’Estudi dels Limfomes de Catalunya i Balears (GELCAB). MYC Protein Expression And Genetic Alterations Have Prognostic Impact In Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy. Haematologica 2013; 98 (10): 1554–62.
18. Green TM, Nielsen O, de SK et al. High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma. Am J Surg Pathol 2012; 36 (4): 612–9.
19. Horn H, Ziepert M, Becher C et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 2013; 121 (12): 2253–63.
20. Perry AM, Alvarado-Bernal Y, Laurini JA. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol 2014; 165 (3): 382–91.
21. Dunleavy K, Pittaluga S, Shovlin M et al. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med 2013; 369 (20): 1915–25.
22. Hu S, Xu-Monette ZY, Tzankov A et al. MYC/BCL2 protein co-expression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Study. Blood 2013; 121 (20): 4021–31.
23. Green TM et al, MD Аndersen Cancer Center, 2012. Immunohistochemical detection of MYC protein correlates with MYC gene status in aggressive B-cell lymphoma. Histopathology 2011; 59 (4): 678–8.
24. Scott DW, Mottok AM, Ennishi D et al. Cell-of-Origin Assignement in Diffuse Large B-cell Lymphoma Determined By Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Has Prognostic Significance Independent of IPI and MYC/BCL2 Immunohistochemistry. 56th ASH Annual Meeting and Exposition. Abstract book 2014; 124 (21): 1624.
25. Аль-Ради Л.С., Барях Е.А., Белоусова И.Э. и др. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Современная Онкология. 2013; 15 (5): 9–10. / Al'-Radi L.S., Bariakh E.A., Belousova I.E. i dr. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniiu limfoproliferativnykh zabolevanii. Journal of Modern Oncology. 2013; 15 (5): 9–10. [in Russian]
26. Мисюрина А.Е. Экспрессия MYC и BCL2 у больных диффузной В-крупноклеточной лимфомой. Дис. … канд. мед. наук. М., 2015. / Misiurina A.E. Ekspressiia MYC i BCL2 u bol'nykh diffuznoi V-krupnokletochnoi limfomoi. Dis. … kand. med. nauk. M., 2015. [in Russian]
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1. Kluin PM, Harris NL, Stein H et al. B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma in Who Classification of tumors of haematopoietic and lymphoid tissues. Ed. SH Swerdlow, E Campo, NL Harris et al. 2008; 265–6.
2. Subar M, Neri A, Inghirami G et al. Frequent c-myc oncogne activation and infrequent presense of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood 1988; 72: 667–71.
3. Johnson NA, Savage KJ, Ludkovski O et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009; 114: 2273–9.
4. Le Gouill S, Talmant P, Touzeau C et al. The clinical presentation and prognosis of diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC rearrangement. Haematologica 2007; 92: 1335–42.
5. Petrich AM, Gandhi M, Jovanovic B et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood 2014; 124 (15): 2354–61.
6. Greenwood M, Armytage T, Fay K. Outcomes of allogeneic stem cell transplantation for non-Hodgkin lymphoma with concurrent MYC and BCL2 translocations: a single center retrospective analysis. Hematol Oncol 2013; 3 (Suppl. 1): 103.
7. Kanungo A, Medeiros LJ, Abruzzo LV, Lin P. Lymphoid neoplasms associated with concurrent t(14;18) and 8q24/c-MYC translocation generally have a poor prognosis. Modern Pathology 2006; 19: 25–33.
8. Tomita N, Tokunaka M, Nakamura N et al. Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations. Haematologica 2009; 94 (7): 935–43.
9. Li S, Lin P, Fayad LE et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol 2012; 25 (1): 145–56.
10. Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations. Leukemia 2009; 23: 777–83.
11. Snuderl M, Kolman OK, Chen YB et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol 2010; 34 (3): 327–40.
12. Oki Y, Noorani M, Davis RE et al. Double hit lymphoma: M.D.Anderson Experince. Blood 2013; 122 (21): 1776.
13. Sun H, Savage K, Karsan A. Outcome of patients wits double-hit lymphomas treated with CODOX-M/IVAC + R followed by hematopoietic stem cell transplantation in British Columbia. Blood 2013; 122 (21): 1788.
14. Leucci E, Cocco M, Onnis A et al. MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation J Pathol 2008; 216 (4): 440–50.
15. Onnis A, De Falco G, Antonicelli G et al. Аlteration of microRNAs regulated by c-MYC in Burkitt lymphoma. PLoS One 2010; 5 (9): pii: e12960.
16. Tzankov A, Xu-Monette ZY, Gerhard MV et al. Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Mod Pathol 2014; 27 (7): 958–71.
17. Valera A, López-Guillermo A, Cardesa-Salzmann T et al. Grup per l’Estudi dels Limfomes de Catalunya i Balears (GELCAB). MYC Protein Expression And Genetic Alterations Have Prognostic Impact In Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy. Haematologica 2013; 98 (10): 1554–62.
18. Green TM, Nielsen O, de SK et al. High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma. Am J Surg Pathol 2012; 36 (4): 612–9.
19. Horn H, Ziepert M, Becher C et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 2013; 121 (12): 2253–63.
20. Perry AM, Alvarado-Bernal Y, Laurini JA. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol 2014; 165 (3): 382–91.
21. Dunleavy K, Pittaluga S, Shovlin M et al. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med 2013; 369 (20): 1915–25.
22. Hu S, Xu-Monette ZY, Tzankov A et al. MYC/BCL2 protein co-expression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Study. Blood 2013; 121 (20): 4021–31.
23. Green TM et al, MD Аndersen Cancer Center, 2012. Immunohistochemical detection of MYC protein correlates with MYC gene status in aggressive B-cell lymphoma. Histopathology 2011; 59 (4): 678–8.
24. Scott DW, Mottok AM, Ennishi D et al. Cell-of-Origin Assignement in Diffuse Large B-cell Lymphoma Determined By Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Has Prognostic Significance Independent of IPI and MYC/BCL2 Immunohistochemistry. 56th ASH Annual Meeting and Exposition. Abstract book 2014; 124 (21): 1624.
25. Al'-Radi L.S., Bariakh E.A., Belousova I.E. i dr. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniiu limfoproliferativnykh zabolevanii. Journal of Modern Oncology. 2013; 15 (5): 9–10. [in Russian]
26. Misiurina A.E. Ekspressiia MYC i BCL2 u bol'nykh diffuznoi V-krupnokletochnoi limfomoi. Dis. … kand. med. nauk. M., 2015. [in Russian]
1 ГБУЗ Городская клиническая больница №52 Департамента здравоохранения г. Москвы. 123182, Россия, Москва, ул. Пехотная, д. 3;
2 ФГБОУ ВО Российский национальный исследовательский медицинский университет им. Н.И.Пирогова Минздрава России. 117997, Россия, Москва, ул. Островитянова, д. 1;
3 ФГБУ Гематологический научный центр Минздрава России. 125167, Россия, Москва, Новый Зыковский пр., д. 4
*ebaryakh@gmail.com
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E.A.Baryakh*1,2, A.E.Misyurina3, A.M.Kovrigina3, T.N.Obukhova3, S.K.Kravchenko3, A.U.Magomedova3, B.V.Zingerman3, E.N.Misyurina1, N.G.Poteshkina1,2, M.A.Lysenko1, A.I.Vorobev3
1 City Clinical Hospital №52 of the Department of Health of Moscow. 123182, Russian Federation, Moscow, ul. Pekhotnaia, d. 3;
2 N.I.Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation. 117997, Russian Federation, Moscow, ul. Ostrovitianova, d. 1;
3 Hematology Research Center of the Ministry of Health of the Russian Federation. 125167, Russian Federation, Moscow, Novyi Zykovskii pr., d. 4
*ebaryakh@gmail.com