Journal of Modern OncologyJournal of Modern OncologyСовременная онкология1815-14341815-1442LLC Obyedinennaya Redaktsiya27021ArticlesСтатьиResearch ArticleDiagnosis and treatment of diffuse large B cell lymphoma in children and adults (review of literature)Современные возможности диагностики и лечения диффузной В-крупноклеточной лимфомы у детей и взрослых (обзор литературы)LevashovA SЛевашовА С

науч. сотр. отд-ния химиотерапии гемобластозов НИИ детской онкологии и гематологии ФГБУ РОНЦ им. Н.Н.Блохина

andreyslevashov@mail.ruValievT TВалиевТ Т

канд. мед. наук, ст. науч. сотр. отд-ния химиотерапии гемобластозов НИИ детской онкологии и гематологии ФГБУ РОНЦ им. Н.Н.Блохина

KovriginaA MКовригинаА М

д-р биол. наук, проф., зав. патологоанатомическим отд-нием ФГБУ ГНЦ

PopaA VПопаА В

д-р мед. наук, зав. отд-нием химиотерапии гемобластозов НИИ детской онкологии и гематологии ФГБУ РОНЦ им. Н.Н.Блохина

MentkevichG LМенткевичГ Л

д-р мед. наук, проф., зав. отд. химиотерапии НИИ детской онкологии и гематологии ФГБУ РОНЦ им. Н.Н.Блохина

N.N.Blokhin Russian Cancer Research CenterФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава РоссииNational Research Center for Hematology of the Ministry of Health of the Russian FederationФГБУ Гематологический научный центр Минздрава России15092015173VOL 17, NO3 (2015)ТОМ 17, №3 (2015)304109042020Copyright ©; 2015, Consilium MedicumCopyright ©; 2015, ООО "Консилиум Медикум"2015Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc/4.0https://modernonco.orscience.ru/1815-1434/article/view/27021

Diffuse large B-cell lymphoma (DLBCL) includes heterogeneous disease variants according to clinical, morphological, immunological, cytogenetic and molecular-biological features. Several different pediatric and adult protocols are presented in this article (AIEOP NHL92, B-NHL-BFM90, POG APO - IDM/HiDAC, B-NHL-BFM95, FAB/LMB96, BNHL03, FAB/LMB96 + rituximab, B-NHL2004m + rituximab, R-CHOP, DA-EPOCH-R, RB-CHOP, RBV-CHOP). There were revealed some factors of unfavorable outcome of disease in adult patients with DLBCL, that allow to improve risk group stratification and reduce chemotherapy intensiveness in some patients but require additional study in pediatric patients at the present time. Particular attention is paid to study of sensitiveness to target therapy (anti-CD20 monoclonal antibodies).

Диффузная В-крупноклеточная лимфома (ДВККЛ) включает разные варианты заболевания, гетерогенные по клиническим, морфологическим, иммунологическим, цитогенетическим и молекулярно-биологическим параметрам. В данной статье представлены результаты лечения детей и взрослых с ДВККЛ по различным программам (AIEOP NHL92, B-NHL-BFM90, POG APO - IDM/HiDAC, B-NHL-BFM95, FAB/LMB96, BNHL03, FAB/LMB96 + ритуксимаб, Б-НХЛ2004м + ритуксимаб, R-CHOP, DA-EPOCH-R, RB-CHOP, RBV-CHOP). Выделены молекулярно-биологические факторы неблагоприятного прогноза заболевания у взрослых пациентов с ДВККЛ, которые позволят улучшить стратификацию групп риска, уменьшить интенсивность проводимой терапии у некоторых пациентов, но в настоящее время требуют дополнительного изучения у детей. Особое внимание уделено изучению чувствительности опухоли к таргетной терапии, в частности к анти-CD20 моноклональным антителам.

diffuse large B-cell lymphomadiagnostictreatmentchildren and adultsдиффузная В-крупноклеточная лимфомадиагностикалечениедети и взрослыеReiter A et al. Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma. Hematology 2007; 1: 285-96.Burkhardt В, Oschlies I, Klapper W et al. Non-Hodgkin’s lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 2011; 25: 153-60.Ковригина А.М., Пробатова Н.А. Лимфома Ходжкина и крупноклеточные лимфомы. М.: МИА, 2007; с. 212.Swerdlow S.H, Campo E, Harris N.L et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, 2008.Reiter A et al. Recent advances in the understanding and management of diffuse large B-cell lymphoma in children. Br J Hematol 2008; 142: 329-47.Jaffe E.S et al. Aggressive B-cell lymphomas: a review of new and old entities in the WHO classification. Hematology 2011; 506-14.Heerema N.A, Bernheim A.B, Lim M.S et al. Meeting report, State of the art and future needs in cytogenetic/molecular genetics/arrays in childhood lymphoma: summary report of workshop at the first international symposium on childhood and adolescent non-Hodgkin lymphoma. Ped Blood Cancer 2005; 45: 616-22.Oschlies I et al. Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal - center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Francfurt-Munster) multicenter trial. Blood 2006; 107 (10): 4047-52.Miles R, Raphael M, Mc Carthy et al. Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c - myc protein expression, and a high incidence of germinal center subtype: report of the French-American-British (FAB) International Study Group. Ped Blood Cancer 2008; 51 (3): 369-74.Валиев Т.Т., Морозова О.В., Ковригина А.М. и др. Диагностика и лечение анапластических крупноклеточных лимфом у детей. Гематология и трансфузиология. 2012; 51 (1): 3-9.Барышников А.Ю., Валиев Т.Т., Губин А.Н. Лимфомы у детей: практ. рук. Под ред. Г.Л.Менткевича, С.А.Маяковой. М.: Практическая медицина, 2014.Pillon M et al. Long - term results of the first Italian association of pediatric hematology and oncology protocol for the treatment of pediatric B-cell non-Hodgkin lymphoma (AIEOP LNH92). Cancer 2004; 101 (2): 385-94.Reiter A, Schrappe M, Tieman M et al. Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin-Frankfurt-Munster group Trial NHL-BFM90. Blood 1999; 94 (10): 3294-306.Laver J.H, Kraveka J.M, Hutchison R.E et al. Advanced-Stage Large-Cell Lymphoma in Children and Adolescents: Results of a Randomized Trial Incorporating intermediate-Dose Methotrexate and High-Dose Cytarabine in the Maintenance Phase of the APO Regimen: A Pediatric Oncology Group Phase III Trial. J Clin Oncol 2005; 23 (3): 541-7.Woessmann W, Seidemann K, Mann G et al. The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM group study NHL-BFM95. Blood 2005; 105 (3): 948-58.Cairo M, Sposto R, Gerrard M. Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescents age (>15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of the FAB LMB 96 study. J Clin Oncol 2012; 30 (4): 387-93.Patte C, Auperin A, Gerard M et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 2007; 109: 2773-80.Gerrard M, Waxman I.M, Sposto R et al. Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 2013; 121 (2): 278-85.Worth J, Rohde M, Burkhardt B. Mature B-cell lymphoma and leukemia in children and adolescents - review of standartd chemotherapy regimen and perspectives. Ped Hematol Oncol 2013; 30: 465-83.Tsurusawa M, Mori T, Kikuchi A et al. Improved treatment results of Children with B-cell non-Hodgkin lymphoma: a report from Japanese pediatric leukemia/lymphoma study group B-NHL03 study. Ped Blood Cancer 2014; 61: 1215-21.Goldman S, Smith L, Anderson J.R et al. Rituximab and FAB/LMB96 chemotherapy in children with stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology group report. Leukemia 2013; 27: 1174-7.Barth M.J, Goldman S, Smith L et al. Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukemia: a Children’s Oncology group report. Br J Haematol 2013; 162: 678-83.Самочатова Е.В., Шелихова Л.Н., Мякова Н.В. Лечение диффузной Б-крупноклеточной лимфомы у детей с применением интенсивной химиотерапии с ритуксимабом: предварительные результаты. Детская онкология. 2007; 3-4: 51-6.Самочатова Е.В., Шелихова Л.Н., Белогурова М.Б. Комбинированная химиоиммунотерапия больных неходжкинскими лимфомами из зрелых В-клеток возрастной группы до 18 лет: результаты многоцентрового исследования НХЛ2004м с применением ритуксимаба и модифицированного протокола Б-НХЛ БФМ 90. Онкогематология. 2009; 3: 4-14.Самочатова Е.В., Шелихова Л.Н., Мякова Н.В. Возможности и проблемы современной терапии неходжкинских лимфом у детей и подростков. Педиатрия. 2011; 90 (4): 37-43.Lange J et al. Treatment of adolescents with aggressive B-cell malignancies: the pediatric experience. Curr Hematol Malig Rep 2013; 8 (3): 226-35.Meinhardt A, Burkhardt B, Zimmermann M et al. Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin’s lymphoma and Burkitt Leukemia. J Clin Oncol 2010; 28 (19): 3115-21.Meyer P.N, Fu K, Greiner T.G et al. Immunohistocemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 2011; 29 (2): 200-7.Hu S, Xu-Monette Z.Y, Tzankov A et al. MYC/BCL2 protein coexpression 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. Blood 2013; 121 (20): 4021-31.Wilson W.H, Jung S.H et al. A cancer and leukemia group B multi - center study of DA-EPOCH - rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Hematologyca 2012; 97 (5): 758-65.Нечунаева И.Н., Агеева Т.А., Маслова Л.М. Эффективность лечения диффузных В-клеточных крупноклеточных лимфом по данным городского гематологического центра г. Новосибирска. Бюллетень СО РАМН. 2011; 31 (2): 71-4.Klapper W, Kreuz M, Kohler C.W et al. Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood 2012; 119 (8): 1882-7.Chen Y, Sun X.F, Cai R.Q. Germinal - center type B-cell classification and clinical characteristics of Chinese pediatric diffuse large B-cell lymphoma: a report of 76 cases. Chin J Cancer 2013; 32 (10): 561-6.Poirel H.A, Cairo M.S, Heerema N.A et al. Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB 96 international study. Leukemia 2009; 23 (2): 323-31.Hans C.P, Weisenburger D.D, Greiner T.C et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immuhistochemistry using a tissue microarray. Blood 2004; 103 (1): 275-82.Hoeller S, Schneider A, Haralambieva E et al. FOXP1 protein overexpression is associated with inferior outcome in nodal diffuse large B-cell lymphomas with non - germinal centre phenotype, indepemdent of gains and structural aberrations at 3p14.1. Histopathology 2010; 57: 73-80.Perry A.M, Zdravko M et al. Biological prognostic markers in diffuse large B-cell lymphoma. Cancer Control 2012; 19 (3): 214-26.Culpin R.E, Sieniawski M, Angus B et al. Prognostic significance of immunohistochemistry - based markers and algorithms in immunochemotherapy - treated diffuse large B cell lymphoma patients. Histopathology 2013; 63: 788-801.Visco Y, Li Y, Xu-Monette Z.Y et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Prorram Study. Leukemia 2012.Troppan K, Wenzl K, Deutsch A et al. MicroRNAs in diffuse large B-cell lymphoma: implications for pathogenesis, diagnosis, prognosis and therapy. Anticancer Res 2014; 34: 557-64.Guo Y, Takeuchi I, Karnan S et al. Array - comparative genomic hybridization profiling of immunohistochemical subgroups of diffuse large B-cell lymphoma shows distinct genomic alterations. Cancer Sci 2014; 105 (4): 481-9.Scott D.W, Wright G.W, Williams P.M et al. Determining cell - of - origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin - fixed paraffin - embedded tissue. Blood 2014; 123 (8): 1214-7.Deffenbacher K.E, Iqbal J, Sanger W et al. Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling. Blood 2012; 119 (16): 3757-66.Мисюрина А.Е., Мисюрин В.А., Барях Е.А., Ковригина А.М. Роль экспрессии генов C-MYC, BCL2, BCL6 в патогенезе диффузной В-крупноклеточной лимфомы. Клин. онкогематология. 2014; 7 (4): 512-21.Johnson N.A, Slack G.W, Savage K.J et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphomide, doxorubicin, vincristine and prednisone. J Clinical Oncol 2012; 30 (28): 3452-8.Perry A.M, Alvarado-Bernal Y, Laurini J.A et al. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol 2014; 165: 382-91.Valera A, Lopez-Guillermo A, Cardesa-Salzmann T et al. 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.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: 2253-63.Tzankov A, Xu-Monette Z, Gerhard M et al. Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Modern Pathol 2014; 27: 958-71.Visco C, Tzankov A, Xu-Monette Z et al. Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP consortium program study. Haematologica 2013; 98 (2): 255-63.Hu S, Xu-Monette Z.Y, Balasubramanyam A et al. CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Blood 2013; 121: 2715-24.Ok C.J, Xu-Monette Z.Y, Tzankov A et al. STAT3 expression and clinical inplications in de novo diffuse large B cell lymphoma: a report from the International DLBCL Rituximab-CHOP consortium program. Blood 2013; 122: 21.Wu Z.L, Song Y.Q, Shi Y.F et al. High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma.J Hematol Oncol 2011; 4 (31): 1-6.Ok C.Y, Chen J, Xu-Monette Z et al. Clinical implications of phosphorylated STAT3 expre ssion in de novo diffuse large B-cell lymphoma. Clin Cancer Res 2014.Soldini D, Montagna C, Schuffer P et al. A new diagnostic algorithm for Burkitt and diffuse large B-cell lymphomas based on the expression of CSE1L and STAT3 and on MYC rearrangement predicts outcome. Ann Oncol 2013; 24: 193-201.Aquino G, Marra L, De Chiara A et al. MYC chromosomal aberration in differential diagnosis between Burkitt and other aggressive lymphomas. Infect Agents Cancer 2013; 8: 37.Dunleavy K, Pittaluga S, Shovlin M et al. Concurrent expression of MYC/BCL2 protein in newly diagnosed DLBCL is not associated with an inferior survival following EPOCH-R therapy. Blood 2013; 122: 21.Мисюрина А.Е., Ковригина А.М., Барях А.Е. Экспрессия белков MYC и BCL2 у больных с диффузной В-крупноклеточной лимфомой. Клин. онкогематология. 2015; 8 (1): 44-53.Ichikava S, Fukuhara N, Katsushima H et al. Association between BACH2 expression and clinical prognosis in diffuse large B cell lymphoma. Cancer Sci 2014; 105 (4): 437-44.Yamamoto W et al. Human leukocyte antigen - DR expression on flow cytometry and tumor associated macrophages in diffuse large B cell lymphoma treated by: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone therapy: retrospective cogort study. Leukemia/Lymphoma 2014; 55 (12): 2721-7.Miyazaki K. Yamaguchi M, Suzuki R et al. CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab. Ann Oncol 2011; 22: 1601-7.Laurent C, Do C, Gascoyne R.D et al. Anaplastic lymphoma kinase - positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis. J Clin Oncol 2009; 27 (25): 4211-6.Valera A, Colomo L, Martinez A et al. ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements. Modern Pathol 2013; 26: 1329-37.Cox C.M, Di Napoli A., Scarpino S et al. Clinicopathologic characterization of diffuse large B cell lymphoma with an associated serum monoclonal IgM component.Roschewski M, Dunleavy K, Wilson W.H. Diffuse large B-cell lymphoma: molecular targeted therapy. Int J Hematol 2012; 96 (5): 552-61.Horie R. Molecularly - targeted strategy and NFkB in lymphoid malignancies. J Clin Experiment Hematopathol 2013; 53 (3): 185-95.Roschewski M, Staudt L.M, Wilson W.H. Diffuse large B-cell lymphoma - treatment approaches in the molecular era. Nature. Reviews. Clin Oncol 2014; 11 (1): 12-23.Nagel D, Vincendeau M, Eitelhuber A.C et al. Mechanisms and consequences of constitutive NFkB activation in B-cell lymphoid malignancies. Oncogene 2014; p. 1-11.Schneider C, Pasqualucci L, Dalla-Favera R. Molecular pathogenesis of diffuse large B-cell lymphoma. Semin Diagnost Pathol 2011; 28: 167-77.Witzig T.E et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 2011; 25: 341-7.Furman R.R, Martin P, Ruan J et al. Phase1 trial of bortezomib plus R-CHOP in previously untreated patients with aggressive non-Hodgkin lymphoma. Cancer 2010; p. 5432-9.Ruan J, Martin P, Furman R.R et al. Bortezomib plus CHOP-Rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clinical Oncol 2011; 29 (6): 690-7.Maishman T, Stanton L, Davies A et al. A novel adaptive trial design: randomized evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib (REMODL-B) with two interim analyses to explore safety and efficacy. Trials 2013; 14: 77.Johnston P.B et al. Combination of everolimus with R-CHOP (ever R-CHOP) as an initial therapy for diffuse large B-cell lymphoma (DLBCL): A phase I and feasibility study (NCCTG N1085). J Clin Oncol 2015; 33 (Suppl.; abstr 8518).Nam S.J et al. An increase of M2 macrophages predicts poor prognosis in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Leukemia Lymphoma 2014; 55 (11): 2466-76.Xie M et al. The prognostic significance of tumor - associated macrophages and NK cells in patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2014; 124 (21).Togunaga T, Tomita A, Sugimoto K et al. De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry - positive and flow cytometry - negative phenotype: molecular mechanisms and correlation with rituximab sensitivity. Cancer Sci 2014; 105 (1): 35-43.Song G, Cho W.C, Gu L et al. Increased CD59 protein expression is associated with the outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP. Med Oncol 2014.Fen Liu et al. FCGR3A 158 V/F polymorphism and response to frontline R-CHOP therapy in diffuse large B-cell lymphoma. DNA Cell Biol 2014; 33: 616-23.Morschhauser F.A et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the Phase II GAUGUIN study. J Clin Oncol 2013; 31: 2912-9.Coiffier B et al. A multicentre, phase II trial ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma. Br J Hematol 2013; 163: 334-42.Bartlett N et al. Updated results of a phase II trial of brentuximab vedotin combined with R-CHOP in frontline treatment of patients (pts) with high - intermediate/high - risk diffuse large B-cell lymphoma (DLBCL). J Clinl Oncol 2015; 33 (Suppl.; abstr 8506).Younes A, Bartlett N.L, Leonard J.P et al. Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas. N Engl J Med 2010; 363: 1812-21.Pro B et al. Brentuximab Vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large - cell lymphoma: results of a phase II study. J Clin Oncol 2012; 30 (18): 2190-6.http://www.childrensoncologygroup.org. A Randomized Phase II study of Brentuximab Vedotin (NSC# 749710) and Crizotinib (NSC# 749005) in Patients with Newly Diagnosed Anaplastic Large Cell Lymphoma (ALCL) IND #117117.Wagner-Johnston N.D et al. A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B cell lymphoma. Leukemia Lymphoma 2015; p. 1-7.Гаврилина О.А., Габеева Н.Г., Морозова А.К. Роль высокодозной химиотерапии и аутотрансплантации стволовых клеток крови у пациентов с диффузной В крупноклеточной лимфомой. Терапевт. арх. 2013; 7: 90-7.Rytting M et al. Initial experience with CMC-544 (inotuzumab ozogamicin) in pediatric patients with relapsed B-cell acute lymphoblastic leukemia. Ped Blood Cancer 2014; 61 (2): 369-72.Friedberg J et al. R-CHOP with iodine-131 tositumomab consolidation for advanced stage diffuse large B-cell lymphoma (DLBCL): SWOG S0433. Br J Hematol 2014; 166 (3): 382-9.Briones J et al. Autologous stem cell transplantation after conditioning with yttrium-90 ibritumomab tiuxetan plus BEAM in refractory non-Hodgkin diffuse large B cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica 2014; 99 (3): 505-10.Cooney-Qualter E et al. A phase I study of yttrium-90 ibritumomab tiuxitan in children and adolescents with relapsed/refractory CD20-positive non-Hodgkin lymphoma: a Children’s Oncology Group Study. Clin Cancer Res 2007; 13: 5652-60.Kraeber-Bodere F et al. Consolidation anti-CD22 fractionated radioimmunotherapy (RIT) with 90Y- epratuzumab tetraxetan following R-CHOP in elderly diffuse large B cell lymphoma (DLBCL) patients. J Nucl Med 2013; 54 (Suppl. 2): 179.Witzig T.E et al. Anti-CD22 90Y-epratuzumab tetraxetan combined with anti-CD20 veltuzumab: a phase I study in patients with relapsed/refractory, aggressive non-Hodgkin lymphoma. Haematologica 2014; 99 (11): 1738-45.Viardot A et al. Treatment of relapsed/refractory diffuse large B cell lymphoma with the bispecific T-cell engager (BiTE) antibody construct blinatumomab: primary analysis results from an open - label, phase II study. ASH annual meeting abstracts book, 2014; p. 4460.Portell C.A et al. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol Adv Appl 2013; 5: 5-11.Schlegel P et al. Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica 2014; 99 (7): 1212-18.Stackelberg A et al. Phase 1/2 study in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) receiving blinatumomab treatment. ASH annual meeting abstracts book, 2014; p. 2292.Schuster F.R et al. Immunotherapy with trifunctional anti-CD20 x anti-CD3 antibody FBTA05 (Lymphomun) in pediatric high - risk patients with recurrent CD20-positive B-cell malignancies. Br J Haematol 2015; 169 (1): 90-102.Kochenderfer J.N et al. Chemotherapy - refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T-cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 2014; p. 1-11.Wang Y et al. Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor - modified T cells. Clin Immunol 2014; 155: 160-75.Maude S et al. Chimeric antigen receptor (CAR) modified N cells induce durable remissions in children with relapsed/refractory ALL. ASPHO annual meeting book, 2015; p. 4003.Suzuki M et al. Chimeric antigen receptors and bispecific antibodies to retarget T cells in pediatric oncology. Ped Blood Cancer 2015; 62: 1326-36.