OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press87410.17650/1818-8346-2023-18-4-135-144NEW DIRECTIONS, DIAGNOSTIC OPPORTUNITIES, AND TREATMENT ADVANCESНОВЫЕ НАПРАВЛЕНИЯ, ВОЗМОЖНОСТИ ДИАГНОСТИКИ И УСПЕХИ ЛЕЧЕНИЯDiagnostic and therapeutic approaches for lymphoblastic lymphomas from progenitor cells in children and adolescentsДиагностические и терапевтические подходы при лимфобластных лимфомах из клеток-предшественниц у детей и подростковhttps://orcid.org/0000-0003-4999-5195PavlovaT. Yu.ПавловаТ. Ю.
Russian Federation

Tatyana Yu. Pavlova 

23 Kashirskoe Shosse, Moscow 115478

Татьяна Юрьевна Павлова 

115478 Москва, Каширское шоссе, 23

md.pavlovaty@mail.ruhttps://orcid.org/0000-0002-1469-2365ValievT. T.ВалиевТ. Т.
Russian Federation

23 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 23

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России091220231841351440812202308122023https://oncohematology.abvpress.ru/ongm/article/view/874

Lymphoblastic lymphomas (LBL) are the second most common subtype of non-Hodgkin’s lymphomas in children and adolescents, accounting for 25–35 % of all non-Hodgkin’s lymphomas cases. The majority of all lymphoblastic lymphomas (80–85 %) are T-lymphoblastic origin; 15–20 % origins from B-cell precursors, biphenotypic LBL are extremely rare. Currently, the overall and relapse-free survival of children and adolescents with LBL exceeds 80 %, uses of modern therapy programs. However, the survival rates of patients with recurrent or refractory LBL remain low – 10 %. Optimization of therapeutic approaches in LBL follows the path of clarifying clinical, morpho-immunological and molecular biological risk groups, modification of treatment programs using new drugs (including immunotherapy, inhibitors of multifunctional intracellular signaling pathways (NOTCH, PI3K/AKТ/mTOR, JAK/STAT and MAPK), affecting the cell cycle regulation), and also a reduction in immediate and long-term toxicity. This article presents modern approaches to the diagnosis of LBL, staging and choosing of a treatment method.

Лимфобластные лимфомы (ЛбЛ) являются 2-м по распространенности вариантом неходжкинских лимфом в детском и подростковом возрасте, на долю которых приходится 25–35 % всех случаев неходжкинских лимфом. большинство ЛбЛ (80–85 %) – это лимфомы Т-лимфобластного происхождения, 15–20 % – В-лимфобластного, бифенотипические ЛбЛ встречаются очень редко. С использованием современных программ терапии безрецидивная и общая выживаемость детей и подростков с ЛбЛ в настоящее время превышает 80 %. Однако показатели общей выживаемости пациентов с рецидивирующим или рефрактерным течением ЛбЛ остаются невысокими – 10 %. Оптимизация терапевтических подходов при ЛбЛ идет по пути уточнения клинических, морфоиммунологических и молекулярно-биологических групп риска, модификации лечебных программ с использованием новых препаратов (включение иммунотерапии, ингибиторов мультифункциональных внутриклеточных сигнальных путей (NOTCH, PI3K/AKТ/mTOR, JAK/STAT и MAPK), влияющих на регуляцию клеточного цикла), а также снижения непосредственной и отдаленной токсичности. В настоящей статье представлены современные подходы к диагностике ЛбЛ, стадированию и выбору программы терапии.

lymphoblastic lymphomanon-Hodgkin’s lymphomaschildrenadolescentsdiagnosticstreatmentлимфобластная лимфоманеходжкинские лимфомыдетиподросткидиагностикалечениеRaetz E.A., Perkins S.L., Bhojwani D. et al. Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Pediatr Blood Cancer 2006;47(2):130–40. DOI: 10.1002/pbc.20550Borowitz M.J., Chan J.K., Downing J.R. et al. B-lymphoblastic leukaemia/lymphoma, not otherwise specified (NOS). In: WHO classification of tumours of haematopoietic and lymphoid tissues. Revised. 4th edn. Eds.: S.H. Swerdlow, E. Campo, N.L. Harris et al. Lyon, France: IARC, 2017. Pp. 200–202.Pavlova T.Yu., Valiev T.T. Experience in the treatment of progenitor cells lymphoblastic lymphomas in children and adolescents according to the ALL IC-BFM 2002/2009 protocols. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology 2023; 22(2, Suppl. 1): 141. (In Russ.).Aleshina O.A., Galtseva I.V., Kotova E.S. et al. Treatment outcomes for acute Tlymphoblastic leukemias/lymphomas: data from the ALL2016 multicenter prospective randomized trial. Onkogematologiya = Oncohematology 2023;18(1):20–30. (In Russ.). DOI: 10.17650/1818834620231812030Chen H., Qin Y., Yang J. et al. Dismal outcome of relapsed or primary refractory adult T-cell lymphoblastic lymphoma: a retrospective study from China. Asia Pac J Clin Oncol 2022;18(2):87–95. DOI: 10.1111/ajco.13562Burkhardt B., Zimmermann M., Oschlies I. et al. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 2005;131(1):39–49. DOI: 10.1111/j.1365-2141.2005.05735.xPatel J.L., Smith L.M., Anderson J. et al. The immunophenotype of T-lymphoblastic lymphoma in children and adolescents: a Children’s Oncology Group report. Br J Haematol 2012;159(4):454–61. DOI: 10.1111/bjh.12042Minard-Colin V., Brugières L., Reiter A. et al. Non-Hodgkin lymphoma in children and adolescents: progress through effective collaboration, current knowledge, and challenges ahead. J Clin Oncol 2015;33(27):2963–74. DOI: 10.1200/JCO.2014.59.5827Ducassou S., Ferlay C., Bergeron C. et al. Clinical presentation, evolution, and prognosis of precursor B-cell lymphoblastic lymphoma in trials LMT96, EORTC 58881, and EORTC 58951. Br J Haematol 2011;152(4):441–51. DOI: 10.1111/j.1365-2141.2010.08541.xSioka C. The utility of FDG PET in diagnosis and follow-up of lymphoma in childhood. Eur J Pediatr 2013;172(6):733–8. DOI: 10.1007/s00431-013-1993-8Bárdi E., Csóka M., Garai I. et al. Value of FDG-PET/CT examinations in different cancers of children, focusing on lymphomas. Pathol Oncol Res 2014;20(1):139–43. DOI: 10.1007/s12253-013-9676-3Rosolen A., Perkins S.L., Pinkerton C.R. et al. Revised International pediatric non-Hodgkin lymphoma staging system. J Clin Oncol 2015;33(18):2112–8. DOI: 10.1200/JCO.2014.59.7203Campana D. Monitoring minimal residual disease in pediatric hematologic malignancies. Clin Adv Hematol Oncol 2007;5(11):876–7, 915.Stark B., Avigad S., Luria D. et al. Bone marrow minimal disseminated disease (MDD) and minimal residual disease (MRD) in childhood T-cell lymphoblastic lymphoma stage III, detected by flow cytometry (FC) and real-time quantitative polymerase chain reaction (RQ-PCR). Pediatr Blood Cancer 2009;52(1):20–5. DOI: 10.1002/pbc.21823Graux C., Cools J., Michaux L. et al. Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006;20(9):1496–510. DOI: 10.1038/sj.leu.2404302Wenzinger C., Williams E., Gru A.A. Updates in the pathology of precursor lymphoid neoplasms in the revised fourth edition of the WHO classification of tumors of hematopoietic and lymphoid tissues. Curr Hematol Malig Rep 2018;13(4):275–88. DOI: 10.1007/s11899-018-0456-8Coustan-Smith E., Mullighan C.G., Onciu M. et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 2009;10(2):147–56. DOI: 10.1016/S1470-2045(08)70314-0You M.J., Medeiros L.J., Hsi E.D. T-lymphoblastic leukemia/ lymphoma. Am J Clin Pathol 2015;144(3):411–22. DOI: 10.1309/AJCPMF03LVSBLHPJHaydu J.E., Ferrando A.A. Early T-cell precursor acute lymphoblastic leukaemia. Curr Opin Hematol 2013;20(4):369–73. DOI: 10.1097/MOH.0b013e3283623c61Dworzak M.N., Buldini B., Gaipa G. et al. International-BFMFLOW-network. AIEOP-BFM consensus guidelines 2016 for flow cytometric immunophenotyping of Pediatric acute lymphoblastic leukemia. Cytometry B Clin Cytom 2018;94(1):82–93. DOI: 10.1002/cyto.b.21518Meyer J.A., Zhou D., Mason C.C. et al. Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues. Pediatr Blood Cancer 2017;64(7). DOI: 10.1002/pbc.26363Pui C.H., Roberts K.G., Yang J.J. Philadelphia chromosome-like acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk 2017;17(8):464–70. DOI: 10.1016/j.clml.2017.03.299Burkhardt B., Bruch J., Zimmermann M. et al. Loss of heterozygosity on chromosome 6q14-q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma. Leukemia 2006;20(8):1422–9. DOI: 10.1038/sj.leu.2404275Lones M.A., Heerema N.A., Le Beau M.M. et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet 2007;172(1):1–11. DOI: 10.1016/j.cancergencyto.2006.07.011Basso K., Mussolin L., Lettieri A. et al. T-cell lymphoblastic lymphoma shows differences and similarities with T-cell acute lymphoblastic leukemia by genomic and gene expression analyses. Genes Chromosomes Cancer 2011;50(12):1063–75. DOI: 10.1002/gcc.20924Feng H., Stachura D.L., White R.M. et al. T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. Cancer Cell 2010;18(4):353–66. DOI: 10.1016/j.ccr.2010.09.009Veltri G., Lovisa F., Cortese G. et al. Phosphoproteomic Analysis reveals a different proteomic profile in pediatric patients with T-Cell lymphoblastic lymphoma or T-cell acute lymphoblastic leukemia. Front Oncol 2022;12:913487. DOI: 10.3389/fonc.2022.913487Bonn B.R., Huge A., Rohde M. et al. Whole exome sequencing hints at a unique mutational profile of paediatric T-cell lymphoblastic lymphoma. Br J Haematol 2015;168(2):308–13. DOI: 10.1111/bjh.13105Tancioni I., Miller N.L., Uryu S. et al. FAK activity protects nucleostemin in facilitating breast cancer spheroid and tumor growth. Breast Cancer Res 2015;17:47. DOI: 10.1186/s13058-015-0551-xZhou J., Yi Q., Tang L. The roles of nuclear focal adhesion kinase (FAK) on cancer: a focused review. J Exp Clin Cancer Res 2019;38(1):250. DOI: 10.1186/s13046-019-1265-1Breit S., Stanulla M., Flohr T. et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006;108(4):1151–7. DOI: 10.1182/blood-2005-12-4956Kox C., Zimmermann M., Stanulla M. et al. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia 2010;24(12):2005–13. DOI: 10.1038/leu.2010.203Burkhardt B., Moericke A., Klapper W. et al. Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 2008;49(3):451–61. DOI: 10.1080/10428190701824551Balbach S.T., Makarova O., Bonn B.R. et al. Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia. Leukemia 2016;30(4):970–3. DOI: 10.1038/leu.2015.203Burkhardt B., Hermiston M.L. Lymphoblastic lymphoma in children and adolescents: review of current challenges and future opportunities. Br J Haematol 2019;185(6):1158–70. DOI: 10.1111/bjh.15793Pomari E., Lovisa F., Carraro E. et al. Clinical impact of miR-223 expression in pediatric T-Cell lymphoblastic lymphoma. Oncotarget 2017;8(64):107886–98. DOI: 10.18632/oncotarget.22386Mora J., Filippa D.A., Qin J. et al. Lymphoblastic lymphoma of childhood and the LSA2-L2 protocol: the 30-year experience at Memorial-Sloan-Kettering Cancer Center. Cancer 2003;98(6):1283–91. DOI: 10.1002/cncr.11615Termuhlen A.M., Smith L.M., Perkins S.L. et al. Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children’s Oncology Group trial A5971: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2012;59(7):1229–33. DOI: 10.1002/pbc.24149Sterba J., Kovacs G., Matus M. et al. Capizzi methotrexate with BFM backbone without craniospinal irradiation is effective treatment for pediatric lymphoblastic lymphoma: results from 5 countries with I-BFM LL 09 protocol. In 5th International Symposium on Childhood, Adolescent and Young Adult NonHodgkin Lymphoma, 2015.Dunsmore K.P., Winter S., Devidas M. et al. COG AALL0434: a randomized trial testing nelarabine in newly diagnosed T-cell malignancy. J Clin Oncol 2018;36:10500.Winter S.S., Dunsmore K.P., Devidas M. et al. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children’s Oncology Group AALL0434 methotrexate randomization. J Clin Oncol 2018;36(29):2926–34. DOI: 10.1200/JCO.2018.77.7250. Erratum in: J Clin Oncol 2019;37(9):761.