GN Salogub¹, EB Rusanova², MV Gorchakova², EA Belyakova³

¹ VA Almazov National Medical Research Center, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341

² IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022

³ II Mechnikov North-Western State Medical University, 41 Kirochnaya ul., Saint Petersburg, Russian Federation, 191015

For correspondence: Galina Nikolaevna Salogub, MD, PhD, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341; e-mail: salogub@bk.ru

For citation: Salogub GN, Rusanova EB, Gorchakova MV, Belyakova EA. The Prognostic Value of Immunophenotypic Characteristics of Plasma Cells in Newly Diagnosed Multiple Myeloma Patients Treated with First-Generation Proteasome Inhibitor Bortezomib. Clinical oncohematology. 2022;15(4):377–87. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-377-387

ABSTRACT

Aim. To assess the number of plasma cells (PC) in the bone marrow and their immunophenotype using flow cytometry (FC) and light microscopy. To analyze clinical and prognostic value of the data obtained in newly diagnosed multiple myeloma (MM) patients treated with first-generation proteasome inhibitor bortezomib.

Materials & Methods. The study enrolled 153 newly diagnosed MM patients treated and followed-up at the IP Pavlov First Saint Petersburg State Medical University in the period from 2007 to 2017. The median age of patients was 69 years. In 115 patients, the regimens based on first-generation proteasome inhibitor bortezomib were used as induction therapy. To determine the immunophenotypic profile of PC, the CD19, CD20, CD27, CD38, CD45, CD56, CD138, and CD117 monoclonal antibodies were used. PC immunophenotyping in the bone marrow was performed by FC using Cytomics FC500 (Beckman Coulter, USA).

Results. Patients with different phenotypes did not show any considerable differences in monocloncal production of certain classes and types of immunoglobulin heavy and/or light chains. In case of immunophenotypic profile of CD20+CD27– myeloma cells, the secretion of the monoclonal κ-chain predominated over that of λ-chain. By and large, the secretion of light chains was observed more often in ММ CD20+ and more seldom in ММ CD56+. In case of CD56 expression, IgAλ secretion was more often reported; IgAκ secretion was more common in case of CD117 expression. Worst survival scores were shown by patients with PC immunophenotype CD27–CD56–. At the primary MM diagnosis, the advanced stages of the disease, according to the ISS, were more commonly characterized by phenotype CD45–CD27–CD56+.

Conclusion. The flow cytometry characteristics of PC immunophenotype can be applied to evaluate the prognosis of MM and to optimize the therapy.

Keywords: multiple myeloma, flow cytometry, bortezomib, immunophenotypic profile, plasma cells, overall survival, progression-free survival.

Received: May 22, 2022

Accepted: August 28, 2022

Read in PDF

REFERENCES

1. Saxe D, Seo E-J, Bergeron MB, Han J-Y. Recent advances in cytogenetic characterization of multiple myeloma. Int J Lab Hematol. 2019;41(1):5–14. doi: 10.1111/ijlh.12882.
2. Johnsen HE, Bogsted M, Klausen TW, et al. Multiparametric flow cytometry profiling of neoplastic plasma cells in multiple myeloma. Cytometry B Clin Cytom. 2010;78(5):338–47. doi: 10.1002/cyto.b.20523.
3. Dispenzieri A, Kumar S. Treatment for high-risk smoldering myeloma. N Engl J Med. 2013;369(18):1762–5. doi: 10.1056/NEJMc1310911#SA1.
4. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):538–48. doi: 10.1016/S1470-2045(14)70442-5.
5. Dimopoulos MA, Sonneveld P, Leung N, et al. International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. J Clin Oncol. 2016;34(13):1544–57. doi: 10.1200/JCO.2015.65.0044.
6. Flores-Montero J, de Tute R, Paiva B, et al. Immunophenotype of normal vs. myeloma plasma cells: toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytom. 2016;90(1):61–72. doi: 10.1002/cyto.b.21265.
7. Flores-Montero J, Sanoja-Flores L, Paiva B, et al. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31(10):2094–103. doi: 10.1038/leu.2017.29.
8. Kumar SK, Kimlinger T, Morice W. Immunophenotyping in multiple myeloma and related plasma cell disorders. Best Pract Res Clin Haematol. 2010;23(3):433–51. doi: 10.1016/j.beha.2010.09.002.
9. Kumar S, Rajkumar SV, Kimlinger T, et al. CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations. Leukemia. 2005;19(8):1466–70. doi: 10.1038/sj.leu.2403823.
10. Iriyama N, Miura K, Hatta Y, et al. Clinical effect of immunophenotyping on the prognosis of multiple myeloma patients treated with bortezomib. Oncol Lett. 2017;13(5):3803–8. doi: 10.3892/ol.2017.5920.
11. Grigoriadis G, Gilbertson M, Came N, et al. Is CD20 positive plasma cell myeloma a unique clinicopathological entity? A study of 40 cases and review of the literature. Pathology. 2012;44(6):552–6. doi: 10.1097/PAT.0b013e3283583f5d.
12. Arana P, Paiva B, Cedena MT, et al. Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1265 patients enrolled in four consecutive clinical trials. Leukemia. 2018;32(4):971–8. doi: 10.1038/leu.2017.320.
13. Li Z, Xu Y, An G, et al. The characteristics of 62 cases of CD20-positive multiple myeloma. 2015;36(1):44–8. doi: 10.3760/cma.j.issn.0253-2727.2015.01.011.
14. Shen C, Xu H, Alvarez X, et al. Reduced expression of CD27 by collagenase treatment: implications for interpreting B cell data in tissue. PLoS One. 2015;10(3):213–20. doi: 10.1371/journal.pone.0116667.
15. Moreau P, Robillard N, Jego G, et al. Lack of CD27 in myeloma delineates different presentation and outcome. Br J Haematol. 2006;132(2):168–70. doi: 10.1111/j.1365-2141.2005.05849.x.
16. Lok R, Golovyan D, Smith J. Multiple myeloma causing interstitial pulmonary infiltrates and soft-tissue plasmacytoma. Respir Med Case Rep. 2018;24:155–7. doi: 10.1016/j.rmcr.2018.05.023.
17. Klimiene I, Radzevicius M, Matuzeviciene R, et al. Adhesion molecule immunophenotype of bone marrow multiple myeloma plasma cells impacts the presence of malignant circulating plasma cells in peripheral blood. Int J Lab Hematol. 2021;43(3):403–8. doi: 10.1111/ijlh.13387.
18. Khallaf SM, Yousof EA, Ahmed EH, et al. Prognostic value of CD56 expression in multiple myeloma. Res Oncol. 2020;16(1):6–1. doi: 10.21608/resoncol.2020.24758.1091.
19. Yoshida T, Ri M, Kinoshita S, et al. Low expression of neural cell adhesion molecule, CD56, is associated with low efficacy of bortezomib plus dexamethasone therapy in multiple myeloma. PLoS One. 2018;13(5):e0196780. doi: 10.1371/journal.pone.0196780.
20. Baughn LB, Sachs Z, Noble-Orcutt KE, et al. Phenotypic and functional characterization of a bortezomib resistant multiple myeloma cell line by flow and mass cytometry. Leuk Lymphoma. 2017;58(8):1931–40. doi: 10.1080/10428194.2016.1266621.
21. Pan Y, Wang H, Tao Q, et al. Absence of both CD56 and CD117 expression on malignant plasma cells is related with a poor prognosis in patients with newly diagnosed multiple myeloma. Leuk Res. 2016;40:77–82. doi: 10.1016/j.leukres.2015.11.003.
22. Chen F, Hu Y, Wang X, et al. Expression of CD81 and CD117 in plasma cell myeloma and the relationship to prognosis. Cancer Med. 2018;7(12):5920–7. doi: 10.1002/cam4.1840.
23. Wang H, Zhou X, Zhu JW. Association of CD117 and HLA-DR expression with shorter overall survival and/or progression-free survival in patients with multiple myeloma treated with bortezomib and thalidomide combination treatment without transplantation. Oncol Lett. 2018;16(5):5655–66. doi: 10.3892/ol.2018.9365.
24. Skerget M, Skopec B, Zadnik V, et al. CD56 Expression is an important prognostic factor in multiple myeloma even with bortezomib induction. Acta Haematol. 2018;139(4):228–34. doi: 10.1159/000489483.
25. Raja KR, Kovarova L, Hajek R. Review of phenotypic markers used in flow cytometric analysis of MGUS and MM, and applicability of flow cytometry in other plasma cell disorders. Br J Haematol. 2010;149(3):334–51. doi: 10.1111/j.1365-2141.2010.08121.x.
26. Sahara N, Takeshita A, Shigeno K, et al. Clinicopathological and prognostic characteristics of CD56-negative multiple myeloma. Br J Haematol. 2002;117(4):882–5. doi: 10.1046/j.1365-2141.2002.03513.x.

IV Galtseva, KA Nikiforova, YuO Davydova, NM Kapranov, MV Solov’ev, EN Parovichnikova, LP Mendeleeva

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Kseniya Aleksandrovna Nikiforova, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-62-21; e-mail: nikiforovaksenya@gmail.com

For citation: Galtseva IV, Nikiforova KA, Davydova YuO, et al. Multiple Myeloma: Nuances of Minimal Residual Disease Diagnosis and Monitoring with the Use of Multicolor Flow Cytometry. Clinical oncohematology. 2022;15(4):365–76. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-365-376

ABSTRACT

The assessment of minimal residual disease (MRD) by multicolor flow cytometry (MFC) is a rapidly growing area of laboratory studies. In recent years, it has become particularly valuable for hematologists. Although the MFC analysis of plasma cells in multiple myeloma patients is sufficiently standardized, there are differences in methods of sample preparation, monoclonal antibody combinations being used as well as in cytometric data evaluation. The present paper summarizes the key international and domestic data on the MFC analysis of plasma cells and documents the authors’ own experience with MFC analysis in multiple myeloma over the last few years.

Keywords: minimal residual disease, multiple myeloma, multicolor flow cytometry, gating, immunophenotyping.

Received: May 24, 2022

Accepted: August 10, 2022

Read in PDF

REFERENCES

1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–e548. doi: 10.1016/S1470-2045(14)70442-5.
2. Каприн А.Д., Старинский В.В., Шахзадова А.О. и др. Злокачественные новообразования в России в 2019 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2020.
   [Kaprin AD, Starinskii VV, Shakhzadova AO, et al. Zlokachestvennye novoobrazovaniya v Rossii v 2019 godu (zabolevaemost’ i smertnost’). (Malignant neoplasms in Russia in 2019 (incidence and mortality.) Moscow: MNIOI im. P.A. Gertsena — filial FGBU “NMITs radiologii” Publ.; 2020. (In Russ)]
3. Соловьев М.В., Менделеева Л.П., Алексеева А.Н. и др. Эффективность терапии множественной миеломы в России (результаты многоцентрового проспективного исследования). Гематология и трансфузиология. 2020;65(1):103–4.
   [Solov’ev MV, Mendeleeva LP, Alekseeva AN, et al. The efficacy of multiple myeloma therapy in Russia (results of a multi-center prospective study). Gematologiya i transfuziologiya. 2020;65(1):103–4. (In Russ)]
4. Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(7):719–34. doi: 10.1002/ajh.24402.
5. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–e346. doi: 10.1016/S1470-2045(16)30206-6.
6. Paiva B, Vidriales M-B, Mateo G, et al. The persistence of immunophenotypically normal residual bone marrow plasma cells at diagnosis identifies a good prognostic subgroup of symptomatic multiple myeloma patients. Blood. 2009;114(20):4369–72. doi: 10.1182/blood-2009-05-221689.
7. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31(20):2540–7. doi: 10.1200/JCO.2012.46.2119.
8. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123(20):3073–9. doi: 10.1182/blood-2014-01-550020.
9. Korde N, Mailankody S, Roschewski M, et al. Minimal Residual Disease (MRD) Testing in Newly Diagnosed Multiple myeloma (MM) Patients: A Prospective Head-to-Head Assessment of Cell-Based, Molecular, and Molecular-Imaging Modalities. Blood. 2014;124(21):2105. doi: 10.1182/blood.V124.21.2105.2105.
10. Avet-Loiseau H, Corre J, Lauwers-Cances V, et al. Evaluation of Minimal Residual Disease (MRD) By Next Generation Sequencing (NGS) Is Highly Predictive of Progression Free Survival in the IFM/DFCI 2009 Trial. Blood. 2015;126(23):191. doi: 10.1182/blood.V126.23.191.191.
11. Гальцева И.В., Менделеева Л.П., Давыдова Ю.О. и др. Исследование минимальной остаточной болезни методом многоцветной проточной цитофлуориметрии у больных множественной миеломой после трансплантации аутологичных гемопоэтических стволовых клеток. Онкогематология. 2017;12(2):62–9. doi: 10.17650/1818-8346-2017-12-2-62-69.
    [Galtseva IV, Mendeleeva LP, Davydova YuO, et al. Study of minimal residual disease by multicolor flow cytometry in multiple myeloma after autologous hematopoietic stem cell transplantation. Oncohematology. 2017;12(2):62–9. doi: 10.17650/1818-8346-2017-12-2-62-69. (In Russ)]
12. Соловьев М.В., Менделеева Л.П., Покровская О.С. и др. Множественная миелома: поддерживающая терапия после трансплантации гемопоэтических стволовых клеток в зависимости от минимальной остаточной болезни. Терапевтический архив. 2017;89(7):25–31. doi: 10.17116/terarkh201789725-31.
    [Solovyev MV, Mendeleeva LP, Pokrovskaia OS, et al. Multiple myeloma: Maintenance therapy after autologous hematopoietic stem cell transplantation, depending on minimal residual disease. Terapevticheskii arkhiv. 2017;89(7):25–31. doi: 10.17116/terarkh201789725-31. (In Russ)]
13. Munshi NC, Avet-Loiseau H, Anderson KC, et al. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv. 2020;4(23):5988–99. doi: 10.1182/BLOODADVANCES.2020002827.
14. Stetler-Stevenson M, Paiva B, Stoolman L, et al. Consensus guidelines for myeloma minimal residual disease sample staining and data acquisition. Cytometry B Clin Cytom. 2016;90(1):26–30. doi: 10.1002/cyto.b.21249.
15. Менделеева Л.П., Вотякова О.М., Рехтина И.Г. и др. Множественная миелома: Клинические рекомендации [электронный документ]. Доступно по: https://cr.minzdrav.gov.ru/schema/144_1. Ссылка активна на 24.05.2022.
    [Mendeleeva LP, Votyakova OM, Rekhtina IG, et al. Multiple Myeloma: Clinical Guidelines [Internet]. Available from: https://cr.minzdrav.gov.ru/schema/144_1. Accessed 24.05.2022. (In Russ)]
16. Менделеева Л.П., Покровская О.С. Множественная миелома. Клиническая онкогематология. 2009;2(1):96–8.
    [Mendeleeva LP, Pokrovskaya OS. Multiple myeloma. Klinicheskaya onkogematologiya. 2009;2(1):96–8. (In Russ)]
17. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1-S2-1-24.
    [Mendeleeva LP, Votyakova OM, Pokrovskaya OS, et al. National clinical guidelines on diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl 2):1–24. doi: 10.18821/0234-5730-2016-61-1-S2-1-24. (In Russ)]
18. Bergstrom DJ, Kotb R, Louzada ML, et al. Consensus Guidelines on the Diagnosis of Multiple Myeloma and Related Disorders: Recommendations of the Myeloma Canada Research Network Consensus Guideline Consortium. Clin Lymphoma Myeloma Leuk. 2020;20(7):e352–e367. doi: 10.1016/j.clml.2020.01.017.
19. Kumar SK, Callander NS, Adekola K, et al. Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2020;18(12):1685–717. doi: 10.6004/jnccn.2020.0057.
20. Perez-Persona E, Vidriales M-B, Mateo G, et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood. 2007;110(7):2586–92. doi: 10.1182/blood-2007-05-088443.
21. Hogan KA, Chini CCS, Chini EN. The Multi-faceted Ecto-enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases. Front Immunol. 2019;10:1187. doi: 10.3389/FIMMU.2019.01187.
22. Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005;130(3):325–32. doi: 10.1111/j.1365-2141.2005.05550.x.
23. Flores-Montero J, de Tute R, Paiva B, et al. Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytom. 2016;90(1):61–72. doi: 10.1002/CYTO.B.21265.
24. Bataille R, Jego G, Robillard N, et al. The phenotype of normal, reactive and malignant plasma cells. Identification of “many and multiple myelomas” and of new targets for myeloma therapy. Haematologica. 2006;91(9):1234–40.
25. Tembhare PR, Yuan CM, Venzon D, et al. Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases. Leuk Res. 2014;38(3):371–6. doi: 10.1016/J.LEUKRES.2013.12.007.
26. Arroz M, Came N, Lin P, et al. Consensus guidelines on plasma cell myeloma minimal residual disease analysis and reporting. Cytometry B Clin Cytom. 2016;90(1):31–9. doi: 10.1002/cyto.b.21228.
27. Peceliunas V, Janiulioniene A, Matuzeviciene R, Griskevicius L. Six color flow cytometry detects plasma cells expressing aberrant immunophenotype in bone marrow of healthy donors. Cytometry B Clin Cytom. 2011;80B(5):318–23. doi: 10.1002/cyto.b.20601.
28. Rawstron AC, Orfao A, Beksac M, et al. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica. 2008;93(3):431–8. doi: 10.3324/HAEMATOL.11080.
29. Manasanch EE, Salem DA, Yuan CM, et al. Flow cytometric sensitivity and characteristics of plasma cells in patients with multiple myeloma or its precursor disease: influence of biopsy site and anticoagulation method. Leuk Lymphoma. 2015;56(5):1416. doi: 10.3109/10428194.2014.955020.
30. Stetler-Stevenson M, Ahmad E, Barnett D, et al. Clinical Flow Cytometric Analysis of Neoplastic Hematolymphoid Cells; Approved Guideline, CLSI Document H43-A2. 2nd edn. Wayne: Clinical and Laboratory Standards Institute; 2007.
31. Гальцева И.В., Давыдова Ю.О., Капранов Н.М. и др. Способ оценки качества аспирата костного мозга в процессе проведения мониторинга минимальной резидуальной болезни при множественной миеломе. Патент РФ № 2639382/21.12.2017. Бюлл. № 36. Доступно по: https://findpatent.ru/patent/263/2639382.html. Ссылка активна на 09.04.2022.
    [Galtseva IV, Davydova YuO, Kapranov NM, et al. Sposob otsenki kachestva aspirata kostnogo mozga v protsesse provedeniya monitoringa minimalnoi rezidualnoi bolezni pri mnozhestvennoi mielome. Patent RUS No. 2639382/21.12.2017. Byul. No. 36. Available from: https://findpatent.ru/patent/263/2639382.html. Accessed 09.04.2022. (In Russ)]
32. Rawstron AC. Immunophenotyping of Plasma Cells. Curr Protoc Cytom. 2006;36(1). doi: 10.1002/0471142956.cy0623s36.
33. Britt Z, O’Donahue M, Mills D. Surface staining for kappa and lambda, how many washes are sufficient? You might be surprised. Available from: http://www.cytometry.org/public/newsletters/eICCS-6–3/article2.php. (accessed 24.05.2022).
34. Flores-Montero J, Sanoja-Flores L, Paiva B, et al. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31(10):2094–103. doi: 10.1038/LEU.2017.29.
35. Paiva B, Gutierrez NC, Rosinol L, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119(3):687–91. doi: 10.1182/blood-2011-07-370460.
36. Puig N, Sarasquete ME, Balanzategui A, et al. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia. 2014;28(2):391–7. doi: 10.1038/leu.2013.217.

MV Firsova, MV Solov’ev, AM Kovrigina, LP Mendeleeva

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Maiya Valerevna Firsova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: firs-maia@yandex.ru

For citation: Firsova MV, Solov’ev MV, Kovrigina AM, Mendeleeva LP. Plasmablastic Lymphoma with Primary Impairment of Bone Marrow in a HIV-Negative Patient: A Literature Review and a Case Report. Clinical oncohematology. 2022;15(4):356–64. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-356-364

ABSTRACT

Background. Plasmablastic lymphoma (PBL) is a rare variant of large B-cell lymphoma. This disease is usually associated with HIV infection and is predominantly identified in male patients. Tumor lesion is typically localized in oral cavity. PBL is characterized by aggressivity and low rate of long-term survival.

Aim. To report a clinical case of a rare localization of PBL with primary impairment of bone marrow in a 19-year-old HIV-negative patient.

Materials & Methods. The diagnosis of the disease turned out to be challenging and was based on the results of a multi-step complex immunohistochemical analysis of a bone marrow core biopsy sample.

Results. Intensive block-based mNHL-BFM-90 polychemotherapy combined with bortezomib and daratumumab resulted in remission which allowed to perform consecutive autologous and then allogeneic hematopoietic stem cell transplantations. For the lack of immune control of allogeneic transplant over the tumor the conducted therapy was disappointingly unsuccessful. In other words, graft-versus-tumor effect could not be achieved. The patient died in 11 months after diagnosis because of tumor progression. A post-mortem report is required.

Conclusion. New approaches are definitely called for in order to explore methods of treating this complex disease. A study of mechanisms underlying PBL pathogenesis can contribute to better understanding of tumor biology and personalized choice of chemotherapy.

Keywords: plasmablastic lymphoma, CD38, bortezomib, daratumumab, auto-HSCT, allo-HSCT, bone marrow.

Received: May 4, 2022

Accepted: August 30, 2022

Read in PDF

REFERENCES

1. Delecluse HJ, Anagnostopoulos I, Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood. 1997;89(4):1413–20.
2. Salmon SE, Dalton WS, Grogan TM, et al. Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer. Blood. 1991;78(1):44–50.
3. Castillo JJ, Bibas M, Miranda RN. The biology and treatment of plasmablastic lymphoma. Blood. 2015;125(15):2323–30. doi: 10.1182/blood-2014-10-567479.
4. Castillo JJ, Winer ES, Stachurski D, et al. HIV-negative plasmablastic lymphoma: Not in the mouth. Clin Lymphoma Myeloma Leuk. 2011;11(2):185–9. doi: 10.1016/j.clml.2011.03.008.
5. Natkunam Y. The biology of the germinal center. Hematology Am Soc Hematol Educ Program. 2007:210–5. doi: 10.1182/asheducation-2007.1.210.
6. Chan TD, Brink R. Affinity-based selection and the germinal center response. Immunol Rev. 2012;247(1):11–23. doi: 10.1111/j.1600-065X.2012.01118.x.
7. Spender LC, Inman GJ. Inhibition of germinal centre apoptotic programmes by Epstein-Barr virus. Adv Hematol. 2011;2011:829525. doi: 10.1155/2011/829525.
8. Kilger E, Kieser A, Baumann M, Hammerschmidt W. Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J. 1998;17(6):1700–9. doi: 10.1093/emboj/17.6.1700.
9. Vega F, Chang CC, Medeiros LJ, et al. Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. Mod Pathol. 2005;18(6):806–15. doi: 10.1038/modpathol.3800355.
10. Morscio J, Dierickx D, Nijs J, et al. Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: Single-center series of 25 cases and meta-analysis of 277 reported cases. Am J Surg Pathol. 2014;38(7):875–86. doi: 10.1097/PAS.0000000000000234.
11. Shaarani MA, Shackelford RE, Master SR, et al. Plasmablastic Lymphoma, a Rare Entity in Bone Marrow with Unusual Immunophenotype and Challenging Differential Diagnosis. Case Rep Hematol. 2019;2019:1586328. doi: 10.1155/2019/1586328.
12. Chang CC, Zhou X, Taylor JJ, et al. Genomic profiling of plasmablastic lymphoma using array comparative genomic hybridization (aCGH): Revealing significant overlapping genomic lesions with diffuse large B-cell lymphoma. J Hematol Oncol. 2009;2:47. doi: 10.1186/1756-8722-2-47.
13. Cattaneo C, Re A, Ungari M, et al. Plasmablastic lymphoma among human immunodeficiency virus-positive patients: Results of a single center’s experience. Leuk Lymphoma. 2015;56(1):267–9. doi: 10.3109/10428194.2014.911867.
14. Castillo JJ, Furman M, Beltran BE, et al. Human immunodeficiency virus-associated plasmablastic lymphoma: Poor prognosis in the era of highly active antiretroviral therapy. Cancer. 2012;118 (21):5270–7. doi: 10.1002/cncr.27551.
15. Schommers P, Wyen C, Hentrich M, et al. Poor outcome of HIV-infected patients with plasmablastic lymphoma: Results from the German AIDS-related lymphoma cohort study. AIDS. 2013;27(5):842–5. doi: 10.1097/QAD.0b013e32835e069d.
16. Armstrong R, Bradrick J, Liu YC. Spontaneous Regression of an HIV-Associated Plasmablastic Lymphoma in the Oral Cavity: A Case Report. J Oral Maxillofac Surg. 2007;65(7):1361–4. doi: 10.1016/j.joms.2005.12.039.
17. Nasta SD, Carrum GM, Shahab I, et al. Regression of a plasmablastic lymphoma in a patient with HIV on highly active antiretroviral therapy. Leuk Lymphoma. 2002;43(2):423–6. doi: 10.1080/10428190290006260.
18. Castillo J, Pantanowitz L, Dezube BJ. HIV-associated plasmablastic lymphoma: Lessons learned from 112 published cases. Am J Hematol. 2008;83(10):804–9. doi: 10.1002/ajh.21250.
19. NCCN Guidelines В-Cell Lymphomas. Version 3.2022. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480 (accessed 06.06.2022).
20. Валиев Т.Т., Барях Е.А. Эволюция взглядов на диагностику и лечение лимфомы Беркитта. Клиническая онкогематология. 2014;7(1):46–56.
    [Valiev TT, Baryakh EA. Evolution of concepts for diagnosis and treatment of Burkitt’s lymphoma. Klinicheskaya onkogematologiya. 2014;7(1):46–56. (In Russ)]
21. Валиев Т.Т. Лимфома Беркитта у детей: 30 лет терапии. Педиатрия. Журнал им. Г.Н. Сперанского. 2020;99(4):35–41. doi: 10.24110/0031-403X-2020-99-4-35-42.
    [Valiev TT. Burkitt lymphoma in children: 30-year treatment expirience. Pediatria n.a. G.N. Speransky. 2020;99(4):35–41. doi: 10.24110/0031-403X-2020-99-4-35-42. (In Russ)]
22. Lopez A, Abrisqueta P. Plasmablastic lymphoma: current perspectives. Blood Lymphat Cancer. 2018;8:63–70. doi: 10.2147/BLCTT.S142814.
23. Liu JJ, Zhang L, Ayala E, et al. Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: A single institutional experience and literature review. Leuk Res. 2011;35(12):1571–7. doi: 10.1016/j.leukres.2011.06.023.
24. Al-Malki MM, Castillo JJ, Sloan JM, Re A. Hematopoietic Cell Transplantation for Plasmablastic Lymphoma: A Review. Biol Blood Marrow Transplant. 2014;20(12):1877–84. doi: 10.1016/j.bbmt.2014.06.009.
25. Bibas M, Grisetti S, Alba L, et al. Patient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone, gemcitabine, oxaliplatin, cytarabine, and pegfilgrastim chemotherapy and lenalidomide alone. J Clin Oncol. 2010;28(34):e704–е708. doi: 10.1200/JCO.2010.30.0038.
26. Saba NS, Dang D, Saba J, et al. Bortezomib in plasmablastic lymphoma: A case report and review of the literature. Onkologie. 2013;36(5):287–91. doi: 10.1159/000350325.
27. Pretscher D, Kalisch A, Wilhelm M, Birkmann J. Refractory plasmablastic lymphoma—a review of treatment options beyond standard therapy. Ann Hematol. 2017;96(6):967–70. doi: 10.1007/s00277-016-2904-7.
28. Sharma P, Sreedharanunni S, Koshy A, et al. Plasmablastic lymphoma of bone marrow: Report of a rare case and immunohistochemistry based approach to the diagnosis. Indian J Pathol Microbiol. 2019;62(1):107–10. doi: 10.4103/IJPM.IJPM_180_18.
29. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2018. Т. 2. 1255 с.
    [Savchenko VG, ed. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. (Diagnostic algorithms and treatment protocols in hematological diseases.) Moscow: Praktika; 2018. Vol. 2. 1255 p. (In Russ)]
30. Dittus C, Sarosiek S. A case of HIV-negative plasmablastic lymphoma of the bone marrow with a unique immunophenotype. Clin Case Rep. 2017;5(6):902–4. doi: 10.1002/ccr3.878.
31. Marvyin K, Tjonnfjord EB, Breland UM, Tjonnfjord GE. Transformation to plasmablastic lymphoma in CLL upon ibrutinib treatment. BMJ Case Rep. 2020;13(9):e235816. doi: 10.1136/bcr-2020-235816.

LS Al-Radi, SYu Smirnova, TN Moiseeva, IS Piskunova, LV Plastinina, DV Novikova, EG Gemdzhian, GM Galstyan

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Svetlana Yurevna Smirnova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(926)879-65-94; e-mail: smirnova-s-ju@yandex.ru

For citation: Al-Radi LS, Smirnova SYu, Moiseeva TN, et al. Experience with the Use of B-RAF Inhibitor Vemurafenib in the Treatment of Hairy Cell Leukemia. Clinical oncohematology. 2022;15(4):349–55. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-349-355

ABSTRACT

Background. The standard and effective treatment of hairy cell leukemia (HCL) involves purine analogs, interferon-α (IFN-α) administration, and splenectomy. However, primary resistant HCL and early relapses (within 2–3 years after achieving remission) remain clinical challenges. Due to myelotoxicity of cladribine and slow effect of IFN-α, these drugs can be administered neither in deep neutropenia/agranulocytosis patients (especially in case of infectious complications) nor in patients with IFN-α allergy/intolerance.

Aim. To report clinical experience with vemurafenib, a B-RAF inhibitor, in HCL with BRAFV600E mutation in treatment-resistant patients with contraindications to standard therapy.

Materials & Methods. The study enrolled 39 HCL patients aged 24–78 years (median 55 years), 13 women and 26 men. HCL was diagnosed in accordance with the WHO 2017 criteria. Vemurafenib 240 mg was administered once or twice a day within 3 months. Three groups of patients were analyzed: those with early relapses and resistant HCL (n = 7), those with deep neutropenia/agranulocytosis (with and without infectious complications, n = 29), and those with IFN-α intolerance (n = 3).

Results. In 6 (86 %) out of 7 patients from group 1 (with early relapses and resistant HCL) a complete course of treatment was carried out, which included vemurafenib with subsequent standard cladribine chemotherapy and further consolidation with rituximab. Complete remission was achieved in 5 (71 %) patients, and partial remission was achieved in 1 (14 %) patient. The 7th patient was a non-responder. In 28 (97 %) out of 29 patients from group 2 with deep neutropenia/agranulocytosis, hematologic recovery was reported which allowed for further basic treatment with cladribine. In 1 patient vemurafenib appeared to be ineffective. In 3 patients from group 3 with IFN-α intolerance, vemurafenib administration was used as a stage of treatment preceding cladribine therapy. Cladribine treatment resulted in complete remission in 2 (67 %) patients and partial remission in 1 (33 %) patient.

Conclusion. In HCL with BRAFV600E mutation, low-dose vemurafenib can be effective in patients with relapsed/refractory disease as well as deep neutropenia with life-threatening infectious complications. In addition to that, vemurafenib administration can be used in cases of IFN-α intolerance as a stage of treatment of HCL with BRAFV600E mutation which precedes the basic cladribine therapy.

Keywords: hairy cell leukemia, B-RAF inhibitor, vemurafenib, relapsed/refractory disease, agranulocytosis, infectious complications.

Received: April 25, 2022

Accepted: September 2, 2022

Read in PDF

REFERENCES

1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90. doi: 10.1182/blood-2016-01-643569.
2. Grever MR. How I treat hairy cell leukemia. Blood. 2010;115(1):21–8. doi: 10.1182/blood-2009-06-195370.
3. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2018. Т. 2. С. 363–84.
   [Savchenko VG, ed. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. (Diagnostic algorithms and treatment protocols in hematological diseases.) Moscow: Praktika; 2018. Vol. 2. pр. 363–84. (In Russ)]
4. Аль-Ради Л.С. Волосатоклеточный лейкоз: особенности течения, современная тактика терапии: Дис.… канд. мед. наук. М., 2008.
   [Al-Radi LS. Volosatokletochnyi leikoz: osobennosti techeniya, sovremennaya taktika terapii. (Hairy cell leukemia: clinical features, current treatment strategy.) [dissertation] Moscow; 2008. (In Russ)]
5. Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med. 1990;322(16):1117–21. doi: 10.1056/NEJM199004193221605.
6. Tallman MS, Hakimian D, Variakojis D, et al. A single cycle of 2-chlorodeoxyadenosine results in complete remission in the majority of patients with hairy cell leukemia. Blood. 1992;80(9):2203–9.
7. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364(24):2305–15. doi: 10.1056/NEJMoa1014209.
8. Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood. 2017;129(5):553–60. doi: 10.1182/blood-2016-01-689422.
9. Tiacci E, Schiavoni G, Martelli MP, et al. Constant activation of the RAF-MEK-ERK pathway as a diagnostic and therapeutic target in hairy cell leukemia. Haematologica. 2013;98(9):635–9. doi: 10.3324/haematol.2012.078071.
10. Урнова Е.С., Аль-Ради Л.С., Кузьмина Л.А. и др. Успешное применение вемурафениба у больного с резистентной формой волосатоклеточного лейкоза. Терапевтический архив. 2013;85(7):76–8.
    [Urnova ES, Al’-Radi LS, Kuz’mina LA, et al. Successful use of vemurafenib in a patient with resistant hairy cell leukemia. Terapevticheskii arkhiv. 2013;85(7):76–8. (In Russ)]
11. Dietrich S, Zenz T. BRAF inhibitor therapy in HCL. Best Pract Res Clin Haematol. 2015;28(4):246–52. doi: 10.1016/j.beha.2015.10.001.
12. Fiskus W, Mitsiades N. B-Raf inhibition in the clinic: present and future. Annu Rev Med. 2016;67(1):29–43. doi: 10.1146/annurev-med-090514-030732.
13. Dietrich S, Glimm H, Andrulis M, et al. BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med. 2012;366(21):2038–40. doi: 10.1056/NEJMc1202124.
14. Shallis RM, Patel TH, Podoltsev NA, et al. Disseminated, yet dissembled: Rare infections behind the veil of classical hairy cell leukemia. Leuk Res. 2020;90:106315. doi: 10.1016/j.leukres.2020.106315.
15. Maurer H, Haas P, Wengenmayer T, et al. Successful vemurafenib salvage treatment in a patient with primary refractory hairy cell leukemia and pulmonary aspergillosis. Ann Hematol. 2014;93(8):1439–40. doi: 10.1007/s00277-013-1987-7.
16. Peyrade F, Re D, Ginet C, et al. Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E Haematologica. 2013;98(2):e20–e22. doi: 10.3324/haematol.2012.082404.
17. Robak T, Wolska A, Robak P. Potential breakthroughs with investigational drugs for hairy cell leukemia. Expert Opin Investig Drugs. 2015;24(11):1419–31. doi: 10.1517/13543784.2015.1081895.
18. Jain P, Polliack A, Ravandi F. Novel therapeutic options for relapsed hairy cell leukemia. Leuk Lymphoma. 2015;56(8):2264–72. doi: 10.3109/10428194.2014.1001988.
19. Sarvaria A, Topp Z, Saven A. Current therapy and new directions in the treatment of hairy cell leukemia: a review. JAMA Oncol. 2016;2(1):123–9. doi: 10.1001/jamaoncol.2015.4134.
20. Dearden CE, Else M, Catovsky D. Long-term results for pentostatin and cladribine treatment of hairy cell leukemia. Leuk Lymphoma. 2011;52(Suppl 2):21–4. doi: 10.3109/10428194.2011.565093.
21. Goodman GR, Burian C, Koziol JA, Saven A. Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol. 2003;21(5):891–6. doi: 10.1200/JCO.2003.05.093.
22. Tadmor T. Purine Analog Toxicity in Patients With Hairy Cell Leukemia. Leuk Lymphoma. 2011;52(Suppl 2):38–42. doi: 10.3109/10428194.2011.565097.
23. Epperla N, Pavilack M, Olufade T, et al. Adverse event rates and economic burden associated with purine nucleoside analogs in patients with hairy cell leukemia: a US population-retrospective claims analysis. Orphanet J of Rare Dis. 2020;15(1):47. doi: 10.1186/s13023-020-1325-9.
24. Dasanu CA, Ichim TE, Alexandrescu DT. Inherent and iatrogenic immune defects in hairy cell leukemia: revisited. Expert Opin Drug Saf. 2010;9(1):55–9. doi: 10.1517/14740330903427951.
25. Golomb HM, Hadad LJ. Infectious complications in 127 patients with hairy cell leukemia. Am J Hematol 1984;16(4):393–401. doi: 10.1002/ajh.2830160410.
26. Kraut E. Infectious complications in hairy cell leukemia. Leuk Lymphoma. 2011;52(Suppl 2):50–2. doi: 10.3109/10428194.2011.570819.
27. Damaj G, Kuhnowski F, Marolleau JP, et al. Risk factors for severe infections in patients with hairy cell leukemia: a long-term study of patients. Eur J Haematol. 2009;83(3):246–50. doi: 10.1111/j.1600-0609.2009.01259.x.
28. Аль-Ради Л.С., Моисеева Т.Н., Смирнова С.Ю., Шмаков Р.Г. Волосатоклеточный лейкоз и беременность. Терапевтический архив. 2017;89(7):99–104.
    [Al’-Radi LS, Moiseeva TN, Smirnova SYu, Shmakov RG. Hairy cell leukemia and pregnancy. Terapevticheskii arkhiv. 2017;89(7):99–104. (In Russ)]
29. Волкова М.А. Волосатоклеточный лейкоз. В кн.: Клиническая онкогематология. Руководство для врачей, 2-е изд. Под ред. М.А. Волковой. М.: Медицина, 2007. С. 819–34.
    [Volkova MA. Hairy cell leukemia. In: Volkova MA, ed. Klinicheskaya onkogematologiya. Rukovodstvo dlya vrachei. (Clinical oncohematology. A physician’s manual.) 2nd edition. Moscow: Meditsina Publ.; 2007. pр. 819–34. (In Russ)]
30. Bohn JP, Gastl G, Steurer M. Long-term treatment of hairy cell leukemia with interferon-α: still a viable therapeutic option. MEMO. 2016;9:63–5. doi: 10.1007/s12254-016-0269-1.
31. Аль-Ради Л.С., Пивник А.В. Особенности течения и современная тактика терапии волосатоклеточного лейкоза. Клиническая онкогематология. 2009;2(2):111–20.
    [Al’-Radi LS, Pivnik AV. Clinical features and current strategy of hairy cell leukemia treatment. Klinicheskaya onkogematologiya. 2009;2(2):111–20. (In Russ)]
32. Thompson J, Tallman MS, Pulliack A. Past and present role of interferon in hairy cell leukemia. In: Tallmlan MS, Pulliack A, eds. Advances in Blood Disorders. Vol. 5. UK: Harwood academic Publishers; 2000. рр. 127–39.
33. Скопец А.А., Корнилов И.А., Афонин Е.С. Роль экстракорпоральной мембранной оксигенации в терапии легионеллезной пневмонии у пациентки с волосатоклеточным лейкозом. Инновационная медицина Кубани. 2019;(3):44–8. doi: 10.35401/2500-0268-2019-15-3-44-48.
    [Skopets AA, Kornilov IA, Afonin ES. Importance of extracorporeal membrane oxygenation (ECMO) in therapy for legionella pneumonia in patient with hairy-cell leucosis. Innovative Medicine of Kuban. 2019;(3):44–8. doi: 10.35401/2500-0268-2019-15-3-44-48. (In Russ)]
34. Галстян Г.М., Баженов А.В., Данишян К.И. и др. Роль спленэктомии в лечении острой дыхательной недостаточности у больной волосатоклеточным лейкозом. Гематология и трансфузиология. 2017;62(1):51–4.
    [Galstyan GM, Bazhenov AV, Danishyan KI, et al. The role of splenectomy in the treatment of acute respiratory distress in a female patient with hairy cell leukemia. Gematologiya i transfuziologiya. 2017;62(1):51–4. (In Russ)]
35. Smirnova SY, Al-Radi LS, Moiseeva TN, et al. Inhibitor of BRAF(V600E) mutation as a treatment option for hairy cell leukemia with deep neutropenia and infectious complications. Clin Lymphoma Myeloma Leuk. 2021;21(7):427–30. doi: 10.1016/j.clml.2021.02.005
36. Tiacci E, Park JH, De Carolis L, et al. Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. N Engl J Med. 2015;373(18):1733–47. doi: 10.1056/NEJMoa1506583.
37. Tiacci E, De Carolis L, Simonetti E, et al. Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia. N Engl J Med. 2021;384(19):1810–23. doi: 10.1056/NEJMoa2031298.
38. Bohn JP, Pircher A, Wanner D, et al. Low-dose Vemurafenib in hairy cell leukemia patients with active infection. Am J Hematol. 2019;94(6):E180–E182. doi: 10.1002/ajh.25474.
39. Shenoi DP, Andritsos AL, Blachly JS. Classic hairy cell leukemia complicated by pancytopenia and severe infection: a report of 3 cases treated with vemurafenib. Blood Adv. 2019;3(2):116–8. doi: 10.1182/bloodadvances.2018027466.
40. Dietrich S, Hullein S, Hundemer M, et al. Continued response off treatment after BRAF inhibition in refractory hairy cell leukemia. J Clin Oncol. 2013;31(19):e300–e303. doi: 10.1200/JCO.2012.45.9495.
41. Robert C, Arnault JP, Mateus C. RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr Opin Oncol. 2011;23(2):177–82. doi: 10.1097/CCO.0b013e3283436e8c.
42. Zimmer L, Hillen U, Livingstone E, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol. 2012;30(19):2375–83. doi: 10.1200/JCO.2011.41.1660.

MV Neklesova, SV Smirnov, AA Shatilova, KA Levchuk, AE Ershova, SA Silonov

Center for Personalized Medicine, VA Almazov National Medical Research Center, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341

For correspondence: Sergei Vladimirovich Smirnov, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341; Tel.: +7(964)612-57-14; e-mail: sergeiismirnoff@gmail.com

For citation: Neklesova MV, Smirnov SV, Shatilova AA, et al. Production of CD87 Antigen-Specific CAR-T Lymphocytes and Assessment of Their In Vitro Functional Activity. Clinical oncohematology. 2022;15(4):340–8. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-340-348

ABSTRACT

Aim. To generate anti-CD87 CAR-T lymphocytes and to assess their in vitro functional activity.

Materials & Methods. Т-lymphocytes isolated from healthy donor peripheral blood were transduced with the anti-CD87-CAR, T2A, and FusionRed gene coding lentiviral vector. Transduction efficacy assessed by reporter protein FusionRed signal, subpopulation structure, and functional status of CAR-T lymphocytes were determined by flow cytometry. Interferon-γ (IFN-γ) expression by CAR-T lymphocytes was analyzed using immunoassay. Cytotoxic activity of CAR-T lymphocytes was evaluated during their co-cultivation with HeLa target cells by means of xCELLigence real-time assay.

Results. The efficacy of T-lymphocyte transduction was 8.4 %. The obtained CAR-T cells contained the markers of both CD27 and/or CD28 activation (92.91 % cases) and PD1 exhaustion (20.66 % cases). The population of CAR-T lymphocytes showed 98.51 % central memory T-cell phenotype and CD4/CD8 ratio of 1:7. IFN-γ concentration in the medium after co-cultivation of CAR-T lymphocytes with target cells appeared to be significantly higher than in control samples. The study demonstrates that generated CAR-T lymphocytes manifest specific cytotoxicity towards target cells with both unmodified expression and overexpression of CD87 antigen in HeLa cell lines. Cytotoxicity proved to be more pronounced with respect to the cell line with CD87 antigen overexpression.

Conclusion. Despite overexpression of PD1 exhaustion marker, CAR-T lymphocytes showed specific IFN-γ secretion and pronounced cytotoxic activity in interaction with CD87 antigen on target cell membranes. Therefore, anti-CD87 CAR-T lymphocytes can be applied in the treatment of hematologic as well as solid tumors. Since the observed difference in cytotoxicity does not linearly correlate with CD87 antigen density on the surface of attacked cells, the in vivo administration of a CAR-T cell drug should be designed to prevent cytotoxic risk for CD87-expressing healthy cells.

Keywords: CD87, uPAR, CAR-T lymphocytes, acute myeloid leukemias.

Received: June 27, 2022

Accepted: September 10, 2022

Read in PDF

REFERENCES

1. Stoppelli MP, Corti A, Soffientini A, et al. Differentiation-enhanced binding of the amino-terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc Natl Acad Sci USA. 1985;82(15):4939–43. doi: 10.1073/pnas.82.15.4939.
2. Behrendt N, Ronne E, Dano K. The structure and function of the urokinase receptor, a membrane protein governing plasminogen activation on the cell surface. Biol Chem Hoppe Seyler. 1995;376(5):269–79.
3. Кугаевская Е.В., Гуреева Т.А., Тимошенко О.С., Соловьева Н.И. Система активатора плазминогена урокиназного типа в норме и при жизнеугрожающих процессах (обзор). Общая реаниматология. 2018;14(6):61–79. doi: 10.15360/1813-9779-2018-6-61-79.
   [Kugaevskaya EV, Gureeva TA, Timoshenko OS, Solovyeva NI. Urokinase-type plasminogen activator system in norm and in life-threatening processes (Review). General Reanimatology. 2018;14(6):61–79. doi: 10.15360/1813-9779-2018-6-61-79. (In Russ)]
4. Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front Oncol. 2018;8(2):8–24. doi: 10.3389/fonc.2018.00024.
5. Alfano D, Gorrasi A, Li Santi A, et al. Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells. J Cell Mol Med. 2015;19(9):2262–72. doi: 10.1111/jcmm.12617.
6. Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol. 2010;11(1):23–36. doi: 10.1038/nrm2821.
7. Gorantla B, Asuthkar S, Rao JS, et al. Suppression of the uPAR-uPA system retards angiogenesis, invasion, and in vivo tumor development in pancreatic cancer cells. Mol Cancer Res. 2011;9(4):377–89. doi: 10.1158/1541-7786.MCR-10-0452.
8. Amor C, Feucht J, Leibold J, et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020;583(7814):127–32. doi: 10.1038/s41586-020-2403-9.
9. Kusch A, Gulba D. Die Bedeutung des uPA/uPAR-Systems fur die Entwicklung von Arteriosklerose und Restenose. Z Kardiol. 2001;90(1):307–18. doi: 10.1007/s003920170160.
10. Laurenzana A, Chilla A, Luciani C, et al. uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells. Int J Cancer. 2017;141(6):1190–200. doi: 10.1002/ijc.30817.
11. Ahmad A, Kong D, Sarkar SH, et al. Inactivation of uPA and its receptor uPAR by 3,3’-diindolylmethane (DIM) leads to the inhibition of prostate cancer cell growth and migration. J Cell Biochem. 2009;107(3):516–27. doi: 10.1002/jcb.22152.
12. Fox SB, Taylor M, Grondahl-Hansen J, et al. Plasminogen activator inhibitor-1 as a measure of vascular remodelling in breast cancer. J Pathol. 2001;195(2):236–43. doi: 10.1002/path.931.
13. Fisher JL, Field CL, Zhou H, et al. Urokinase plasminogen activator system gene expression is increased in human breast carcinoma and its bone metastases – a comparison of normal breast tissue, non-invasive and invasive carcinoma and osseous metastases. Breast Cancer Res Treat. 2000;61(1):1–12. doi: 10.1007/s10549-004-6659-9.
14. Pierga JY, Bonneton C, Magdelenat H, et al. Real-time quantitative PCR determination of urokinase-type plasminogen activator receptor (uPAR) expression of isolated micrometastatic cells from bone marrow of breast cancer patients. Int J Cancer. 2005;114(2):291–8. doi: 10.1002/ijc.20698.
15. Hildenbrand R, Schaaf A, Dorn-Beineke A, et al. Tumor stroma is the predominant uPA-, uPAR-, PAI-1-expressing tissue in human breast cancer: prognostic impact. Histol Histopathol. 2009;24(7):869–77. doi: 10.14670/HH-24.869.
16. Boonstra MC, Verbeek FP, Mazar AP, et al. Expression of uPAR in tumor-associated stromal cells is associated with colorectal cancer patient prognosis: a TMA study. BMC Cancer. 2014;14:269. doi: 10.1186/1471-2407-14-269.
17. Graf M, Reif S, Hecht K, et al. High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis. Am J Hematol. 2005;79(1):26–35. doi: 10.1002/ajh.20337.
18. Plesner T, Ralfkiaer E, Wittrup M, et al. Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue. Am J Clin Pathol. 1994;102(6):835–41. doi: 10.1093/ajcp/102.6.835.
19. Bene MC, Castoldi G, Knapp W, et al. CD87 (urokinase-type plasminogen activator receptor), function and pathology in hematological disorders: a review. Leukemia. 2004;18(3):394–400. doi: 10.1038/sj.leu.2403250.
20. Cummins KD, Gill S. Will CAR T cell therapy have a role in AML? Promises and pitfalls. Semin Hematol. 2019;56(2):155–63. doi: 10.1053/j.seminhematol.2018.08.008.
21. Kramer MD, Spring H, Todd RF, et al. Urokinase-type plasminogen activator enhances invasion of human T cells (Jurkat) into a fibrin matrix. J Leukoc Biol. 1994;56(2):110–6. doi: 10.1002/jlb.56.2.110.
22. Bianchi E, Ferrero E, Fazioli F, et al. Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes. J Clin Invest. 1996;98(5):1133–41. doi: 10.1172/JCI118896.
23. Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123(24):3750–9. doi: 10.1182/blood-2014-01-552174.
24. Sommermeyer D, Hudecek M, Kosasih PL, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500. doi: 10.1038/leu.2015.247.
25. Baumeister SH, Murad J, Werner L, et al. Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Cancer Immunol Res. 2019;7(1):100–12. doi: 10.1158/2326-6066.CIR-18-0307.
26. Barber A, Meehan KR, Sentman CL. Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther. 2011;18(5):509–16. doi: 10.1038/gt.2010.174.
27. Roybal KT, Rupp LJ, Morsut L, et al. Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits. Cell. 2016;164(4):770–9. doi: 10.1016/j.cell.2016.01.011.
28. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4(6):437–47. doi: 10.1038/nrc1367.
29. Kosti P, Larios-Martinez KI, Maher J, Arnold JN. Generation of hypoxia-sensing chimeric antigen receptor T cells. STAR Protoc. 2021;2(3):100723. doi: 10.1016/j.xpro.2021.100723.

OYu Baranova, AD Shirin

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Olga Yurevna Baranova, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(925)837-27-08; e-mail: baranova-crc@mail.ru

For citation: Baranova OYu, Shirin AD. A Current View on Pathogenesis, Diagnosis, and Treatment of Some Rare Acute Leukemia Variants. Clinical oncohematology. 2022;15(4):307–26. (In Russ).

DOI: 10.21320/2500-2139-2022-15-4-307-326

ABSTRACT

Fundamental discoveries in immunobiology of normal hematopoiesis, emerging views on malignant growth mechanisms together with further improvement of diagnostic capabilities led to a crucial change in perception of leukemiology as one of separate important areas of modern clinical oncohematology. The now available detailed molecular genetic classification of acute leukemias is being complemented by new disease variants. New categories of acute leukemias and progenitor cell tumors have been identified. Nevertheless, many issues related to pathogenesis and classification of some variants of this heterogeneous disease remain unsolved and require further study. The present review provides thorough analysis of some rare variants of acute leukemias which are particularly challenging in terms of pathogenesis, diagnosis, and choice of treatment.

Keywords: rare acute leukemia variants, blastic plasmacytoid dendritic cell neoplasm, early T-cell precursor acute lymphoblastic leukemia, acute leukemias of indeterminate lineage, pure erythroid leukemia, lineage switch.

Received: June 2, 2022

Accepted: September 1, 2022

Read in PDF

REFERENCES

1. Воробьев А.И., Дризе Н.И., Чертков И.Л. Схема кроветворения: 2005. Терапевтический архив. 2006;78(7):5–12.
   [Vorob’ev AI, Drize NI, Chertkov IL. Diagram of hematopoiesis: 2005. Terapevticheskii arkhiv. 2006;78(7):5–12. (In Russ)]
2. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16(1):395–419. doi: 10.1146/annurev.immunol.16.1.395.
3. Ashkenazi A, Dixit VM. Death Receptors: Signaling and Modulation. Science. 1998;281(5381):1305–8. doi: 10.1126/science.281.5381.1305.
4. Domen J, Weissman I. Hematopoietic Stem Cells Need Two Signals to Prevent Apoptosis; Bcl-2 Can Provide One of These, Kitl/C-KIT Signaling the Other. J Exp Med. 2000;192(12):1707–18. doi: 1084/jem.192.12.1707.
5. Akashi K, He X, Chen J, et al. Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood. 2003;101(2):383–9. doi: 10.1182/blood-2002-06-1780.
6. Фрадкин В. Перепрограммирование живых клеток: новые успехи [электронный документ]. Доступно по: https://www.dw.com/ru/%D0%BF%D0%B5%D1%80%D0%B5%D0%BF%D1%80%D0%BE%D0%B3%D1%80%D0%B0%D0%BC%D0%BC%D0%B8%D1%80%D0%BE%D0%B2%D0%B0%D0%BD%D0%B8%D0%B5-%D0%B6%D0%B8%D0%B2%D1%8B%D1%85-%D0%BA%D0%BB%D0%B5%D1%82%D0%BE%D0%BA-%D0%BD%D0%BE%D0%B2%D1%8B%D0%B5-%D1%83%D1%81%D0%BF%D0%B5%D1%85%D0%B8/a-15194138. Ссылка активна на 02.06.2022.
   [Fradkin V. Reprogramming of living cells: new achievements (Internet). Available from: https://www.dw.com/ru/%D0%BF%D0%B5%D1%80%D0%B5%D0%BF%D1%80%D0%BE%D0%B3%D1%80%D0%B0%D0%BC%D0%BC%D0%B8%D1%80%D0%BE%D0%B2%D0%B0%D0%BD%D0%B8%D0%B5-%D0%B6%D0%B8%D0%B2%D1%8B%D1%85-%D0%BA%D0%BB%D0%B5%D1%82%D0%BE%D0%BA-%D0%BD%D0%BE%D0%B2%D1%8B%D0%B5-%D1%83%D1%81%D0%BF%D0%B5%D1%85%D0%B8/a-15194138. Accessed 06.2022. (In Russ)]
7. Копнин Б.П. Современные представления о механизмах злокачественного роста: сходства и различия солидных опухолей и лейкозов. Клиническая онкогематология. 2012;5(3):165–83.
   [Kopnin BP. Modern concepts of the mechanisms of tumor growth: similarities and differences between solid tumors and leukemia. Klinicheskaya onkogematologiya. 2012;5(3):165–83. (In Russ)]
8. Киселевский М.В., Самойленко И.В., Жаркова О.В. и др. Прогностические биомаркеры эффективности иммунотерапии злокачественных новообразований ингибиторами контрольных точек иммунного ответа. Российский журнал детской гематологии и онкологии. 2021;8(2):73–83. doi: 10.21682/2311-1267-2021-8-2-73-83.
   [Kiselevskii MV, Samoilenko IV, Zharkova OV, et al. Predictive biomarkers of inhibitors immune checkpoints therapy in malignant tumors. Russian Journal of Pediatric Hematology and Oncology. 2021;8(2):73–83. doi: 10.21682/2311-1267-2021-8-2-73-83. (In Russ)]
9. Voelkerding KV, Dames SA, Durtschi JD. Next-generation Sequencing: From Basic Research to Diagnostics. Clin Chem. 2009;55(4):641–8. doi: 10.1373/clinchem.2008.112789.
10. Ansorge WJ. Next-generation DNA sequencing techniques. New Biotechnol. 2009;25(4):195–203. doi: 10.1016/j.nbt.2008.12.009.
11. Kchouk M, Gibrat JF, Elloumi M. Generations of Sequencing Technologies: From First to Next Generation. Biol Med. 2017;9(03). doi: 10.4172/0974-8369.1000395.
12. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. doi: 10.1056/NEJMoa1516192.
13. Ross JS, Cronin M. Whole cancer genome sequencing by next-generation methods. Am J Clin Pathol. 2011;136(4):527–39. doi: 10.1309/ajcpr1svt1vhugxw.
14. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the Classification of the Acute Leukaemias. Br J Haematol. 1976;33(4):451–8. doi: 10.1111/j.1365-2141.1976.tb03563.x.
15. Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med. 1985;103(4):620–5. doi: 10.7326/0003-4819-103-4-620.
16. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51(2):189–99. doi: 10.1111/j.1365-2141.1982.tb02771.x.
17. Bennett JM, Catovsky D, Daniel MT, et al. Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-M0). Br J Haematol. 1991;78(3):325–9. doi: 10.1111/j.1365-2141.1991.tb04444.x.
18. Jaffe ES, Harris NL, Stein H, et al, eds. Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues (WHO Classification of Tumours). Lyon: IARC Press; 2001.
19. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 4th edition. Lyon: WHO Press; 2008.
20. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Revised 4th edition. Lyon: IARC Press;
21. Coustan-Smith E, Mullighan CG, 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)70314-0.
22. Neumann M, Heesch S, Schlee C, et al. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood. 2013;121(23):4749–52. doi: 10.1182/blood-2012-11-465138.
23. Neumann M, Coskun E, Fransecky L, et al. FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors. PLoS One. 2013;8(1):e53190. doi: 10.1371/journal.pone.0053190.
24. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481(7380):157–63. doi: 10.1038/nature10725.
25. Di Guglielmo G. Le Maltase Eritremiche Ed Eritroleucemiche. II Pensiero Scientifico. Haematologica. 1928;9:301–47.
26. Boddu P, Benton CB, Wang W, et al. Erythroleukemia – Historical perspectives and recent advances in diagnosis and management. Blood Rev. 2018;32(2):96–105. doi: 10.1016/j.blre.2017.09.002.
27. Liu W, Hasserjian RP, Hu Y, et al. Pure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification. Mod Pathol. 2010;24(3):375–83. doi: 10.1038/modpathol.2010.194.
28. Grossmann V, Bacher U, Haferlach C, et al. Acute erythroid leukemia (AEL) can be separated into distinct prognostic subsets based on cytogenetic and molecular genetic characteristics. Leukemia. 2013;27(9):1940–3. doi: 10.1038/leu.2013.144.
29. Lessard M, Struski S, Leymarie V, et al. Cytogenetic study of 75 erythroleukemias. Cancer Genet Cytogenet. 2005;163(2):113–22. doi: 10.1016/j.cancergencyto.2005.05.006.
30. Guillermo M, Benton C, Wang S, et al. More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia. Blood. 2017;129(18):2584–7. doi: 10.1182/blood-2016-11-749903.
31. Almeida A, Prebet T, Itzykson R, et al. Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study. Int J Mol Sci. 2017;18(4):837. doi: 10.3390/ijms18040837.
32. Taylor J, Kim SS, Stevenson KE, et al. Loss-Of-Function Mutations In The Splicing Factor ZRSR2 Are Common In Blastic Plasmacytoid Dendritic Cell Neoplasm and Have Male Predominance. Blood. 2013;122(21):741. doi: 10.1182/blood.v122.21.741.741.
33. Voelkl A, Flaig M, Roehnisch T, et al. Blastic plasmacytoid dendritic cell neoplasm with acute myeloid leukemia successfully treated to a remission currently of 26 months duration. Leuk Res. 2011;35(6):61–3. doi: 10.1016/j.leukres.2010.11.019.
34. Facchetti F, Wolf-Peeters CD, Kennes C, et al. Leukemia-associated lymph node infiltrates of plasmacytoid monocytes (so-called plasmacytoid T-cells). Evidence for two distinct histological and immunophenotypical patterns. Am J Surg Pathol. 1990;14(2):101–12. doi: 10.1097/00000478-199002000-00001.
35. Fitzgerald-Bocarsly P. Human natural interferon-alpha producing cells. Pharmacol Ther. 1993;60(1):39–62. doi: 10.1016/0163-7258(93)90021-5.
36. Liu Y-J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors Annu Rev Immunol. 2005;23(1):275–306. doi: 10.1146/annurev.immunol.23.021704.115633.
37. Colonna M, Trinchieri G, Liu Y-J. Plasmacytoid dendritic cells in immunity. Nat Immunol. 2004;5(12):1219–26. doi: 10.1038/ni1141.
38. Gill MА, Bajwa G, George TA, et al. Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells. J Immunol. 2010;184(11):5999–6006. doi: 10.4049/jimmunol.0901194.
39. Shi Y, Wang E. Blastic Plasmacytoid Dendritic Cell Neoplasm: A Clinicopathologic Review. Arch Pathol Lab Med. 2014;138(4):564–9. doi: 10.5858/ 2013–0101-rs.
40. Zheng YY, Chen G, Zhou XG, et al. Retrospective analysis of 4 cases of the so-called blastic NK-cell lymphoma, with reference to the 2008 WHO classification of tumors of haematopoietic and lymphoid tissues. Zhonghua Bing Li Xue Za Zhi. 2010;39(9):600–5.
41. Takiuchi Y, Maruoka H, Aoki K, et al. Leukemic manifestation of blastic plasmacytoid dendritic cell neoplasm lacking skin lesion: a borderline case between acute monocytic leukemia. J Clin Exp Hematopathol. 2012;52(2):107–11. doi: 10.3960/jslrt.52.107.
42. Petrella T, Comeau MR, Maynadie M, et al. Agranular CD4+ CD56+ hematodermic neoplasm’ (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes. Am J Surg Pathol. 2002;26(7):852–62. doi: 10.1097/00000478-200207000-00003.
43. Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms). Am J Clin Pathol. 2005;123(5):662–75. doi: 10.1309/gjwnpd8hu5maj837.
44. Garnache-Ottou F, Vidal C, Biichle S, et al. How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients. Blood Adv. 2019;3(24):4238–51. doi: 10.1182/bloodadvances.2019000647.
45. Lucioni M, Novara F, Fiandrino G, et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood. 2011;118(17):4591–4. doi: 10.1182/blood-2011-03-337501.
46. Dijkman R, Doorn R, Szuhai K, et al. Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood. 2007;109(4):1720–7. doi: 10.1182/blood-2006-04-018143.
47. Sapienza MR, Fuligni F, Agostinelli C, et al. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition. Leukemia. 2014;28(8):1606–16. doi: 10.1038/leu.2014.64.
48. Menezes J, Acquadro F, Wiseman M, et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia. 2014;28(4):823–9. doi: 10.1038/leu.2013.283.
49. Stenzinger A, Endris V, Pfarr N, et al. Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm. Oncotarget. 2014;5(15):6404–13. doi: 10.18632/oncotarget.2223.
50. Cota C, Vale E, Viana I, et al. Cutaneous manifestations of blastic plasmacytoid dendritic cell neoplasm-morphologic and phenotypic variability in a series of 33 patients. Am J Surg Pathol. 2010;34(1):75–87. doi: 10.1097/PAS.0b013e3181c5e26b.
51. Jacob MC, Chaperot L, Mossuz P, et al. CD4+ CD56+ lineage negative malignancies: a new entity developed from malignant early plasmacytoid dendritic cells. Haematologica. 2003;88(8):941–55.
52. Julia F, Petrella T, Beylot-Barry M, et al. Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients. Br J Dermatol. 2013;169(3):579–86. doi: 10.1111/bjd.12412.
53. Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study. Haematologica. 2013;98(2):239–46. doi: 10.3324/haematol.2012.072645.
54. Trottier AM, Cerquozzi S, Owen CJ. Blastic plasmacytoid dendritic cell neoplasm: challenges and future prospects. Blood Lymphat Cancer. 2017;7:85–93. doi: 10.2147/blctt.s132060.
55. Riaz W, Zhang L, Horna P, Sokol L. Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. Cancer Control. 2014;21(4):279–89. doi: 10.1177/107327481402100404.
56. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, et al. Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: A focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19(7):1006–12. doi: 10.1016/j.bbmt.2013.01.027.
57. Gruson B, Vaida I, Merlusca L, et al. L-asparaginase with methotrexate and dexamethasone is an effective treatment combination in blastic plasmacytoid dendritic cell neoplasm. Br J Haematol. 2013;163(4):543–5. doi: 10.1111/bjh.12523.
58. Gilis L, Lebras L, Bouafia-Sauvy F, et al. Sequential combination of high dose methotrexate and L-asparaginase followed by allogeneic transplant: A first-line strategy for CD4+/CD56+ hematodermic neoplasm. Leuk Lymphoma. 2012;53(8):1633–7. doi: 10.3109/10428194.2012.656627.
59. Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: An Italian multicenter study. Haematologica. 2013;98(2):239–46. doi: 10.3324/haematol.2012.072645.
60. Tsagarakis NJ, Kentrou NA, Papadimitriou K, et al. Acute lymphoplasmacytoid dendritic cell (DC2) leukemia: Results from the Hellenic Dendritic Cell Leukemia Study Group. Leuk Res. 2010;34(4):438–46. doi: 10.1016/j.leukres.2009.09.006.
61. Deotare U, Yee KWL, Le LW, et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10-Color flow cytometry diagnosis and HyperCVAD therapy: BPDCN Diagnosis and Therapy. Am J Hematol. 2016;91(3):283–6. doi: 10.1002/ajh.24258.
62. Bekkenk MW, Jansen PM, Meijer CJLM, Willemze R. CD56+ hematological neoplasms presenting in the skin: A retrospective analysis of 23 new cases and 130 cases from the literature. Ann Oncol. 2004;15(7):1097–108. doi: 10.1093/annonc/mdh268.
63. Khwaja R, Daly A, Wong M, et al. Azacitidine in the treatment of blastic plasmacytoid dendritic cell neoplasm: A report of 3 cases. Leuk Lymphoma. 2016;57(11):2720–2. doi: 10.3109/10428194.2016.1160084.
64. Laribi K, Denizon N, Ghnaya, H, et al. Blastic plasmacytoid dendritic cell neoplasm: The first report of two cases treated by 5-azacytidine. Eur J Haematol. 2014;93(1):81–5. doi: 10.1111/ejh.12294.
65. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. doi: 10.1182/blood-2018-08-868752.
66. DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93(3):401–7. doi: 10.1002/ajh.25000.
67. Agha ME, Monaghan SA, Swerdlow SH, et al. Venetoclax in a Patient with a Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med. 2018;379(15):1479–81. doi: 10.1056/NEJMc1808354.
68. Pemmaraju N, Lane AA, Sweet K, et al. Results of pivotal phase 2 clinical trial of tagraxofusp (sl-401) in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). HemaSphere. 2019;3(S1):481. doi: 10.1097/01.hs9.0000562548.32991.bc.
69. Dubois SG, Etzell JE, Matthay KK, et al. Pediatric acute blastic natural killer cell leukemia. Leuk Lymphoma. 2002;43(4):901–6. doi: 10.1080/10428190290017088.
70. Hyakuna N, Toguchi S, Higa T, et al. Childhood blastic NK cell leukemia successfully treated with L-asparaginase and allogeneic bone marrow transplantation. Pediatr Blood Cancer. 2004;42(7):631–4. doi: 10.1002/pbc.20034.
71. Liang X, Greffe B, Garrington T, Graham DK. Precursor natural killer cell leukemia. Pediatr Blood Cancer. 2008;50(4):876–8. doi: 10.1002/pbc.21189.
72. Matano S, Nakamura S, Nakamura S, et al. Monomorphic agranular natural killer cell lymphoma/leukemia with no Epstein-Barr virus association. Acta Haematol. 1999;101(4):206–8. doi: 10.1159/000040955.
73. Suzuki Y, Kato S, Kohno K, et al. Clinicopathological analysis of 46 cases with CD4+ and/or CD56+ immature haematolymphoid malignancy: reappraisal of blastic plasmacytoid dendritic cell and related neoplasms. 2017;71(6):972–84. doi: 10.1111/his.13340.
74. Khoury JD. Blastic Plasmacytoid Dendritic Cell Neoplasm. Curr Hematol Malig Rep. 2018;13(6):477–83. doi: 10.1007/s11899-018-0489-z.
75. Julia F, Dalle S, Duru G, et al. Blastic plasmacytoid dendritic cell neoplasms: clinico-immunohistochemical correlations in a series of 91 patients. Am J Surg Pathol. 2014;38(5):673–80. doi: 10.1097/pas.0000000000000156.
76. Massone C, Chott A, Metze D, et al. Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol. 2004;28(6):719–35. doi: 10.1097/01.pas.0000126719.71954.4f.
77. Santucci M, Pimpinelli N, Massi D, et al. Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer. 2003;97(3):610–27. doi: 10.1002/cncr.11107.
78. Sanchez MJ, Muench MO, Roncarolo MG, et al. Identification of a common T/natural killer cell progenitor in human fetal thymus. J Exp Med. 1994;180(2):569–76. doi: 10.1084/jem.180.2.569.
79. Oshimi K. Progress in understanding and managing natural killer-cell malignancies. Br J Haematol. 2007;139(4):532–44. doi: 10.1111/j.1365-2141.2007.06835.x.
80. Grzywacz B, Kataria N, Kataria N, et al. Natural killer-cell differentiation by myeloid progenitors. Blood. 2011;117(13):3548–58. doi: 10.1182/blood-2010-04-281394.
81. Suzuki R, Nakamura S, Suzumiya J, et al. Blastic natural killer cell lymphoma/leukemia (CD56-positive blastic tumor). Cancer. 2005;104(5):1022–31. doi: 10.1002/cncr.21268.
82. Sedick Q, Alotaibi S, Alshieban S, et al. Natural Killer Cell Lymphoblastic Leukaemia/Lymphoma: Case Report and Review of the Recent Literature. Case Rep Oncol. 2017;10(2):588–95. doi: 10.1159/000477843.
83. Spits H, Lanier LL, Phillips JH. Development of human T and natural killer cells. Blood. 1995;85(10):2654–70. doi: 10.1182/blood.v85.10.2654.bloodjournal85102654.
84. Marquez C, Trigueros C, Franco JM, et al. Identification of a common developmental pathway for thymic natural killer cells and dendritic cells. Blood. 1998;91(8):2760–71. doi: 1182/blood.v91.8.2760.2760_2760_2771.
85. Hanna J, Gonen-Gross T, Fitchett J, et al. Novel APC-like properties of human NK cells directly regulate T cell activation. J Clin Invest. 2004;114(11):1612–23. doi: 10.1172/jci22787.
86. Spits H, Lanier LL. Natural killer or dendritic: what’s in a name? Immunity. 2007;26(1):11–6. doi: 10.1016/j.immuni.2007.01.004.
87. Френкель М.А., Баранова О.Ю., Антипова А.С. и др. NK-клеточный лимфобластный лейкоз/лимфома (обзор литературы и собственные наблюдения). Клиническая онкогематология. 2016;9(2):208–17. doi: 10.21320/2500-2139-2016-9-2-208-217.
    [Frenkel’ MA, Baranova OYu, Antipova AS, et al. NK-Cell Lymphoblastic Leukemia/Lymphoma (Literature Review and Authors’ Experience). Clinical oncohematology. 2016;9(2):208–17. doi: 10.21320/2500-2139-2016-9-2-208-217. (In Russ)]
88. Coustan-Smith E, Mullighan CG, 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)70314-0.
89. Inukai T, Kiyokawa N, Campana D, et al. Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children’s Cancer Study Group Study L99-15. Br J Haematol 2012;156(3):358–65. doi: 10.1111/j.1365-2141.2011.08955.x.
90. Wood B, Winter S, Dunsmore K, et al. Patients with early T-сell precursor (ETP) acute lymphoblastic leukemia (ALL) have high levels of minimal residual disease (MRD) at the of induction-A Children’s Oncology Group (COG) Study. Blood. 2009;114(22):9. doi: 10.1182/blood.v114.22.9.9.
91. Sin C-F, Man PM. Early T-Cell Precursor Acute Lymphoblastic Leukemia: Diagnosis, Updates in Molecular Pathogenesis, Management, and Novel Therapies. Front Oncol. 2021;11:750789. doi: 10.3389/fonc.2021.750789.
92. Neumann M, Coskun E, Fransecky L, et al. FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors. PLoS One. 2013;8(1):e53190. doi: 10.1371/journal.pone.0053190.
93. Neumann M, Heesch S, Schlee C, et al. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood. 2013;121(23):4749–52. doi: 10.1182/blood-2012-11-465138.
94. Van Vlierberghe P, Ambesi-lmpiombato A, Perez-Garcia A, et al. ETV6 mutations in early immature human T cell leukemias. J Exp Med. 2011;208(13):2571–9. doi: 10.1084/jem.20112239.
95. Conter V, Valsecchi MG, Buldini B, et al. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis. Lancet Haematol. 2016;3(2):e80–е86. doi: 10.1016/S2352-3026(15)00254-9.
96. Ma M, Wang X, Tang J, et al. Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia. Front Med. 2012;6(4):416–20. doi: 10.1007/s11684-012-0224-4.
97. Wood BL, Winter SS, Dunsmore KP, et al. T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s Oncology Group (COG) Study AALL0434. Blood. 2014;124(21):1. doi: 10.1182/blood.v124.21.1.1.
98. Bond J, Marchand T, Touzart A, et al. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. Haematologica. 2016;101(6):732–40. doi: 10.3324/haematol.2015.141218.
99. McEwan A, Pitiyarachchi O, Viiala Relapsed/Refractory ETP-ALL Successfully Treated With Venetoclax and Nelarabine as a Bridge to Allogeneic Stem Cell Transplant. HemaSphere 2020;4(3):e379. doi: 10.1097/hs9.0000000000000379.
100. Mullighan C, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80. doi: 10.1056/NEJMoa0808253.
101. Mullighan C, Zhang J, Harvey R, еt al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2009;106(23):9414–8. doi: 10.1073/pnas.0811761106.
102. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–34. doi: 10.1016/S1470-2045(08)70339-5.
103. Корзик А.В., Вшивкова О.С. BCR-ABL1-подобный острый лимфобластный лейкоз: от биологии к перспективным методам терапии. Гематология. Трансфузиология. Восточная Европа. 2021;7(3):313–27. doi: 10.34883/PI.2021.7.3.005.
     [Korzik AV, Vshyukova OS. BCR-ABL1-like acute lymphoblastic leukemia: from biology to promising therapies. Hematology. Transfusiology. Eastern Europe. 2021;7(3):313–27. doi: 10.34883/PI.2021.7.3.005. (In Russ)]
104. Цаур Г.А., Ольшанская Ю.В., Друй А.Е. BCR-ABL1-подобный острый лимфобластный лейкоз у детей. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2019;18(1):112‒26. doi: 10.24287/1726-1708-2019-18-1-112-126.
     [Tsaur GA, Olshanskaya YuV, Druy AE. BCR-ABL1-like pediatric acute lymphoblastic leukemia. Pediatric Hematology/Oncology and Immunopathology. 2019;18(1):112–126. doi: 10.24287/1726-1708-2019-18-1-112-126. (In Russ)]
105. Boer JM, Koenders JE, van der Holt B, et al. Expression profiling of adult acute lymphoblastic leukemia identifies a BCR-ABL 1-like subgroup characterized by high non-response and relapse rates. Haematologica. 2015;100(7):e261–е264. doi: 10.3324/haematol.2014.117424.
106. Boer JM, Marchante JR, Evans WE, et al. (2015). BCR-ABL 1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures. Haematologica. 2015;100(9):e354–е357. doi: 10.3324/haematol.2015.124941.
107. Roberts KG, Pei D, Campana D, et al. Outcomes of children with BCR-ABL 1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32(27):3012–20. doi: 10.1200/JCO.2014.55.4105.
108. Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31(25):e413–е416. doi: 10.1200/JCO.2012.47.6770.
109. Xu X-Q, Wang J-M, Lu S-Q, et al. Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population. Haematologica. 2009;94(7):919–27. doi: 10.3324/haematol.2008.003202.
110. Rubnitz JE, Onciu M, Pounds S, et al. Acute mixed lineage leukemia in children: the experience of St Jude Children’s Research Hospital. Blood. 2009;113(21):5083–9. doi: 10.1182/blood-2008-10-187351.
111. Mirro J, Zipf TF, Pui HC, et al. Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance. Blood. 1985;66(5):1115–23. doi: 1182/blood.v66.5.1115.bloodjournal6651115.
112. Gale RP, Ben Bassat I. Hybrid acute leukaemia. Br J Haematol. 1987;65(3):261–4. doi: 10.1111/j.1365-2141.1987.tb06851.x.
113. Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. 1995;9(10):1783–6.
114. Catovsky D, Matutes E, Buccheri V, et al. A classification of acute leukaemia for the 1990s. Ann Hematol. 1991;62(1):16–21. doi: 10.1007/BF01714978.
115. Bene MC, Bernier M, Casasnovas RO, et al. The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. The European Group for the Immunological Classification of Leukemias (EGIL). Blood. 1998;92(2):596–9.1182/blood.v92.2.596.414k05_596_599.
116. Manola KN. Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview. Br J Haematol. 2013;163(1):24–39. doi: 1111/bjh.12484.
117. Matutes E, Pickl WF, Van’t Veer M, et al. Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. 2011;117(11):3163–71. doi: 10.1182/blood-2010-10-314682.
118. Gerr H, Zimmermann M, Schrappe M, et al. Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J 2010;149(1):84–92. doi: 10.1111/j.1365-2141.2009.08058.x.
119. Maruffi M, Sposto R, Oberley MJ, et al. Therapy for children and adults with mixed phenotype acute leukemia: a systematic review and meta-analysis. Leukemia. 2018;32(7):1515–28. doi: 10.1038/s41375-018-0058-4.
120. Al-Seraihy AS, Owaidah TM, Ayas M, et al. Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica. 2009;94(12):1682–90. doi: 10.3324/haematol.2009.009282.
121. Orgel E, Alexander TB, Wood BL, et al. Mixed-phenotype acute leukemia: a cohort and consensus research strategy from the Children’s oncology group acute leukemia of ambiguous lineage task force. Cancer. 2020;126(3):593–601. doi: 10.1002/cncr.32552.
122. Hrusak O, de Haas V, Stancikova J, et al. International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood. 2018;132(3):264–76. doi: 1182/blood-2017-12-821363.
123. Wolach O, Stone RM. Optimal therapeutic strategies for mixed phenotype acute leukemia. Curr Opin Hematol. 2020;27(2):95–102. doi: 1097/moh.0000000000000570.
124. Shimizu H, Yokohama A, Hatsumi N, et al. Philadelphia chromosome-positive mixed phenotype acute leukemia in the imatinib era. Eur J Haematol. 2014;93(4):297–301. doi: 10.1111/ejh.12343.
125. Qasrawi A, Ramlal R, Munker R, Hildebrandt GC. Prognostic impact of Philadelphia chromosome in mixed phenotype acute leukemia (MPAL): A cancer registry analysis on real-world outcome. Am J Hematol. 2020;95(9):1015–21. doi: 10.1002/ajh.25873.
126. Park JA, Ghim TT, Bae K, et al. Stem cell transplant in the treatment of childhood biphenotypic acute leukemia. Pediatr Blood Cancer. 2009;53(3):444–52. doi: 10.1002/pbc.22105.
127. Tian H, Xu Y, Liu L, et al. Comparison of outcomes in mixed phenotype acute leukemia patients treated with chemotherapy and stem cell transplantation versus chemotherapy alone. Leuk Res. 2016;45:40–6. doi: 10.1016/j.leukres.2016.04.002.
128. Munker R, Brazauskas R, Wang HL, et al. Allogeneic hematopoietic cell transplantation for patients with mixed phenotype acute leukemia. Biol Blood Marrow Transplant. 2016;22(6):1024–9. doi: 10.1016/j.bbmt.2016.02.013.
129. Rossi JG, Bernasconi AR, Alonso CN, et al. Lineage switch in childhood acute leukemia: an unusual event with poor outcome. Am J Hematol. 2012;87(9):890–7. doi: 10.1002/ajh.23266.
130. Dorantes-Acosta E, Pelayo R. Lineage switching in acute leukemias: a consequence of stem cell plasticity? Bone Marrow Res. 2012;2012:406796. doi: 10.1155/2012/406796.
131. Rath A, Panda T, Dhawan R, et al. A paradigm shift: lineage switch from T-ALL to B/myeloid MPAL. Blood Res. 2021;56(1):50–3. doi: 10.5045/br.2021.2020268.
132. Kobayashi S, Teramura M, Mizoguchi H, Tanaka J. Double Lineage Switch from Acute Megakaryoblastic Leukemia (AML-M7) to Acute Lymphoblastic Leukemia (ALL) and Back Again: A Case Report. J Blood Disorders Transf. 2014;5(3):199. doi: 10.4172/2155-9864.1000199.
133. Lounici A, Cony-Makhoul P, Dubus P, et al. Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia: report of an adult case and review of the literature. Am J Hematol. 2000;65(4):319–21. doi: 10.1002/1096-8652(200012)65:4<319::aid-ajh13>3.0.co;2-1.
134. Mantadakis E, Danilatou V, Stiakaki E, et al. T-cell acute lymphoblastic leukemia relapsing as acute myelogenous leukemia. Pediatr Blood Cancer. 2007;48(3):354–7. doi: 10.1002/pbc.20543.
135. Emami A, Ravindranath Y, Inoue S, et al. Phenotypic change of acute monocytic leukemia to acute lymphoblastic leukemia on therapy. Am J Pediatr Hematol Oncol. 1983;5(4):341–3. doi: 10.1097/00043426-198324000-00004.
136. Hatae Y, Yagyu K, Yanazume N, et al. Lineage switch on recurrence from minimally differentiated acute leukemia (M0) to acute megakaryocytic leukemia (M7). Rinsho Ketsueki. 2002;43(7):543–7.
137. Haddox C, Mangaonkar A, Chen D, et al. Blinatumomab-induced lineage switch of B-ALL with t(4:11)(q21;q23) KMT2A/AFF1 into an aggressive AML: pre- and post-switch phenotypic, cytogenetic and molecular analysis. Blood Cancer. 2017;7(9):e607. doi: 10.1038/bcj.2017.89.
138. Gentles AJ, Plevritis SK, Majeti R, et al. Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA. 2010;304(24):2706–15. doi: 10.1001/jama.2010.1862.
139. Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med. 2004;350(16):1617–28. doi: 10.1056/NEJMoa040465.
140. Beck K. Plasticity Cell Definition. Available from: https://sciencing.com/plasticity-cell-definition-6239472.html. (accessed 06.2022).
141. Shannon K, Armstrong SA. Genetics, epigenetics, and leukemia. N Engl J Med. 2010;363(25):2460–1. doi: 10.1056/NEJMe1012071.
142. He X, Li C, Kapinova A, Nguyen K. Stem cell plasticity: fact or fiction. Available from: https://web.wpi.edu/Pubs/E-project/Available/E-project-082713-220018/unrestricted/8-27-13__Stem-2_Final_IQP_Report.pdf. (accessed 06.2022).
143. Corbett JL, Tosh D. Conversion of one cell type into another: implications for understanding organ development, pathogenesis of cancer and generating cells for therapy. Biochem Soc Trans. 2014;42(3):609–16. doi: 10.1042/BST2014005.
144. Kondo M, Scherer DC, Miyamoto T, et al. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature. 2000;407(6802):383–6. doi: 10.1038/35030112.
145. Bell JJ, Bhandoola A. The earliest thymic progenitors for T-cells possess myeloid lineage potential. Nature. 2008;452(7188):764–7. doi: 10.1038/nature06840.
146. Зеркаленкова Е.А., Илларионова О.И., Казакова А.Н. и др. Смена линейной дифференцировки в рецидиве острого лейкоза с перестройкой гена MLL (KMT2A). Обзор литературы и описание случаев. Онкогематология. 2016;11(2):21–9. doi: 10.17650/1818-8346-2016-11-2-21-29.
     [Zerkalenkova EA, Illarionova OI, Kazakova AN, et al. Lineage switch in relapse of acute leukemia with rearrangement of MLL gene (KMT2A). Literature review and case reports. Oncohematology. 2016;11(2):21–9. doi: 10.17650/1818-8346-2016-11-2-21-29. (In Russ)]
147. Представление о кроветворении и стволовых кроветворных клетках [электронный документ]. Доступно по: http://www.ispms.ru/files/Publications/sharkeev_2013/pdf/4_19.pdf. Ссылка активна на 02.06.2022.
     [A view on hematopoiesis and hematopoietic stem cells (Internet). Available from: http://www.ispms.ru/files/Publications/sharkeev_2013/pdf/4_19.pdf. Accessed 02.06.2022. (In Russ)]
148. Ramesh T, Lee SH, Lee CS, et al. Somatic cell dedifferentiation/reprogramming for regenerative medicine. Int J Stem Cells. 2009;2(1):18–27. doi: 10.15283/ijsc.2009.2.1.18.
149. Oliveri RS. Epigenetic dedifferentiation of somatic cells into pluripotency: cellular alchemy in the age of regenerative medicine? Regen Med. 2007;2(5):795–816. doi: 2217/17460751.2.5.795.