Hodgkin’s Lymphoma: Analysis Results of Volgograd Regional Registry

KD Kaplanov1,2, NP Volkov1, TYu Klitochenko1, IV Matveeva1, AL Shipaeva1, MN Shirokova1, NV Davydova3, EG Gemdzhian4

1 Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

2 Volgograd Medical Scientific Center, 1G Rokossovskogo str., Volgograd, Russian Federation, 400081

3 Consultation and Diagnosis Polyclinic No. 2, 114A Angarskaya str., Volgograd, Russian Federation, 400081

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

For correspondence: Kamil Daniyalovich Kaplanov, MD, PhD, 78 Zemlyachki str., Volgograd, Russian Federation, 400138; e-mail: kamilos@mail.ru

For citation: Kaplanov KD, Volkov NP, Klitochenko TYu, et al. Hodgkin’s Lymphoma: Analysis Results of Volgograd Regional Registry. Clinical oncohematology. 2019;12(4):363–76 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-363-376


ABSTRACT

Background. The present paper discusses feasibility of first- and second-line therapies as well as the significance of different risk factors in the population of all patients with newly diagnosed Hodgkin’s lymphomas (HL) in a 14-year period based on the data of Volgograd regional registry.

Materials & Methods. During the period 2003 to 2017 the population registry of Department of Hematology of Volgograd Regional Clinical Oncology Dispensary included the data of all the patients with newly diagnosed HL (n = 622): 272 (44 %) men and 350 (56 %) women aged 18 to 84 years (mean age 38 years, median age 33 years). There were 97 (16 %) patients with early stages and without risk factors, 165 (27 %) patients with early stages and risk factors, 360 (59 %) patients with advanced stages, 308 (50 %) patients with toxic symptoms (stage B), and 179 (29 %) patients with bulky tumor lesions (≥ 10 cm). ABVD treatment regimen was administered in 190 (30.5 %) patients, increased-dose BEACO(D)PP in 39 (6 %) patients, BEACO(D)PP-14 in 159 (26 %) patients, standard BEACO(D)PP in 200 (32 %) patients, IVDG in 25 (4 %) patients, and other regimens in 9 (1.5 %) patients. The second-line treatment was administered in 120 (19 %) out of 622 patients. By the end of August 2018, the number of followed-up patients was 514 (83 %), 108 (17 %) patients had died. The prognostic value of the International Prognostic Score (IPS), PET, and other factors was assessed by means of Cox’s multivariate regression analysis. Pharmacoeconomic analysis of differences between options of first-line therapy was based on Markov model.

Results. In the group of patients with advanced HL stages treated with escalated BEACO(D)PP (the increased-dose regimen and BEACO(D)PP-14) 5- and 10-year overall survival (OS) was 83 % and 74 %, respectively, OS median was not reached. On standard BEACO(D)PP patients with advanced HL stages had OS median of 139 months (11.6 years) and 5- and 10-year OS of 68 % and 54 %, respectively (= 0,012). In the group of patients with early stages and poor prognosis treated with escalated regimens BEACO(D)PP 5- and 10- year OS was 100 % and 90 %, respectively, in the combined group treated with ABVD and standard BEACO(D)PP it was 83 % and 75 % (= 0.035). Replacement of procarbazine with dacarbazine in the standard and increased-dose BEACOPP regimens did not affect treatment efficacy. Markov analysis demonstrated the advantages of the escalated regimens for treatment of early stages with poor prognosis and advanced stages in terms of life years gained. Out of 7 IPS factors male sex, age ≥ 45 years, hemoglobin < 105 g/L, and albumin < 40 mg/L significantly impacted OS. Based on these data an adjusted prognostic index was suggested.

Conclusion. The advantage of the escalated strategy of first-line therapy in HL is reflected in survival parameters and is based on pharmacoeconomic evidence. The significance of some laboratory IPS risk factors can be reviewed; most obvious is increasing importance of PET for predicting the need for salvage therapy.

Keywords: Hodgkin’s lymphoma, BEACO(D)PP, ABVD, International Prognostic Score, survival analysis, pharmacoeconomics, Markov model, life years gained (LYG), incremental cost-effectiveness ratio (ICER).

Received: February 21, 2019

Accepted: September 17, 2019

Read in PDF


REFERENCES

  1. Jaffe ES, Arber DA, Campo E, et al. Hematopathology, 2nd edition. Elsevier Ltd.; 2017. 1216 p.

  2. Glaser SL, Jarrett RF. The epidemiology of Hodgkin’s disease. Baill Clin Haematol. 1996;9(3):401–16. doi: 10.1016/s0950-3536(96)80018-7.

  3. Злокачественные новообразования в России в 2017 г. (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, Г.В. Петровой. М.: МНИОИ им. П.А. Герцена, 2018. 250 с.

    [Kaprin AD, Starinskii VV, Petrova GV, eds. Zlokachestvennye novoobrazovaniya v Rossii v 2017 godu (zabolevaemost’ i smertnost’). (Malignancies in Russia in 2017: incidence and mortality.) Moscow: MNIOI im. P.A. Gertsena; 2018. 250 p. (In Russ)]

  4. Grufferman S, Cole P, Smith PG, et al. Hodgkin’s disease in siblings. N Engl J Med. 1977;296(5):248–50. doi: 10.1056/NEJM197702032960504.

  5. Lynch HT, Marcus JN, Lynch JF. Genetics of Hodgkin’s and non-Hodgkin’s lymphoma: a review. Cancer Invest. 1992;10(3):247–56. doi: 10.3109/07357909209032768.

  6. Mack TM, Cozen W, Shibata DK, et al. Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N Engl J Med. 1995;332(7):413–8. doi: 10.1056/NEJM199502163320701.

  7. Horwitz M, Wiernik PH. Pseudoautosomal linkage of Hodgkin disease. Am J Hum Genet. 1999;65(5):1413–22. doi: 10.1086/302608.

  8. Weiss LM, Strickler JG, Warnke RA, et al. Epstein-Barr viral DNA in tissues of Hodgkin’s disease. Am J Pathol. 1987;129(1):86–91.

  9. Alexander FE, Jarrett RF, Lawrence D, et al. Risk factors for Hodgkin’s disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br J Cancer. 2000;82(5):1117–21. doi: 10.1054/bjoc.1999.1049.

  10. Andrieu JM, Roithmann S, Tourani JM, et al. Hodgkin’s disease during HIV1 infection: the French registry experience. French Registry of HIV-associated Tumors. Ann Oncol. 1993;4(8):635–41. doi: 10.1093/oxfordjournals.annonc.a058617.

  11. Tirelli U, Errante D, Dolcetti R, et al. Hodgkin’s disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol. 1995;13(7):1758–67. doi: 10.1200/JCO.1995.13.7.1758.

  12. Tubiana M, Henry-Amar M, Carde P, et al. Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II Hodgkin’s disease. The EORTC Lymphoma Group controlled clinical trials: 1964–1987. Blood. 1989;73(1):47–56.

  13. Diehl V, Stein H, Hummel M, et al. Hodgkin’s lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease. Hematology. 2003;2003(1):225–47. doi: 10.1182/asheducation-2003.1.225.

  14. Hasenclever D, Diehl V, Armitage JO, et al. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506–14. doi: 10.1056/NEJM199811193392104.

  15. Andre MP, Girinsky T, Federico M, et al. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017;35(16):1786–94. doi: 10.1200/JCO.2016.68.6394.

  16. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016;374(25):2419–29. doi: 10.1056/NEJMoa1510093.

  17. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77. doi: 10.1182/blood-2010-05-282780.

  18. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34(23):2690–7. doi: 10.1200/JCO.2016.66.4482.

  19. Roemer MGM, Redd RA, Cader FZ, et al. Major histocompatibility complex Class II and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic Hodgkin lymphoma. J Clin Oncol. 2018;36(10):942–50. doi: 10.1200/JCO.2017.77.3994.

  20. Liu L, Giusti F, Schaapveld M, et al. Survival differences between patients with Hodgkin lymphoma treated inside and outside clinical trials. A study based on the EORTC-Netherlands Cancer Registry linked data with 20 years of follow-up. Br J Haematol. 2017;176(1):65–75. doi: 10.1111/bjh.14379.

  21. Капланов К.Д., Шипаева А.Л., Васильева В.А. и др. Эффективность программ химиотерапии первой линии при различных стадиях лимфомы Ходжкина. Клиническая онкогематология. 2012;5(1):22–9.

    [Kaplanov KD, Shipaeva AL, Vasil’eva VA, et al. Efficacy of first line chemotherapy programs for different stages of Hodgkin’s lymphomas. Klinicheskaya onkogematologiya. 2012;5(1):22–9. (In Russ)]

  22. Капланов К.Д., Шипаева А.Л., Васильева В.А. и др. Международный прогностический индекс при распространенных стадиях лимфомы Ходжкина в условиях современной терапии. Клиническая онкогематология. 2013;6(3):294–302.

    [Kaplanov KD, Shipaeva AL, Vasil’eva VA, et al. International prognostic score in advanced Hodgkin’s lymphoma. Klinicheskaya onkogematologiya. 2013;6(3):294–302. (In Russ)]

  23. Капланов К.Д., Волков Н.П., Клиточенко Т.Ю. и др. Первая линия терапии лимфомы из клеток зоны мантии: анализ эффективности и клинико-экономическая оценка. Клиническая онкогематология. 2018;11(2):150–9. doi: 10.21320/2500-2139-2018-11-2-150-159.

    [Kaplanov KD, Volkov NP, Klitochenko TYu, et al. First-Line Treatment of Mantle-Cell Lymphoma: Analysis of Effectiveness and Cost-Effectiveness. Clinical oncohematology. 2018;11(2):150–9. doi: 10.21320/2500-2139-2018-11-2-150-159. (In Russ)]

  24. Капланов К.Д., Волков Н.П., Клиточенко Т.Ю. и др. Результаты анализа регионального регистра пациентов с диффузной В-крупноклеточной лимфомой: факторы риска и проблемы иммунохимиотерапии. Клиническая онкогематология. 2019;12(2):154–64. doi: 10.21320/2500-2139-2019-12-2-154-164.

    [Kaplanov KD, Volkov NP, Klitochenko TYu, et al. Analysis Results of the Regional Registry of Patients with Diffuse Large B-cell Lymphoma: Risk Factors and Chemo-Immunotherapy Issues. Clinical oncohematology. 2019;12(2):154–64. doi: 10.21320/2500-2139-2019-12-2-154-164. (In Russ)]

  25. Kaplanov K, Klitochenko T, Shipaeva A, et al. Combination of idarubicin, vinblastine, dacarbazine, and gemcitabine (IVDG) as therapy for elderly patients with Hodgkin lymphoma with cardiac and pulmonary comorbidity. Hematol Oncol. 2017;35(Suppl 2):317. doi: 1002/hon.2439_57.

  26. Капланов К.Д., Клиточенко Т.Ю., Шипаева А.Л. и др. Программа IVDG — возможный выбор первой линии терапии лимфомы Ходжкина у пациентов пожилого возраста с сопутствующими сердечно-сосудистыми и легочными заболеваниями. Клиническая онкогематология. 2017;10(3):358–65. doi: 10.21320/2500-2139-2017-10-3-358-365.

    [Kaplanov KD, Klitochenko TYu, Shipaeva АL, et al. The IVDG Regimen is the Possible Treatment of Choice as First Line Therapy For Hodgkin’s Lymphoma in Elderly Patients with Cardiovascular and Pulmonary Comorbidity. Clinical oncohematology. 2017;10(3):358–65. doi: 10.21320/2500-2139-2017-10-3-358-365. (In Russ)]

  27. Bosh TM. Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy. Meth Mol Biol. 2008;448:63–76. doi: 10.1007/978-1-59745-205-2_5.

  28. Lee NH. Pharmacogenetics of drug metabolizing enzymes and transporters: effects on pharmacokinetics and pharmacodynamics of anticancer agents. Anti-cancer Agents Med Chem. 2010;10(8):583–92. doi: 10.2174/187152010794474019.

  29. Ekhart C, Rodenhuis S, Smits PH, et al. An overview of the relations between polymorphisms in drug metabolising enzymes and drug transporters and survival after cancer drug treatment. Cancer Treat Rev. 2009;35(1):18–31. doi: 10.1016/j.ctrv.2008.07.003.

  30. Von Treschkow B, Kreissl S, Goergen H, et al. Intensive treatment strategies in advanced stage Hodgkin’s lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trial. Lancet Haematol. 2018;5(10):e462–e473. doi: 10.1016/S2352-3026(18)30140-6.

  31. Skoetz N, Will A, Monsef I. Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavorable or advanced stage Hodgkin lymphoma. Cochrane Database Syst Rev. 2017;5:CD007941. doi: 10.1002/14651858.CD007941.pub3.

  32. Rancea M, Monsef I, von Tresckow B, et al. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev. 2013;6:CD009411. doi: 10.1002/14651858.CD009411.pub2.

  33. von Tresckow B, Moskowitz CH. Treatment of relapsed and refractory Hodgkin lymphoma. Semin Hematol. 2016;53(3):180–5. doi: 10.1053/j.seminhematol.2016.05.010.

  34. Kobe C, Goergen H, Baues C, et al. Outcome-based interpretation of early interim PET in advanced-stage Hodgkin lymphoma. Blood. 2018;132(21):2273–9. doi: 10.1182/blood-2018-05-852129.

  35. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386–95. doi: 10.1056/NEJMoa022473.

  36. Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in Advanced-Stage Hodgkin’s Lymphoma: Altered Utility in the Modern Era. J Clin Oncol. 2012;30(27):3383–8. doi: 10.1200/JCO.2011.41.0910.

  37. Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684–91. doi: 10.1200/JCO.2012.43.4803.

  38. Dann EJ, Blumenfeld Z, Bar-Shalom R, et al. A 10-year experience with treatment of high and standard risk Hodgkin disease: six cycles of tailored BEACOPP, with interim scintigraphy, are effective and female fertility is preserved. Am J Hematol. 2012;87(1):32–6. doi: 10.1002/ajh.22187.

  39. Dann EJ, Bairey O, Bar-Shalom R, et al. Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicenter trial of 355 patients. Br J Haematol. 2017;178(5):709–18. doi: 10.1111/bjh.14734.

  40. Sieber M, Bredenfeld H, Josting A, et al. 14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin’s lymphoma: results of a pilot study of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2003;21(9):1734–9. doi: 10.1200/JCO.2003.06.028.

  41. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791–9. doi: 10.1016/S0140-6736(11)61940-5.

  42. Engert A, Diehl V, Franklin J, et al. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009;27(27):4548–54. doi: 10.1200/JCO.2008.19.8820.

  43. Skoetz N, Trelle S, Rancea M, et al. Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14(10):943–52. doi: 10.1016/S1470-2045(13)70341-3.

Expression of Adhesion Molecule CD56 in Tumor Plasma Cells in Bone Marrow as a Prognostic Factor in Multiple Myeloma

MV Firsova, LP Mendeleeva, AM Kovrigina, MV Solov’ev, NL Deineko, MYu Drokov, VG Savchenko

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

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

For citation: Firsova MV, Mendeleeva LP, Kovrigina AM, et al. Expression of Adhesion Molecule CD56 in Tumor Plasma Cells in Bone Marrow as a Prognostic Factor in Multiple Myeloma. Clinical oncohematology. 2019;12(4):377–84 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-377-384


ABSTRACT

Aim. To study immunohistochemical parameters of tumor plasma cells in bone marrow and to assess how the expression of adhesion molecule CD56 impacts overall survival (OS) of multiple myeloma (MM) patients.

Materials & Methods. The trial included 35 patients (19 men and 16 women) aged 23 to 73 years (with median age of 58 years) with newly diagnosed MM. At disease onset plasmacytoma was diagnosed in 21 patients. In all patients bone marrow core biopsy was performed followed by histologic and immunohistochemical (IHC) examinations. IHC examination was based on the panel of CD56, CD166, CXCR4, Ki-67, and c-MYC/CD138 antibodies. Kaplan-Meier survival curves and significance assessment by means of Cox’s F-Test were used.

Results. Expression mean values of most of studied markers (CD56, CXCR4, c-MYC, and Ki-67) in bone marrow of patients without plasmacytoma (n = 14) appeared to be higher than in patients with plasmacytoma at MM onset. Expression mean value is understood as percentage ratio of plasma cells expressing a studied marker to total cell count of tumor substrate. High expression of chemokine receptors (CXCR4), and adhesion molecules (CD56) probably inhibits plasma cell migration and impedes extramedullary tumor progression. Comparison of protein expression by tumor plasma cells in bone marrow in the groups with bone extramedullary plasmacytoma shows a distinct regularity referring to CD56 adhesion molecule. For example, CD56 expression is significantly (< 0.05) lower in terms of the count of tumor plasma cells with marker expression in bone marrow of MM patients with extramedullary plasmacytoma compared with patients with bone plasmacytoma (1 ± 1 % vs. 65.71 ± 12.12 %). Comparison of MM patients’ OS depending on CD56 expression by tumor plasma cells in bone marrow showed that 4-year OS of patients with CD56 expression in bone marrow was significantly higher being 80 % vs. 38 % in the group with CD56 expression less than in 10 % of tumor cells.

Conclusion. Expression of adhesion molecule CD56 in tumor plasma cells in bone marrow can be regarded as a prognostic factor in MM. Probably, when at disease onset CD56 expression is identified in less than 10 % of tumor cells in bone marrow, more detailed additional examination of patients should be carried out to rule out extramedullary lesions in different organs and tissues.

Keywords: multiple myeloma, bone plasmacytoma, extramedullary plasmacytoma, bone marrow core biopsy, CD56.

Received: May 12, 2019

Accepted: September 2, 2019

Read in PDF


REFERENCES

  1. Фрейдлин И.С. Система мононуклеарных фагоцитов. М.: Медицина, 1984. 272 c.

    [Freidlin IS. Sistema mononuklearnykh fagotsitov. (The system of mononuclear phagocytes.) Moscow: Meditsina Publ.; 1984. 272 p. (In Russ)]

  2. Van Furth R, Raeburn JA, van Zwet TL. Characteristics of human mononuclear phagocytes. Blood. 1979;54(2):485–500.

  3. Mitsiades CS, McMillin DW, Klippel S, et al. The role of the bone marrow microenvironment in the pathophysiology of myeloma and its significance in the development of more effective therapies. Hematol Oncol Clin N Am. 2007;21(6):1007–34. doi: 10.1016/j.hoc.2007.08.007.

  4. Van Camp B, Durie BG, Spier C, et al. Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH-1; Leu-19). Blood. 1990;76(2):377–82.

  5. 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.

  6. Cayrol R, Wosik K, Berard JL, et al. Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol. 2008;9(2):137–45. doi: 10.1038/ni1551.

  7. Masedunskas A, King JA, Tan F, et al. Activated leukocyte cell adhesion molecule is a component of the endothelial junction involved in transendothelial monocyte migration. FEBS Lett. 2006;580(11):2637–45. doi: 10.1016/j.febslet.2006.04.013.

  8. Avet-Loiseau H, Gerson F, Magrangeas F, et al. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood. 2001;98(10):3082–6. doi: 10.1182/blood.v98.10.3082.

  9. Gabrea A, Martelli ML, Qi Y, et al. Secondary genomic rearrangements involving immunoglobulin or MYC loci show similar prevalences in hyperdiploid and nonhyperdiploid myeloma tumors. Genes Chromos Cancer. 2008;47(7):573–90. doi: 10.1002/gcc.20563.

  10. Gerdes J. Ki-67 and other proliferation markers useful for immunohistological diagnostic and prognostic evaluations in human malignancies. Semin Cancer Biol. 1990;1(3):199–206.

  11. Endl E, Steinbach P, Knuchel R, et al. Analysis of cell cycle-related Ki-67 and p120 expression by flow cytometric BrdUrd-Hoechst/7AAD and immunolabeling technique. Cytometry. 1997;29(3):233–41. doi: 10.1002/(sici)1097-0320(19971101)29:3<233::aid-cyto6>3.3.co;2-3.

  12. Kausch I, Lingnau A, Endl E, et al. Antisense treatment against Ki-67 mRNA inhibits proliferation and tumor growth in vitro and in vivo. Int J Cancer. 2003;105(5):710–6. doi: 10.1002/ijc.11111.

  13. Greipp PR, Lust JA, O’Fallon WM, et al. Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood. 1993;81(12):3382–7.

  14. Tsirakis G, Pappa CA, Spanoudakis M, et al. Clinical significance of sCD105 in angiogenesis and disease activity in multiple myeloma. Eur J Intern Med. 2012;23(4):368–73. doi: 10.1016/j.ejim.2012.01.012.

  15. Tsirakis G, Pappa CA, Psarakis FE, et al. Serum concentrations and clinical significance of soluble CD40 ligand in patients with multiple myeloma. Med Oncol. 2012;29(4):2396–401. doi: 10.1007/s12032-012-0203-2.

  16. Tsirakis G, Pappa CA, Kaparou M, et al. The relationship between soluble receptor of interleukin-6 with angiogenic cytokines and proliferation markers in multiple myeloma. Tumour Biol. 2013;34(2):859–64. doi: 10.1007/s13277-012-0618-6.

  17. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000;18(1):217–42. doi: 10.1146/annurev.immunol.18.1.217.

  18. Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996;382(6594):833–5. doi: 10.1038/382833a0.

  19. Piazza R, Valletta S, Winkelmann N, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet. 2013;45(1):18–24. doi: 10.1038/ng.2495.

  20. Blade J, Fernandez de Larrea C, Rosinol L, et al. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol. 2011;29(28):3805–12. doi: 10.1200/JCO.2011.34.9290.

  21. Usmani SZ, Heuck C, Mitchell A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica. 2012;97(11):1761–7. doi: 10.3324/haematol.2012.065698.

  22. Varettoni M, Corso A, Pica G, et al. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol. 2009;21(2):325–30. doi: 10.1093/annonc/mdp329.

  23. Weinstock M, Aljawai Y, Morgan EA, et al. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation. Br J Haematol. 2015;169(6):851–8. doi: 10.1111/bjh.13383.

  24. Bao L, Lai Y, Liu Y, et al. CXCR4 is a good survival prognostic indicator in multiple myeloma patients. Leuk Res. 2013;37(9):1083–8. doi: 10.1016/j.leukres.2013.06.002.

  25. Xu L, Mohammad KS, Wu H, et al. Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma. Cancer Res. 2016;76(23):6901–10. doi: 10.1158/0008-5472.CAN-16-0517.

Immunohistochemical Subtype and Parameters of International Prognostic Index in the New Prognostic Model of Diffuse Large B-Cell Lymphoma

SV Samarina1, AS Luchinin1, NV Minaeva1, IV Paramonov1, DA D’yakonov1, EV Vaneeva1, VA Rosin1, SV Gritsaev2

1 Kirov Research Institute of Hematology and Transfusiology, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027

2 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Svetlana Valer’evna Samarina, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027; Tel.: +7(912)732-47-56; e-mail: samarinasv2010@mail.ru

For citation: Samarina SV, Luchinin AS, Minaeva NV, et al. Immunohistochemical Subtype and Parameters of International Prognostic Index in the New Prognostic Model of Diffuse Large B-Cell Lymphoma. Clinical oncohematology. 2019;12(4):385–90 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-385-390


ABSTRACT

Aim. To develop an integrated prognostic model of diffuse large B-cell lymphoma (DLBCL) on the basis of immunohistochemical tumor subtype and parameters of International Prognostic Index (IPI).

Materials & Methods. Out of 104 DLBCL patients in the data base 81 (77.9 %) met the eligibility criteria. Median age was 58 years (range 23–83). All patients were treated with R-СНОР. The creation of overall survival (OS) prognostic model for DLBCL patients was based on machine learning with classification and regression trees. OS was analyzed using Kaplan-Meier method. Survival curves were compared by means of log rank test and hazard ratio (HR). Any test was considered significant if two-sided level of < 0.05 was reached.

Results. Following the developed model three groups of patients were identified: the 1st group of low risk (the combination of low, intermediate-low, and intermediate-high risks according to IPI and GCB subtype); the 2nd group of intermediate risk (the combination of low, intermediate-low, and intermediate-high risks according to IPI and non-GCB subtype); the 3d group of high risk (irrespective of subtype). In the group of low risk (n = 26) 2-year OS during the monitoring period was 100 %. In the group of intermediate risk (n = 34) median OS was not reached, 2-year OS was 74 %, and expected 5-year OS was 68 %. In the group of high risk (n = 21) median OS was 25 months, 2-year OS was 46 %, and expected 5-year OS was 37 % (log rank< 0.0001). HR calculated for the high-risk group compared with the low- and intermediate-risk groups was 5.1 (95% CI 2.1–12.1; p = 0.0003).

Conclusion. A new integrated system of DLBCL prognosis is suggested which includes IPI risk parameters and immunohistochemical subtype based on Hans algorithm. This prognostic system can be used in clinical practice for DLBCL patient stratification and risk-adapted therapy.

Keywords: diffuse large B-cell lymphoma, overall survival, prognosis, International Prognostic Index, machine learning.

Received: March 18, 2019

Accepted: August 27, 2019

Read in PDF


REFERENCES

  1. Martellia M, Ferrerib AJM, Agostinellic C, et al. Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013;87(2):146–71. doi: 10.1016/j.critrevonc.2012.12.009.

  2. Lynch RC, Gratzinger D, Advani RH. Clinical Impact of the 2016 Update to the WHO Lymphoma Classification. Curr Treat Options Oncol. 2017;18(7):45. doi: 10.1007/s11864-017-0483-z.

  3. Li X, Huang H, Xu B, et al. Dose-Dense Rituximab-CHOP versus Standard Rituximab-CHOP in Newly Diagnosed Chinese Patients with Diffuse Large B-Cell Lymphoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Cancer Res Treat. 2019;51(3):919–32. doi: 10.4143/crt.2018.230.

  4. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42. doi: 10.1056/NEJMoa011795.

  5. Castellino A, Chiappella A, LaPlant BR, et al. Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials. Blood Cancer J. 2018;8(11):108. doi: 10.1038/s41408-018-0145-9.

  6. Sharman JP, Forero-Torres A, Costa LJ, et al. Obinutuzumab plus CHOP is effective and has a tolerable safety profile in previously untreated, advanced diffuse large B-cell lymphoma: the phase II GATHER study. Leuk Lymphoma. 2018;60(4):894–903. doi: 10.1080/10428194.2018.1515940.

  7. Kameoka Y, Akagi T, Murai K, et al. Safety and efficacy of high-dose ranimustine (MCNU) containing regimen followed by autologous stem cell transplantation for diffuse large B-cell lymphoma. Int J Hematol. 2018;108(5):510–5. doi: 10.1007/s12185-018-2508-1.

  8. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857–61. doi: 10.1182/blood-2006-08-038257.

  9. Biccler J, Eloranta S, de Nully Brown P, et al. Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCN-IPI. Cancer Med. 2018;7(1):114–22. doi: 10.1002/cam4.1271.

  10. Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987–94. doi: 10.1056/NEJM199309303291402.

  11. Li JM, Wang L, Shen Y, et al. Rituximab in combination with CHOP chemotherapy for the treatment of diffuse large B cell lymphoma in Chinese patients. Annals Hematol. 2007;86(9):639–45. doi: 10.1007/s00277-007-0320-8.

  12. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene-expression profiling. Nature. 2000;403(6769):503–51. doi: 10.1038/35000501.

  13. Wang KL, Chen C, Shi PF, et al. Prognostic Value of Morphology and Hans Classification in Diffuse Large B Cell Lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018;26(4):1079–85. doi: 10.7534/j.issn.1009-2137.2018.04.023.

  14. Rashidi A, Oak E, Carson KR, et al. Outcomes with R-CEOP for R-CHOP-ineligible patients with diffuse large B-cell lymphoma are highly dependent on cell of origin defined by Hans criteria. Leuk Lymphoma. 2016;57(5):1191–3. doi: 10.3109/10428194.2015.1096356.

  1. Ye ZY, Cao YB, Lin TY, Lin HL. Subgrouping and outcome prediction of diffuse large B-cell lymphoma by immunohistochemistry. Zhonghua Bing Li Xue Za Zhi. 2007;36(10):654–9.

  1. Montalban C, Diaz-Lopez A, Martin A, et al. Differential prognostic impact of GELTAMO-IPI in cell of origin subtypes of Diffuse Large B Cell Lymphoma as defined by the Hans algorithm. Br J Haematol. 2018;182(4):534–41. doi: 10.1111/bjh.15446.

  2. Tibiletti MG, Martin V, Bernasconi B, et al. BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of fluorescent in situ hybridization probes and correlation with clinical outcome. Hum Pathol. 2009;40(5):645–52. doi: 10.1016/j.humpath.2008.06.032.

  3. Jaglal MV, Peker D, Tao J, Cultrera JL. Double and Triple Hit Diffuse Large B Cell Lymphomas and First Line Therapy. Blood. 2012;120:4885 [abstract].

  4. Kim M, Suh C, Kim J, Hong JY. Difference of Clinical Parameters between GCB and Non-GCB Subtype DLBCL. Blood. 2017;130:5231 [abstract].

  5. Da Costa CBT. Machine Learning Provides an Accurate Classification of Diffuse Large B-Cell Lymphoma from Immunohistochemical Data. J Pathol Inform. 2018;9(1):21. doi: 10.4103/jpi.jpi_14_18.

  6. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2016.

    [Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines on diagnosis and treatment of lymphoproliferative disorders). Moscow: Buki Vedi Publ.; 2016. (In Russ)]

  7. Leval L, Harris NL. Variability in immunophenotype in diffuse large B-cell lymphoma and it‘s clinical relevance. Histopathol. 2003;43(6):509–28. doi: 10.1111/j.1365-2559.2003.01758.x.

  8. Skarbnik AP, Donato ML. Safety and Efficacy Data for Combined Checkpoint Inhibition with Ipilimumab (Ipi) and Nivolumab (Nivo) As Consolidation Following Autologous Stem Cell Transplantation (ASCT) for High-Risk Hematological Malignancies. Blood. 2018;132:256.

  9. Matsuki E, Younes A. Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-Hodgkin Lymphoma. Curr Treat Options Oncol. 2016;17(6):31. doi: 10.1007/s11864-016-0401-9.

  10. Kaneko H, Tsutsumi Y, Fujino T, et al. Favorable event free-survival of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for higher risk diffuse large B-cell lymphoma in first complete remission. Hematol Rep. 2015;7(2):5812 [abstract]. doi: 10.4081/hr.2015.5812.

Experience with the Use of Thio/Mel Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

SV Gritsaev1, II Kostroma1, AA Zhernyakova1, IM Zapreeva1, EV Karyagina2, ZhV Chubukina1, SA Tiranova1, IS Martynkevich1, SS Bessmeltsev1, AV Chechetkin1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

For correspondence: Ivan Ivanovich Kostroma, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(921)784-82-82; e-mail: obex@rambler.ru

For citation: Gritsaev SV, Kostroma II, Zhernyakova AA, et al. Experience with the Use of Thio/Mel Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma. Clinical oncohematology. 2019;12(3):282–8 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-282-288


ABSTRACT

Background. In multiple myeloma (MM) treatment a single autologous hematopoietic stem cell transplantation (auto-HSCT) is preceded by conditioning regimens aimed at intensifying cytoreductive effect. In the course of ongoing search for combined conditioning regimens an attractive option proved to be thiotepa/melphalan combination.

Aim. Data analysis of a pilot study of the efficacy of conditioning regimens including administration of two alkylating agents (thiotepa and melphalan) with subsequent auto-HSCT.

Materials & Methods. 9 patients received 10 auto-HSCTs with conditioning regimen including administration of 250 mg/m2 of thiotepa on Day –5 and 140 mg/m2 of melphalan on Day –2. After auto-HSCT pegylated filgrastim was administered in 8 patients. Engraftment period was calculated on the basis of absolute neutrophil count ≥ 0,5 × 109/L and thrombocyte level ≥ 20 × 109/L. Regimen toxicity was assessed according to CTCAE v5.0. Survival rates were estimated by Kaplan-Meier curves.

Results. The use of thiotepa did not require administration of any additional drugs. The incidence of mucositis and enteropathy of grade 1–2 was 100 % and 70 %, respectively. Pyrexia was reported in 7 auto-HSCTs. Pneumonia occurred in 1 patient. The infusion of 1–3 doses of platelet concentrate (median of 2 doses) was required in all patients except for one. Donor erythrocytes were transfused to 3 patients. Engraftment was reported in all patients within the period of 10–14 days. Median hospitalization duration from Day 0 to hospital discharge was 16 patient-days. After auto-HSCT the quality of response improved in 6 out of 9 patients. MM progression was reported in one patient with complex karyotype. Further follow-up showed progression in 2 patients. By December 2018 median follow-up of 9 patients from the date of auto-HSCT was 9 months (range 3–20 months), median progression-free survival was 17 months, median overall survival was not reached.

Conclusion. Acceptable toxicity, improvement of response quality, and maintenance of it for up to 20 months allow to consider combined conditioning regimen Thio/Mel to be a possible alternative to the standard Mel200 regimen.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, conditioning regimen, thiotepa, melphalan.

Received: December 26, 2018

Accepted: May 25, 2019

Read in PDF 


REFERENCES

  1. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома: руководство для врачей. М.: СИМК, 2016. 512 с.

    [Bessmeltsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma: rukovodstvo dlya vrachei. (Multiple myeloma: manual for physicians.) Moscow: SIMK Publ.; 2016. 512 p. (In Russ)]

  2. 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)]

  3. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046–60. doi: 10.1056/NEJMra1011442.

  4. Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. 2011;117(23):6063–73. doi: 10.1182/blood-2011-02-297325.

  5. Engelhardt M, Terpos E, Kleber M, et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica. 2014;99(2):232–42. doi: 10.3324/haematol.2013.099358.

  6. Sidiqi MH, Aljama MA, Bin Riaz I, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant for multiple myeloma. Blood Cancer J. 2018;8(8):106. doi: 10.1038/s41408-018-0147-7.

  7. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311–20. doi: 10.1056/NEJMoa1611750.

  8. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91–7.

  9. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905. doi: 10.1056/NEJMoa1402888.

  10. Thoennissen GB, Gorlich D, Bacher U, et al. Autologous stem cell transplantation in multiple myeloma in the era of novel drug induction: a retrospective single-center analysis. Acta Haematol. 2017;137(3):163–72. doi: 10.1159/000463534.

  11. Ozaki S, Harada T, Saitoh T, et al. Survival of multiple myeloma patients aged 65–70 years in the era of novel agents and autologous stem cell transplantation. A multicenter retrospective collaborative study of the Japanese Society of Myeloma and the European Myeloma Network. Acta Haematol. 2014;132(2):211–9. doi: 10.1159/000357394.

  12. Cavo M, Salwender H, Rosinol L, et al. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: an integrated analysis of patient-level data from phase III European studies. Blood. 2013;122(21):767.

  13. Cavo M, Beksac M, Dimopoulos M, et al. Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM trial). 2016;128(22):673.

  14. Sonneveld P, Beksac M, van der Holt B, et al. Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM Trial). 2016;128(22):242.

  15. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide and dexamethasone (RVD) consolidation with lenalidomide maintenance (ACM), tandem autoHCT with lenalidomide maintenance (TAM), and autoHCT with lenalidomide maintenance (AM) for upfront treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). 2016;128(22):LBA-1.

  16. Yhim HY, Kim K, Kim JS, et al. Matched-pair analysis to compare the outcomes of a second salvage auto-SCT to systemic chemotherapy alone in patients with multiple myeloma who relapsed after front-line auto-SCT. Bone Marrow Transplant. 2013;48(3):425–32. doi: 10.1038/bmt.2012.164.

  17. Olin RL, Vogl DT, Porter DL, et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone Marrow Transplant. 2009;43(5): 417–22. doi: 10.1038/bmt.2008.334.

  18. Abbi KKS, Zheng J, Devlin SM, et al. Second autologous stem cell transplant: an effective therapy for relapsed multiple myeloma. Biol Blood Marrow Transplant. 2015;21(3):468–72. doi: 10.1016/j.bbmt.2014.11.677.

  19. Cook G, Williams C, Brown JM, et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(8):874–85. doi: 10.1016/S1470-2045(14)70245-1.

  20. Benson DM, Panzner K, Hamadani M, et al. Effects of induction with novel agents versus conventional chemotherapy on mobilization and autologous stem cell transplant outcomes in multiple myeloma. Leuk Lymphoma. 2010;51(2):243–51. doi: 10.3109/10428190903480728.

  21. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation following IMiD-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118(6):1585–92. doi: 10.1002/cncr.26422.

  22. Ashcroft J, Judge D, Dhanasiri S, et al. Chart review across EU5 in MM post-ASCT patients. Int J Hematol Oncol. 2018;7(1):IJH05. doi: 10.2217/ijh-2018-0004.

  23. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35(29):3279–89. doi: 10.1200/JCO.2017.72.6679.

  24. Kumar S, Lacy MQ, Dispenzieri A, et al. High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy. Bone Marrow Transplant. 2004;34(2):161–7. doi: 10.1038/sj.bmt.1704545.

  25. Kim JS, Kim K, Cheong JW, et al. Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation. Biol Blood Marrow Transplant. 2009;15(4):463–70. doi: 10.1016/j.bbmt.2008.12.512.

  26. Gertz MA, Kumar S, Lacy MQ, et al. Stem cell transplantation in multiple myeloma: impact of response failure with thalidomide or lenalidomide induction. Blood. 2010;115(12):2348–53. doi: 10.1182/blood-2009-07-235531.

  27. Грицаев С.В., Кузяева А.А., Бессмельцев С.С. Отдельные аспекты аутологичной трансплантации гемопоэтических стволовых клеток при множественной миеломе. Клиническая онкогематология. 2017;10(1):7–12. doi: 21320/2500-2139-2017-10-1-7-12.

    [Gritsaev SV, Kuzyaeva AA, Bessmeltsev SS. Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma. Clinical oncohematology. 2017;10(1):7–12. doi: 10.21320/2500-2139-2017-10-1-7-12. (In Russ)]

  28. Musso M, Messina G, Marcacci G, et al. High-dose melphalan plus thiotepa as conditioning regimen before second autologous stem cell transplantation for “de novo” multiple myeloma patients: a phase II study. Biol Blood Marrow Transplant. 2015;21(11):1932–8. doi: 10.1016/j.bbmt.2015.06.011.

  29. 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):e328–46. doi: 10.1016/S1470-2045(16)30206-6.

  30. Schiffman KS, Bensinger WI, Appelbaum FR, et al. Phase II study of high-dose busulfan, melphalan and thiotepa with autologous peripheral blood stem cell support in patients with malignant disease. Bone Marrow Transplant. 1996;17(6):943–50.

  31. Zaid AB, Abdul-Hai A, Grotto I, et al. Autologous transplant in multiple myeloma with an augmented conditioning protocol. Leuk Lymphoma. 2013;54(11):2480–4. doi: 10.3109/10428194.2013.782608.

  32. Anagnostopoulos A, Aleman A, Ayers G, et al. Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Cancer. 2004;100(12):2607–12. doi: 10.1002/cncr.20294.

  33. Hari P, Reece DE, Randhawa J, et al. Final outcomes of escalated melphalan 280 mg/m2 with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival. Bone Marrow Transplant. 2019;54(2):293–9. doi: 10.1038/s41409-018-0261-y.

  34. Auner HW, Iacobelli S, Sbianchi G, et al. Melphalan 140 mg/m2 or 200 mg/m2 for autologous transplantation in myeloma: results from the collaboration to collect autologous transplant outcomes in lymphoma and myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018;103(3):514–21. doi: 10.3324/haematol.2017.181339.

  35. Dimopoulos M, Wang M, Maisnar V, et al. Response and progression-free survival according to planned treatment duration in patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in the phase III ASPIRE study. J Hematol Oncol. 2018;11(1):49. doi: 10.1186/s13045-018-0583-7.

  36. Costa LJ, Landau HJ, Chhabra S, et al. Phase 1/2 trial of carfilzomib plus high-dose melphalan preparative regimen for salvage autologous hematopoietic cell transplantation followed by maintenance carfilzomib in patients with relapsed/refractory multiple myeloma. Biol Blood Marrow Transplant. 2018;24(7):1379–85. doi: 10.1016/j.bbmt.2018.01.036.

The Use of Ibrutinib in Refractory Chronic Lymphocytic Leukemia and in High-Risk Patients

NV Kurkina1,2, EA Repina1, NN Mashnina2

1 NP Ogarev Mordovia National Research State University, 68 Bol’shevistskaya str., Saransk, Republic of Mordovia, Russian Federation, 430032

2 Republican Clinical Hospital No. 4, 32 Ul’yanova str., Saransk, Republic of Mordovia, Russian Federation, 430032

For correspondence: Nadezhda Viktorovna Kurkina, MD, PhD, 68 Bol’shevistskaya str., Saransk, Republic of Mordovia, Russian Federation, 430032; e-mail: nadya.kurckina@yandex.ru

For citation: Kurkina NV, Repina EA, Mashnina NN. The Use of Ibrutinib in Refractory Chronic Lymphocytic Leukemia and in High-Risk Patients. Clinical oncohematology. 2019;12(3):278–81 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-278-281


ABSTRACT

Despite advances in chemo-immunotherapy of chronic lymphocytic leukemia, a choice of therapy is a frequent challenge in patients with a refractory form of the disease, autoimmune hemolytic complications, and also in high-risk patients with cytogenetic changes. The use of ibrutinib, one of Bruton’s tyrosine kinase inhibitors, allows to overcome the resistance to anticancer therapy without adverse effects on patients’ quality of life.

Keywords: chronic lymphocytic leukemia, chemo-immunotherapy, ibrutinib, refractoriness, relapse.

Received: January 21, 2018

Accepted: May 10, 2019

Read in PDF 


REFERENCES

  1. Zenz T, Gribben JG, Hallek M, et al. Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood. 2012;119(18):4101. doi: 10.1182/blood-2011-11-312421.

  2. Никитин Е.А., Судариков А.Б. Хронический лимфолейкоз высокого риска: история, определение, диагностика и лечение. Клиническая онкогематология. 2013;6(1):59–67.

    [Nikitin EA, Sudarikov AB. High­risk chronic lymphocytic leukemia: history, definition, diagnosis, and management. Klinicheskaya onkogematologiya. 2013;6(1):59–67. (In Russ)]

  3. Byrd JС, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. doi: 10.1056/nejmoa1215637.

  4. Kil LP, de Bruijn MJ, van Hulst JA, et al. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3(1):71–83.

  5. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30(23):2820–2. doi: 10.1200/jco.2012.43.3748.

  6. Byrd JС, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497–506. doi: 10.1182/blood-2014-10-606038.

  7. Имбрувика® (инструкция по медицинскому применению). Джонсон & Джонсон (Россия). Доступно по: https://www.vidal.ru/drugs/imbruvica Ссылка активна на 21.01.2019.

    [Imbruvica® (package insert). Johnson & Johnson (Russia). Available from: https://www.vidal.ru/drugs/imbruvica__43861. (accessed 21.01.2019) (In Russ)]

  8. Chavez J, Sahakian E, Pinilla-Ibarz J. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia. Core Evid. 2013;8:37–45. doi: 10.2147/CE.S34068.

  9. Программное лечение заболеваний системы крови: сборник алгоритмов диагностики и протоколов лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2012. 1056 с.

    [Savchenko VG, ed. Programmnoe lechenie zabolevanii sistemy krovi: sbornik algoritmov diagnostiki i protokolov lecheniya zabolevanii sistemy krovi. (Program treatment of blood system diseases: collection of diagnostic algorithms and treatment protocols for blood system diseases.) Moscow: Praktika Publ.; 1056 p. (In Russ)]

Rearrangement of Immunoglobulin Genes in Tumor Cells of Patients with Primary Mediastinal (Thymic) Large B-Cell Lymphoma

YaK Mangasarova, YuV Sidorova, AU Magomedova, BV Biderman, EE Nikulina, AB Sudarikov, AM Kovrigina, SK Kravchenko

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

For correspondence: Yana Konstantinovna Mangasarova, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(926)395-82-52; e-mail: v.k.jana@mail.ru

For citation: Mangasarova YaK, Sidorova YuV, Magomedova AU. Rearrangement of Immunoglobulin Genes in Tumor Cells of Patients with Primary Mediastinal (Thymic) Large B-Cell Lymphoma. Clinical oncohematology. 2019;12(3):271–7 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-271-277


ABSTRACT

Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a malignant tumor with large atypical lymphoid cells expressing post-germinal differentiation markers. Rearrangements of immunoglobulin genes in PMBCL are revealed in 30–65 % of cases. Immunoglobulin molecules, however, are expressed neither on the surface, nor in cytoplasm of tumor cells.

Aim. To assess cell clonality rate on the basis of rearrangements of immunoglobulin heavy/light chain genes; to determine rearrangement stability at the time of relapse development; to study the range of rearrangements and clonal relationship with primary tumor in metachronous development of mediastinal gray zone lymphoma.

Materials & Methods. The assessment of rearrangements of immunoglobulin heavy/light chain genes was based on molecular analysis of 29 primary tumor biopsies and 4 tissue samples with histologically and immunohistochemically verified relapses or metachronous lymphoma development.

Results. In 16 (55.2 %) out of 29 cases a rearrangement of immunoglobulin heavy chain genes was reported, in 7 (24.1 %) cases a rearrangement of light chain genes was identified, in 6 (20.7 %) cases no rearrangements of immunoglobulin heavy/light chain genes were found. On the basis of immunoglobulin gene analysis in 2 patients with early relapse a tumor clone was detected that was identical with the one identified at the onset of the disease. In 2 patients with complete remission a metachronous development of mediastinal gray zone lymphoma was reported, whereas molecular genetic analysis revealed a change/disappearance of initial clonal rearrangements of immunoglobulin genes.

Conclusion. Total detection rate of B-cell clonality in PMBCL was 79.3 %. Molecular genetic analysis confirmed that initial clonal rearrangements of immunoglobulin genes were preserved in early relapses, and invalidated tumor clonal relationship in a metachronous development of mediastinal gray zone lymphoma.

Keywords: primary mediastinal (thymic) large B-cell lymphoma, rearrangement of immunoglobulin heavy/light chain genes, polymerase chain reaction, metachronous development of lymphoma.

Received: November 2, 2018

Accepted: May 29, 2019

Read in PDF 


REFERENCES

  1. Evans PA, Pott Ch, Groenen PJ, et al. Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia. 2007;21(2):207–14. doi: 10.1038/sj.leu.2404479.

  2. Мангасарова Я.К., Магомедова А.У., Ковригина А.М. и др. Первичная медиастинальная (тимическая) В-крупноклеточная лимфома: диагностика отдаленных экстрамедиастинальных поражений и возможности лечения. Клиническая онкогематология. 2018;11(3):220–6. doi: 21320/2500-2139-2018-11-3-220-226.

    [Mangasarova YaK, Magomedova AU, Kovrigina AM, et al. Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Diagnostics of Extramediastinal Lesions and Treatment Opportunities. Clinical oncohematology. 2018;11(3):220–6. doi: 10.21320/2500-2139-2018-11-3-220-226. (In Russ)]

  3. Harris NL; The International Lymphoma Study Group. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Curr Diagn Pathol. 1995;2(1):58–9. doi: 10.1016/S0968-6053(00)80051-4.

  4. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–62. doi: 10.1084/jem.20031074.

  5. Pileri SA, Zinzani PL, Gaidano G, et al. Pathobiology of primary mediastinal B-cell lymphoma. Leuk Lymphoma. 2003;44(Suppl 3):S21–6. doi: 10.1080/10428190310001623810.

  6. Loddenkemper C, Anagnostopoulos I, Hummel M, et al. Differential Emu enhancer activity and expression of BOB.1/OBF.1, Oct2, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas, and Hodgkin lymphomas. J Pathol. 2004;202(1):60–9. doi: 10.1002/path.1485.

  7. De Leval L, Ferry JA, Falini B, et al. Expression of bcl-6 and CD10 in primary Mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells? Am J Surg Pathol. 2001;25(10):1277–82. doi: 10.1097/00000478-200110000-00008.

  8. Rosenquist R, Lindstrom A, Holmberg D, et al. V(H) gene family utilization in different B-cell lymphoma subgroups. Eur J Haematol. 1999;62(2):123–8. doi: 10.1111/j.1600-0609.1999.tb01732.x.

  9. Zhong DR, Ling Q, Shi XH, et al. Comparative study between primary mediastinal B-cell lymphoma and non-mediastinal diffuse large B-cell lymphoma by immunoglobulin gene rearrangement and Epstein-Barr virus infection detection. J Hematop. 2009;2(1):45–9. doi: 1007/s12308-009-0022-3.

  10. Leithauser F, Bauerle M, Quang Huynh M, et al. Isotype-switched immunoglobulin genes with a high load of somatic hypermutation and lack of ongoing mutational activity are prevalent in mediastinal B-cell lymphoma. 2001;98(9):2762–70; doi: 10.1182/blood.v98.9.2762.

  11. Burack WR, Laughlin TS, Friedberg JW, et al. PCR assays detect B-lymphocyte clonality in formalin-fixed, paraffin-embedded specimens of classical Hodgkin lymphoma without microdissection. Am J Clin Pathol. 2010;134(1):104–11. doi: 10.1309/AJCPK6SBE0XOODHB.

  12. Evens AM, Kanakry JA, Sehn LH, et al. Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. Am J Hematol. 2015;90(9):778–83. doi: 10.1002/ajh.24082.

  13. Eberle FC, Salaverria I, Steidl C, et al. Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. Mod Pathol. 2011;24(12):1586–97. doi: 10.1038/modpathol.2011.116.

  14. Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17(12):2257–317. doi: 10.1038/sj.leu.2403202.

TP53 Gene Mutations in Tumor Cells of Patients with Aggressive B-Cell Lymphomas

AE Misyurina1, SK Kravchenko1, VA Misyurin2, AM Kovrigina1, AU Magomedova1, EA Baryakh3, FE Babaeva1, AV Misyurin4

1 National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

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

3 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

4 GenoTekhnologiya, 11 800-letiya Moskvy str., Moscow, Russian Federation, 127247

For correspondence: Anna Evgen’evna Misyurina, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(909)637-32-49; e-mail: anna.lukina1@gmail.com

For citation: Misyurina AE, Kravchenko SK, Misyurin VA, et al. TP53 Gene Mutations in Tumor Cells of Patients with Aggressive B-Cell Lymphomas. Clinical oncohematology. 2019;12(3):263–70 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-263-270


ABSTRACT

Background. TP53 gene mutations impede cell apoptosis and lead to additional oncogenic events contributing to tumor progression.

Aim. To assess TP53 gene mutation rate in patients with high-grade B-cell lymphoma double-hit (HGBCL DH) and not otherwise specified (HGBL NOS); to analyse its relationship to disease prognosis.

Materials & Methods. Retrospective materials from medical records of 10 HGBL DH and 26 HGBL NOS patients were analyzed. Median follow-up was 26.5 months (range 0.6–160.9 months). Selection was based on the presence of available biological materials (paraffin blocks) for Sanger sequencing of TP53 gene from exon 5 to exon 8 (encoding DNA-binding domain of TP53 gene). FISH analysis of the tumor was performed in all patients to identify translocations involving cMYC/8q24, BCL2/18q21, and BCL6/3q27 gene locus. To analyze differences between groups χ2 and Mann-Whitney tests were applied. Univariate event analysis (Kaplan-Meier and log-rank tests) and Cox regression analysis were used to assess the influence of molecular markers on the disease prognosis.

Results. TP53 gene mutations in lymphoma cells were found in 13 (36 %) out of 36 patients, 10/ (77 %) out of 13 mutations were pathogenic. In 8 out of 10 patients with TP53 mutations cMYC/8q24 gene translocation was identified. Groups with wild (TP53-WT) and mutant (TP53-MUT) types of TP53 gene were similar in terms of main clinical characteristics. Patients with TP53-MUT in tumor cells showed worse 3-year overall survival (OS) compared with the group without TP53-MUT (30 % vs. 73 %; = 0.026) as well as higher probability of disease progression in the period of 3 years (66 % vs. 15 %; = 0.004). In multivariate analysis significant OS predictor proved to be the presence of TP53 mutation (= 0.006). Relapse/progression probability was higher in combined cases of TP53 mutation and translocation involving cMYC gene locus (= 0.0003).

Conclusion. Translocation involving cMYC gene along with TP53 gene mutation in tumor cells can serve as a criterion for dividing HGBL DH and HGBL NOS patients into different lymphoma relapse/progression risk groups.

Keywords: high-grade B-cell lymphoma double-hit, high-grade B-cell lymphoma not otherwise specified, TP53 mutation in tumor cells, translocation involving cMYC gene locus.

Received: January 25, 2019

Accepted: June 3, 2019

Read in PDF 


REFERENCES

  1. Matlashewski G, Lamb P, Pim D, et al. Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO J. 1984;3(13):3257–62. doi: 10.1002/j.1460-2075.1984.tb02287.x.

  2. Kern SE, Kinzler KW, Bruskin A, et al. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991;252(5013):1708–11. doi: 10.1126/science.2047879.

  3. McBride OW, Merry D, Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci USA. 1986;83(1):130–4. doi: 10.1073/pnas.83.1.130.

  4. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9(10):749–58. doi: 10.1038/nrc2723.

  5. Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137(3):413–31. doi: 10.1016/j.cell.2009.04.037.

  6. Eischen CM, Weber JD, Roussel MF, et al. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 1999;13(20):2658–69. doi: 10.1101/gad.13.20.2658.

  7. Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356(6366):215–21. doi: 10.1038/356215a0.

  8. Gudkov AV, Komarova EA. The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer. 2003;3(2):117–29. doi: 10.1038/nrc992.

  9. Xu-Monette ZY, Medeiros LJ, Li Y, et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood. 2012;119(16):3668–83. doi: 10.1182/blood-2011-11-366062.

  10. Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11(3):577–90. doi: 10.1016/s1097-2765(03)00050-9.

  11. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28(6):622–9. doi: 10.1002/humu.20495.

  12. Young KH, Weisenburger DD, Dave BJ, et al. Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAIL receptor-2, predict for poor survival in diffuse large B-cell lymphoma. Blood. 2007;110(13):4396–405. doi: 10.1182/blood-2007-02-072082.

  13. Haupt S, Raghu D, Haupt Y. Mutant p53 drives cancer by subverting multiple tumor suppression pathways. Front Oncol. 2016;6:12. doi: 10.3389/fonc.2016.00012.

  14. Soussi T, Beroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer. 2001;1(3):233–9. doi: 10.1038/35106009.

  15. Soussi T, Lozano G. P53 mutation heterogeneity in cancer. Biochem Biophys Res Commun. 2005;331(3):834–42. doi: 10.1016/j.bbrc.2005.03.190.

  16. Kato S, Han SY, Liu W, et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA. 2003;100(14):8424–9. doi: 10.1073/pnas.1431692100.

  17. Xu-Monette ZY, Young KH. The TP53 tumor suppressor and autophagy in malignant lymphoma. Autophagy. 2012;8(5):842–5. doi: 10.4161/auto.19703.

  18. Vousden KH, Prives C. P53 and prognosis: new insights and further complexity. Cell. 2005;120(1):7–10. doi: 10.1016/s0092-8674(04)01252-8.

  19. Young KH, Leroy K, Moller MB, et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood. 2008;112(8):3088–98. doi: 10.1182/blood-2008-01-129783.

  20. Joerger AC, Ang HC, Fersht AR. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci USA. 2006;103(41):15056–61. doi: 10.1073/pnas.0607286103.

  21. Joerger AC, Fersht AR. Structural biology of the tumor suppressor p53. Annu Rev Biochem. 2008;77(1):557–82. doi: 10.1146/annurev.biochem.77.060806.091238.

  22. Peroja P, Pedersen M, Mantere T, et al. Mutation of TP53, translocation analysis and immunohistochemical expression of MYC, BCL-2 and BCL-6 in patients with DLBCL treated with R-CHOP. Sci Rep. 2018;8(1):14814. doi: 10.1038/s41598-018-33230-3.

  23. Clipson A, Barrans S, Zeng N, et al. The prognosis of MYC translocation positive diffuse large B-cell lymphoma depends on the second hit. J Pathol Clin Res. 2015;1(3):125–33. doi: 10.1002/cjp2.10.

  24. Aukema SM, Kreuz M, Kohler CW, et al. Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma. Haematologica. 2014;99(4):726–35. doi: 10.3324/haematol.2013.091827.

  25. Swerdlow SH, Campo E, Harris NL, et al. Classification of tumours of haematopoietic and lymphoid tissues. WHO classification of tumours. Revised 4th edition, Vol. 2. Lyon: IARC Press; 2017.

  26. Gebauer N, Bernard V, Gebauer W, et al. TP53 mutations are frequent events in double-hit B-cell lymphomas with MYC and BCL2 but not MYC and BCL6 translocations. Leuk Lymphoma. 2015;56(1):179–85. doi: 10.3109/10428194.2014.907896.

  27. Xu-Monette ZY, Wu L, Visco C, et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2012;120(19):3986–96. doi: 10.1182/blood-2012-05-433334.

  28. Schiefer AI, Kornauth C, Simonitsch-Klupp I, et al. Impact of Single or Combined Genomic Alterations of TP53, MYC, and BCL2 on survival of patients with diffuse large B-cell lymphomas: A retrospective cohort study. Medicine (Baltimore). 2015;94(52):e2388. doi: 10.1097/MD.0000000000002388.

  29. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from the international DLBCL rituximab-CHOP consortium program. Blood. 2013;121(20):4021–31. doi: 10.1182/blood-2012-10-460063.

  30. Schuster C, Berger A, Hoelzl MA, et al. The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas. Blood. 2011;118(17):4635–45. doi: 10.1182/blood-2010-10-313098.

  31. Tzankov A, Xu-Monette ZY, Gerhard M, et al. Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Mod Pathol. 2014;27(7):958–71. doi: 10.1038/modpathol.2013.214.

  32. Moll UM, Wolff S, Speidel D, Deppert W. Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol. 2005;17(6):631–6. doi: 10.1016/j.ceb.2005.09.007.

  33. MacLean KH, Keller UB, Rodriguez-Galindo C, et al. c-Myc augments gamma irradiation-induced apoptosis by suppressing Bcl-XL. Mol Cell Biol 2003;23(20):7256–70. doi: 10.1128/mcb.23.20.7256-7270.2003.

  34. Adams JM, Harris AW, Pinkert CA, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985;318(6046):533–8. doi: 10.1038/318533a0.

Primary Bone Lymphomas: Long-Term Results of a Prospective Single-Center Trial

AK Smol’yaninova, NG Gabeeva, VE Mamonov, SA Tatarnikova, LG Gorenkova, DS Badmadzhapova, AM Kovrigina, EG Gemdzhian, EE Zvonkov

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

For correspondence: Anna Konstantinovna Smol’yaninova, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-23-61, +7(926)912-31-16; e-mail: annmo8@mail.ru

For citation: Smol’yaninova AK, Gabeeva NG, Mamonov VE, et al. Primary Bone Lymphomas: Long-Term Results of a Prospective Single-Center Trial. Clinical oncohematology. 2019;12(3):247–62 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-247-262


ABSTRACT

Background. Primary bone lymphomas (PBL) are rare extranodal lymphomas. In more than 90 % of cases they are reported as diffuse large B-cell lymphomas (DLBCL). At local (IE) stage of PBL the standard R-CHOP immunotherapy demonstrates efficacy over 90 %. If, however, such poor prognostic factors (PPF) as multiple bone lesions (IVЕ stage), increased lactate dehydrogenase (LDH) activity, B-symptoms, and large tumor mass are identified, R-CHOP efficacy tends to decrease. There is currently no optimal regimen for treatment of PBL patients with PPF. We suggest intensified multi-agent chemotherapy for this category of patients.

Aim. To assess long-term results of prospective single-center trial on the use of high-dose mNHL-BFM-90 program in patients with primary bone DLBCL and PPF.

Materials & Methods. The trial included 33 patients with primary bone DLBCL followed-up at the National Medical Hematology Research Center from 2006 to 2018. The median age of patients was 44 years (range 16–78 years). The spectrum of assessed data included main clinical, laboratory, X-ray and MRI tumor characteristics as well as survival rates and prognostic factors.

Results. PPF were identified in 29 (88 %) patients, out of them 20 (61 %) patients had an advanced stage (˃ IE), 20 (59 %) patients showed an increased LDH activity, B-symptoms were identified in 15 (45 %) patients, and large tumor mass was reported in 23 (71 %) patients. High-dose antitumor treatment (mNHL-BFM-90) was administered in 27 out of 33 patients. Overall and progression-free survival within the period of 5 years was 92 %. None of PPF significantly influenced survival rates.

Conclusion. The use of high-dose mNHL-BFM-90 program in PBL with poor prognosis achieves long-term remissions in 92 % patients. We recommend mNHL-BFM-90 as a therapy of choice for PBL patients with poor prognosis.

Keywords: primary bone lymphoma, diffuse large B-cell lymphoma, high-dose intensified multi-agent mNHL-BFM-90 program.

Received: January 25, 2019

Accepted: May 12, 2019

Read in PDF 


REFERENCES

  1. Matikas A, Briasoulis A, Tzannou I, et al. Primary bone lymphoma: a retrospective analysis of 22 patients treated in a single tertiary center. Acta Haematol. 2013;130(4):291–6. doi: 10.1159/000351051.

  2. Bacci G, Jaffe N, Emiliani E, et al. Therapy for primary non-Hodgkin’s lymphoma of bone and a comparison of results with Ewing’s sarcoma. Ten year’s experience at the Istituto Ortopedico Rizzoli. Cancer. 1986;57(8):1468–72. doi: 10.1002/1097-0142(19860415)57:8<1468::aid-cncr2820570806>3.0.co;2-0.

  3. Fidias P, Spiro I, Scobczak ML, et al. Long-term results of combined modality therapy in primary bone lymphomas. Int J Radiat Oncol Biol Phys. 1999;45(5):1213–8. doi: 10.1016/s0360-3016(99)00305-3.

  4. Lewis VO, Primus G, Anastasi J, et al. Oncologic outcomes of primary lymphomas of bone in adults. Clin Orthop Rel Res. 2003;415:90–7. doi: 10.1097/01.blo.0000093901.12372.ad.

  5. Ostrowski ML, Unni KK, Banks PM, et al. Malignant Lymphoma of Bone. Cancer. 1986;58(12):2646–55. doi: 10.1002/1097-0142(19861215)58:12<2646::aid-cncr2820581217>3.0.co;2-u.

  6. Ramadan KM, Shenkier T, Sehn LH, et al. A clinicopathological retrospective study of 131 patients with primary bone lymphoma: a population-based study of successively treated cohorts from the British Columbia Cancer Agency. Ann Oncol. 2006;18(1):129–35. doi: 10.1093/annonc/mdl329.

  7. Ueda T, Aozasa K, Ohsawa M, et al. Malignant lymphomas of bone in Japan. Cancer. 1989;64(11):2387–92. doi: 10.1002/1097-0142(19891201)64:11<2387::aid-cncr2820641132>3.0.co;2-1.

  8. Звонков Е.Е., Красильникова Б.Б., Махиня В.А. и др. Первый опыт применения модифицированной программы NHL-BFM-90 у взрослых больных первичной диффузной В-крупноклеточной лимфосаркомой желудка с неблагоприятным прогнозом. Терапевтический архив. 2006;78(7):38–46.

    [Zvonkov EE, Krasil’nikova BB, Makhinya VА, et al. Pilot experience with the modified program NHLBFM90 in adult patients with primary diffuse large В-cell gastric lymphosarcoma with unfavorable prognosis. Terapevticheskii arkhiv. 2006;78(7):38–46. (In Russ)]

  9. Кравченко С.К., Барях Е.А., Замятина В.И. и др. Высокодозная терапия лимфомы Беркитта у больных старше 40 лет. Терапевтический архив. 2008;80(7):9–18.

    [Kravchenko SK, Baryakh EA, Zamyatina VI, et al. Highdose therapy of Berkitt’s lymphoma in patients over 40 years of age. Terapevticheskii arkhiv. 2008;80(7):9–18. (In Russ)]

  10. Магомедова А.У., Кравченко С.К., Кременецкая А.М. и др. Модифицированная программа NHL-BFM-90 для лечения больных диффузной В-крупноклеточной лимфосаркомой. Терапевтический архив. 2006;78(10):44–7.

    [Magomedova AU, Kravchenko SK, Kremenetskaya AM, et al. The modified program NHL-BFM-90 in the treatment of patients with diffuse large B-cell lymphosarcoma. Terapevticheskii arkhiv. 2006;78(10):44–7. (In Russ)]

  11. Горенкова Л.Г., Кравченко С.К., Мисюрин А.В. и др. Клиническая и молекулярная оценки эффективности высокодозной химиотерапии при анаплазированной Т-крупноклеточной АЛК-позитивной лимфоме у взрослых. Гематология и трансфузиология. 2012;57(3):43.

    [Gorenkova LG, Kravchenko SK, Misyurin AV, et al. Clinical and molecular evaluation of the efficacy of high-dose chemotherapy in adult patients with anaplastic large T-cell ALK-positive lymphoma. Gematologiya i transfuziologiya. 2012;57(3):43. (In Russ)]

  12. Морозова А.К., Звонков Е.Е., Кременецкая А.М. и др. Первый опыт применения модифицированной программы NHL-BFM-90 при лечении первичной диффузной B-крупноклеточной лимфосаркомы костей и мягких тканей с факторами неблагоприятного прогноза. Терапевтический архив. 2009;81(7):61–5.

    [Morozova AK, Zvonkov EE, Kremenetskaya AM, et al. Initial experience with using modified NHL-BFM-90 program in management of primary diffuse large B-cell lymphosarcoma of bones and soft tissues with unfavorable prognostic factors. Terapevticheskii arkhiv. 2009;81(7):61–5. (In Russ)]

  13. Морозова А.К., Звонков Е.Е., Мамонов В.Е. и др. Первичные лимфатические опухоли костей и мягких тканей: сравнительная оценка результатов лечения. Терапевтический архив. 2012;84(7):42–9.

    [Morozova AK, Zvonkov EE, Mamonov VE, et al. Primary lymphomas of bones and soft tissues: comparative assessment of treatment results. Terapevticheskii arkhiv. 2012;84(7):42–9. (In Russ)]

  14. Gill P, Wenger D, Inwards D. Primary lymphomas of bone. Clin Lymph Myel. 2005;6(2):140–2. doi: 10.3816/CLM.2005.n.041.

  15. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4):1244. doi: 10.1200/JCO.1999.17.4.1244.

  16. Juweid ME, Wiseman GA, Vose JM, et al. Response assessment of aggressive non-Hodgkin’s lymphoma by integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography. J Clin Oncol. 2005;23(21):4652–61. doi: 10.1200/JCO.2005.01.891.

  17. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007; 25(5):579–86. doi: 10.1200/JCO.2006.09.2403.

  18. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007;25(5):571–8. doi: 10.1200/JCO.2006.08.2305.

  19. Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE). Published August 9, 2006. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. (accessed 14.04.2019).

  20. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275–82. doi: 10.1182/blood-2003-05-1545.

  21. Messina C, Ferreri AJ, Govi S, et al. Clinical features, management and prognosis of multifocal primary bone lymphoma: a retrospective study of the international Extranodal Lymphoma Study Group (the IELSG 14 study). Br J Haematol. 2014;164(6):834–40. doi: 10.1111/bjh.12714.

  22. Reddy N, Greer JP. Primary bone lymphoma: a set of unique problems in management. Leuk 2009;51(1):1–2. doi: 10.3109/10428190903470877.

  23. Baar J, Burkes R, Bell R, et al. Primary Non-Hodgkin’s Lymphoma of Bone. A clinicopathologic study. Cancer. 1994;73(4):1194–9. doi: 10.1002/1097-0142(19940215)73:4<1194::aid-cncr2820730412>3.0.co;2-r.

  24. Bacci G, Ferraro A, Casadei R, et al. Primary lymphoma of bone: Long term results in patients treated with vincristine–adriamycin–cyclophosphamide and local radiation. J Chemother. 1991;3(3):189–93. doi: 10.1080/1120009x.1991.11739091.

  25. Jones D, Kraus MD, Dorfman DM. Lymphoma presenting as a solitary bone lesion. Am J Clin Pathol. 1999;111(2):171–8. doi: 10.1093/ajcp/111.2.171.

  26. Limb D, Dreghorn C, Murphy JK, Mannion R. Primary lymphoma of bone. Int Orthop. 1994;18(3):180–3. doi: 10.1007/bf00192476.

  27. Govi S, Christie D, Messina C, et al. The clinical features, management and prognostic effects of pathological fractures in a multicenter series of 373 patients with diffuse large B-cell lymphoma of the bone. Ann Oncol. 2013;25(1):176–81. doi: 10.1093/annonc/mdt482.

  28. Pilorge S, Harel S, Ribrag V, et al. Primary bone diffuse large B-cell lymphoma: a retrospective evaluation on 76 cases from French institutional and LYSA studies. Leuk Lymphoma. 2016;57(12):2820–6. doi: 10.1080/10428194.2016.1177180.

  29. Christie DR, Barton MB, Bryant G, et al. Osteolymphoma (primary bone lymphoma): An Australian review of 70 cases. Australasian Radiation Oncology Lymphoma Group (AROLG). Aust N Z J Med. 1999;29(2):214–9. doi: 10.1111/j.1445-5994.1999.tb00686.x.

  30. Santini D, Vincenzi B, Hannon RA, et al. Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy. J Clin Oncol. 2006;24(30):4895–900. doi: 10.1200/JCO.2006.05.9212.

  31. Shoji H, Miller TR. Primary reticulum cell sarcoma of bone: Significance of clinical features upon the prognosis. Cancer. 1971;28(5):1234–44. doi: 10.1002/1097-0142(1971)28:5<1234::aid-cncr2820280522>3.0.co;2-l.

  32. Hayase E, Kurosawa M, Suzuki H, et al. Primary Bone Lymphoma: A Clinical Analysis of 17 Patients in a Single Institution. Acta Haematol. 2015;134(2):80–5. doi: 10.1159/000375437.

  33. Tao R, Allen PK, Rodriguez A, et al. Benefit of consolidative radiation therapy for primary bone diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys. 2015;92(1):122–9. doi: 10.1016/j.ijrobp.2015.01.014.

  34. Ali SM, Demers LM, Leitzel K, et al. Baseline serum NTx levels are prognostic in metastatic breast cancer patients with bone-only metastasis. Ann Oncol. 2004;15(3):455–9. doi: 10.1093/annonc/mdh089.

  35. Doll C, Wulff B, Rossler J, et al. Primary B-cell lymphoma of bone in children. Eur J Pediatr. 2001;160(4):239–42. doi: 10.1007/s004310000711.

  36. Dosoretz DE, Murphy GF, Raymond AK, et al. Radiation Therapy for Primary Lymphoma of Bone. Cancer. 1983;51(1):44–6. doi: 10.1002/1097-0142(19830101)51:1<44::aid-cncr2820510111>3.0.co;2-d.

  37. Kransdorf MJ. Malignant soft-tissue tumors in a large referral population: distribution of diagnoses by age, sex, and location. Am J Roentgenol. 1995;164(1):129–34. doi: 10.2214/ajr.164.1.7998525.

  38. Wang CC. Treatment of primary reticulum-cell sarcoma of bone by radiation. N Engl J Med. 1968;278(24):1331–2. doi: 10.1056/NEJM196806132782407.

  39. Jacobs AJ, Michels R, Stein J, et al. Socioeconomic and demographic factors contributing to outcomes in patients with primary lymphoma of bone. J Bone Oncol. 2015;4(1):32–6. doi: 10.1016/j.jbo.2014.11.002.

  40. Dos Santos TM, Zumarraga JP, Reaes FM, et al. Primary bone lymphomas: retrospective analysis of 42 consecutive cases. Acta Ortop Bras. 2018;26(2):103–7. doi: 10.1590/1413-785220182602185549.

  41. Wu H, Zhang L, Shao M, Sokol L, et al. Prognostic Significance Of Soft Tissue Involvement, International Prognostic Index In Primary Bone Lymphoma: A Single Institutional Experience. Br J Haematol. 2014;166(1):60-8. doi: 10.1111/bjh.12841.

  42. Zhang HY, Zhu J, Song YQ, et al. Clinical characterization and outcome of primary bone lymphoma: a retrospective study of 61 Chinese patients. Sci Rep. 2016;6(1):28834. doi: 10.1038/srep28834.

  43. Alencar A, Pitcher D, Byrne G at al. Primary bone lymphoma – the University of Miami Experience. Leuk Lymphoma. 2009;51(1):39–49. doi. 10.3109/10428190903308007.

  44. Kim SY, Shin DY, Lee SS. Clinical characteristics and outcomes of primary bone lymphoma in Korea. Korean J Hematol. 2012;47(3): 213–8. doi: 10.5045/kjh.2012.47.3.213.

  45. Held G, Zeynalova S, Murawski N, et al. Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement. J Clin Oncol. 2013;31(32):4115–22. doi: 10.1200/JCO.2012.48.0467.

  46. Zhu Y, Yue C, Wu B, et al. Clinical characteristics and outcomes of 31 patients with primary bone lymphoma. Nan Fang Yi Ke Da Xue Xue Bao. 2013;33(3):444–7.

  47. Barbieri E, Cammellin C, Mauro F et al. Primary Non-Hodgkin lymphoma of the bone: treatment and analysis of prognostic factors. Int J Radiat Oncol Biol Phys. 2004;59(3):760–4. doi: 10.1016/j.ijrobp.2003.11.020.

  48. Fairbanks RK, Bonner JA, Inwards CY, et al. Treatment stage 1E primary lymphoma of bone. Int J Radiat Oncol Biol Phys. 1994;28(2):363–72. doi. 10.1016/0360-3016(94)90059-0.

  49. Marshall DT, Amdur RJ, Scarborough MT, et al. Stage 1E primary non Hodgkin’s lymphoma of bone. Clin Orthop Rel Res. 2002;405:216–22. doi: 10.1097/00003086-200212000-00028.

  50. Remier RR, Chabner BA, Yong RC, et al. Lymphoma Presenting in Bone. Results of Histopathology, Staging, and Therapy. Ann Intern Med. 1977;87(1):50–5. doi: 10.7326/0003-4819-87-1-50.

  51. Singh Т, Satheesh С, Lakshmaiah С, et al. Primary bone lymphoma: A report of two cases and review of the literature. J Cancer Res Ther. 2010;6(3):296–8. doi: 10.4103/0973-1482.73366.

  52. Coley BL, Higinbotham NL, Groesbeck HP. Primary reliculum-cell sarcoma of bone. Radiology. 1950;55(5):641–58. doi: 10.1148/55.5.641.

  53. Francis KC, Higinbotham NL, Coley BL. Primary reticulum cell sarcoma of bone; report of 44 cases. Surg Gynecol Obstet. 1954;99(2):142–6.

  54. Badoo S, Sidhu GS. Primary Bone Lymphoma (PBL): Impact Of Novel Treatment On Need For Radiation Therapy (RT), a Population Based Study. Blood. 2013;122(21):3059.

  55. Гаврилина О.А., Звонков Е.Е., Паровичникова Е.Н. и др. Лечение больных диффузной В-крупноклеточной лимфомой с факторами неблагоприятного прогноза по протоколу R-DA-EPOCH/R-HMA: первые результаты российского пилотного многоцентрового исследования. Гематология и трансфузиология. 2016;61(1, прил. 1):38.

    [Gavrilina OA, Zvonkov EE, Parovichnikova EN, et al. Treatment of diffuse large B-cell lymphoma patients with poor prognosis factors using R-DA-EPOCH/R-HMA regimen: first results of the Russian pilot multi-center trial. Gematologiya i transfuziologiya. 2016;61(1, Suppl 1):38. (In Russ)]

  56. Meignan M, Barrington S, Itti E, et al. Report on the 4th international workshop on positron emission tomography in lymphoma held in Menton, France, 3–5 October 2012. Leuk 2014;55(1):31–7. doi: 10.3109/10428194.2013.802784.

  57. Rigacci L, Kovalchuk S, Berti V, et al. The use of Deauville 5-point score could reduce the risk of false-positive fluorodeoxyglucose-positron emission tomography in the posttherapy evaluation of patients with primary bone lymphomas. W J Nucl Med. 2018;17(3):157–65. doi: 10.4103/wjnm.WJNM_42_17.

  58. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol. 2014;32(27):3059–67. doi: 1200/JCO.2013.54.8800.

  59. Reddy N, Greer JP. Primary bone lymphoma: a set of unique problems in management. Leuk 2009;51(1):1–2. doi: 10.3109/10428190903470877.

  60. Borst AJ, States LJ, Reilly AF, et al. Determining response and recurrence in pediatric B-cell lymphomas of the bone. Pediatr Blood Cancer. 2013;60(8):1281–6. doi: 10.1002/pbc.24523.

  61. Ferreri AJ, Reni M, Ceresoli GL, et al. Therapeutic management with adriamycin-containing chemotherapy and radiotherapy of monostotic and polyostotic primary non-Hodgkin’s lymphoma of bone in adults. Cancer Invest. 1998;16(8):554–61. doi: 10.3109/07357909809032885.

  62. Messina C, Christie D, Zucca E, et al. Primary and secondary bone lymphomas. Cancer Treat Rev. 2015;41(3):235–46. doi: 10.1016/j.ctrv.2015.02.001.

  63. Tomita N, Yokoyama M, Yamamoto W, et al. Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era. Cancer Sci. 2012;103(2):245–51. doi: 10.1111/j.1349-7006.2011.02139.x.

  64. Seymour JF. Extra-nodal lymphoma in rare localisations: bone, breast and testes. Hematol Oncol. 2013;31(Suppl 1):60–3. doi: 10.1002/hon.2081.

  65. Guirguis HR, Cheung MC, Mahrous M, et al. Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single center experience and review of the literature. Br J Haematol. 2012;159(1):39–49. doi: 10.1111/j.1365-2141.2012.09247.x.

  66. Dosoretz DE, Raymond AK, Murphy GF, et al. Primary lymphoma of bone. The relationship of morphologic diversity to clinical behavior. Cancer. 1982;50(5):1009–14. doi: 10.1002/1097-0142(19820901)50:5<1009::aid-cncr2820500532>3.0.co;2-0.

  67. Rathmell AJ, Gospodarowicz MK, Sutcliffe SB, et al. Localised lymphoma of bone: prognostic factors and treatment recommendations. The Princess Margaret Hospital Lymphoma Group. Br J Cancer. 1992;66(3):603–6. doi: 10.1038/bjc.1992.322.

  68. Dubey P, Ha CS, Besa PC, et al. Localized primary malignant lymphoma of bone. Int J Radiat Oncol Biol Phys. 1997;37(5):1087–93. 10.1016/S0360-3016(97)00106-5.

  69. Gianelli U, Patriarca C, Moro A, et al. Lymphomas of the bone: a pathological and clinical study of 54 cases. Int J Surg Pathol 2002;10(4):257–66. doi: 1177/106689690201000403.

  70. Zinzani PL, Carrillo G, Ascani S, et al. Primary bone lymphoma: experience with 52 patients. Haematologica. 2003;88(3):280–5.

  71. Bayrakci K, Yildiz Y, Saglik Y, et al. Primary lymphoma of bones. Int Orthop. 2001;25(2):123–6. doi: 10.1007/s002640100224.

  72. Horsman JM, Thomas J, Hough R, Hancock BW. Primary bone lymphoma: a retrospective analysis. Int J Oncol. 2006;28(6):1571–5. doi: 10.3892/ijo.28.6.1571.

  73. Catlett JP, Williams SA, O’Connor SC, et al. Primary lymphoma of bone: an institutional experience. Leuk 2008;49(11):2125–32. doi: 10.1080/10428190802404030.

  74. Heyning FH, Hogenndoorn PC, Kramer MH, et al. Primary lymphoma of bone: extranodal lymphoma with favourable survival independent of germinal centre, post-germinal centre or indeterminate phenotype. J Clin Pathol. 2009;62(9):820–4. doi: 10.1136/jcp.2008.063156.

  75. Jawad MU, Schneiderbauer MM, Min ES, et al. Primary Lymphoma of Bone in Adult Patients. Cancer. 2010;116(4):871–9. doi: 10.1002/cncr.24828.

  76. Nasiri MR, Varshoee F, Mohtashami S, et al. Primary bone lymphoma: a clinicopathological retrospective study of 28 patients in a single institution. J Res Med Sci. 2011;16(6):814–20.

  77. Christie DR, Dear K, Le T, et al. Limited chemotherapy and shrinking field radiotherapy for Osteolymphoma (primary bone lymphoma): results from the trans-Tasman Radiation Oncology Group 99.04 and Australasian Leukaemia and Lymphoma Group LY02 prospective trial. Int J Radiat Oncol Biol Phys. 2011;80(4):1164–70. doi: 10.1016/j.ijrobp.2010.03.036.

  78. Cai L, Stauder MC, Zhang YJ, et al. Early-stage primary bone lymphoma: a retrospective, multicenter rare cancer network (RCN) study. Int J Radiat Oncol Biol Phys. 2012;83(1):284–91. doi: 10.1016/j.ijrobp.2011.06.1976.

  79. Ventre BM, Ferreri AJM, Gospodarowicz M, et al. Clinical features, management, and prognosis of an international series of 161 patients with limited-stage diffuse large B-cell lymphoma of the bone (the IELSG-14 study). Oncologist. 2014;19(3):291–8. doi: 10.1634/theoncologist.2013-0249.

  80. Jamshidi K, Jabalameli MD, Hoseini MG, et al. Stage IE Primary Bone Lymphoma: Limb Salvage for Local Recurrence. Arch Bone Jt Surg. 2015;3(1):39–44.

  81. Ayed BC, Laabidi S, Said N, et al. Primary bone lymphoma: tunisian multicentric retrospective study about 32 cases. Tunis Med. 2018;96(5):269–72.

A Case of Hairy Cell Leukemia Diagnosed Simultaneously with Lymphoplasmacytic Lymphoma by Anti-CD Antibody Microarray Method

AN Khvastunova1,2, LS Al-Radi3, OS Fedyanina1,2, SA Lugovskaya4, SA Kuznetsova1,2

1 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

2 Center for Theoretical Problems of Physicochemical Pharmacology, 4 Kosygina str., Moscow, Russian Federation, 119991

3 National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

4 Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya str., Moscow, Russian Federation, 1125993

For correspondence: Alina Nikolaevna Khvastunova, PhD in Biology, 1 Samory Mashela str., Moscow, Russian Federation, 117997; Tel.: +7(495)287-65-70; e-mail: alina_shunina@mail.ru

For citation: Khvastunova AN, Al-Radi LS, Fedyanina OS, et al. A Case of Hairy Cell Leukemia Diagnosed Simultaneously with Lymphoplasmacytic Lymphoma by Anti-CD Antibody Microarray Method. Clinical oncohematology. 2019;12(3):243–6 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-243-246


ABSTRACT

The paper deals with a combined case of hairy cell leukemia and lymphoplasmacytic lymphoma with IgMκ paraprotein secretion. The use of anti-CD antibody microarray enabled the simultaneous assessment of immunophenotype as well as morphological and cytochemical analysis. Small populations of hairy (3 % of total lymphocyte count) and plasma (2 %) cells including Mott cells (0.2 %) were found in the peripheral blood of a patient with leukopenia. The results obtained by the anti-CD antibody microarray method speeded up provisional diagnosis which was later confirmed by standard diagnostic methods.

Keywords: anti-CD antibody microarray, hairy cell leukemia, lymphoplasmacytic lymphoma, hairy cells, plasma cells, Mott cells.

Received: November 12, 2018

Accepted: May 2, 2019

Read in PDF 


REFERENCES

  1. Khvastunova AN, Kuznetsova SA, Al-Radi LS, et al. Anti-CD antibody microarray for human leukocyte morphology examination allows analyzing rare cell populations and suggesting preliminary diagnosis in leukemia. Sci Rep. 2015;5(1):12573. doi: 10.1038/srep12573.

  2. Хвастунова А.Н., Аль-Ради Л.С., Капранов Н.М. и др. Использование клеточного биочипа в диагностике волосатоклеточного лейкоза. Онкогематология. 2015;10(1):37–45. doi: 10.17650/1818-8346-2015-1-37-45.

    [Khvastunova AN, Al-Radi LS, Kapranov NM, et al. Cell-binding microarray application in diagnosis of hairy cell leukemia. Oncohematology. 2015;10(1):37–45. doi: 10.17650/1818-8346-2015-1-37-45. (In Russ)]

  3. Khvastunova AN, Al‐Radi LS, Fedyanina OS, Kuznetsova SA. Simultaneous finding of chronic lymphocytic leukemia and residual hairy cell leukemia using a lymphocyte‐binding anti‐CD antibody microarray. Clin Case Rep. 2018;6(4):753–5. doi: 10.1002/ccr3.1416.

  4. Bain BJ. Leukemia Diagnosis. 4th edition. Singapore: Blackwell Publishing; 2010. doi: 10.1002/9781444318470.

  5. Луговская С.А., Почтарь М.Е. Гематологический атлас. М. – Тверь: Триада, 2011. 368 с.

    [Lugovskaya SA, Pochtar ME. Gematologicheskii atlas. (Hematology atlas.) Moscow – Tver: Triada Publ.; 2011. 368 р. (In Russ)]

  6. Shao H, Calvo KR, Gronborg M, et al. Distinguishing hairy cell leukemia variant from hairy cell leukemia: Development and validation of diagnostic criteria. Leuk Res. 2013;37(4):401–9. doi: 10.1016/j.leukres.2012.11.021.

  7. Robak T. Hairy-cell leukemia variant: recent view on diagnosis, biology and treatment. Cancer Treat Rev. 2011;37(1):3–10. doi: 10.1016/j.ctrv.2010.05.003.

  8. Traverse-Glehen A, Baseggio L, Callet-Bauchu E, et al. Splenic red pulp lymphoma with numerous basophilic villous lymphocytes: a distinct clinicopathologic and molecular entity? Blood. 2008;111(4):2253–60. doi: 10.1182/blood-2007-07-098848.

  9. Хвастунова А.Н., Аль-Ради Л.С., Федянина О.С. и др. Особенности морфологии и иммунофенотипа опухолевых клеток лимфомы из клеток маргинальной зоны селезенки (исследование с помощью клеточного биочипа). Онкогематология. 2017;12(1):71–7. doi: 10.17650/1818-8346-2017-12-1-71-77.

    [Khvastunova AN, Al-Radi LS, Fedyanina OS, et al. Determination of morphology and immunophenotype of circulating lymphoma cells in patients with splenic marginal zone lymphoma using an anti-CD antibody microarray. Oncohematology. 2017;12(1):71–7. doi: 10.17650/1818-8346-2017-12-1-71-77. (In Russ)]

  10. Mott F. Observations on the brains of men and animals infected with various forms of trypanosomes. Preliminary note. Proc Royal Soc London B. 1905;76(509):235–42. doi: 10.1098/rspb.1905.0016.

  11. Jacob H, Lutcke A. Subakute sklerosierende leukoencephalitis unter dem initialbild einer akuten epidemischen encephalitis (akute parkinsonistische encephalitis) mit ausgepragter entwicklung von Maulbeerzellen und Russell-Korperchen. J Neurol Sci. 1971;12(2):137–53. doi: 10.1016/0022-510X(71)90045-1.

  12. Greenwood BM, Whittle HC. Cerebrospinal fluid IgM in patients with sleeping sickness. Lancet. 1973;302(7828):525–7. doi: 10.1016/s0140-6736(73)92348-9.

  13. Alanen A, Pira U, Lassila O, et al. Mott cells are plasma cells defective in immunoglobulin secretion. Eur J Immunol. 1985;15(3):235–42. doi: 10.1002/eji.1830150306.

  14. Posnett DN, Mouradian J, Mangraviti DJ, Wolf DJ. Mott cells in a patient with a lymphoproliferative disorder. Differentiation of a clone of B lymphocytes into Mott cells. Am J Med. 1984;77(1):125–30. doi: 10.1016/0002-9343(84)90446-7.

  15. El-Okda M, Hyeh Y, Xie SS, Hsu SM. Russell bodies consist of heterogeneous glycoproteins in B-cell lymphoma cells. Am J Clin Pathol. 1992;97(6):866–71. doi: 10.1093/ajcp/97.6.866.

  16. Kurihara K, Sakai H, Hashimoto N. Russell body-like inclusions in oral B-lymphomas. J Oral Pathol.1984;13(6):640–9. doi: 10.1111/j.1600-0714.1984.tb01466.x.

  17. Джулакян У.Л., Двирнык В.Н., Менделеева Л.П. Селезеночная В-клеточная лимфома из клеток маргинальной зоны с выраженной плазмоклеточной дифференцировкой: вариант опухоли из клеток Мотта? Онкогематология. 2015;10(4):34–7. doi: 10.17650/1818-8346-2015-10-4-34-37.

    [Dzhulakyan UL, Dvirnyk VN, Mendeleeva LP. Splenic B-cell marginal zone lymphoma with marked plasmocytic differentiation: tumor variant from Mott cells? Oncohematology. 2015;10(4):34–7. doi: 10.17650/1818-8346-2015-10-4-34-37. (In Russ)]

  18. Mossafa H, Malaure H, Maynadie M, et al. Persistent polyclonal B lymphocytosis with binucleated lymphocytes: a study of 25 cases. Br J Haematol. 1999;104(3):486–93. doi: 10.1046/j.1365-2141.1999.01200.x.