Hodgkin’s lymphoma

Brentuximab Vedotin: New Possibilities for Treatment of Relapses and Refractory Hodgkin’s Lymphomas

LYMPHOID TUMORS , , ,

EA Demina

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

For correspondence: Elena Andreevna Demina, DSci, Professor, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel: +7 (499)324-90-89; e-mail: drdemina@yandex.ru

For citation: Demina EA. Brentuximab Vedotin: New Possibilities for Treatment of Relapses and Refractory Hodgkin’s Lymphomas. Clinical oncohematology. 2016;9(4):398–405 (In Russ).

DOI: http://dx.doi.org/10.21320/2500-2139-2016-9-4-398-405

ABSTRACT

The concept of total curability of Hodgkin’s lymphoma was introduced as early as in 1970s. However, 10–30 % of patients develop relapses; in addition, resistant tumors cannot be excluded. A high-dose chemotherapy with autologous hematopoietic stem cell transplantation is a modern treatment standard for relapses and refractory Hodgkin’s lymphomas. However, long-term remissions are achieved only in a half of these patients. The toxicity of effective first-line treatment regimens and insufficient effectiveness of regimens prescribed for relapses and refractory disease are the reason for further search of new therapeutic options for this malignant tumor. Invention of an immunoconjugate, brentuximab vedotin, became one of the new steps in the treatment of Hodgkin’s lymphomas. This review presents data on the pharmacological properties of the drug, the mechanism of the anti-tumor effect, as well as results of large international, randomized clinical trials.

Keywords: brentuximab vedotin, Hodgkin’s lymphoma, relapse, treatment.

Received: June 14, 2016

Accepted: June 17, 2016

Read in PDF (RUS) pdficon

REFERENCES

  1. De Vita VT. The consequences of the chemotherapy of Hodgkin’s disease: the 10th David A. Karnofsky memorial lecture. Cancer. 1981;47(1):1–13. doi: 10.1002/1097-0142(19810101)47:1<1::AID-CNCR2820470102>3.0.co;2-2.
  2. Engert A, Younes A, eds. Hematologic malignancies: Hodgkin lymphoma. 2nd edition. A Comprehensive Update on Diagnostics and Clinics. Berlin Heidelberg: Springer; 2015. doi: 10.1007/978-3-319-12505-3.
  3. Horning S, Fanale M, deVos S, et al. Defining a population of Hodgkin lymphoma patients for novel therapeutics: An international effort. Ann Oncol. 2008;19(Suppl 4): Abstract 118.
  4. Falini B, Pileri S, Pizzolo G, et al. CD30 (Ki-1) molecule: A new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995;85(1):1–14.
  5. Matsumoto K, Terakawa M, Miura K, et al. Extremely rapid and intense induction of apoptosis in human eosinophils by anti-CD30 antibody treatment in vitro. J Immunol. 2004;172(4):2186–93. doi: 10.4049/jimmunol.172.4.2186.
  6. Ansell SM, Horwitz SM, Engert A, et al. Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin’s lymphoma and anaplastic large-cell lymphoma. J Clin Oncol. 2007;25(19):2764–9. doi: 10.1200/jco.2006.07.8972.
  7. Forero-Torres A, Leonard JP, Younes A, et al. A Phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009;146(2):171–9. doi: 10.1111/j.1365-2009.07740.x.
  8. Dosio F, Brusa P and Cattel L Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components. 2011;3(12):848–83. doi: 10.3390/toxins3070848.
  9. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity. 2003;102(4):1458–65. doi: 10.1182/blood-2003-01-0039.
  10. Sutherland MSK, Sanderson RJ, Gordon KA, et al. Lysosomal Trafficking and Cysteine Protease Metabolism Confer Target-specific Cytotoxicity by Peptide-linked Anti-CD30-Auristatin Conjugates. J Biol Chem. 2006;281(15):10540–7. doi: 10.1074/jbc.M510026200.
  11. Katz J, Janik JA, Yones A. Brentuximab vedotin (SGN-35). Clin Cancer Res. 2011;17(20):6428–36. doi: 10.1158/1078-0432.CCR-11-0488.
  12. Chen R, Gopal AK, Smith SE, et al. Five-year survival data demonstrating durable responses from a pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;126(Suppl 23): Abstract 2736. doi: 10.1182/blood-2016-02-699850.
  13. Gardai SJ, Epp A, Law C-L. Brentuximab vedotin-mediated immunogenic cell death. Cancer Res. 2015;75(15): Abstract 2469. doi: 10.1158/1538-7445.am2015-2469.
  14. Oflazoglu E, Stone IJ, Gordon KA. Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. Blood. 2007;110(13):4370–2. doi: 10.1182/blood-2007-06-097014.
  15. Fu L, Xinqun Z, Kim E, et al. Relationship between in vivo antitumor activity of ADC and payload release in preclinical models. Cancer Res. 2014;74(19): Abstract 3694. doi: 10.1158/1538-am2014-3694.
  16. Kim YH, Tavallaee M, Sundram U, et al. Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sezary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol. 2015;33(32):3750–8. doi: 10.1200/jco.2014.60.3969.
  17. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9. doi: 10.1200/jco.2011.38.0410.
  18. Arai S, Fanale M, DeVos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell Leuk Lymphoma. 2013;54(11):2531–3. doi: 10.3109/10428194.2013.798868.
  19. Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(8):1236–43. doi: 10.1182/blood-2014-08-595801.
  20. Lee JJ, Swain SM. Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol. 2006;24(10):1633–42. doi: 10.1200/jco.2005.04.0543.
  21. Swain SM, Arezzo JC. Neuropathy associated with microtubule inhibitors: Diagnosis, incidence, and management. Clin Adv Hematol Oncol. 2008;6(6):455–67.
  22. Zinzani PL, Corradini P, Gianni AM, et al. Brentuximab Vedotin in CD30-Positive Lymphomas: A SIE, SIES, and GITMO Position Paper. Clin Lymph Myel Leuk. 2015;15(9):507–13. doi: 10.1016/j.clml.2015.06.008.
  23. Rothe A, Sasse S, Goergen H, et al. Brentuximab vedotin for relapsed or refractory CD30 hematologic malignancies: the German Hodgkin Study Group experience. Blood. 2012;120(7):1470–2. doi: 10.1182/blood-2012-05-430918.
  24. Gibb A, Jones C, Bloor A, et al. Brentuximab vedotin in refractory CD30 lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center. Haematologica. 2013;98(4):611–4. doi: 10.3324/haematol.2012.069393.
  25. Zinzani PL, Viviani S, Anastasia A, et al. Brentuximab vedotin in relapsed/refractory Hodgkin’s lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials. Haematologica. 2013;98(8):1232–6. doi: 10.3324/haematol.2012.083048.
  26. Perrot A, Monjanel H, Bouabdallah R, et al. Brentuximab vedotin as single agent in refractory or relapsed CD30-positive Hodgkin lymphoma: the French name patient program experience in 241 patients. Haematologica. 2014;99(s1):498, abstr. S1293.
  27. Perrot A, Monjanel H, Bouabdallah R, et al. Lymphoma Study Association (LYSA). Impact of post-brentuximab vedotin consolidation on relapsed/refractory CD30+ Hodgkin lymphomas: a large retrospective study on 240 patients enrolled in the French Named-Patient Program. 2016;101(4):466–73. doi: 10.3324/haematol.2015.134213. Epub 2016 Jan 14.
  28. Moskowitz CH, Yahalom J, Zelenetz AD, et al. High-Dose Chemo-Radiotherapy for Relapsed or Refractory Hodgkin Lymphoma and the Significance of Pre-transplant Functional Imaging. Br J Haematol. 2010;148(6):890–7. doi: 10.1111/j.1365-2141.2009.08037.x.
  29. Moskowitz AJ, Schoder H, Gerecitano JF. FDG-PET Adapted Sequential Therapy with Brentuximab Vedotin and Augmented ICE Followed By Autologous Stem Cell Transplant for Relapsed and Refractory Hodgkin Lymphoma. Blood (ASH Annual Meeting Abstracts). 2013;122(21): Abstract 2099.
  30. Moskowitz AJ, Hamlin PA Jr, Perales M-A, et al. Phase II Study of Bendamustine in Relapsed and Refractory Hodgkin Lymphoma. J Clin Oncol. 2013;31(4):456–60. doi: 10.1200/jco.2012.45.3308.
  31. LaCasce A, Sawas A, Bociek RG, et al. A phase 1/2 single-arm, open-label study to evaluate the safety and efficacy of brentuximab vedotin in combination with bendamustine for patients with Hodgkin lymphoma in the first salvage setting: interim results. Biol Blood Marrow Transplant. 2014;20(2):S161. doi: 10.1016/j.bbmt.2013.12.257.
  32. Aparicio J, Segura A. Garcera S, et al. ESHAP is an Active Regimen for Relapsing Hodgkin’s Disease. Ann Oncol. 1999;10(5):593–5. doi: 10.1023/A:1026454831340.
  33. Garcia-Sanz R, Sureda A, Alonso-Alvarez S, et al. Evaluation of the Regimen Brentuximab Vedotin Plus ESHAP (BRESHAP) in Refractory or Relapsed Hodgkin Lymphoma Patients: Preliminary Results of a Phase I-II Trial from the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO). Blood. 2015: Abstract 582.
  34. Bartlett NL, Chen R, Fanale MA, et al. Retreatment with brentuximab vedotin in CD30-positive hematologic malignancies. J Hematol Oncol. 2014;7(1):24. doi: 10.1186/1756-8722-7-24.
  35. Batlevi CL, Younes A. Novel therapy for Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2013;2013(1):394–9. doi: 10.1182/asheducation-2013.1.394.
  36. Majhail NS, Weisdorf DJ, Defor TE, et al. Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma. Biol Blood Marrow Transplant. 2006;12(10):1065–72. doi: 10.1016/j.bbmt.2006.06.006.
  37. Moskowitz CH, Paszkiewicz-Kozik E, Nadamanee A, et al. Analysis of primary-refractory Hodgkin lymphoma pts in a randomized, placebo-controlled study of brentuximab vedotin consolidation after autologous stem cell transplant. Hematol Oncol. 2015;33:165, abstr. 120.
  38. Moskowitz CH, Nademanee A, Masszi T, et Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853–62. doi: 10.1016/S0140-6736(15)60165-9.
  39. Walewski JA, Nademanee A, Masszi T, et al. Multivariate analysis of PFS from the AETHERA trial: a phase 3 study of brentuximab vedotin consolidation after autologous stem cell transplant for HL. J Clin Oncol. 2015;33(Suppl): Abstract 8519.
  40. Sweetenham JW, Walewski J, Nadamanee A, et al. Updated Efficacy and Safety Data from the AETHERA Trial of Consolidation with Brentuximab Vedotin after Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse. Biol Blood Marrow Transplant. 2016;22(3):S19e–S481, abstr. 24. doi: 10.1016/j.bbmt.2015.11.315.
  41. Bonthapally V, Ma E, Viviani S, et al. Healthcare utilization in the AETHERA trial: phase 3 study of brentuximab vedotin in patients at increased risk of residual Hodgkin lymphoma post-ASCT. Hematol Oncol. 2015;33:193, abstr. 177.
  42. Kuruvilla J, Connors JM, Sawas A, et al. A phase 1 study of brentuximab vedotin (BV) and bendamustine (B) in relapsed or refractory Hodgkin lymphoma (HL) and anaplastic large T-cell lymphoma (ALCL). Hematol Oncol. 2015;33:148, abstr. 090.
  43. Theurich S, Malcher J, Wennhold K, et al. Brentuximab Vedotin Combined With Donor Lymphocyte Infusions for Early Relapse of Hodgkin Lymphoma After Allogeneic Stem-Cell Transplantation Induces Tumor-Specific Immunity and Sustained Clinical Remission. J Clin Oncol. 2013;31(5):e59–e63. doi: 10.1200/jco.2012.43.6832.
  44. Vaklavas C, Forero-Torres A. Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Ther Adv Hematol. 2012;3(4):209–25. doi: 10.1177/2040620712443076.

 

Epstein-Barr Virus and Classical Hodgkin’s Lymphoma

REVIEWS , , , ,

VE Gurtsevich

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vladimir Eduardovich Gurtsevich, DSci, Professor, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-25-64; e-mail: gurvlad532@yahoo.com

For citation: Gurtsevitch VE. Epstein-Barr Virus and Classical Hodgkin’s Lymphoma. Clinical oncohematology. 2016;9(2):101–14 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-101-114

ABSTRACT

Among other oncogenic human viruses, the Epstein-Barr virus (EBV) drew special attention due to its unique properties. Being widespread among the population of the planet, the virus is also a leader in the number of associated different benign and malignant neoplasms of lymphoid and epithelial origin. The oncogenic potential of EBV is related to its ability to infect and transform human lymphocytes. In cases, when the interaction between reproduction of EBV, its latent state and immune control of the body is impaired, conditions for long-term proliferation of EBV-infected cells and their malignant transformation are formed. According to some investigators, the molecular mechanisms of EBV-associated carcinogenesis are due to the ability of the viral genome to promote the expression of series of products that simulate a number of growth factors and transcription and produce an anti-apoptotic effect. These products impair EBV-encoded signaling pathways that regulate a variety of cellular functions of homeostasis giving a cell the ability to proliferate indefinitely. However, the exact mechanism by which the EBV initiates tumor formation is not clear. The review provides summarized information on the structure and oncogenic potential of EBV, morphological and clinical cases of Hodgkin’s lymphoma (HL), and the role of EBV in the pathogenesis of types of HL associated with the virus. The review also dwells on the latest data on the use of EBV DNA plasma levels of patients with HL as a biomarker reflecting the effectiveness of the treatment performed and the prognosis of the disease.

Keywords: Epstein-Barr virus, EBV, latent membrane protein 1, LMP1, Hodgkin’s lymphoma, copies of EBV DNA.

Received: February 5, 2016

Accepted: February 8, 2016

Read in PDF (RUS) pdficon

REFERENCES

  1. Zur Hausen H, de Villiers EM. Reprint of: cancer “causation” by infections—individual contributions and synergistic networks. Semin Oncol. 2015;42(2):207–22. doi: 10.1053/j.seminoncol.2015.02.019.
  2. Santos-Juanes J, Fernandez-Vega I, Fuentes N, et al. Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol. 2015;173(1):42–9. doi: 10.1111/bjd.13870.
  3. Rickinson AB, Young LS, Rowe M. Influence of the Epstein-Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J Virol. 1987;61(5):1310–7.
  4. Rickinson AB, Long HM, Palendira U, et al. Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol. 2014;35(4):159–69. doi: 10.1016/j.it.2014.01.003.
  5. Woodman CB, Collins SI, Vavrusova N, et al. Role of sexual behavior in the acquisition of asymptomatic Epstein-Barr virus infection: a longitudinal study. Pediatr Infect Dis J. 2005;24(6):498–502. doi: 10.1097/01.inf.0000164709.40358.b6.
  6. Henle G, Henle W, Diehl V. Relation of Burkitt’s tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA. 1968;59(1):94–101. doi: 10.1073/pnas.59.1.94.
  7. Tanner J, Weis J, Fearon D, et al. Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell. 1987;50(2):203–13. doi:10.1016/0092-8674(87)90216-9.
  8. Connolly SA, Jackson JO, Jardetzky TS, et al. Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol. 2011;9(5):369–81. doi: 10.1038/nrmicro2548.
  9. Janz A, Oezel M, Kurzeder C, et al. Infectious Epstein-Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. J Virol. 2000;74(21):10142–52. doi: 10.1128/jvi.74.21.10142-10152.2000.
  10. Ogembo JG, Kannan L, Ghiran I, et al. Human complement receptor type 1/CD35 is an Epstein-Barr Virus receptor. Cell Rep. 2013;3(2):371–85. doi:10.1016/j.celrep.2013.01.023.
  11. Kempkes B, Robertson ES. Epstein-Barr virus latency: current and future perspectives. Curr Opin Virol. 2015;14:138–44. doi: 10.1016/j.coviro.2015.09.007.
  12. Sample J, Kieff E. Transcription of the Epstein-Barr virus genome during latency in growth-transformed lymphocytes. J Virol. 1990;64(4):1667–74.
  13. Babcock GJ, Decker LL, Volk M, et al. EBV persistence in memory B cells in vivo. Immunity. 1998;9(3):395–404. doi: 10.1016/S1074-7613(00)80622-6.
  14. Shannon-Lowe C, Adland E, Bell AI, et al. Features distinguishing Epstein-Barr virus infections of epithelial cells and B cells: viral genome expression, genome maintenance, and genome amplification. J Virol. 2009;83(15):7749–60. doi: 10.1128/JVI.00108-09.
  15. Rickinson A. Epstein-Barr virus. Virus Res. 2002;82(1–2):109–13. doi: 10.1016/s0168-1702(01)00436-1.
  16. Rowe M, Lear AL, Croom-Carter D, et al. Three pathways of Epstein-Barr virus gene activation from EBNA1-positive latency in B lymphocytes. J Virol. 1992;66(1):122–31.
  17. Portis T, Dyck P, Longnecker R. Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2003;102(12):4166–78. doi: 10.1182/blood-2003-04-1018.
  18. Sample J, Young L, Martin B, et al. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J Virol. 1990;64(9):4084–92.
  19. Sixbey JW, Shirley P, Chesney PJ, et al. Detection of a second widespread strain of Epstein-Barr virus. The Lancet. 1989;2(8666):761–5. doi: 10.1016/s0140-6736(89)90829-5.
  20. Gratama JW, Ernberg I. Molecular epidemiology of Epstein-Barr virus infection. Adv Cancer Res. 1995;67:197–255. doi: 10.1016/s0065-230x(08)60714-9.
  21. Young LS, Dawson CW, Eliopoulos AG. The expression and function of Epstein-Barr virus encoded latent genes. Mol Pathol. 2000;53(5):238–47. doi: 10.1136/mp.53.5.238.
  22. Mosialos G, Birkenbach M, Yalamanchili R, et al. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995;80(3):389–99. doi: 10.1016/0092-8674(95)90489-1.
  23. Nitta T, Chiba A, Yamashita A, et al. NF-kappaB is required for cell death induction by latent membrane protein 1 of Epstein-Barr virus. Cell Signal. 2003;15(4):423–33. doi: 10.1016/S0898-6568(02)00141-9.
  24. Aviel S, Winberg G, Massucci M, Ciechanover A. Degradation of the Epstein-Barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J Biol Chem. 2000;275(31):23491–9. doi: 10.1074/jbc.M002052200.
  25. Gires O, Kohlhuber F, Kilger E, et al. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J. 1999;18(11):3064–73. doi: 10.1093/emboj/18.11.3064.
  26. Bentz GL, Whitehurst CB, Pagano JS. Epstein-Barr virus latent membrane protein 1 (LMP1) C-terminal-activating region 3 contributes to LMP1-mediated cellular migration via its interaction with Ubc9. J Virol. 2011;85(19):10144–53. doi: 10.1128/JVI.05035-11.
  27. Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985;43(3):831–40. doi: 10.1016/0092-8674(85)90256-9.
  28. Dawson CW, Port RJ, Young LS. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol. 2012;22(2):144–53. doi: 10.1016/j.semcancer.2012.01.004.
  29. Смирнова К.В., Дидук С.В., Сенюта Н.Б., Гурцевич В.Э. Молекулярно-биологические свойства гена LMP1 вируса Эпштейна—Барр: структура, функции и полиморфизм. Вопросы вирусологии. 2015;60(3):5–13.
    [Smirnova KV, Diduk SV, Senyuta NB, Gurtsevich VE. Molecular biological properties of the Epstein-Barr virus LMP1 gene: structure, function, and polymorphism. Voprosy virusologii. 2015;60(3):5–13. (In Russ)]
  30. Vockerodt M, Morgan SL, Kuo M, et al. The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin’s Reed-Sternberg-like phenotype. J Pathol. 2008;216(1):83–92. doi: 10.1002/path.2384.
  31. Raab-Traub N. Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol. 2002;12:431–41. doi: 10.1016/s1044579x0200086x.
  32. Raab-Traub N. Novel mechanisms of EBV-induced oncogenesis. Curr Opin Virol. 2012;2(4):453–8. doi: 10.1016/j.coviro.2012.07.001.
  33. Soni V, Cahir-McFarland E, Kieff E. LMP1 TRAFficking activates growth and survival pathways. Adv Exp Med Biol. 2007;597:173–87. doi: 10.3390/v5041131.
  34. Man C, Rosa J, Lee LT, et al. Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells. Oncogene. 2007;26(21):3069–80. doi: 10.1038/sj.onc.1210106.
  35. Guo L, Tang M, Yang L, et al. Epstein-Barr virus oncoprotein LMP1 mediates surviving upregulation by p53 contributing to G1/S cell cycle progression in nasopharyngeal carcinoma. Int J Mol Med. 2012;29(4):574–80. doi: 10.3892/ijmm.2012.889.
  36. Horikawa T, Yoshizaki T, Kondo S, et al. Epstein-Barr Virus latent membrane protein 1 induces Snail and epithelial-mesenchymal transition in metastatic nasopharyngeal carcinoma. Br J Cancer. 2011;104(7):1160–7. doi: 10.1038/bjc.2011.38.
  37. Xiao L, Hu ZY, Dong X, et al. Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene. 2014;33(37):4568–78. doi: 10.1038/onc.2014.32.
  38. Sun W, Liu DB, Li WW, et al. Interleukin-6 promotes the migration and invasion of nasopharyngeal carcinoma cell lines and upregulates the expression of MMP-2 and MMP-9. Int J Oncol. 2014;44(5):1551–60. doi: 10.3892/ijo.2014.2323.
  39. Tzellos S, Farrell PJ. Epstein-Barr virus sequence variation-biology and disease. Pathogens. 2012;1(2):156–74. doi: 10.3390/pathogens1020156.
  40. Walling DM, Shebib N, Weaver SC, et al. The molecular epidemiology and evolution of Epstein-Barr virus: sequence variation and genetic recombination in the latent membrane protein-1 gene. J Infect Dis. 1999;179(4):763–74. doi: 10.1086/314672.
  41. Hu LF, Zabarovsky ER, Chen F, et al. Isolation and sequencing of the Epstein-Barr virus BNLF-1 gene (LMP1) from a Chinese nasopharyngeal carcinoma. J Gen Virol. 1991;72(Pt 10):2399–409. doi: 10.1099/0022-1317-72-10-2399.
  42. Nitta T, Chiba A, Yamamoto N, et al. Lack of cytotoxic property in a variant of Epstein-Barr virus latent membrane protein-1 isolated from nasopharyngeal carcinoma. Cell Signal. 2004;16(9):1071–81. doi: 10.1016/s0898-6568(04)00032-4.
  43. da Costa VG, Marques-Silva AC, Moreli ML. The Epstein-Barr virus latent membrane protein-1 (LMP1) 30-bp deletion and XhoI-polymorphism in nasopharyngeal carcinoma: a meta-analysis of observational studies. Syst Rev. 2015;4(1):46. doi: 10.1186/s13643-015-0037-z.
  44. Rowe M, Peng-Pilon M, Huen DS, et al. Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappaB activation and to induction of cell surface markers. J Virol. 1994;68(9):5602–12.
  45. Trivedi P, Hu LF, Chen F, et al. Epstein-Barr virus (EBV)-encoded membrane protein LMP1 from a nasopharyngeal carcinoma is non-immunogenic in a murine model system, in contrast to a B cell-derived homologue. Eur J Cancer. 1994;30(1):84–8. doi: 10.1016/s0959-8049(05)80024-3.
  46. Knecht H, Bachmann E, Brousset P, et al. Deletions within the LMP1 oncogene of Epstein-Barr virus are clustered in Hodgkin’s disease and identical to those observed in nasopharyngeal carcinoma. Blood. 1993;82(10):2937–42.
  47. Miller WE, Edwards RH, Walling DM, et al. Sequence variation in the Epstein-Barr virus latent membrane protein 1. J Gen Virol. 1994;75(Pt 10):2729–40. doi: 10.1099/0022-1317-75-10-2729.
  48. Weiss LM. Epstein-Barr virus and Hodgkin’s disease. Curr Oncol Rep. 2000;2(2):199–204. doi: 10.1007/s11912-000-0094-9.
  49. Ковригина А.М., Пробатова Н.А. Лимфома Ходжкина и крупноклеточные лимфомы. М.: МИА, 2007.
    [Kovrigina AM, Probatova NA. Limfoma Khodzhkina i krupnokletochnye limfomy. (Hodgkin’s lymphomas and large cell lymphomas.) Moscow: MIA Publ.; 2007. (In Russ)]
  50. Клиническая онкогематология: Руководство для врачей, 2-е изд. Под ред. М.А. Волковой. М.: Медицина, 2007.
    [Volkova MA, ed. Klinicheskaya  onkogematologiya: Rukovodstvo dlya vrachei. (Clinical oncohematology: manual for physicians.) 2nd edition. Moscow: Meditsina Publ.; 2007. (In Russ)]
  51. Dorsett Y, Robbiani DF, Jankovic M, et al. A role for AID in chromosome translocations between c-myc and the IgH variable region. J Exp Med. 2007;204(9):2225–32. doi: 10.1084/jem.20070884.
  52. Stein H. Hodgkin lymphoma – introduction. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008. pp. 321–34.
  53. Diehl V, Stein H, Hummel M, et al. Hodgkin’s lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease. Hematology Am Soc Hematol Educ Program. 2003;1:225–47. doi: 10.1182/asheducation-2003.1.225.
  54. Chapman AL, Rickinson AB. Epstein-Barr virus in Hodgkin’s disease. Ann Oncol. 1998;9(Suppl 5):S5–16. doi: 10.1093/annonc/9.suppl_5.s5.
  55. Deacon EM, Pallesen G, Niedobitek G, et al. Epstein-Barr virus and Hodgkin’s disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med. 1993;177(2):339–49. doi: 10.1084/jem.177.2.339.
  56. Kuppers R, Rajewsky K, Zhao M, et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA. 1994;91(23):10962–6. doi: 10.1073/pnas.91.23.10962.
  57. Thomas RK, Re D, Wolf J, et al. Part I: Hodgkin’s lymphoma—molecular biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol. 2004;5(1):11–8. doi: 10.1016/S1470-2045(03)01319-6.
  58. Cartwright RA, Watkins G. Epidemiology of Hodgkin’s disease: a review. Hematol Oncol. 2004;22(1):11–26. doi: 10.1002/hon.723.
  59. Jarrett AF, Armstrong AA, Alexander E. Epidemiology of EBV and Hodgkin’s lymphoma. Ann Oncol. 1996;7(Suppl 4):5–10. doi: 10.1093/annonc/7.suppl_4.s5.
  60. Glaser SL, Lin RJ, Stewart SL, et al. Epstein-Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer. 1997;70(4):375–82. doi: 10.1002/(sici)1097-0215(19970207)70:4<375::aid-ijc1>3.0.co;2-t.
  61. Cader FZ, Kearns P, Young L, et al. The contribution of the Epstein-Barr virus to the pathogenesis of childhood lymphomas. Cancer Treat Rev. 2010;36(4):348–53. doi: 10.1016/j.ctrv.2010.02.011.
  62. Jarrett RF, Gallagher A, Jones DB, et al. Detection of Epstein-Barr virus genomes in Hodgkin’s disease: relation to age. J Clin Pathol. 1991;44(10):844–8. doi: 10.1136/jcp.44.10.844.
  63. Armstrong AA, Alexander FE, Cartwright R, et al. Epstein-Barr virus and Hodgkin’s disease: further evidence for the three disease hypothesis. Leukemia. 1998;12(8):1272–6. doi: 10.1038/sj.leu.2401097.
  64. Oyama T, Ichimura K, Suzuki R, et al. Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol. 2003;27(1):16–26. doi: 10.1097/00000478-200301000-00003.
  65. Oyama T, Yamamoto K, Asano N, et al. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007;13(17):5124–32. doi: 10.1158/1078-0432.ccr-06-2823.
  66. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med. 2004;350(13):1328–37. doi: 10.1056/NEJMra032015.
  67. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5(4):251–62. doi: 10.1038/nrc1589.
  68. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol. 2008;8(1):22–33. doi: 10.1038/nri2217.
  69. Caldwell RG, Wilson JB, Anderson SJ, et al. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity. 1998;9(3):405–11. doi: 10.1016/s1074-7613(00)80623-8.
  70. Gires O, Zimber-Strobl U, Gonnella R, et al. Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 1997;16(20):6131–40. doi: 10.1093/emboj/18.11.3064.
  71. Laichalk LL, Thorley-Lawson DA. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol. 2005;79(2):1296–307. doi: 10.1128/JVI.79.2.1296-1307.2005.
  72. 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.
  73. Mueller N, Evans A, Harris NL, et al. Hodgkin’s disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med. 1989;320(11):689–95. doi: 10.1056/nejm198903163201103.
  74. 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.
  75. Anagnostopoulos I, Herbst H, Niedobitek G, et al. Demonstration of monoclonal EBV genomes in Hodgkin’s disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood. 1989;74(2):810–6.
  76. Re D, Kuppers R, Diehl V. Molecular pathogenesis of Hodgkin’s lymphoma. J Clin Oncol. 2005;23(26):6379–86. doi: 10.1200/JCO.2005.55.013.
  77. Mancao C, Altmann M, Jungnickel B, et al. Rescue of “crippled” germinal center B cells from apoptosis by Epstein-Barr virus. Blood. 2005;106(13):4339–44. doi: 10.1182/blood-2005-06-2341.
  78. Chaganti S, Bell AI, Pastor NB, et al. Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes. Blood. 2005;106(13):4249–52. doi: 10.1182/blood-2005-06-2327.
  79. Kapatai G, Murray P. Contribution of the Epstein Barr virus to the molecular pathogenesis of Hodgkin lymphoma. J Clin Pathol. 2007;60(12):1342–9. doi: 10.1136/jcp.2007.050146.
  80. Kuppers R. B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol. 2003;3(10):801–12. doi: 10.1038/nri1201.
  81. Huen DS, Henderson SA, Croom-Carter D, et al. The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene. 1995;10:549–60.
  82. Kieser A, Kilger E, Gires O, et al. Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J. 1997;16(21):6478–85. doi: 10.1093/emboj/16.21.6478.
  83. Kube D, Holtick U, Vockerodt M, et al. STAT3 is constitutively activated in Hodgkin cell lines. Blood. 2001;98(3):762–70. doi: 10.1182/blood.V98.3.762.
  84. Dutton A, Reynolds GM, Dawson CW, et al Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin’s lymphoma cells through a mechanism involving Akt kinase and mTOR. J Pathol. 2005;205(4):498–506. doi: 10.1002/path.1725.
  85. Brielmeier M, Mautner J, Laux G, et al. The latent membrane protein 2 gene of Epstein-Barr virus is important for efficient B cell immortalization. J Gen Virol. 1996;77(Pt 11):2807–18. doi: 10.1099/0022-1317-77-11-2807.
  86. Casola S, Otipoby KL, Alimzhanov M, et al. B cell receptor signal strength determines B cell fate. Nat Immunol. 2004;5(3):317–27. doi: 10.1038/ni1036.
  87. Engels N, Yigit G, Emmerich CH, et al. Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B cell antigen receptor-like activation signal. Cell Commun Signal. 2012;10(1):9. doi: 10.1186/1478-811X-10-9.
  88. Portis T, Dyck P, Longnecker R. Epstein-Barr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2003;102(12):4166–78. doi: 10.1182/blood-2003-04-1018.
  89. Portis T, Longnecker R. Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway. Oncogene. 2004;23(53):8619–28. doi: 10.1038/sj.onc.1207905.
  90. Farrell K, Jarrett RF. The molecular pathogenesis of Hodgkin lymphoma. Histopathology. 2011;58(1):15–25. doi: 10.1111/j.1365-2559.2010.03705.x.
  91. Herbst H, Foss HD, Samol J, et al. Frequent expression of interleukin-10 by Epstein-Barr virus-harboring tumor cells of Hodgkin’s disease. Blood. 1996;87:2918–29.
  92. Hsu SM, Lin J, Xie SS, et al. Abundant expression of transforming growth factor-beta 1 and -beta 2 by Hodgkin’s Reed-Sternberg cells and by reactive T lymphocytes in Hodgkin’s disease. Hum Pathol. 1993;24(3):249–55. doi: 10.1016/0046-8177(93)90034-e.
  93. Kapp U, Yeh WC, Patterson B, et al. Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med. 1999;189(12):1939–46. doi: 10.1084/jem.189.12.1939.
  94. Munz C, Moormann A. Immune escape by Epstein-Barr virus associated malignancies. Semin Cancer Biol. 2008;18(6):381–7. doi: 10.1016/j.semcancer.2008.10.002.
  95. Lichtenstein AV, Melkonyan HS, Tomei LD, et al. Circulating nucleic acids and apoptosis. Ann NY Acad Sci. 2001;945(1):239–49. doi: 10.1111/j.1749-6632.2001.tb03892.x.
  96. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2(3):210–9. doi: 10.1038/nrc755.
  97. Skvortsova TE, Rykova EY, Tamkovich SN, et al. Cell-free and cell-bound circulating DNA in breast tumours: DNA quantification and analysis of tumour-related gene methylation. Br J Cancer. 2006;94(10):1492–5. doi: 10.1038/sj.bjc.6603117.
  98. Lo YM, Chan LY, Lo KW, et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res. 1999;59(6):1188–91.
  99. Hou X, Zhao C, Guo Y, et al. Different Clinical Significance of Pre- and Post-treatment Plasma Epstein-Barr Virus DNA Load in Nasopharyngeal Carcinoma Treated with Radiotherapy. Clin Oncol. (R Coll Radiol) 2011;23(2):128–33. doi: 10.1016/j.clon.2010.09.001.
  100. Wang WY, Twu CW, Chen HH, et al. Plasma EBV DNA clearance rate as a novel prognostic marker for metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer Res. 2010;16(3):1016–24. doi: 10.1158/1078-0432.ccr-09-2796.
  101. Lo YM, Chan AT, Chan LY, et al. Molecular prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating Epstein-Barr virus DNA. Cancer Res. 2000;60:6878–81.
  102. Lo YM, Chan LY, Chan AT, et al. Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res. 1999;59:5452–5.
  103. Au WY, Pang A, Choy C, et al. Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood. 2004;104(1):243–9. doi: 10.1182/blood-2003-12-4197.
  104. Wang ZY, Liu QF, Wang H, et al. Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy. Blood. 2012;120(10):2003–10. doi: 10.1182/blood-2012-06-435024.
  105. Kasamon YL, Jacene HA, Gocke CD, et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012;119(18):4129–32. doi: 10.1182/blood-2012-01-402792.
  106. Kanakry JA, Li H, Gellert LL, et al. Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood. 2013;121(18):3547–53. doi: 10.1182/blood-2012-09-454694.
  107. Hohaus S, Santangelo R, Giachelia M, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17(9):2885–92. doi: 10.1158/1078-0432.ccr-10-3327.
  108. Dinand V, Sachdeva A, Datta S, et al. Plasma Epstein Barr Virus (EBV) DNA as a Biomarker for EBV associated Hodgkin lymphoma. Indian Pediatr. 2015;52(8):681–5. doi: 10.1007/s13312-015-0696-9.
  109. Vockerodt М, Yap L-F, Shannon-Lowe C, et al. The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol. 2015;235(2):312–22. doi: 10.1002/path.4459.
  110. Grywalska E, Markowicz J, Grabarczyk P, et al. Epstein-Barr virus-associated lymphoproliferative disorders. Postepy Hig Med Dosw (Online). 2013;67:481–90. doi 10.5604/17322693.1050999.

Treatment of Relapsed and Refractory Hodgkin’s Lymphoma in Children

LYMPHOID TUMORS , , , ,

NS Kulichkina, ES Belyaeva, GL Mentkevich, VK Boyarshinov, AS Levashov, IV Glekov, AV Popa

Scientific Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Aleksandr Valentinovich Popa, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-55-03; e-mail: apopa@list.ru

For citation: Kulichkina NS, Belyaeva ES, Mentkevich GL, et al. Treatment of Relapsed and Refractory Hodgkin’s Lymphoma in Children. Clinical oncohematology. 2016;9(1):13–21 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-13-21

ABSTRACT

Background & Aims. Most children with Hodgkin’s lymphoma (HL) can be cured irrespective of the disease stage using modern risk adapted protocols. But 3–5 % of children develop relapse of the disease or refractoriness to the treatment performed. The aim of the study was to perform a comparative analysis of ViGePP vs ICE antitumor treatment regimens in patients with relapsed and refractory Hodgkin’s lymphoma, as well as to evaluate the need in auto-HSCT and the site for a combined chemoradiation therapy in this patient population.

Methods. From June, 2003, till December, 2014, 35 patients with relapsed (18) and refractory (17) HL received chemotherapy based on two regimes: ICE (n = 14; 40 %) and ViGePP (n = 14; 40 %). 7 (20 %) children were switched to another regimen due to a poor antitumor response to the first two courses of chemotherapy.

Results. The direct effectiveness of the therapy was significantly higher in patients on ViGePP as compared to ICE irrespective of the disease status (relapsed or refractory). A complete response was achieved more often in those children with relapse HL whose initial treatment included radiation therapy. Higher survival rates were registered in girls, as well as in children with a complete overall response to the antirelapse therapy. In case of relapses, delayed treatment effects (disease free survival and overall survival) were higher in children treated with 4 courses of ViGePP than 2 courses of ICE. High-dose chemotherapy with subsequent auto-HSCT is not able to overcome refractoriness to the chemotherapy.

Conclusion. Children with relapsed and refractory HL need an intensive antirelapse chemotherapy with subsequent HDC and auto-HSCT to achieve CR.

Keywords: Hodgkin’s lymphoma, children, relapse, refractoriness, auto-HSCT.

Received: November 9, 2015

Accepted: December 25, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Беляева Е.С. Современные подходы к лечению детей с распространенными стадиями лимфомы Ходжкина: Автореф. дис. … канд. мед. наук. М., 2009. С. 1–29.
    [Belyaeva ES. Sovremennye podkhody k lecheniyu detei s rasprostranennymi stadiyami limfomy Khodzhkina. (Modern approaches to treatment of children with advanced Hodgkin’s lymphoma.) [dissertation] Moscow; 2009. p. 1–29. (In Russ)]
  2. Schellong G, Dorfell W, Claviez A, et al. Salvage therapy of progressive and recurrent Hodgkin’s disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group. J Clin Oncol. 2005;23:6181–9. doi: 10.1200/JCO.2005.07.930.
  3. Behrend H, Van Buningen BN, Van Leeuwen EF. Treatment of Hodgkin’s disease in children with or without radiotherapy. Cancer. 1987;59:1870–3. doi: 10.1002/1097-0142(19870601)59:11<1870::aid-cncr2820591105>3.0.co;2-d.
  4. Hudson MM, Krasin M, Link MP, et al. Risk-adapted combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin’s disease. J Clin Oncol. 2004;22:4541–50. doi: 10.1200/jco.2004.02.139.
  5. Gorde-Grosjean S, Oberlin O, Leblanc T, et al. Outcome of children and adolescents with recurrent/refractory classical Hodgkin lymphoma, a study from the Societe Francaise de Lutte contre le Cancer des Enfants et des Adolescents (SFCE). Br J Haematol. 2012;158(5):649–56. doi: 10.1111/j.1365-2141.2012.09199.x.
  6. Metzger ML, Hudson MM, Rrasin MJ, et al. Initial Response to Salvage Therapy Determines Prognosis in Relapsed Pediatric Hodgkin Lymphoma Patient. Cancer. 2010;116(18):4376–84. doi: 10.1002/cncr.25225.
  7. Schellong G, Dorfell W, Clavez A, et al. Salvage therapy of progressive and recurrent Hodgkin’s disease: results from multicenter study of the pediatric DAL/GPOH-HD study group. J Clin Oncol. 2005;23:6181–9. doi: 10.1200/jco.2005.07.930.
  8. Stoneham S, Ashley S, Pincerton CR, et al. Outcome after autologous stem cell transplantation in relapse or refractory childhood Hodgkin’s disease. J Pediatr Hematol Oncol. 2004;26:740–5. doi: 10.1097/00043426-200411000-00010.
  9. Brice P, Bouabdallah R, Moreau P, et al. Prognostic factors for survival after high-doses therapy and autologous stem cell transplantation for patients with relapsing Hodgkin’s lymphoma: analysis of 280 patients from the French registry. Society Francaise de Greefe de Moelle. Bone Marrow Transplant. 1997;20:21–6. doi: 10.1038/sj.bmt.1700838.
  10. Harris RT, Termuhlen AM, Smith LM, et al. Autologous Stem Cell Transplantation in Children with Refractory and Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962. Biol Blood Marrow Transplant. 2011;17(2):249–58. doi: 10.1016/j.bbmt.2010.07.002.
  11. Morschhauser F, Brice P, Ferme C, et al. Risk-Adapted Salvage Treatment With Single or Tandem Autologous Stem-Cell Transplantation for First Relapse/Refractory Hodgkin’s Lymphoma: Results of the Prospective Multicenter H96 Trial by the GELA/SFGM Study Group. J Clin Oncol. 2008;26(36):5980–7. doi: 10.1200/jco.2007.15.5887.
  12. Claviez A, Canals C, Dierickx D, et al. Allogenic Hematopoietic Stem Sells Transplantation in Children and Adolescents with Recurrent and Refractory Hodgkin Lymphoma: an Analysis of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(10):2060–7. doi: 10.1182/blood-2008-11-189399.
  13. Shafer JA, Heslop HE, Brenner MK, et al. Outcome of hematopoietic stem cell transplant as salvage therapy for Hodgkin’s lymphoma in adolescents and young adults at a single institution. Leuk Lymphoma. 2010;51(4):664–70. doi: 10.3109/10428190903580410.
  14. Okeley NM, Miyamoto JB, Zhang X, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody–drug conjugate. Clin Cancer Res. 2010;163:888–97. doi: 10.1158/1078-0432.ccr-09-2069.
  15. Bonthapally V, Yang H, Ayyagari R, et al. Brentuximab Vedotin Compared with Other Therapies in Relapsed/Refractory Hodgkin Lymphoma Post ASCT: Median Overall Survival Meta-Analysis. Curr Med Res Opin. 2015;7:1–48. doi: 10.1185/03007995.2015.1048208.

Prognostic Significance of Thymidine Kinase-1 versus β2-Microglobulin and Lactate Dehydrogenase in Lymphoproliferative Diseases

LYMPHOID TUMORS , , , ,

N.K. Parilova1, N.S. Sergeeva1,2, N.V. Marshutina1, N.G. Tyurina1, I.S. Meisner2

1 P.A. Hertzen Moscow Cancer Research Institute, a branch of the National Medical Research Radiological Center under the Ministry of Health of the Russian Federation, 3 Botkinskii pr-d, Moscow, Russia 125284

2 N.I. Pirogov Russian National Research Medical University under the Ministry of Health of the Russian Federation, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

For correspondence: Natal’ya Konstantinovna Parilova, junior researcher, 3 2nd Botkinskii pr-d, Moscow, Russia, 125284; Tel.: + 7(495)945-74-15; e-mail: parilochka@mail.ru.

For citation: Parilova NK, Sergeeva NS, Marshutina NV, et al. Prognostic Significance of Thymidine Kinase-1 versus b2-Microglobulin and Lactate Dehydrogenase in Lymphoproliferative Diseases. Clinical oncohematology. 2016;9(1):6–12 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-6-12

ABSTRACT

Background & Aims. Lactate dehydrogenase (LDH) and b2-microglobulin (b2-MG) are usually detected as serological tumor markers (TM) in malignant lymphoproliferative diseases (LPD); however, their use in monitoring of chemotherapy (CT) is limited due to their low sensitivity and specificity. The aim of this paper is to evaluate the prognostic value of baseline levels of thymidine kinase-1 (TK-1) versus b2-MG and LDH in patients with non-Hodgkin’s lymphomas (NHL) and Hodgkin’s lymphoma (HL) and to assess their clinical significance of changes in these parameters during CT as criteria of its effectiveness.

Methods. TK-1, b2-MG and LDH levels were evaluated in 61 NHL patients and 34 HL patients at baseline and after each subsequent CT cycle. The average age of patients enrolled in the study was 42.5 years (range 18–77 years). Of them 45 were men and 50 were women. Marker levels were determined in serum using the following tests: enzyme-linked immunosorbent assay (ELISA) for TK-1, immunoturbidimetry for b2-MG, and biochemical method for LDH. Discriminatory levels specified by test-system manufacturers were used in calculations: 50 DU/l for TK-1, 800–2400 mg/l for b2-MG, and 225–450 U/l for LDH.

Results. The study demonstrated that lower baseline levels of all three TM were associated with higher probability of complete or partial remission, and the statistical difference was higher. Baseline levels of TK-1 < 150 DU/l and b2-MG < 2200 mg/l may serve as prognostic factors of higher probability of achievement of complete or partial remission.

Conclusion. 4-fold increase in TK-1 serum activity from baseline after the 1st course of CT can predict the effectiveness of antitumor therapy. At the same time, no significant associations between b2-MG and LDH serum levels changes during the treatment and efficacy of the treatment were found.

Keywords: thymidine kinase-1, b2-microglobulin, lactate dehydrogenase, Hodgkin’s lymphoma, non-Hodgkin’s lymphomas.

Received: June 17, 2015

Accepted: November 3, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Павлова О.А., Тюрина Н.Г. Лимфома Ходжкина. Лимфопролиферативные опухоли. В кн.: Онкология. Клинические рекомендации. Под ред. В.И. Чиссова, С.Л. Дарьяловой. 2-е изд., испр. и доп. М.: ГЭОТАР-Медиа, 2009. С. 829–88.
    [Pavlova OA, Tyurina NG. Hodgkin’s lymphoma. Lymphoproliferative diseases. In Chissov VI, Dar’yalova SL, eds. Onkologiya. Klinicheskie rekomendatsii. (Oncology. Clinical recommendations.) 2nd revised edition. Moscow: GEOTAR-Media Publ.; 2009. p. 829–88. (In Russ)]
  2. Долгов В.В., Козлов А.В., Раков С.С. Лабораторная энзимология. М.: Витал Диагностикс, 2002. С. 104–18.
    [Dolgov VV, Kozlov AV, Rakov SS. Laboratornaya enzimologiya. (Laboratory methods in enzymology.) Moscow: Vital Diagnostiks Publ.; 2002. p. 104–18. (In Russ)]
  3. Bien E, Balcerska A. Serum soluble interleukin-2 receptor, beta2-microglobulin, lactate dehydrogenase and erythrocyte sedimentation rate in children with Hodgkin’s lymphoma. Scand J Immunol. 2009;70(5):490–500. doi: 10.1111/j.1365-3083.2009.02313.x.
  4. Shipp MA, Harrington DP, Andersen JR, et al. A predictive model for aggressive non-Hodgkin’s lymphoms. N Engl J Med. 1993;329(14):987–94. doi: 10.1056/nejm199309303291402.
  5. Дати Ф., Метцманн Э. Белки. Лабораторные тесты и их клиническое применение: Пер. с англ. М.: Лабора, 2007. 560 с.
    [Dati F, Metzman E. Proteins. Laboratory testing and clinical use. Holzheim; 2005. (Russ. ed.: Dati F, Metzman E. Belki. Laboratornye testy i ikh klinicheskoe primenenie. Moscow: Labora Publ.; 2007. 560 p.)]
  6. Votava T, Topolcan O, Holubec L Jr, et al. Changes of serum thymidine kinase in children with acute leukemia. Anticancer Res. 2007;27(4A):1925–8.
  7. Chen F, Tang L, Xia T, et al. Serum thymidine kinase 1 levels predict cancer-free survival following neoadjuvant, surgical and adjuvant treatment of patients with locally advanced breast cancer. Mol Clin Oncol. 2013;1(5):894–902. doi: 10.3892/mco.2013.149.
  8. Chen Y, Ying M, Chen YS, et al. Serum thymidine kinase 1 correlates to clinical stages and clinical reactions and monitors the outcome of therapy of 1,247 cancer patients in routine clinical settings. Int J Clin Oncol. 2010;15(4):359–68. doi: 10.1007/s10147-010-0067-4.
  9. Pan ZL, Ji XY, Shi YM, et al. Serum thymidine kinase 1 concentration as a prognostic factor of chemotherapy-treated non-Hodgkin’s lymphoma patients. J Cancer Res Clin Oncol. 2010;136(8):1193–9. doi: 10.1007/s00432-010-0769-z.
  10. Парилова Н.К., Сергеева Н.С., Тюрина Н.Г. и др. Сывороточные уровни тимидинкиназы-1 (ТК-1) у больных с лимфопролиферативными заболеваниями. Онкология. Журнал им. П.А. Герцена. 2012;1:33–8.
    [Parilova NK, Sergeeva NS, Tyurina NG, et al. Serum thymidine kinase 1 (TK-1) levels in patients with lymphoproliferative disorders. Onkologiya. Zhurnal im PA Gertsena. 2012;1:33–8. (In Russ)]
  11. Bogni A, Cortinois A, Grasseli G, et al. Thymidine kinase (TK) activity as a prognostic parameter of survival in lymphoma patients. J Biol Regul Homeost Agents. 1994;8(4):10.
  12. Nisman B, Nechushtan H, Biran H, et al. Serum thymidine kinase 1 activity in the prognosis and monitoring of chemotherapy in lung cancer patients: a brief report. J Thorac Oncol. 2014;9(10):1568–72. doi: 10.1097/jto.0000000000000276.
  13. Nisman B, Nchushtan H, Biran H, et al. Serum thymidine kinase 1 activity in prognosis and monitoring chemotherapy in lung cancer patients. Tumor Biol. 2014;35(1):22–3. doi: 10.1097/jto.0000000000000276.

 

Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug?

BONE MARROW TRANSPLANTATION , , , ,

GD Petrova1, KN Melkova1, TZ Chernyavskaya1, NV Gorbunova1, BV Afanas’ev2, EA Demina1, VN Kostrykina1, VA Doronin1

1 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022

For correspondence: Galina Dmitrievna Petrova, graduate student, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-13-59; e-mail: galina_petrova@bk.ru

For citation: Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug? Clinical oncohematology. 2015;8(3):321–30 (In Russ).

ABSTRACT

Background & Aims. The role of single and double autologous hematopoietic stem cell transplantations (autoSCT) in patients with primary refractory Hodgkin’s lymphoma (HL) has not been determined yet. The aim of the study is to present the results of a one-center prospective study evaluating the role of single and double autoSCT in patients with HL who have not achieved the complete remission (CR) after first line induction polychemotherapy (PCT).

Methods. 62 HL patients were enrolled in the study over the period from 2007 till 2014. High-dose chemotherapy (HDCT) with autoSCT was performed once in 53 patients, and twice in 10 patients.

Results. The study demonstrated an unfavorable prognostic impact of the large volume of previous chemotherapy on the overall survival (OS) rate after the autoSCT (p = 0.03). Results of the 1st autoSCT had an independent prognostic value for the OS rate (p = 0.004). The study identified the main indication for the 2nd autoSCT, namely, partial remission (PR) or stable disease (SD) achieved after the 1st autoSCT (when the 2nd HDCT with autoSCT should be preferred to the alternative treatment; p = 0.004). Progressive disease (PD) after the first autoSCT is a contraindication for the second one. Due to low efficacy and high toxicity, the 2nd autoSCT does not improve outcomes when compared to alternative approaches (p = 0.6). The importance of achieving CR at any stage of treatment which is associated with a long life span with no signs of disease and good quality of life has been demonstrated.

Conclusion. AutoSCT is an effective treatment option for patients without complete remission after the first line antitumor treatment. Carrying out 2nd autoSCT is advisable for patients who have reached the PR/SD after the first one. Patients with PD after the 1st autoSCT require an alternative treatment option.

Keywords: Hodgkin’s lymphoma, high-dose chemotherapy, autologous hematopoietic stem cell transplantation, primary resistance, double autoSCT.

Received: May 5, 2015

Accepted: June 2, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109(12):5143–50. doi: 10.1182/blood-2006-11-056028.
  2. Kantarjian H, Giles F, Bhalla K, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117(4):1141–5. doi: 10.1182/blood-2010-03-277152.
  3. Лазорко Н.С., Ломаиа Е.Г., Сбитякова Е.И., Зарицкий А.Ю. Нилотиниб и дазатиниб в первой линии терапии больных хроническим миелолейкозом в хронической фазе. Современная онкология. 2011;13(1):38–40.
    [Lazorko NS, Lomaia EG, Sbityakova EI, Zaritskii AYu. Nilotinib and dazatinib as first line therapy of patients in chronic phase of chronic myeloid leukemia. Sovremennaya onkologiya. 2011;13(1):38–40. (In Russ)]
  4. Ломаиа Е.Г., Романова Е.Г., Сбитякова Е.И., Зарицкий А.Ю. Эффективность и безопасность ингибиторов тирозинкиназ 2-го поколения (дазатиниб, нилотиниб) в терапии хронической фазы хронического миелолейкоза. Онкогематология. 2013;2:22–33.
    [Lomaia EG, Romanova EG, Sbityakova EI, Zaritskii AYu. Efficacy and safety of 2nd generation tyrosine kinase inhibitors (dasatinib, nilotinib) in teatment of chronic phase of chronic myeloid leukemia. Onkogematologiya. 2013;2:22–33. (In Russ)]
  5. Туркина А.Г., Хорошко Н.Д., Гусарова Г.А. и др. Российский опыт применения нилотиниба во второй линии терапии больных хроническим миелолейкозом с резистентностью или непереносимостью иматиниба: оценка безопасности и эффективности в исследовании ENACT (расширенный доступ к нилотинибу в клинических исследованиях). Вестник гематологии. 2010;1(2):92–3.
    [Turkina AG, Khoroshko ND, Gusarova GA, et al. Russian experience in use of nilotinib in second line therapy of patients with chronic myeloid leukemia and imatinib resistance or intolerance: evaluation of safety and efficacy in ENACT trial (Expanding Nilotinib Access in Clinical Trials). Vestnik gematologii. 2010;1(2):92–3. (In Russ)]
  6. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
  7. Kantarjian H, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6. doi: 10.1182/blood-2007-03-080689.
  8. Saglio G, Kim D, Issaragrisil S, et al. Nilotinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–9. doi: 10.1517/14656566.2011.534780.
  9. Hochhaus A, Kantarjian H, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303–9. doi: 10.1182/blood-2006-09-047266.
  10. Kantarjian H, Shah N, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70. doi: 10.1056/nejmoa1002315.
  11. Shah R. Drug-induced hepatotoxicity: pharmacokinetic perspectives and strategies for risk reduction. Adv Drug React Toxicol Rev. 1999;18:181–233.
  12. Russmann S, Kullak-Ublick G, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16(23):3041–53.
  13. Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: A meta-analysis. Cancer Treat Rev. 2013;39(2):199–206. doi: 10.1016/j.ctrv.2012.09.004.
  14. Saglio G, Pinilla-Ibarz J, Cortes J, et al. Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia. Blood. 2011;117(4):688−697. doi: 10.1002/cncr.25648.
  15. Rosti G, Castagnetti F, Gugliotta G, et al. Dasatinib and nilotinib in imatinib resistant Philadelphia-positive chronic myelogenous leukemia: a ‘head-to-head’ comparison. Leuk Lymphoma 2010;51(4):583–91. doi: 10.3109/10428191003637282.
  16. Shah R, Morganroth J, Shah D. Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives. Drug Saf. 2013;36(7):491–503. doi: 10.1007/s40264-013-0048-4.
  17. Lammie A, Drobnjak M, Gerald W, et al. Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem. 1994;42(11):1417–25. doi: 10.1177/42.11.7523489.
  18. Grichnik J, Burch J, Burchette J, Shea C. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol. 1998;111(2):233–8.
  19. Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115(18):4136–47. doi: 10.1002/cncr.24504.
  20. Irvine E, Williams C. Treatment-, Patient-, and Disease-Related Factors and the Emergence of Adverse Events with Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. Pharmacotherapy. 2013;33(8):868–81. doi: 10.1002/phar.1266.
  21. Van Etten RA. Cycling, stressed-out and nervous: cellular functions of cAbl. Trends Cell Biol. 1999;9(5):179–86. doi: 10.1016/s0962-8924(99)01549-4.
  22. Wasle B, Edwardson J. The regulation of exocytosis in the pancreatic acinar cell. Cell Signal. 2002;14(3):191–7. doi: 10.1016/s0898-6568(01)00257-1.
  23. Mooren F, Hlouschek V, Finkes T, et al. Early changes in pancreatic acinar cell calcium signalling after pancreatic duct obstruction. J Biol Chem. 2003;278(11):9361–9. doi: 10.1074/jbc.m207454200.
  24. Fitter S, Vandyke K, Gronthos S, Zannettino AC. Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogsis and adiponectin secretion. J Mol Endocrinol. 2012;48(3):229–40. doi: 10.1530/jme-12-0003.
  25. Racil Z, Razga F, Drapalova J, et al. Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica. 2013;98(10):e124–6. doi: 10.3324/haematol.2013.086355.
  26. le Coutre P, Giles F, Hochhaus A, et al. Analysis of glucose profiles in imatinib resistant or intolerant chronic myelogenous leukemia (CML) patients treated with nilotinib: lack of correlation between glucose levels and nilotinib efficacy. Blood. 2007;110: Abstract 4588.
  27. Breccia M, Alimena G. Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development. Exp Opin Drug Saf. 2010;9(5):713–21. doi: 10.1517/14740331003742935.
  28. de Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol. 2008;141(5):745–7. doi: 10.1111/j.1365-2141.2008.07108.x.
  29. Porkka K, Khoury H, Paquette R, et al. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010;116(2):377–86. doi: 10.1002/cncr.24734.
  30. Shah N, Kantarjian H, Kim D, et al. Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. J Clin Oncol. 2012;30:6506.
  31. Hasinoff BB. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. Toxicol Appl Pharmacol. 2010;244(2):190–5. doi: 10.1016/j.taap.2009.12.032.
  32. Albini A, Pennesi G, Donatelli F, et al. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010;102(1):14–25. doi: 10.1093/jnci/djp440.
  33. Strevel E, Ing D, Siu L. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol. 2007;25(22):3362–71. doi: 10.1200/jco.2006.09.6925.
  34. Haverkamp W, Breithardt G, Camm A, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J. 2000;21(15):1216–31. doi: 10.1053/euhj.2000.2249.
  35. Priori S, Schwartz P, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–74. doi: 10.1056/nejmoa022147.
  36. Sauer A, Moss A, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49(3):329–37. doi: 10.1016/j.jacc.2006.08.057.
  37. Center for Drug Evaluation and Research: Nilotinib Pharmacology/Toxicology Review and Evaluation; 2007.
  38. Le Coutre P, Ottmann O, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111(4):1834–9. doi: 10.1182/blood-2007-04-083196.
  39. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542–51. doi: 10.1056/nejmoa055104.
  40. Kim T, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia. 2013;27(6):1316–21. doi: 10.1038/leu.2013.70.
  41. Larson R, Hochhaus A, Hughes T, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26(10):2197–203. doi: 10.1038/leu.2012.134.
  42. Aichberger K, Herndlhofer S, Schernthaner G, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86(7):533–9. doi: 10.1002/ajh.22037.
  43. Verma D, Verstovsek S, Kantarjian H, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood. 2011;118(16):4353–8. doi: 10.1182/blood-2011-06-362889.
  44. Hoffmann V, Baccarani M, Hasford J. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia. 2015;29(6):1336–43. doi: 10.1038/leu.2015.73 [Epub 2015 Mar 18]

Efficacy and Toxicity of Therapy for Patients with Intermediate-Risk Hodgkin’s Lymphoma: Results of Multicenter Randomized Study

AUTOIMMUNE THROMBOCYTOPENIA, LYMPHOID TUMORS , , ,

IA Kryachok1, AA Amdiev2, IB Titorenko1, EM Aleksik1, EO Ul’yanchenko1, OI Novosad1, ES Filonenko1, MI Kasich2, MYa Kiseleva2

1 National Cancer Institute, 33/43 Lomonosova str., Kyiv, Ukraine, 03022

2 V.M. Efetov Crimean National Clinical Oncology Dispensary, 49a Bespalova str., Simferopol, Russian Federation, 295023

For correspondence: Alim Anvarovich Amdiev, 49a Bespalova str., Simferopol, Russian Federation, 295023; Tel.: +38(0652)60-22-09; e-mail: amdiev@gmail.com

For citation: Kryachok IA, Amdiev AA, Titorenko IB, et al. Efficacy and Toxicity of Therapy for Patients with Intermediate-Risk Hodgkin’s Lymphoma: Results of Multicenter Randomized Study. Clinical oncohematology. 2015;8(3):281–6 (In Russ).

ABSTRACT

Objective. To study the efficacy and toxicity of various treatment schemes for patients with intermediate-risk Hodgkin’s lymphoma (HL).

Methods. This article presents an analysis of the immediate results of complex treatment of 103 intermediate-risk HL patients (stage IIA and IIB with one or more unfavorable prognostic factors), who have been treated at the National Cancer Institute (Kyiv) and the Crimean Oncology Dispensary (Simferopol) from 2009 to 2014 (study group). Patients were divided into two study groups and treated with 6xBEACOPP-esc or 2xBEACOPP-esc + 4xABVD, followed by radiotherapy on the affected areas at a dose of 30–36 Gy in both groups. The control group included 53 patients who received treatment according to the 6xABVD scheme, followed by radiotherapy on the affected areas at a dose of 30–36 Gy over the period from 2000 to 2008. The immediate efficiency of the therapy, as well as its toxicity was evaluated.

Results. The study results demonstrated that treatment of the intermediate-risk HL patients that included 6xBEACOPP-esc and 2xBEACOPP-esc + 4xABVD proved to be an effective approach. Overall immediate efficacy of 2xBEACOPP-esc + 4xABVD protocol with subsequent radiation therapy was 95.83 %, and that of the 6xBEACOPP-esc was 96.36 %, which was significantly higher than the efficacy in the control group (83.02 %; p < 0.05). The toxicity level of the therapy was lower in the 2xBEACOPP-esc + 4xABVD group than that in the 6xBEACOPP-esc group (63.19 % and 83.03 %, respectively, p < 0.001).

Conclusion. Treatment of patients with intermediate-risk HL with 2xBEACOPP-esc + 4xABVD is comparable to that with 6xBEACOPP-esc, but it demonstrates a better toxicity profile.

Keywords: Hodgkin’s lymphoma, chemotherapy, efficacy, toxicity.

Received: March 31, 2015

Accepted: May 31, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Diehl V, ed. 25 Years German Hodgkin Study Group. Medizin & Wissen; 2004.
  2. Демина Е.А. Лимфома Ходжкина: от Томаса Ходжкина до наших дней. Клиническая онкогематология. 2008;1(2):114–8.
    [Demina EA. Hodgkin’s lymphoma: from Thomas Hodgkin till present days. Klinicheskaya onkogematologiya. 2008;1(2):114–8. (In Russ)]
  3. 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.
  4. Федоренко З.П., Гайсенко А.В., Гулак Л.О. [та ін.] Рак в Украiні, 2009–2010. Захворюваність, смертність, показники діяльності онкологічноi служби. Бюл. Національного канцер-ре’стру Украiни. 2011;12:73–4.
    [Fedorenko ZP, Gaisenko AV, Gulak LO, et al. Cancer in Ukraine, 2009–2010. Morbidity and mortality rates and cancer service performance indicators. Byulleten’ Natsіonal’nogo kantser-re’stru Ukraini. 2011;12:73–4. (In Ukr.)]
  5. 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.
  6. Lister TA. Staging for Hodgkin’s disease. Semin Oncol. 1990;17(6):696–703.
  7. Aleman BM, Raemaekers JM, Tirelli U, et al. Involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med. 2003;348(24):2396–406. doi: 10.1056/nejmoa022628.
  8. Bonadonna G, Zucali R, Monfardini S, et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252–9. doi: 10.1002/1097-0142(197507)36:1<252::aid-cncr2820360128>3.0.co;2-7.
  9. Bonadonna G, Bonfante V, Viviani S, et al. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol. 2004;22(14):2835–41. doi: 10.1200/jco.2004.12.170.
  10. Engert A, Plutschow A, Eich HT, et al. Reduced Treatment Intensity in Patients with Early-Stage Hodgkin’s Lymphoma. N Engl J Med. 2010;363(7):640–52. doi: 10.1056/nejmoa1000067.
  11. Horning SJ. Risk, cure and complications in advanced Hodgkin disease. ASH Educ Program. 2007;1:197–203. doi: 10.1182/asheducation-2007.1.197.
  12. Horning SJ, Hoppe RT, Advani R, et al. Efficacy and late effects of Stanford V chemotherapy and radiotherapy in untreated Hodgkin’s disease: mature data in early and advanced stage patients. Blood. 2004;104:92a, abstract 308.
  13. Diehl V, Haverkamp H, Mueller RP, et al. Eight Cycles of BEACOPP escalated compared with 4 cycles of BEACOPP escalated followed by 4 cycles of BEACOPP baseline with or without radiotherapy in patients in advanced stage Hodgkin lymphoma (HL): final analysis of the randomised HD12 trial of the German Hodgkin Study Group (GHSG). Blood. 2008;112(11): Abstract 1558.
  14. Sieber M, Bredenfeld H, Josting А, 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.
  15. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trail): a randomised, open-label, phase 3 non-inferiority trail. The Lancet. 2012;379(9828):1791–9. doi: 10.1016/s0140-6736(11)61940-5.
  16. 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.
  17. Engert A, Franklin J, Eich HT, et al. Two cycles of ABVD plus extended field radiotherapy is superior to radiotherapy alone in early-favorable Hodgkin lymphoma: final results of the GHSG HD7 Trial. J Clin Oncol. 2007;10(10):3495–502. doi: 10.1200/jco.2006.07.0482.
  18. Engert A, Diehl V, Pluetschow A, et al. Two cycles of ABVD followed by involved field radiotherapy with 20 Gray (Gy) the new standard of care in the treatment of patients with early-stage Hodgkin lymphoma: final analysis of the randomized German Hodgkin Study Group (GHSG) HD10. Blood. 2009;114: Abstract 716.
  19. Diehl V, Franklin J, Pfistner B, Engert A. German Hodgkin Study Group. Ten-year results of a German Hodgkin Study Group randomized trial of standart and increased dose BEACOPP chemotherapy for advanced Hodgkin lymphoma (HD9). J Clin Oncol (Meeting Abstracts). 2007;25(Suppl 18):LBA8015.

Treatment of Advanced Stage Hodgkin’s Lymphoma: Literature Review

REVIEWS , , , ,

AA Leont’eva, EA Demina

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Anna Aleksandrovna Leont’eva, graduate student, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-90-89; e-mail: aurevoir-nut@yandex.ru

For citation: Leont’eva AA, Demina EA. Treatment of Advanced Stage Hodgkin’s Lymphoma: Literature Review. Clinical oncohematology. 2015;8(3):255–66 (In Russ).

ABSTRACT

Over the past decade, major research centers with large databases in Europe and the USA have conducted a comprehensive analysis of the effectiveness of treatment programs, delayed treatment-related complications and long-term survival of patients with advanced stage Hodgkin’s lymphoma. This analysis allowed us to develop new, more effective programs and introduce them into practical medicine, as well as to start searching for less toxic treatment options. However, in Russian scientific literature, this complex analysis has not been presented. Available publications and scientific investigations cover only some aspects of diagnosis and treatment of Hodgkin’s lymphoma or selectively discuss the problem of complications. The proposed literature review allows the reader to see the changes in the approach to management of advanced-stage Hodgkin’s lymphoma over the last 75 years: from absolutely pessimistic prognosis for the disease to modern high achievements with further improvement of treatment options for this disease.

Keywords: Hodgkin’s lymphoma, advanced stages, treatment, effectiveness of treatment, toxicity.

Received: February 20, 2015

Accepted: May 28, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Med Chir Trans. 1832;17:68–114. doi: 10.1177/095952873201700106.
  2. Bonadonna G. Historical review of Hodgkin’s disease. Br J Haematol. 2000;110(3):504–11. doi: 10.1046/j.1365-2141.2000.02197.x.
  3. Diehl V, guest ed. Bailliere’s Clinical Haematology. International Practice and Research. Hodgkin’s Disease. London, Philadelphia, Sydney: Bailliere Tindall; 1996.
  4. Переслегин И.А., Филькова Е.М. Лимфогранулематоз. М.: Медицина, 1975.
    [Pereslegin IA, Fil‘kova EM. Limfogranulematoz. (Lymphogranulomatosis.) Moscow: Meditsina Publ.; 1975. (In Russ)]
  5. Sternberg C. Uber eine Eigenartige, unter dem Bilde der Pseudoleukemie verlaufende Tuberkulose des lymphatische Apparates. Zschr F Heilkunde. 1898;19:21–90.
  6. Reed D. On the pathological changes in Hodgkin’s disease, with especial reference to its relation to tuberculosis. Johns Hopkins Hosp Bull. 1902;10:133–96.
  7. Diehl V, ed. 25 Years German Hodgkin Study Group. Medizin & Wissen; 2004.
  8. Hjalgrim H, Askling J, Sorensen P, et al. Risk of Hodgkin’s disease and other cancer after infectious mononucleosis. J Natl Cancer Inst. 2000;92(18):1522–8. doi: 10.1093/jnci/92.18.1522.
  9. Демина Е.А. Современная терапия первичных больных лимфомой Ходжкина: Автореф. дис. ¼ д-ра мед. наук. М., 2006.
    [Demina EA. Sovremennaya terapiya pervichnykh bol’nykh limfomoi Khodzhkina. (Modern management of primary Hodgkin’s lymphoma patients.) [dissertation] Moscow; 2006. (In Russ)]
  10. Lukes RJ, Butler JJ, Hicks ED. Natural history of Hodgkin’s disease as related to its pathologic picture. Cancer. 1966;19(3):317–44. doi: 10.1002/1097-0142(196603)19:3<317::aid-cncr2820190304>3.0.co;2-o.
  11. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  12. Engert A, Horning SJ, eds. Hematologic malignancies: Hodgkin lymphoma. A Comprehensive Update on Diagnostics and Clinics. Berlin, Heidelberg: Springer; 2011. pp. 65–76.
  13. Давыдов М.И., Аксель Е.М. Статистика злокачественных новообразований в России и странах СНГ в 2009 г. Вестник РОНЦ им. Н.Н. Блохина РАМН. 2011;22(3, прил. 1).
    [Davydov MI, Aksel’ EM. Cancer statistica in Russia and CIS in 2009. Vestnik RONTs im. N.N. Blokhina RAMN. 2011;22(3 Suppl 1). (In Russ)]
  14. Granger W, Whitaker R. Hodgkin’s disease in bone with special reference to periosteal reaction. Br J Radiol. 1967;40(480):939–48. doi: 10.1259/0007-1285-40-480-939.
  15. Bichel J. The alcohol-intolerance syndrome in Hodgkin’s disease. Acta Med Scand. 1959;164(2):105–12. doi: 10.1111/j.0954-6820.1959.tb00168.x.
  16. James AH. Hodgkin’s disease with and without alcohol-induced pain. A clinical and histological comparison. Q J Med. 1960;29:47–66.
  17. Winiwarter A. Du lymphome malin et du lymphosarcome et de leur traitement. Arch F Arch Klin Chir. 1875;18:98–102.
  18. Pussey WA. Cases of sarcoma and of Hodgkin’s disease treated by exposures to X-rays: preliminary report. JAMA. 1902;98:166–9. doi: 10.1001/jama.1902.62480030024001h.
  19. Gilbert R. La roengentherapie de la granulematise maligne. J Radiol Electrol. 1925;9:509–14.
  20. Демина Е.А. Лимфома Ходжкина: от Томаса Ходжкина до наших дней. Клиническая онкогематология. 2008;1(2):114–8.
    [Demina EA. Hodgkin’s lymphoma: from Thomas Hodgkin till present days. Klinicheskaya onkogematologiya. 2008;1(2):114–8. (In Russ)]
  21. Hoppe RT, Hanlon A, Hanks G, et al. Progress in treatment of Hodgkin’s disease in the United States, 1973 versus 1983: the patterns of care study. Cancer. 1994;74(12):3198–203. doi: 10.1002/1097-0142(19941215)74:12<3198::aid-cncr2820741219>3.0.co;2-9.
  22. Hoppe RT. Radiation therapy in the management of Hodgkin’s disease. Semin Oncol. 1990;17(6):704–15.
  23. Peters MV. A study of survivals in Hodgkin’s disease treated radiologically. Am J Roent. 1950;63:299–311.
  24. Kaplan H. The radical radiotherapy of Hodgkin’s disease. Radiology. 1962;78(4):553–61. doi: 10.1148/78.4.553.
  25. Самочатова Е.В., Владимирская Е.Б., Жесткова Н.М. и др. Болезнь Ходжкина у детей. М.: Алтус, 1997.
    [Samochatova EV, Vladimirskaya EB, Zhestkova NM, et al. Bolezn’ Khodzhkina u detei. (Hodgkin’s disease in children.) Moscow: Altus Publ.; 1997. (In Russ)]
  26. Hoppe RT, Mauch PT, Armitage JO, et al. Hodgkin Lymphoma. 2nd edition. Philadelphia: Lippincott Williams & Wilkins; 2007.
  27. Prosnitz LR, Farber LR, Fisher JJ, et al. Long term remissions with combined modality therapy for advanced Hodgkin’s disease. Cancer. 1976;37(6):2826–33. doi: 10.1002/1097-0142(197606)37:6<2826::aid-cncr2820370638>3.0.co;2-f.
  28. Goodman LS, Wintrobe MM, Dameshek W, et al. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc. 1946;132:126–32.
  29. DeVita VT Jr, Carbone PP. Treatment of Hodgkin’s disease. Med Ann Dist Columbia. 1967;36(4):232–4.
  30. DeVita VT, Serpick AA, et al. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med. 1970;73(6):881–95. doi: 10.7326/0003-4819-73-6-881.
  31. Longo DL, Young RC, Wesley M, et al. Twenty years of MOPP therapy for Hodgkin’s disease. J Clin Oncol. 1986;4:1295–306.
  32. Bonadonna G, Valagussa P, Santoro A. Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin’s disease. A report of 8-year results. Ann Intern Med. 1986;104(6):739–46. doi: 10.7326/0003-4819-104-6-739.
  33. Даценко П.В., Паньшин Г.А., Сотников В.М. и др. Новые программы комбинированного лечения лимфомы Ходжкина. Онкогематология. 2007;4:27–35.
    [Datsenko PV, Pan’shin GA, Sotnikov VM, et al. New programs of combined treatment of Hodgkin’s lymphoma. Onkogematologiya. 2007;4:27–35. (In Russ)]
  34. Goldman AJ, Goldie JH. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep. 1979;63(11–12):1727–33.
  35. Santoro A, Bonadonna G, Valagussa P, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin’s disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987;5(1):27–37.
  36. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327(21):1478–84. doi: 10.1056/nejm199211193272102.
  37. Stefan DC, Stones D. How much does it cost to treat children with Hodgkin lymphoma in Africa? Leuk Lymphoma. 2009;50(2):196–9. doi: 10.1080/10428190802663205.
  38. Canellos GP, Niedzwiecki D. Long-term follow-up of Hodgkin’s disease trial. N Engl J Med. 2002;346(18):1417–8. doi: 10.1056/nejm200205023461821.
  39. Mauch PV, Armitage JO, Diehl V, et al. Hodgkin’s disease. Philadelphia: Lippincott Williams & Wilkins; 1999.
  40. Specht L. Prognostic factors in Hodgkin’s disease. Cancer Treat Rev. 1991;18(1):21–53. doi: 10.1016/0305-7372(91)90003-i.
  41. DeVita VT, Hellman S, Rosenberg SA. Cancer. Principles & Practice of Oncology. 4th edition. Philadelphia; 1993;1819–58.
  42. Richardson SE, McNamara C. The management of classical Hodgkin’s lymphoma: past, present, and future. Adv Hematol. 2011;2011:865870. doi: 10.1155/2011/865870.
  43. Horning SJ, Hoppe RT, Breslin S, et al. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol. 2002;20(3):630–7. doi: 10.1200/jco.20.3.630.
  44. Hoskin PJ, Lowry L, Horwich A, et al. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2009;27(32):5390–6. doi: 10.1200/jco.2009.23.3239.
  45. 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.
  46. 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.
  47. Ларина Ю.В., Миненко С.В., Биячуев Э.Р. и др. Лечение распространенных форм лимфомы Ходжкина у подростков и молодых взрослых. Проблема эффективности и токсичности. Онкогематология. 2014;1:11–8.
    [Larina YuV, Minenko SV, Biyachuev ER, et al. Treatment of advance stage Hodgkin’s lymphomas in adolescents and young adults. Efficacy and toxicity problem. Onkogematologiya. 2014;1:11–8. (In Russ)]
  48. Hasenclever D, Diehl V. 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.
  49. Diehl V. German Hodgkin Study Group. Haematologica. 2007;92(s5):21, abstract I071.
  50. Богатырева Т.И., Столбовой А.В., Копп М.Ю. и др. Лимфома Ходжкина: трудности на пути реализации стандартов лечения и их преодоление. Врач. 2011;12:34–40.
    [Bogatyreva TI, Stolbovoi AV, Kopp MYu, et al. Hodgkin’s lymphoma: difficulties in implementing treatment standards and ways to overcome them. Vrach. 2011;12:34–40. (In Russ)]
  51. 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)]
  52. Borchmann P, Diehl V, Goergen H, et al. Combined modality treatment with intensified chemotherapy and dose-reduced involved field radiotherapy in patients with early unfavourable Hodgkin Lymphoma: final analysis of the German Hodgkin Study Group HD 11 trial. Blood. 2009;114:299–300.
  53. Thomas J, Ferm C, Noordijk E, et al. Results of the EORTC-GELA H9 randomized trials: the H9-F trials (comparing 3 radiation dose levels) and H9-U trials (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin’s lymphoma (HL). Haematologica. 2007;92(s5):27.
  54. 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.
  55. Kobe C, Dietlein M, Franklin J, et al. Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma. Blood. 2008;112(10):3989–94. doi: 10.1182/blood-2008-06-155820.
  56. Chesson B, Pfistner B, Juweid M, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86. doi: 10.1200/jco.2006.09.2403.
  57. 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.
  58. Шахтарина С.В., Павлов В.В., Даниленко А.А., Афанасова Н.В. Лечение больных лимфомой Ходжкина с локальными стадиями: опыт медицинского радиологического научного центра. Онкогематология. 2007;4:36–46.
    [Shakhtarina SV, Pavlov VV, Danilenko AA, Afanasova NV. Treatment of patients with local stages Hodgkin’s lymphomas: experience of medical radiological scientific center. Onkogematologiya. 2007;4:36–46. (In Russ)]
  59. Gallamini A, Hutchings M, Rigacci I, et al. Early interim FDG-PET overshadows the prognostic role of IPS in advanced-stage Hodgkin’s lymphoma treated by conventional ABVD therapy. Haematologica. 2007;32(s5): Abstract C022.
  60. Hoppe RT. Hodgkin’s disease: Second cancer after treatment Hodgkin’s disease: Complications of therapy and excess mortality. Ann Oncol. 1997;8(1):115.
  61. Шахтарина С.В., Даниленко А.А., Павлов В.В. Злокачественные новообразования у больных лимфомой Ходжкина после лучевой терапии по радикальной программе и комбинированной химиолучевой терапии. Клиническая онкогематология. 2008;1(3):246–51.
    [Shakhtarina SV, Danilenko AA, Pavlov VV. Malignant neoplasms in Hodgkin’s lymphoma patients after radiation therapy (according to radical program) and combined chemoradiation therapy. Klinicheskaya onkogematologiya. 2008;1(3):246–51. (In Russ)]
  62. Ильин Н.В., Виноградова Ю.Н. Поздние осложнения терапии больных лимфомой Ходжкина. Практическая онкология. 2007;8(2):96–101.
    [Il’in NV, Vinogradova YuN. Delayed treatment complications in Hodgkin’s lymphoma patients. Prakticheskaya onkologiya. 2007;8(2):96–101. (In Russ)]
  63. Поддубная И.В. Неходжкинские лимфомы. В кн.: Клиническая онкогематология. Под ред. М.А. Волковой. М.: Медицина, 2007. C. 724–71.
    [Poddubnaya IV. Non-Hodgkin’s lymphomas. In: Volkova MA, ed. Klinicheskaya onkogematologiya. (Clinical oncohematology.) Moscow: Meditsina Publ.; 2007. pp. 724–71. (In Russ)]
  64. Поддубная И.В. Обоснование лечебной тактики при неходжкинских лимфомах. Современная онкология. 2002;4(1):3–7.
    [Poddubnaya IV. Rationale for therapeutic management of non-Hodgkin’s lymphoma. Sovremennaya onkologiya. 2002;4(1):3–7. (In Russ)]
  65. Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Limfomi Trial. J Clin Oncol. 2009;27(5):805–11. doi: 10.1200/jco.2008.17.0910.
  66. 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. The Lancet. 2012;379(9828):1791–9. doi: 10.1016/S0140-6736(11)61940-5.
  67. Bovelli D, Plataniotis G, Roila F. Кардиологическая токсичность химиотерапевтических препаратов и заболевания сердца, обусловленные проведением лучевой терапии. В кн.: Минимальные клинические рекомендации Европейского общества медицинской онкологии. М., 2010. C. 423–33.
    [Bovelli D, Plataniotis G, Roila F. Cardiac toxicity of chemotherapeutic agents and radiotherapy-associated heart diseases. In: Minimal’nye klinicheskie rekomendatsii Evropeiskogo obshchestva meditsinskoi onkologii. (European Society for Medical Oncology (ESMO) Minimum Clinical Recommendations.) Moscow; 2010. pp. 423–33. (In Russ)]
  68. Поддубная И.В., Орел Н.Ф. Кардиотоксичность. В кн.: Руководство по химиотерапии опухолевых заболеваний. Под ред. Н.И. Переводчиковой. М.: Практическая медицина, 2011. С. 435–6.
    [Poddubnaya IV, Orel NF. Cardiac toxicity. In: Perevodchikova NI, ed. Rukovodstvo po khimioterapii opukholevykh zabolevanii. (Guidelines for chemotherapy of tumors.) Moscow: Prakticheskaya Meditsina Publ.; 2011. pp. 435–6. (In Russ)]
  69. Емелина Е.И. Состояние сердечно-сосудистой системы у больных лимфопролиферативными заболеваниями, получавших антрациклиновые антибиотики: Дис. ¼ канд. мед. наук. М., 2007. С. 10–36.
    [Emelina EI. Sostoyanie serdechno-sosudistoi sistemy u bol’nykh limfoproliferativnymi zabolevaniyami, poluchavshikh antratsiklinovye antibiotiki. (Condition of the cardiovascular system inpatients with lymphoproliferative disorders treated with anthracycline antibiotics.) [dissertation] Moscow; 2007. pp. 10–36. (In Russ)]
  70. Матяш М.Г., Кравчук Т.Л., Высоцкая В.В. и др. Индуцированная антрациклинами кардиотоксичность: механизмы развития и клинические проявления. Сибирский онкологический журнал. 2008;6(30):66–75.
    [Matyash MG, Kravchuk TL, Vysotskaya VV, et al. Anthracycline-induced cardiac toxicity: mechanisms of development and clinical manifestations. Sibirskii onkologicheskii zhurnal. 2008;6(30):66–75. (In Russ)]
  71. Семенова А.Е. Кардио- и нейротоксичность противоопухолевых препаратов (патогенез, клиника, профилактика и лечение). Практическая онкология. 2009;10(3):168–76.
    [Semenova AE. Cardiac and neurotoxicity of anti-tumor agents (pathogenesis, clinical presentation, prevention, and treatment). Prakticheskaya onkologiya. 2009;10(3):168–76. (In Russ)]
  72. Brana I, Tabernero J. Cardiotoxicity. Ann Oncol. 2010;21(Suppl 7):173–9. doi: 10.1093/annonc/mdq295.
  73. Гендлин Г.Е., Сторожаков Г.И., Шуйкова К.В. и др. Острые сердечно-сосудистые события во время применения противоопухолевых химиопрепаратов: клинические наблюдения. Клиническая онкогематология. 2011;4(2):155–64.
    [Gendlin GE, Storozhakov GI, Shuikova KV, et al. Acute cardiovascular events during treatment with anti-tumor chemotherapeutic agents: clinical observations. Klinicheskaya onkogematologiya. 2011;4(2):155–64. (In Russ)]
  74. Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin Oncol. 1992;19(5):529–42.
  75. Gewlling M, Mertens L, Moerman P, et al. Idiopathic restrictive cardiomyopathy in childhood. Eur Heart J. 1996;17(9):1413–20. doi: 10.1093/oxfordjournals.eurheartj.a015076.
  76. Матяш М.Г., Кравчук Т.Л., Высоцкая В.В. и др. Неантрациклиновая кардиотоксичность. Сибирский онкологический журнал. 2009;5(35):73–82.
    [Matyash MG, Kravchuk TL, Vysotskaya VV, et al. Non-anthracycline-related cardiac toxicity. Sibirskii onkologicheskii zhurnal. 2009;5(35):73–82. (In Russ)]
  77. Escoto H, Ringewald J, Kalpatthi R. Etoposide-related cardiotoxicity in a child with haemophagocytic lymphohistiocytosis. J Cardiol Young. 2010;20(1):105–7. doi: 10.1017/s1047951109991272.
  78. Calvo-Romero JM, Fernandez-Soria-Pantoja R, Arrebola-Garcia JD. Ischemic heart disease associated with vincristine and doxorubicin chemotherapy. Ann Pharmacother. 2001;35(11):1403–5. doi: 10.1345/aph.10358.
  79. Bovelli D, Plataniotis G, Roila F. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol. 2010;21(Suppl 5):277–82. doi: 10.1093/annonc/mdq200.
  80. Meirow D, Lewis H, Nugent D, Epstein M. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod. 1999;14(7):1903–7. doi: 10.1093/humrep/14.7.1903.
  81. Шахтарина С.В., Даниленко А.А., Щелконогова Л.Н., Павлов В.В. Беременность, роды и состояние здоровья детей, родившихся у женщин с лимфомой Ходжкина после лучевого или комбинированного химиолучевого лечения. Клиническая онкогематология. 2012;5(3):218–24.
    [Shakhtarina SV, Danilenko AA, Shchelkonogova LN, Pavlov VV. Pregnancy, delivery, and health state of children born to women with Hodgkin’s lymphoma after radiation or combined chemoradiation therapy. Klinicheskaya onkogematologiya. 2012;5(3):218–24. (In Russ)]
  82. Familiary G, Caggiani A, Nottola SA, et al. Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin’s disease. Hum Reprod. 1993;8(12):2080–7.
  83. Zhang Y, Xiao Z, Wang Y, et al. Gonadotropin-releasing hormone for preservation of ovarian function during chemotherapy in lymphoma patients of reproductive age: a summary based on 434 patients. PLoS One. 2013;8(11):e80444. doi: 10.1371/journal.pone.0080444.
  84. Huser M, Crha I, Ventruba P, et al. Prevention of ovarian function damage by a GnRh analogue during chemotherapy in Hodgkin lymphoma patients. Hum Reprod. 2008;23(4):863–8. doi: 10.1093/humrep/den005.
  85. Kulkarni SS, Sastry PS, Saikia TK, et al. Gonadal function following ABVD therapy for Hodgkin’s disease. J Clin Oncol. 1997;20(4):354–7. doi: 10.1097/00000421-199708000-00006.
  86. Пивник А.В., Расстригин Н.А., Моисеева Т.Н. и др. Результаты лечения лимфогранулематоза по протоколу МОРР-ABVD в сочетании с лучевой терапией (десятилетнее наблюдение). Терапевтический архив. 2006;8:57–62.
    [Pivnik AV, Rasstrigin NA, Moiseeva TN, et al. Results of treatment of lymphogranulematosis according to the МОРР-ABVD protocol in combination with radiation therapy (10-year follow-up). Terapevticheskii arkhiv. 2006;8:57–62. (In Russ)]
  87. Redman JR, Bajorunas DR, Goldstein MC, et al. Semen cryopreservation and artificial insemination for Hodgkin’s disease. J Clin Oncol. 1987;5(2):233–8.
  88. Винокуров А.А., Варфоломеева С.Р., Тарусин Д.И. Гонадотоксичность терапии лимфомы Ходжкина у подростков и молодых мужчин: актуальность проблемы и пути решения (обзор литературы). Онкогематология. 2011;2:12–8.
    [Vinokurov AA, Varfolomeeva SR, Tarusin DI. Gonadal toxicity of treatment for Hodgkin’s lymphoma in adolescents and young adults: topicality of the problem and ways of its solution (literature review). Onkogematologiya. 2011;2:12–8. (In Russ)]
  89. Sieniawski M, Reineke T, Nogova L, et al. Fertility in male patients with advanced Hodgkin’s lymphoma treated with BEACOPP: a report of the German Hodgkin Study Group (GHSG). Blood. 2008;111(1):71–6. doi: 10.1182/blood-2007-02-073544.
  90. Винокуров А.А., Варфоломеева С.Р., Тарусин Д.И., Моисеева Т.Н. Оценка гонадотоксичности терапии по схеме ВЕАСОРР-14 у молодых мужчин, излеченных от лимфомы Ходжкина. Клиническая онкогематология. 2011;4(3):235–9.
    [Vinokurov AA, Varfolomeeva SR, Tarusin DI, Moiseeva TN. Evaluation of gonadal toxicity of ВЕАСОРР-14 treatment regimen in young males cured from Hodgkin’s lymphoma. Klinicheskaya onkogematologiya. 2011;4(3):235–9. (In Russ)]
  91. Даниленко А.А., Шахтарина С.В., Афанасова Н.В., Павлов В.В. Изменения в легких у больных лимфомой Ходжкина после химиотерапии по схемам СОРР, ABVD, ВЕАСОРР и облучения средостения в суммарной очаговой дозе 20–30 Грей. Клиническая онкогематология. 2010;3(4):354–8.
    [Danilenko AA, Shakhtarina SV, Afanasova NV, Pavlov VV. Changes in lugs of patients with Hodgkin’s lymphoma after chemotherapy according to СОРР, ABVD, ВЕАСОРР and radiation of mediastinum (total focal dose of 20–30 Gray). Klinicheskaya onkogematologiya. 2010;3(4):354–8. (In Russ)]
  92. Даценко П.В. Сбалансированное сочетание лучевого и лекарственного компонентов при комплексном лечении лимфогранулематоза: Автореф. дис. ¼ д-ра мед. наук. М., 2004.
    [Datsenko PV. Sbalansirovannoe sochetanie luchevogo i lekarstvennogo komponentov pri kompleksnom lechenii limfogranulematoza. (Balanced combination of radiation and chemotherapy in complex treatment of lymphogranulematosis.) [dissertation] Moscow; 2004. (In Russ)]
  93. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: Report of an intergroup trial. J Clin Oncol. 2003;21(4):607–14. doi: 10.1200/jco.2003.12.086.
  94. 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.
  95. Onuma T, Holland JF, Hosi S, et al. Microbiological assay of bleomycin: inactivation, tissue distribution, and clearance. Cancer. 1974;33(5):1230–8. doi: 10.1002/1097-0142(197405)33:5<1230::aid-cncr2820330507>3.0.co;2-c.
  96. Santrach PJ, Askin FB, Wells RJ, et al. Nodular form of bleomycin-related pulmonary injury in patients with osteogenic sarcoma. Cancer. 1989;64(4):806–11. doi: 10.1002/1097-0142(19890815)64:4<806::aid-cncr2820640407>3.0.co;2-x.
  97. Holoye PY, Luna MH, Mackay B, et al. Bleomycin hypersensitivity pneumonitis. Ann Intern Med. 1978;88(1):47–9. doi: 10.7326/0003-4819-88-1-47.
  98. Martin WG, Ristow KM, Habermann TM, et al. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma. J Clin Oncol. 2005;23(30):7614–20. doi: 10.1200/jco.2005.02.7243.
  99. Carlson RW, Sikic BJ. Continuous infusion or bolus injection in cancer chemotherapy. Ann Intern Med. 1983;99(6):823–33. doi: 10.7326/0003-4819-99-6-823.
  100. Samuals MI, Johnson PE, Holoye PY, et al. Large-dose bleomycin therapy and pulmonary toxicity. JAMA. 1976;235(11):1117–20. doi: 10.1001/jama.1976.03260370025026.
  101. Catravas LD, Laza JS, Dobuker KJ, et al. Pulmonary endothelial dysfunction in the presence or absence of interstitial injury induced by intratracheally injected bleomycin in rabbits. Am Rev Respir Dis. 1983;128(4):740–6.
  102. Simpson AB, Paul J, Graham J, et al. Fatal bleomycin pulmonary toxicity in the west of Scotland 1991–95; a review of patients with germ cells tumors. Br J Cancer. 1998;78(8):1061–6. doi: 10.1038/bjc.1998.628.
  103. Lower EE, Strohofer S, Baughman RP. Bleomycin causes alveolar macrophages from cigarette smokers to release hydrogen peroxide. Am J Med Sci. 1988;295(3):193–7. doi: 10.1097/00000441-198803000-00006.
  104. Boll B, Gorgen H, Fuchs M, et al. Feasibility and efficacy of ABVD in elderly Hodgkin lymphoma patients: analysis of two randomized prospective multicenter trials of the German Hodgkin Study Group (HD10 and HD11). Blood (ASH Annual Meeting Abstracts). 2010;116:418.
  105. Proctor SJ, Wilkinson J, Culligan D, et al. Comparative clinical responses of three chemotherapy schedules (VEPEMB, ABVD, CLVPP) in 175 Hodgkin lymphoma patients over 60 YS evaluated as part of the SHIELD (Hodgkin Elderly) study. Ann Oncol. 2011;22(4):117–8.
  106. Evens AM, Hong F, Gordon LI, et al. Efficacy and tolerability of ABVD and Stanford V for Elderly Advanced-Stage Hodgkin-Lymphoma (HL): analysis from the Phase III Randomized US Intergroup Trial E2496. Ann Oncol. 2011;22(4):118.
  107. Behringer K, Goergen H, Borchmann P, et al. Impact of bleomycin and dacarbazine within the ABVD regimen in the treatment of early-stage favorable Hodgkin lymphoma: final results of the GHSG HD13 trial. EHA. 2014: Abstract S1290.
  108. Hirsch A, Vander EN, Straus DJ, et al. Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin’s disease. J Clin Oncol. 1996;14(4):1297–305.
  109. Horning SJ, Adhikary A, Rizk N, et al. Effect of treatment for Hodgkin’s disease on pulmonary function: results of a prospective study. J Clin Oncol. 1994;12(2):297–305.
  110. Kaplan HS. Hodgkin’s Disease. 2nd edition. Cambridge: Harvard University Press; 1980.
  111. Prosnitz LR, Farber LR, Fisher JJ, et al. Long term remissions with combined modality therapy for advanced Hodgkin’s disease. Cancer. 1976;37(6):2826–33. doi: 10.1002/1097-0142(197606)37:6<2826::aid-cncr2820370638>3.0.co;2-f.
  112. Mauch PV, Armitage JO, Diehl V, et al, eds. Hodgkin’s disease. Philadelphia; 1999.
  113. Brincker H, Bentzen SM. A re-analysis of available dose-response and time-dose data in Hodgkin’s disease. J Radiother Oncol. 1994;30(3):227–30. doi: 10.1016/0167-8140(94)90462-6.
  114. Loeffler M, Diehl V, Pfreundschuh M, et al. Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin’s disease. J Clin Oncol. 1997;15(6):2275–87. doi: 10.1016/s1278-3218(98)89074-4.
  115. Ярмоненко С.П., Вайнсон А.А. Радиобиология человека и животных. М.: Высшая школа, 2004.
    [Yarmonenko SP, Vainson AA. Radiobiologiya cheloveka i zhivotnykh. (Radiobiology of human and animal.) Moscow: Vysshaya shkola Publ.; 2004. (In Russ)]
  116. Jakobsson PA, Littbrand B. Fractionation scheme with low individual tumor doses and high total dose. Actа Radiol Ther Phys Biol. 1973;12(4):337–46. doi: 10.3109/02841867309131099.
  117. Акимов А.А., Ильин Н.В. Некоторые биологические аспекты лимфомы Ходжкина и новые подходы к ее терапии. Вопросы онкологии. 2003;49(1):31–40.
    [Akimov AA, Il’in NV. Some biological aspects of Hodgkin’s lymphoma and new approaches to its treatment. Voprosy onkologii. 2003;49(1):31–40. (In Russ)]
  118. Hall EJ. Clinical response of normal tissues. In: Hall EJ, ed. Radiobiology for the Radiologist. 5th edition. Philadelphia: Lippincott Williams &Wilkins, 2000. pp. 352.
  119. Ильин Н.В., Виноградова Ю.Н., Николаева Е.Н., Смирнова Е.В. Значение мультифракционирования дозы радиации при первичном лучевом лечении больных лимфомой Ходжкина. Онкогематология. 2007;4:47–52.
    [Il’in NV, Vinogradova YuN, Nikolaeva EN, Smirnova EV. Value of multifractionation radiotherapy dose for primary treatment of patients with Hodgkin’s lymphoma. Onkogematologiya. 2007;4:47–52. (In Russ)]
  120. Magagnoli M, Marzo K, Balzarotti M, et al. Dimension of Residual CT Scan Mass in Hodgkin’s Lymphoma (HL) Is a Negative Prognostic Factor in Patients with PET Negative After Chemo +/– Radiotherapy. Blood (ASH Annual Meeting Abstracts). 2011;118:93.
  121. Russo F, Corazzelli G, Frigeri F, et al. A phase II study of dose-dense and dose-intense ABVD (ABVDDD-DI) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma. Br J Haematol. 2014;166(1):118–29. doi: 10.1111/bjh.12862.
  122. Laskar S, Kumar DP, Khanna N, et al. Radiation therapy for early stage unfavorable Hodgkin lymphoma: is dose reduction feasible? Leuk Lymphoma. 2014;55(10):2356–61. doi: 10.3109/10428194.2013.871631.
  123. Boll B, Bredenfeld H, Gorgen H, et al. Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma. Blood. 2011;118(24):6292–8. doi: 10.1182/blood-2011-07-368167.
  124. Younes A, Oki Y, McLaughlin P, et al. Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood. 2012;119(18):4123–8. doi: 10.1182/blood-2012-01-405456.
  125. 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. The Lancet. 2012;379(9828):1791–9. doi: 10.1016/s0140-6736(11)61940-5.
  126. Younes A, Connors JM, Park S, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348–56. doi: 10.1016/s1470-2045(13)70501-1.
  127. Demina EA, Tumyan GS, Stroyakovskiy DL. Treatment results of six cycles EACOPP-14 ± RT in advanced stage Hodgkin lymphoma. Multicenters study in Russia. 9th International Symposium on Hodgkin Lymphoma, Cologne, Germany, October 12–15, 2013. Haematologica. 2013;98(2): Abstract P013.
  128. Демина Е.А. Дискуссионные вопросы лечения распространенных стадий лимфомы Ходжкина. Материалы XVII Российского онкологического конгресса, Москва, 12–14 ноября 2013 г. Злокачественные опухоли. 2013;2:19–22.
    [Demina EA. Controversial issues of treatment of advanced stage Hodgkin’s lymphoma. (Materials of XVII Russian oncological congress, Moscow, November 12–14, 2013.) Zlokachestvennye opukholi. 2013;2:19–22. (In Russ)]
  129. Younes A, Gopal AK, Smith SE. еt al. Smith еt al. Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin’s Lymphoma. J Clin Oncol. 2012;30(18):2183–9. doi: 10.1200/jco.2011.38.0410.
  130. LaCasce A, Bociek RG, Matous J, et al. Brentuximab Vedotin in Combination with Bendamustine for Patients with Hodgkin Lymphoma who are Relapsed or Refractory after Frontline Therapy. Blood. 2014;124(21): Abstract 293.
  131. Connors J, Ansell S, Park SI, et al. Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: Long Term Outcomes. Blood. 2014;124(21): Abstract 292.
  132. Borchmann P, Eichenauer D, Pluetschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study. Blood. 2013;122(21): Abstract 4344.
  133. Armand P, Ansell SM, Lesokhin AM, et al. Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma – Preliminary Safety, Efficacy and Biomarker Results of a Phase I Study. Blood. 2014;124(21): Abstract 289.
  134. Moskowitz CH, Ribrag V, Michot J, et al. PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study. Blood. 2014;124(21): Abstract 290.
  135. Lesokhin AM, Ansell SM, Armand P, et al. Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. Blood. 2014;124(21): Abstract 291.

Effects of Antitumor Chemotherapy and Radiation Therapy on Thyroid Gland in Hodgkin’s Lymphoma Patients during Follow-up Observations

LYMPHOID TUMORS , , ,

S.V. Shakhtarina, A.A. Danilenko, V.V. Pavlov, V.S. Parshin, O.V. Timokhina, G.A. Simakova

Medical Radiological Research Center under the Ministry of Health of the Russian Federation, 4 Koroleva str., Obninsk, Kaluga Oblast, Russian Federation, 249036

For correspondence: A.A. Danilenko, PhD, Senior scientific worker 4 Koroleva str., Obninsk, Kaluga Oblast, Russian Federation, 249036; Tel: +7(48439)9-31-01; e-mail: danilenko@mrrc.obninsk.ru

For citation: Shakhtarina S.V., Danilenko A.A., Pavlov V.V., Parshin V.S., Timokhina O.V., Simakova G.A. Effects of Antitumor Chemotherapy and Radiation Therapy on Thyroid Gland in Hodgkin’s Lymphoma Patients during Follow-up Observations. Klin. Onkogematol. 2014; 7(4): 533–539 (In Russ.).

ABSTRACT

This paper presents data on Hodgkin’s lymphoma (HL) patients who developed a second tumor — thyroid cancer — after therapy. The cohort includes 1789 patients (1177 women and 612 men) who were treated between 1968 and 1997 in the Medical Radiological Research Center, Obninsk (Russia) with radiotherapy alone or chemo-radiotherapy involving irradiation of supradiaphragmatic nodal areas (including cervico-supraclavicular lymph nodes) and spleen with the total tumor dose (TTD) up to 40 Gy. The total observation period was 18949 person/years. Thyroid cancer was registered in 9 women and 1 man. The expected (standardized) incidence of thyroid cancer was calculated with regard for gender, age, and in accordance with incidence rates for Russian population. For the cohort of 1177 women treated for HL (with 13 032 person/year follow up) the expected incidence was 1.15, while the actual incidence was 9 cases. The relative risk was 7.81 (95% CI: 3.47–13.9). For the cohort of 612 men (with 5917 person/year follow up) the expected incidence of thyroid cancer was 0.11, while the actual one was 1 case. The relative risk was 9.09 (95% CI: 0–0.44). Structural (sonographic, morphological) and functional changes in thyroid gland were studied in 335 HL patients treated with radiotherapy alone or chemo-radiotherapy (including irradiation of cervico-supraclavicular lymph nodes) at TTD of 40, 30, 20 Gy who received therapy between 1970 and 2010 and remained in continuous remission throughout the follow-up period. Nodular masses were found in thyroids of 72 (21.5 %) patients; decreased echogenity of thyroid tissue in 36 (10.7 %) patients; cysts in 21 (6.2 %); and thyroid cancer in 3 (0.9 %) patients. Functional changes were only seen in thyroids of patients (n = 316) who were given cervico-supraclavicular irradiation. Subclinical hypotheriosis was found in 72 (22.8 %), and the clinical one in 5 (1.6 %) patients; elevated antibody levels were found in 80 (25.3 %) patients. Decreased incidence of structural and functional thyroid changes was seen (p < 0.05) with decreased TTD during irradiation of the cervico-supraclavicular area.

Keywords: Hodgkin’s lymphoma, thyroid gland, hypothyroidism, thyroid cancer.

Accepted: September 10, 2014

Read in PDF (RUS)pdficon

REFERENCES

  1. Atahan I.L., Yildiz F., Ozyar E., Uzal D. Thyroid dysfunction in children receiving neck irradiation for Hodgkin’s disease. Radiat. Med. 1998; 16(5): 359–61.
  2. Hancock S.L., McDougall I.R., Constine L.S. Thyroid abnormalities after therapeutic external radiation. Int. J. Radiat. Oncol. Biol. Phys. 1995; 31: 1165–70.
  3. Healy J.C., Shafford E.A., Reznek R.H. et al. Sonographic abnormalities of the thyroid gland following radiotherapy in survivors of childhood Hodgkin’s disease. Br. J. Radiol. 1996; 69: 617–23.
  4. Шахтарина С.В., Павлов В.В., Даниленко А.А., Афанасова Н.В. Лечение больных лимфомой Ходжкина с локальными стадиями I, II, IE, IIE: опыт Медицинского радиологического научного центра. Онкогематология. 2007; 4: 36–46.  [Shakhtarina S.V., Pavlov V.V., Danilenko A.A., Afanasova N.V. Management of patients with Hodgkin’s lymphoma with local stages I, II, IE, IIE: experience of the Medical radiological scientific center. Onkogematologiya. 2007; 4: 36–46. (In Russ.)]
  5. Давыдов М.И., Аксель Е.М. Статистика злокачественных новообразо- ваний в России и странах СНГ в 2008. Вестник РОНЦ им. Н.Н. Блохина РАМН. 2010; 21(2, прил. 1): 60–1. [Davydov M.I., Aksel’ E.M. Statistics of malignancies in Russia and CIS countries in 2008. Vestnik RONTs im. N.N. Blokhina RAMN. 2010; 21(2, suppl. 1): 60–1. (In Russ.)]
  6. Vandenbroucke J.P. A shortcut method for calculating the 95 per cent confidence interval of the standardized mortality ratio. Am. J. Epidemiol. 1982; 115: 303–4.
  7. Hancock S.L., Hoppe R.T. Complications of treatment and causes of mortality after Hodgkin’s disease. Semin. Radiat. Oncol. 1996: 6(3): 225–42.
  8. Tucker M.A., Jones P.H., Boice J.D. Jr. et al. Therapeutic radiation at a young age is linked to secondary thyroid cancer. The Late Effects Study Group. Cancer Res. 1991; 51: 2885–8.
  9. Sklar C., Whitton J., Mertens A. et al. Abnormalities of the thyroid in survivals of Hodgkin’s disease: data from the Childhood Cancer Survivor Study. J. Clin. Endocrinol. Metab. 2000; 85: 3227–32.
  10. Bethge W., Guggenberger D., Bamberg M. et al. Thyroid toxicity of treatment for Hodgkin’s disease. Ann. Hematol. 2000; 79(3): 114–8.
  11. Балашов А.Т., Мясников А.А. Заболевания щитовидной железы при комплексном лечении лимфогранулематоза. Проблемы эндокринологии. 1998; 2: 19–21. [Balashov A.T., Myasnikov A.A. Diseases of the thyroid gland in complex treatment of lymphogranulomatosis. Problemy endokrinologii. 1998; 2: 19–21. (In Russ.)]
  12. Van Santen H.M., Vulsma T., Dijkgraaf M.G. et al. No damaging effect of chemotherapy in addition to radiotherapy on the thyroid axis in young adults survivors of childhood cancer. J. Clin. Endocrinol. Metabol. 2003; 88: 3657–63.
  13. Hancock S.L., Cox R.S., McDougall I.R. Thyroid diseases after treatment of Hodgkin’s disease. N. Engl. J. Med. 1991; 325: 559–605.
  14. Loeffler M.L., Tarbell N.J., Garber J.R., Mauch P. The development of Grave’s disease following radiation therapy in Hodgkin’s disease. Int. J. Radiat. Oncol. Biol. Phys. 1988; 14: 175–8.
  15. Mortimer R.H., Hill G.E., Galligan J.P. et al. Hypothyroidism and Grave’s disease after mantle irradiation: a follow-up study. Aust. N. Z. J. Med. 1986; 16: 347–51.

High-Dose Chemotherapy and Autologous Stem Cells Transplantation for Relapsed/Refractory Hodgkin’s Lymphoma. Is There an Equal Right to Life?

BONE MARROW TRANSPLANTATION , , , ,

N.V. Zhukov1,2, A.G. Rumyantsev1, A.L. Uss3, N.F. Milanovich3, V.V. Ptushkin1, B.V. Afanasyev4, N.B. Mikhaylova4, V.B. Larionova5, E.A. Demina5, E.E. Karamanesht6, N.G. Tyurina7, M.A. Vernyuk7, A.D. Kaprin7

1 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology under the RF MH, Moscow, Russian Federation

2 N.I. Pirogov Russian National Research Medical University, Moscow, Russian Federation

3 National Center for Hematology and Bone Marrow Transplantation, Minsk, Belarus

4 R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation under I.P. Pavlov State Medical University, Saint Petersburg, Russian Federation

5 N.N. Blokhin Cancer Research Center of RAMS, Moscow, Russian Federation

6 Kyiv Center for Bone Marrow Transplantation, Kyiv, Ukraine

7 P.A. Hertsen Moscow Oncological Research Institute, Moscow, Russian Federation

For citation: Zhukov N.V., Rumyantsev A.G., Uss A.L., Milanovich N.F., Ptushkin V.V., Afanas’ev B.V., Mikhailova N.B., Larionova V.B., Demina E.A., Karamanesht E.E., Tyurina N.G., Vernyuk M.A., Kaprin A.D. High-Dose Chemotherapy and Autologous Stem Cells Transplantation for Relapsed/Refractory Hodgkin’s Lymphoma. Is There an Equal Right to Life? Klin. onkogematol. 2014; 7(3): 317–26 (In Russ.).

ABSTRACT

Aim. Hodgkin’s lymphoma (HL) patients with primary refractory (PRef) course of disease or relapses refractory to the previous 2nd line therapy (RRel) often are not given high-dose chemotherapy with autologous stem cell support (ASCS), and this refuse is motivated by its poor efficacy and high toxicity in this population. The objective of this study was to evaluate the efficacy and safety of ASCS in this patient population.

Materials and methods. 372 patients with Hodgkin’s lymphoma undergoing ASCS between 01.1990 and 06.2013 were included in the trial. The reason for ASCS was: primary refractory disease in 132 (35.5 %) patients, relapse of the disease resistant to II line chemotherapy (refractory relapse) in 81 (22 %). The remaining 159 patients (42.5 %) either had a relapse for which they received no II line chemotherapy (a relapse with untested sensitivity) or a relapse that proved to be sensitive to previously performed II line therapy (sensitive relapse). These patients were assigned to a chemosensitive HL group.

Results. With a median follow-up of 51 months, the overall survival rate (OS) and the relapse-free survival rate (RFS) did not differ significantly between patients with RRel, PRef and chemosensitive HL group (p > 0.05). Only freedom from treatment failure survival (FFTS) was significantly worse in patients with PRef HL (5-yrs EFS 42 % vs 58 % in patients with RRel vs 60 % in patients with chemosensitive HL group; p = 0.004). 100-day mortality mostly caused by ASCS toxicity also did not differ significantly between groups (p = 0.2). Irrespectively of primary reason for ASCS, long-term ASCS results significantly depended on response to the cytoreductive therapy. The effect of the cytoreductive therapy was assessed in 309 patients. When patients achieved complete, marked partial or partial remission, the 5-year overall survival rate, FFTS, and relapse-free survival rate was 78 %, 64 %, and 68 %, respectively. In patients with stabilization or progression of disease due to the cytoreductive therapy, these parameters were equal to 33 %, 24 % и 52 %, respectively (p < 0.001 for OS and FFTS, p = 0.005 for RFS).

Conclusion. In patients with primary refractory and refractory relapse of HL, ASCS has acceptable efficacy and early mortality which is comparable to that observed in patients with chemosensitive Hodgkin’s lymphoma, thus permitting to consider ASCS a potential therapeutic approach in patients with primary refractory disease and resistant relapses of Hodgkin’s lymphoma. Irrespectively of the initial disease course, the tumor response to the cytoreductive therapy is the most important predictive factor for the long-term ASCS results.

Keywords: Hodgkin’s lymphoma, high-dose chemotherapy, autologous hematopoietic stem cells transplantation, primary resistance, resistant relapse.

Address correspondence to: zhukov.nikolay@rambler.ru

Accepted: April 13, 2014

Read in PDF (RUS) pdficon

REFERENCES

  1.  Linch D., Winfield D., Goldstone A. et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 1993; 341: 1051.
  2. Schmitz N., Sextro M., Pfistner B. HDR-1: high-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for relapsed chemosensitive Hodgkin’s disease (HD): final results of a randomized GHSG and EBMT trial (HD-R1). Proc. Am. Soc. Clin. Oncol. 1999; 18(Suppl. 5): 18.
  3. Josting A., Franklin J., May M. et al. New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the German Hodgkin’s lymphoma study group. J. Clin. Oncol. 2002; 20: 221–30.
  4. Longo L., Duffey P.L., Young R.C. et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. J. Clin. Oncol. 1992; 10: 210–8.
  5. Brusamolino E., Orlandi E., Canevari A. et al. Results of CAV regimen (CCNU, melphalan, and VP-16) as third-line salvage therapy for Hodgkin’s disease. Ann. Oncol. 1994; 5: 427–32.
  6. Bonfante V., Santoro A., Viviani S. et al. Outcome of patients with Hodgkin’s disease failing after primary MOPP/ABVD. J. Clin. Oncol. 1997; 15: 528–34.
  7. Josting A., Rueffer U., Franklin J. et al. Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood 2000; 96: 1280–6.
  8. Josting A., Rudolph C., Mapara M. et al. Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG). Ann. Oncol. 2005; 16(1): 116–23.
  9. Argiris A., Seropian S., Cooper D.L. High-dose BEAM chemotherapy with autologous peripheral blood progenitor-cell transplantation for unselected patients with primary refractory or relapsed Hodgkin’s disease. Ann. Oncol. 2000; 11: 665–72.
  10. Ferme C., Mounier N., Divine M. et al. Intensive salvage therapy with high dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: Results of the Groupe d’Etudes des Lymphomes de l’Adulte H89 Trial. J. Clin. Oncol. 2002; 20: 467–75.
  11. Constans M., Sureda A., Terol M.J. et al. Autologous stem cell transplantation for primary refractory Hodgkin’s disease: Results and clinical variables affecting outcome. Ann. Oncol. 2003; 14: 745–51.
  12. Sweetenham J.W., Carella A.M., Taghipour G. et al. High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin’s disease who do not enter remission after induction chemotherapy: Results in 175 patients reported to the European Group for Blood and Marrow Transplantation. Lymphoma Working Party. J. Clin. Oncol. 1999; 17: 3101–9.
  13. Gopal A.K., Metcalfe T.L., Gooley T.A. et al. High-Dose Therapy and Autologous Stem Cell Transplantation for Chemoresistant Hodgkin Lymphoma: The Seattle Experience. Cancer 2008; 113(6): 1344–50.
  14. Sureda A., Arranz R., Iriondo A. et al. Autologous stem-cell transplantation for Hodgkin’s disease: results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group. J. Clin. Oncol. 2001; 19(5): 1395–404.
  15. Czyz J., Dziadziuszko R., Knopinska-Postuszuy W. et al. Outcome and prognostic factors in advanced Hodgkin’s disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients. Ann. Oncol. 2004; 15(8): 1222–30.
  16. Sureda A., Constans M., Iriondo A. et al. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann. Oncol. 2005; 16(4): 625–33.

Clinico-immunological features of invasive aspergillosis in patients with Hodgkin’s disease

INFECTIONS IN ONCOHEMATOLOGY , ,

O.V. Shadrivova1, Ye.V. Frolova1, L.V. Filippova1, A.Ye. Uchevatkina1, S.N. Khostelidi1, R.M. Chernopyatova1, Ye.A. Desyatik1, A.G. Volkova2, Ye.V. Shagdileyeva1, L.S. Zubarovskaya2, A.V.Rysev1, S.M. Ignatyeva1, T.S. Bogomolova1, Yu.N. Vinogradova3, N.V. Vasilyeva1, and N.N. Klimko1

1 I.I. Metchnikov Northwest State Medical University, Saint Petersburg, Russian Federation

2 R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, I.P. Pavlov Saint Petersburg State Medical University, Saint Petersburg, Russian Federation

3 Russian Research Centre for Radiology and Surgical Technologies, RF Ministry of Health, Saint Petersburg, Russian Federation

ABSTRACT

Invasive aspergillosis is a serious mycotic infection with high mortality that mostly occurs in patients with hematological malignancies and severe immunodeficiency. Immunological defects in the various groups of hematological patients with invasive aspergillosis are not well understood. We are the first to present the results of studying clinico-immunological features of invasive aspergillosis in the patients with Hodgkin’s lymphoma.

Keywords: invasive aspergillosis, Hodgkin’s lymphoma, immune response.

Read in PDF (RUS) pdficon

REFERERENCES

  1. Kousha M., Tadi R., Soubani A.O. Pulmonary aspergillosis: a clinical review. Eur. Respir. Rev. 2011; 20(21): 156–72.
  2. Попова М.О., Зубаровская Л.С., Климко Н.Н., Афанасьев Б.В. Инва- зивные микозы при трансплантации гемопоэтических стволовых клеток. Тер. арх. 2012; 7: 50–7. [Popova M.O., Zubarovskaya L.S., Klimko N.N., Afanasyev B.V. Invasive mycoses in hematopoietic stem cell transplantation. Ter. arkh. 2012; 7: 50–7. (In Russ.)].
  3. Klimko N.N., Shadrivova O.V., Khostelidi S.N. et al. Invasive aspergillosis in Saint Petersburg, Russia: analysis of 445 proven and probable cases. Mycos. Diagn. Ther. Prophyl. Fungal Dis. 2013; 56(3): 113.
  4. Chaudhary N., Staab J.F., Marr K.A. Healthy Human T-Cell Responses to Aspergillus fumigatus Antigens. PLoS One 2010; 5(2): e9036.
  5. Carvalho A., Cunha C., Bistoni F., Romani L. Immunotherapy of aspergillosis. Microbiol. Infect. 2012; 18(2): 120–5.
  6. De Pauw B., Walsh T.J., Donnelly J.P. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin. Infect. Dis. 2008; 46(12): 1813–21.
  7. Drgona L., Colita A., Klimko N. et al. Triggers for driving treatment of at-risk patients with invasive fungal disease. J. Antimicrob. Chemother. 2013; 68(3): 17–24.
  8. Landgren O., Pfeiffer R.M., Kristinsson S.Y., Bjorkholm M. Survival patterns in patients with Hodgkin’s Lymphoma with a pre-existing hospital discharge diagnosis of autoimmune disease. J. Clin. Oncol. 2010; 28(34): 5081–7.
  9. Landgren O., Engels E.A., Pfeiffer R.M. et al. Autoimmunity and Susceptibility to Hodgkin Lymphoma: A Population-Based Case–Control Study in Scandinavia. J. Nat. Cancer Inst. 2006; 98(18): 1321–30.
  10. Brusamolino E., Carella A.M. Treatment of refractory and relapsed Hodgkin’s lymphoma: facts and perspectives. Hematol. J. Open Access Publ. 2007; 92(1): 6–10.
  11. Лимфомы: научно-практическое издание. Под ред. А.М. Гранова, Н.В. Ильина. СПб., 2010: 272. [Limfomy: nauchno-prakticheskoe izdanie. Pod red. A.M. Granova, N.V. Ilina (Lymphomas: scientific-and-practical publication. Ed. by: A.M. Granov, N.V. Ilin). SPb., 2010: 272 .]
  12. Chai L.Y., Vonk A.G., Kullberg B.-J., Netea M.G. Immune Response to Aspergillus fumigatus in Compromised Hosts: From Bedside to Bench. Fut. Microbiol. 2011; 6(1): 73–83.
  13. Zitvogel L., Apetoh L., Ghiringhelli F., Kroemer G. Immunological aspects of cancer chemotherapy. Immunology 2008; 8: 59–73.
  14. Motoyoshi Y., Kaminoda K., Saitoh O. et al. Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncol. Rep. 2006; 16(1): 141–6.
  15. Segal B.H. Role of macrophages in host defense against aspergillosis and strategies for immune augmentation. Oncologist 2007; 12(2): 7–13.
  16. Stevens D.A. Th1/Th2 in aspergillosis. Med. Mycol. 2006; 44(1): 229–35.
  17. Chai L.Y., Netea M.G., Teerenstra S. et al. Early Proinflammatory Cytokines and C-Reactive Protein Trends as Predictors of Outcome in Invasive Aspergillosis. J. Infect. Dis. 2010; 202(9): 1454–62.
  18. Фролова Е.В., Шадривова О.В., Филиппова Л.В. и др. Состояние иммунного статуса у гематологических пациентов с инвазивным аспергил- лезом. Журн. инфектол. 2012; 4(4): 59–64. [Frolova Ye.V., Shadrivova O.V., Filippova L.V., et al. Immune status in hematological patients with invasive aspergillosis. Zhurn. infektol. 2012; 4(4): 59–64. (In Russ.)].
  19. Park S.J., Mehrad B. Innate Immunity to Aspergillus Species. Clin. Microbiol. Rev. 2009; 22(4): 535–51.
  20. Hebart H., Bollinger C., Fisch P. et al. Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies. Blood 2002; 100(13): 4521–8.
  21. Chai L.Y., van de Veerdonk F., Marijnissen R.J. et al. Anti-Aspergillus human host defense relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity. Immunology 2010; 130(1): 646–54.
  22. Van de Veerdonk F., Netea M.G. T-cell Subsets and Antifungal Host Defenses. Curr. Fung. Infect. Rep. 2010; 4(4): 238–43.