Блокада PD-1-пути ниволумабом — новая возможность иммунотерапии классической лимфомы Ходжкина

Е.А. Демина

ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: Елена Андреевна Демина, д-р мед. наук, профессор, Каширское ш., д. 24, Москва, Российская Федерация, 115478; e-mail: drdemina@yandex.ru

Для цитирования: Демина Е.А. Блокада PD-1-пути ниволумабом — новая возможность иммунотерапии классической лимфомы Ходжкина. Клиническая онкогематология. 2018;11(3):213–19.

DOI: 10.21320/2500-2139-2018-11-3-213-219


РЕФЕРАТ

За последние два десятилетия показано, что индивидуализация программного лечения с одновременной интенсификацией химиотерапии позволяет излечить большинство больных классической лимфомой Ходжкина (кЛХ). Однако у 10–30 % больных развиваются рецидивы или отмечается резистентное течение заболевания. Дальнейшая интенсификация терапии сопровождается токсичностью, снижающей общую выживаемость и качество жизни больных. Современный стандарт терапии второй линии, включающий высокодозную химиотерапию (ВДХТ) с трансплантацией аутологичных гемопоэтических стволовых клеток (аутоТГСК), позволяет достичь длительной 5-летней выживаемости без прогрессирования лишь у 50–60 % больных с рецидивами и не более 40–45 % — при рефрактерном течении. Приблизительно у 50 % больных после ВДХТ и аутоТГСК наблюдается возврат заболевания. Медиана общей выживаемости у пациентов с рецидивами не превышает 2 лет. АллоТГСК несколько улучшает результаты, но ее выполнение возможно далеко не у всех больных. Необходимость повышения эффективности терапии рецидивов и резистентных форм кЛХ и снижения токсичности высокоэффективных программ послужила основанием для поиска новых возможностей лечения. Идея использовать анти-CD30-моноклональные антитела против специфичного маркера опухолевых клеток Березовского—Рид—Штернберга в качестве средства для доставки высокоэффективного противоопухолевого соединения монометилауристатина Е непосредственно в опухолевую клетку привела к созданию нового CD30-таргетного конъюгата брентуксимаба ведотина. Препарат продемонстрировал высокую эффективность, но не решил проблему полностью. Создание анти-PD1-антител ниволумаба открыло новые возможности в лечении кЛХ. В настоящем обзоре представлены сведения о фармакологии препарата, механизме противоопухолевого действия, а также результаты крупных международных рандомизированных клинических исследований.

Ключевые слова: ниволумаб, лимфома Ходжкина, рецидив, резистентность, лечение.

Получено: 5 февраля 2018 г.

Принято в печать: 30 апреля 2018 г.

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ЛИТЕРАТУРА
  1. Engert A, Jounes A, Hematologic malignancies: Hodgkin lymphoma. A Comprehensive Overview. 2nd edition. Berlin, Heidelberg: Springer; 2015. pp. 437. doi: 10.1007/978-3-319-12505-3.
  2. 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:1016/s1470-2045(13)70341-3.
  3. Czyz J, Szydlo R, Knopinska-Posluszny W, et al. Treatment for primary refractory Hodgkin’s disease: a comparison of high-dose chemotherapy followed by ASCT with conventional therapy. Bone Marrow Transplant. 2004;33(12):1225–9. doi: 10.1038/sj.bmt.1704508.
  4. Gerrie AS, Power MM, Shepherd JD, et al. Chemoresistance can be overcome with high-dose chemotherapy and autologous stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. Ann Oncol. 2014;25(11):2218–23. doi: 10.1093/annonc/mdu387.
  5. 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. doi: 10.1093/annonc/mdi119.
  6. Brice P, Bouabdallah R, Moreau P, et al. Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin’s disease: analysis of 280 patients from the French registry. Societe Francaise de Greffe de Moelle. Bone Marrow Transplant. 1997;20(1):21–6. doi: 10.1038/sj.bmt.1700838.
  7. Crump M. Management of Hodgkin lymphoma in relapse after autologous stem cell transplant. Hematology Am Soc Hematol Educ Program. 2008;2008(1):326–33. doi: 10.1182/asheducation-2008.1.326.
  8. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an antiCD30–monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102(4):1458–65. doi: 10.1182/blood-2003-01-0039.
  9. 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.
  10. 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.
  11. Arai S, Fanale M, DeVos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma. 2013;54(11):2531–3. doi: 10.3109/10428194.2013.798868.
  12. 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.
  13. Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med. 2016;375(18):1767–78. doi: 10.1056/NEJMra1514296.
  14. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17. doi: 10.1056/NEJMoa1414428.
  15. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823–33. doi: 10.1056/NEJMoa1606774
  16. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803–13. doi: 10.1056/NEJMoa1510665.
  17. Kuppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9(1):15–27. doi: 10.1038/nrc2542.
  18. Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):3220–4. doi: 1182/blood-2007-05-085159.
  19. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77. doi: 10.1182/blood-2010-05-282780.
  20. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol. 2016;34(23):2690–7. doi: 10.1200/JCO.2016.66.4482.
  21. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):1611–8. doi: 1158/1078-0432.ccr-11-1942.
  22. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19(13):3462–73. doi: 10.1158/1078-0432.CCR-13-0855.
  23. Merryman R, Armand Ph. Hodgkin lymphoma and PD-1 blockade: an unfinished story. Ann Lymphoma. 2017;1:4. doi: 10.21037/aol.2017.08.03.
  24. Ansell SM. Nivolumab in the Treatment of Hodgkin Lymphoma. Clin Cancer Res. 2017;23(7):1623–6. doi: 10.1158/1078-0432.CCR-16-1387.
  25. Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856–67. doi: 10.1056/NEJMoa1602252.
  26. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22. doi: 10.1016/S1470-2045(17)30065-7.
  27. Borghaei H, Paz‑Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627–39. doi: 10.1056/NEJMoa1507643.
  28. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123–35. doi: 10.1056/NEJMoa1504627.
  29. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803–13. doi: 10.1056/NEJMoa1510665.
  30. Wolchok JD, Rollin L, Larkin J. Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(25):2503–4. doi: 10.1056/NEJMc1714339.
  31. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. doi: 10.1056/NEJMoa1411087.
  32. Armand P. Immune checkpoint blockade in hematologic malignancies. Blood. 2015;125(22):3393–400. doi: 10.1182/blood-2015-02-567453.
  33. Kasamon YL, De Carlo RA, Wang Y, et al. FDA Approval Summary: Nivolumab for the Treatment of Relapsed or Progressive Classical Hodgkin Lymphoma. 2017;22(5):585–91. doi: 10.1634/theoncologist.2017-0004.
  34. 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.
  35. Fanale M, Engert A, Younes A. Nivolumab for relapsed/refractory classical Hodgkin lymphoma after autologous transplant: full results after extended follow-up of the phase 2 CheckMate 205 trail. Hematol Oncol. 2017;35:135–6. doi: 10.1002/hon.2437_124.
  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 2006;12(10):1065–72. doi: 10.1016/j.bbmt.2006.06.006
  37. Merryman RW, Kim HT, Zinzani PL, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017;129(10):1380–8. doi: 10.1182/blood-2016-09-738385.
  38. Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122(17):3062–73. doi: 10.1182/blood-2013-05-500801.
  39. Ciurea SO, Zhang MJ, Bacigalupo AA, et al. Haploidentical transplant with posttransplant cyclophosphamidevs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033–40. doi: 10.1182/blood-2015-04-639831.
  40. Опдиво® [инструкция по медицинскому применению]. Принстон, США: Bristol-Myers Squibb Company. Доступно по: https://www.vidal.ru/drugs/opdivo. Ссылка активна на 30.03.2018.[Opdivo® [package insert]. Princeton, NJ, USA: Bristol-Myers Squibb Company. Available from: https://www.vidal.ru/drugs/opdivo. (accessed 30.03.2018) (In Russ)]
  41. Hoppe RT, Advani RH, Ai WZ, et al. NCCN Clinical Practice Guidelines in Oncology. Hodgkin Lymphoma. Version 1.2018. Available from: https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf (accessed 05.04.2018).
  42. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results from a phase 1/2 study of brentuximab vedotin in combination with relapsed or refractory Hodgkin lymphoma. Hematol Oncol. 2017;35:85–6. doi: 10.1002/hon.2437_73.
  43. Ramchandren R, Fanale MA, Rueda A, et al. Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (cHL): Results from the Phase 2 CheckMate 205 Study. ASH Annual Meeting Abstracts. 2017: Abstract 651.
  44. Mikhailova N, Lepik K, Kondakova E, et al. Regaining the Tumor Control in Relapsed/Refractory Hodgkin Lymphoma after Nivolumab Failure with Addition of Another Antineoplastic Agent. ASH Annual Meeting Abstracts. 2017: Abstract

Синдром Стивенса—Джонсона после лечения ритуксимабом у больной с В-клеточной лимфомой из малых лимфоцитов, аутоиммунной гемолитической анемией и антифосфолипидным синдромом

А.Л. Меликян, И.Н. Суборцева, А.М. Ковригина, Т.И. Колошейнова, Е.К. Егорова, Е.И. Пустовая

ФГБУ «Гематологический научный центр» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

Для переписки: Ирина Николаевна Суборцева, канд. мед. наук, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167; тел.: +7(495)612-44-71; e-mail: soubortseva@yandex.ru

Для цитирования: Меликян А.Л., Суборцева И.Н., Ковригина А.М. и др. Синдром Стивенса—Джонсона после лечения ритуксимабом у больной с В-клеточной лимфомой из малых лимфоцитов, аутоиммунной гемолитической анемией и антифосфолипидным синдромом. Клиническая онкогематология. 2017;10(1):120–7.

DOI: 10.21320/2500-2139-2017-10-1-120-127


РЕФЕРАТ

Синдром Стивенса—Джонсона относится к тяжелым системным аллергическим реакциям замедленного типа, при котором отмечается поражение кожи и слизистых оболочек. У взрослых синдром Стивенса—Джонсона, как правило, обусловлен введением лекарственных средств или злокачественным процессом. Представлено наблюдение синдрома Стивенса—Джонсона после лечения ритуксимабом у больной с В-клеточной лимфомой из малых лимфоцитов, аутоиммунной гемолитической анемией, антифосфолипидным синдромом. Интерес представляет как редко встречающееся сочетание синдрома Стивенса—Джонсона, В-клеточной лимфомы из малых лимфоцитов, так и факт развития тяжелой системной аллергической реакции замедленного типа на введение ритуксимаба. Правильно собранный анамнез, клиническая картина заболевания позволили уже на ранних сроках болезни диагностировать синдром Стивенса—Джонсона и назначить адекватную терапию. В результате проведенного лечения состояние больной значительно улучшилось. Полностью купированы симптомы общей интоксикации, наблюдалась полная эпителизация эрозивных дефектов. Таким образом, представленное в работе клиническое наблюдение показывает, что своевременная диагностика, проведение комплексной медикаментозной терапии, тщательный уход могут в кратчайшие сроки, предупредив развитие осложнений, вылечить заболевание.

Ключевые слова: Синдром Стивенса—Джонсона, патогенез, клинические проявления, диагностика, лечение, ритуксимаб.

Получено: 28 июля 2016 г.

Принято в печать: 6 декабря 2016 г.

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ЛИТЕРАТУРА

  1. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6):803–13. doi: 10.1586/eci.11.66.
  2. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens-Johnson syndrome: A review. Crit Care Med. 2011;39(6):1521–32. doi: 10.1097/CCM.0b013e31821201ed.
  3. Yamane Y, Matsukura S, Watanabe Y, et al. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients—Treatment and outcome. Allergol Int. 2016;65(1):74–81. doi: 10.1016/j.alit.2015.09.001.
  4. Teh LK, Selvaraj M, Bannur Z, et al. Coupling Genotyping and Computational Modeling in Prediction of Anti-epileptic Drugs that cause Stevens Johnson Syndrome and Toxic Epidermal Necrolysis for Carrier of HLA-B*15:02. J Pharm Pharm Sci. 2016;19(1):147–60. doi: 10.18433/J38G7X.
  5. Chung W-H, Hung S-I. Genetic Markers and Danger Signals in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Allergol Int. 2010;59(4):325–332 doi: 10.2332/allergolint.10-rai-0261.
  6. Chantaphakul H, Sanon T, Klaewsongkram J. Clinical characteristics and treatment outcome of Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Ther Med. 2015;10(2):519–24. doi: 10.3892/etm.2015.2549.
  7. Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome and toxic epidermal necrolysis in Germany (1990–1992): Structure and results of a population-based registry. J Clin Epidemiol. 1996;49(7):769–73. doi: 10.1016/0895-4356(96)00035-2.
  8. Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR study. J Am Acad Dermatol. 2008;58(1):33–40. doi: 10.1016/j.jaad.2007.08.039.
  9. Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115(2):149–53. doi: 10.1046/j.1523-1747.2000.00061.x.
  10. Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. J Plast Reconstr Aesthet Surg. 2016;69(6):736–41. doi: 10.1016/j.bjps.2016.04.018.
  11. Tripathi A, Ditto AM, Grammer LC, et al. Corticosteroid therapy in an additional 13 cases of Stevens–Johnson syndrome: a total series of 67 cases. Allergy Asthma Proc. 2000;21(2):101–5. doi: 10.2500/108854100778250914.
  12. Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for Stevens–Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87(2):144–8. doi: 10.2340/00015555-0214.
  13. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282(5388):490–3. doi: 10.1126/science.282.5388.490.
  14. French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens–Johnson syndrome: our current understanding. Int Immunopharmacol. 2006;6(4):543–9. doi: 10.1016/j.intimp.2005.11.012.
  15. Prins C, Kerdel FA, Padilla RS, et al. TEN-IVIG Study Group. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol. 2003;139(1):26–32. doi: 10.1001/archderm.139.1.26.
  16. Kim KJ, Lee DP, Suh HS, et al. Toxic epidermal necrolysis: analysis of clinical course and SCORTEN-based comparison of mortality rate and treatment modalities in Korean patients. Acta Derm Venereol. 2005;85:497–502.
  17. Bamichas G, Natse T, Christidou F, et al. Plasma exchange in patients with toxic epidermal necrolysis. Ther Apher. 2002;6(3):225–8. doi: 10.1046/j.1526-0968.2002.00409.x.
  18. Egan CA, Grant WJ, Morris SE, et al. Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol. 1999;40(3):458–61. doi: 10.1016/S0190-9622(99)70497-4.
  19. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol. 1985;121(12):1548–9. doi: 10.1001/archderm.1985.01660120074023.
  20. Kasi PM, Tawbi HA, Oddis CV, Kulkarni HS. Clinical review: Serious adverse events associated with the use of rituximab – a critical care perspective. Crit Care. 2012;16(4):231. doi: 10.1186/cc11304.
  21. Lowndes S, Darby A, Mead G, Lister A. Stevens-Johnson syndrome after treatment with rituximab. Ann Oncol. 2002;13(12):1948–50. doi: 10.1093/annonc/mdf350.
  22. Johnson PW, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer. 2001;85(11):1619–23. doi: 10.1054/bjoc.2001.2127.
  23. Суборцева И.Н. Клинико-биологические особенности первичной экстранодальной диффузной В-крупноклеточной лимфомы: Дис. ¼ канд. мед. наук. М., 2013. 138 с. [Subortseva IN. Kliniko-biologicheskie osobennosti pervichnoi ekstranodal’noi diffuznoi B-krupnokletochnoi limfomy. (Clinical and biological features of the primary extranodal diffuse large B-cell lymphoma.) [dissertation] Moscow; 2013. 138 р. (In Russ)]
  24. Foran JM, Gupta RK, Cunningham D, et al. A UK multicentre phase II study of rituximab in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol. 2000;109(1):81–8. doi: 10.1046/j.1365-2141.2000.01965.x.
  25. Davis TA, White CA, Grillo-Lopez AJ, et al. Single agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma. J Clin Oncol. 1999;17(6):1851–7.
  26. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90(6):2188–95.
  27. Piro LD, White CA, Grillo-Lopez AJ, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1999;10:655–61.
  28. Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukaemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001;19(8):2153–64.
  29. Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med. 2001;345(13):1000. doi: 10.1056/NEJM200109273451315.
  30. Walewski J, Kraszewska E, Mioduszewska O, et al. Rituximab (MabtheraTM, RituxanTM) in patients with recurrent indolent lymphoma. Med Oncol. 2001;18(2):141–8. doi: 10.1385/mo:18:2:141.
  31. Palmieri TL, Greenhalgh DG, Saffle JR, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. Burn centers at the end of the twentieth century. J Burn Care Rehabil. 2002;23(2):87–96. doi: 10.1097/00004630-200203000-00004.
  32. Cummins DL, Mimouni D, Tzu J, et al. Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies. J Am Acad Dermatol. 2007;56(1):153–9. doi: 10.1016/j.jaad.2006.06.007.
 

Первичная медиастинальная (тимическая) В-крупноклеточная лимфома

Г.С. Тумян, И.З. Заводнова, М.Ю. Кичигина, Е.Г. Медведовская

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Moсква, Российская Федерация, 115478

Для переписки: Гаяне Сергеевна Тумян, д-р мед. наук, Каширское ш., д. 24, Moсква, Российская Федерация, 115478; тел.: +7(499)324-98-29; e-mail: gaytum@mail.ru

Для цитирования: Тумян Г.С., Заводнова И.З., Кичигина М.Ю., Медведовская Е.Г. Первичная медиастинальная (тимическая) В-крупноклеточная лимфома. Клиническая онкогематология. 2017;10(1):13–24.

DOI: 10.21320/2500-2139-2017-10-1-13-24


РЕФЕРАТ

Первичная медиастинальная (тимическая) В-крупноклеточная лимфома (ПМВКЛ) относится к первичным экстранодальным опухолям и происходит из В-клеток мозгового слоя тимуса. Болезнь чаще встречается у молодых женщин и проявляется преимущественно местнораспространенным характером роста в пределах переднего верхнего средостения с частым вовлечением органов грудной клетки. ПМВКЛ имеет специфические иммуноморфологическую и генетическую характеристики, которые позволяют идентифицировать ее от остальных, сходных по проявлениям заболеваний: диффузной В-крупноклеточной лимфомы, лимфомы Ходжкина с нодулярным склерозом и медиастинальной лимфомы «серой зоны». Стандартом лечения ПМВКЛ является иммунохимиотерапия с последующим облучением остаточной опухоли в средостении. К настоящему времени преимуществ одного лекарственного режима перед другим в рамках контролируемых исследований не показано. Применение новых методов визуализации (ПЭТ/КТ) позволяют надеяться на возможность отказа от лучевой терапии у определенной части больных ПМВКЛ без ухудшения показателей отдаленной выживаемости.

Ключевые слова: первичная медиастинальная (тимическая) В-крупноклеточная лимфома, первичные экстранодальные лимфомы, диагностика, патогенез, иммуноморфологическая и генетическая характеристики, лечение.

Получено: 22 августа 2016 г.

Принято в печать: 17 декабря 2016 г.

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ЛИТЕРАТУРА

  1. Benjamin SP, McCormack LJ, Effler DB, et al. Primary lymphatic tumors of the mediastinum. Cancer. 1972;30(3):708–12. doi: 10.1002/1097-0142(197209)30:3<708::AID-CNCR2820300318>3.0.CO;2–5.
  2. Lichtenstein AK, Levine A, Taylor CR, et al. Primary mediastinal lymphoma in adults. Am J Med. 1980;68(4):509–14. doi: 10.1016/0002-343(80)90294-6.
  3. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982;49(10):2112–35. doi: 10.1002/1097-0142(19820515)49:10<2112::AID-CNCR2820491024>3.0.CO;2–2.
  4. Stansfeld AG, Diebold J, Noel H, et al. Updated Kiel classification for lymphomas. Lancet. 1988;1(8580):292–3. doi: 10.1016/S0140-6736(88)90367-4.
  5. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361–92. doi: 10.1016/S0968-6053(00)80051-4.
  6. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008. doi: 10.1002/9781118853771.ch51.
  7. Cazals-Hatem D, Lepage E, Brice P, et al. Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA (“Groupe d’Etude des Lymphomes de l’Adulte”) study. Am J Surg Pathol. 1996;20(7):877–88. doi: 10.1097/00000478-199607000-00012.
  8. Harris NL. Shades of gray between large B-cell lymphomas and Hodgkin lymphomas: differential diagnosis and biological implications. Mod Pathol. 2013;26(Suppl 1):S57–70. doi: 10.1038/modpathol.2012.182.
  9. Kanavaros P, Gaulard P, Charlotte F, et al. Discordant expression of immunoglobulin and its associated molecule mb-1/CD79a is frequently found in mediastinal large B cell lymphomas. Am J Pathol. 1995;146(3):735–41.
  10. Pileri SA, Zinzani PL, Gaidano G, et al. Pathobiology of primary mediastinal B-cell lymphoma. Leuk Lymphoma. 2003;44(Suppl 3):S21–6. doi: 10.1080/10428190310001623810.
  11. Loddenkemper C, Anagnostopoulos I, Hummel M, et al. Differential Emu enhancer activity and expression of BOB.1/OBF.1, Oct2, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas, and Hodgkin lymphomas. J Pathol. 2004;202(1):60–9. doi: 10.1002/path.1485.
  12. De Leval L, Ferry JA, Falini B, et al. Expression of bcl-6 and CD10 in primary Mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells? Am J Surg Pathol. 2001;25(10):1277–82. doi: 10.1097/00000478-200110000-00008.
  13. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 2003;198(6):851–62. doi: 10.1084/jem.20031074.
  14. CopieBergman C, Plonquet A, Alonso MA, et al. MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas. Mod Pathol. 2002;15:1172–80. doi: 10.1097/01.MP.0000032534.81894.B3.
  15. Joos S, Otano-Joos MI, Ziegler S, et al. Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood. 1996;87(4):1571–8.
  16. Feuerhake F, Kutok JL, Monti S, et al. NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood. 2005;106(4):1392–9. doi: 10.1182/blood-2004-12-4901.
  17. Zhang B, Wang Z, Li T, et al. NF-kappaB2 mutation targets TRAF1 to induce lymphomagenesis. Blood. 2007;110(2):743–51. doi: 10.1182/blood-2006-11-058446.
  18. Meier C, Hoeller S, Bourgau C, et al. Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Mod Pathol. 2009;22(3):476–87. doi: 10.1038/modpathol.2008.207.
  19. Rossi D, Cerri M, Capello D, et al. Aberrant somatic hypermutation in primary mediastinal large B-cell lymphoma. Leukemia. 2005;19(12):2363–6. doi: 10.1038/sj.leu.2403982.
  20. Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastial large B-cell lymphoma. Blood. 2011;118(10):2659–69. doi: 10.1182/blood-2011-05-326538.
  21. Martelli M, Di Rocco A, Russo E, et al. Primary mediastinal lymphoma: diagnosis and treatment options. Expert Rev Hematol. 2014;8(2):173–86. doi: 10.1586/17474086.2015.994604.
  22. Eberle FC, Salaverria I, Steidl C, et al. Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. Mod Pathol. 2011;24(12):1586–97. doi: 10.1038/modpathol.2011.116.
  23. Eberle FC, Rodriguez-Canales J, Wei L, et al. Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin’s lymphoma and primary mediastinal large B-cell lymphoma. Haematologica. 2011;96(4):558–66. doi: 10.3324/haematol.2010.033167.
  24. Moller P, Lammler B, Herrmann B, et al. The primary mediastinal clear cell lymphoma of B-cell type has variable defects in MHC antigen expression. Immunology. 1986;59(3):411–7. doi: 10.1007/bf00705408.
  25. Hamlin PA, Portlock CS, Straus DJ, et al. Primary mediastinal large B-cell lymphoma: optimal therapy and prognostic factor analysis in 141 consecutive patients treated at Memorial Sloan Kettering from 1980 to 1999. Br J Haematol. 2005;130(5):691–9. doi: 10.1111/j.1365-2141.2005.05661.x.
  26. Jacobson JO, Aisenberg AC, Lamarre L, et al. Mediastinal large cell lymphoma. An uncommon subset of adult lymphoma curable with combined modality therapy. Cancer. 1988;62(9):1893–8. doi: 10.1002/1097-0142(19881101)62:9<1893::AID-CNCR2820620904>3.0.CO;2-X.
  27. Zinzani PL, Martelli M, Magagnoli M, et al. Treatment and clinical management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients. Blood. 1999;94(10):3289–93.
  28. Bishop PC, Wilson WH, Pearson D, et al. CNS involvement in primary mediastinal large B-cell lymphoma. J Clin Oncol. 1999;17(8):2479–85.
  29. Savage K, Al-Rajhi N, Voss N, et al. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Ann Oncol. 2006;17:123–30. doi: 10.1016/s0360-3016(00)80463-0.
  30. Zinzani PL, Martelli M, Bertini M, et al. Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. Haematologica. 2002;87(12):1258–6. doi: 10.3816/clm.2009.n.074.
  31. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328(14):1002–6. doi: 10.1056/NEJM199304083281404.
  32. Levitt LJ, Aisenberg AC, Harris NL, et al. Primary non-Hodgkin’s lymphoma of the mediastinum. Cancer. 1982;50(11):2486–92. doi: 10.1002/1097-0142(19821201)50:11<2486::AID-CNCR2820501138>3.0.CO;2-G.
  33. Todeschini G, Ambrosetti A, Meneghini V, et al. Mediastinal large-B-cell lymphoma with sclerosis: a clinical study of 21 patients. J Clin Oncol. 1990;8(5):804–8.
  34. Bertini M, Orsucci L, Vitolo U, et al. Stage II large B-cell lymphoma with sclerosis treated with MACOP-B. Ann Oncol. 1991;2(10):733–7.
  35. Falini B, Venturi S, Martelli M, et al. Mediastinal large B-cell lymphoma: clinical and immunohistological findings in 18 patients treated with different third-generation regimens. Br J Haematol. 1995;89(4):780–9. doi: 10.1111/j.1365-2141.1995.tb08415.x.
  36. van Besien K, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma: a review of pathology and management. J Clin Oncol. 2001;19(6):1855–64.
  37. Zinzani PL, Martelli M, Bendandi M, et al. Primary mediastinal large B-cell lymphoma with sclerosis: a clinical study of 89 patients treated with MACOP-B chemotherapy and radiation therapy. Haematologica. 2001;86(2):187–91.
  38. Zinzani PL, Stefoni V, Finolezzi E, et al. Rituximab combined with MACOP-B or VACOP-B and radiation therapy in primary mediastinal large B-cell lymphoma: a retrospective study. Clin Lymph Myel. 2009;9(5):381–5. doi: 10.3816/CLM.2009.n.074.
  39. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408–16. doi: 10.1056/NEJMoa1214561.
  40. Moskowitz CH, Schoder H, Teruya-Feldstein J, et al. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol. 2010;28(11):1896–903. doi: 10.1200/JCO.2009.26.5942.
  41. Savage KJ, Yenson PR, Shenkier T, et al. The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. Blood. 2012;120(Suppl 1–2): Abstract 303.
  42. Martelli M, Ceriani L, Zucca E, et al. [18F]fluorodeoxyglucose positron emission tomography predicts survival after chemoimmunotherapy for primary mediastinal large B-cell lymphoma: results of the International Extranodal Lymphoma Study Group IELSG-26 Study. J Clin Oncol. 2014;32(17):1769–75. doi: 10.1200/JCO.2013.51.7524.
  43. Pinnix CC, Dabaja B, Ahmed MAet al. Single-institution experience in the treatment of primary mediastinal B cell lymphoma treated with immunochemotherapy in the setting of response assessment by 18fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys. 2015;92(1):113–21. doi: 10.1016/j.ijrobp.2015.02.006.
  44. Sehn LH, Antin JH, Shulman LN, et al. Primary diffuse large B-cell lymphoma of the mediastinum: outcome following high-dose chemotherapy and autologous hematopoietic cell transplantation. Blood. 1998;91(2):717–23.
  45. Kuruvilla J, Pintilie M, Tsang R, et al. Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma. Leuk Lymphoma. 2008;49(7):1329–36. doi: 10.1080/10428190802108870.
  46. Hao Y, Chapuy B, Monti S, Sun HH. Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo. Clin Cancer Res. 2014;20(10):2674–83. doi: 10.1158/1078-0432.CCR-13-3007.
  47. Dunleavy K, Wilson W. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? Blood. 2015;125(1):33–9. doi: 10.1182/blood-2014-05-575092.
  48. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–51. doi: 10.1158/1078-0432.CCR-07-4079.

Неходжкинские лимфомы у детей: 25 лет терапии

Т.Т. Валиев, А.В. Попа, А.С. Левашов, Е.С. Беляева, Н.С. Куличкина, Б.В. Курдюков, Р.С. Равшанова, Г.Л. Менткевич

НИИ детской онкологии и гематологии ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Москва, Каширское ш., д. 24, Российская Федерация, 115478

Для переписки: Тимур Теймуразович Валиев, д-р мед. наук, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-98-69; e-mail: timurvaliev@mail.ru

Для цитирования: Валиев Т.Т., Попа А.В., Левашов А.С. и др. Неходжкинские лимфомы у детей: 25 лет терапии. Клиническая онкогематология. 2016;9(4):420–37.

DOI: 10.21320/2500-2139-2016-9-4-420-437


РЕФЕРАТ

Актуальность и цели. Современные программы полихимиотерапии, в основе которых лежит дифференцированный риск-адаптированный подход, позволили рассматривать неходжкинские лимфомы (НХЛ), ранее считавшимися фатальными, как потенциально излечимые заболевания. Цель настоящей работы — обобщение и анализ результатов лечения НХЛ за 25-летний период.

Методы. В исследование включено 246 больных, проходивших лечение в отделении химиотерапии гемобластозов НИИ ДОГ ФГБУ «РОНЦ им. Н.Н. Блохина» МЗ РФ за 25 лет: с 1.04.1991 по 1.06.2016 г. При В-клеточных НХЛ (n = 130) использовались программы B-NHL-BFM 90/95, а также модифицированная программа B-NHL-BFM 95 (включен ритуксимаб). Больным лимфобластным лейкозом (n = 75) лечение проводилось по протоколам ALL-mBFM 90/95 и ALL IC-BFM 2002. При анапластической крупноклеточной лимфоме (АККЛ) 21 больной получил лечение по протоколу B-NHL-BFM 90/95, 20 — по программе НИИ ДОГ-АККЛ-2007.

Результаты. С учетом клинико-иммунологических особенностей АККЛ авторами был разработан оригинальный протокол НИИ ДОГ-АККЛ-2007. Особое внимание уделялось возможности модификации стандартных программ лечения НХЛ из зрелых В-клеток (В-НХЛ) путем включения ритуксимаба. Показана эволюция в назначении ритуксимаба при В-НХЛ и возможность редукции общего числа блоков полихимиотерапии при поздних стадиях опухоли без снижения результатов лечения.

Заключение. Полученные данные позволяют считать, что внедрение достижений онкоиммунологии, молекулярной биологии и цитогенетики станет основой последующей модификации существующих программ терапии НХЛ.


Ключевые слова: лимфома Беркитта, диффузная В-крупноклеточная лимфома, анапластическая крупноклеточная лимфома, первичная медиастинальная (тимическая) В-крупноклеточная лимфома, Т- и В-лимфобластные лимфомы, лечение, дети.

Получено: 12 июня 2016 г.

Принято в печать: 17 июня 2016 г.

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ЛИТЕРАТУРА

  1. 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. 439.
  2. Burkhardt B, Zimmermann M, Oschlies I, et al. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol. 2005;131(1):39–49. doi: 10.1111/j.1365-2005.05735.x.
  3. Hochberg J, Waxman IM, Kelly KM, et al. Adolescent non-Hodgkin lymphoma and Hodgkin lymphoma: state of the science. Br J Haematol. 2009;144(1):24–40. doi: 10.1111/j.1365-2008.07393.x.
  4. Baccarani M, Corbelli G, Amadori S, et al. Adolescent and adult lymphoblastic leukemia: prognostic features outcome of therapy. А study of 293 patients. Blood. 1982;60(3):677–84.
  5. Gill PS, Meyer PR, Pavlova Z, et al. B-cell acute lymphoblastic leukemia in adults: clinical, morphologic and immunologic findings. J Clin Oncol. 1986;4(5):737–43.
  6. Bernstein JI, Coleman CN, Strickler JG, et al. Combined modality therapy for adult with small noncleaved cell lymphoma (Burkitt and Burkitt-like type). J Clin Oncol. 1986;4(6):847–58.
  7. Reiter A, Schrappe M, Tiemann M, et al. Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM-90. Blood. 1999;94(10):3294–306.
  8. Patte C, J. Michon, Frappaz D, et al. Therapy of Burkitt and other B-cell acute lymphoblastic leukaemia and lymphoma: experience with the LMB protocols of the SFOP (French Paediatric Oncology Society) in children and adults. Bail Clin Haematol. 1994;7(2):339–48. doi: 10.1016/s0950-3536(05)80206-
  9. Patte C, Philip T, Rodary C, et al. High survival rate in advanced-stage B-cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: results from the French Pediatric Oncology Society of a randomized trial of 216 children. J Clin Oncol. 1991;9(1):123–32.
  10. Sun XF, Su YS, Liu DG, et al. Comparing CHOP, CHOP+HD-MTX, and BFM-90 regimens in the survival rate of children and adolescents with B cell non-Hodgkin’s lymphoma. Ai Zheng. 2004;23(8):933–8.
  11. Muller J, Csoka M, Jakab Z, et al. Hungarian experience with non-Hodgkin’s lymphoma in childhood. Magy Onkol. 2006;50(3):253–9.
  12. Cairo MS, Sposto R, Gerrard M, et al. Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (³ 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of the FAB LMB 96 study. J Clin Oncol. 2012;30(4):387–93. doi: 10.1200/jco.2010.33.3369.
  13. Schwenn M, Blattner S, Lynch E, et al. HiC-COM: a 2-month intensive chemotherapy regimen for children with stage III and IV Burkitt’s lymphoma and B-cell acute lymphoblastic leukemia. J Clin Oncol. 1991;9(1):133–8.
  14. Bowman WP, Shuster JJ, Cook B, et al. Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric oncology group study. J Clin Oncol. 1996;14(4):1252–61.
  15. Magrath I, Adde M, Shad A, et al. Adults and children with small non-cleaved-cell lymphoma have similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996;14(3):925–34.
  16. Atra A, Gerrard M, Hobson R, et al. Improved cure rate in children with B-cell acute lymphoblastic leukemia and IV stage B-cell non-Hodgkin lymphoma – results of the UKCCSG 9003 protocol. Br J Cancer. 1998;77(12):2281–5. doi: 10.1038/bjc.1998.379.
  17. Burkhardt B, Oschlies I, Klapper W, et al. Non-Hodgkin’s lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia. 2011;25(1):153–60. doi: 10.1038/leu.2010.245.
  18. Patte C, Auperin A, Michon J, et al. The Societe Francaise d’Oncologie Pediatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood. 2001;97(11):3370–9. doi: 10.1182/blood.v97.11.3370.
  19. Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood. 2007;109(7):2773–80. doi: 10.1182/blood-2006-07-
  20. Laver JH, Kraveka JM, Hutchison RE, et al. Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. J Clin Oncol. 2005;23(3):541–7. doi: 10.1200/jco.2005.11.075.
  21. Woessmann W, Seidemann K, Mann G.et al. The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood. 2005;105(3):948–58. doi: 10.1182/blood-2004-03-
  22. Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPAD chemotherapy. Br J Haematol. 2008;141(6):840–87. doi: 10.1111/j.1365-2008.07144.x.
  23. Seidemann K, Tiemann M, Lauterbach I, et al. Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Munster Group. J Clin Oncol. 2003;21(9):1782–19. doi: 10.1200/jco.2003.08.151.
  24. Akbayram S, Dogan M, Akgun C, et al. Use of rituximab in three children with relapsed/refractory Burkitt lymphoma. Target Oncol. 2010;5(4):291–4. doi: 10.1007/s11523-010-0161-
  25. Okur VF, Oguz A, Karadeniz C, et al. Refractoriness to rituximab monotherapy in a child with relapsed/refractory Burkitt non-Hodgkin lymphoma. Pediatr Hematol Oncol. 2006;23(1):25–31. doi: 10.1080/08880010500313298.
  26. Holmberg LA, Maloney D, Bensinger W. Immunotherapy with rituximab/interleukin-2 after autologous stem cell transplantation as treatment for CD20+ non-Hodgkin’s lymphoma. Clin Lymph Myel. 2006;7(2):135–9. doi: 10.3816/clm.2006.n.051.
  27. Cooney-Qualter E, Krailo M, Angiolillo A.et al. A Phase I Study of 90Yttrium-Ibritumomab-Tiuxetan in Children and Adolescents with Relapsed/Refractory CD20-Positive Non-Hodgkin’s Lymphoma: A Children’s Oncology Group study. Clin Cancer Res. 2007;13(Suppl 18):5652–60. doi: 10.1158/1078-ccr-07-1060.
  28. Richard H, Termuhlen A, Smith L, et al. Autologous peripheral blood stem cell transplantation in children with refractory or 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.
  29. Pinkel D, Johnson W, Aur RJ. Non-Hodgkin’s lymphoma in children. Br J Cancer. 1975;2:298–23.
  30. Wollner N, Exelby PR, Lieberman PH. Non-Hodgkin’s lymphoma in children: a progress report on the original patients treated with the LSA2-L2 protocol. Cancer. 1979;44(6):1990–9. doi: 10.1002/1097-0142(197912)44:6<1990::aid-cncr2820440605>3.0.co;2-
  31. Asselin BL, Devidas M, Wang C, et al. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children’s Oncology Group (POG 9404). Blood. 2011;118(4):874–83. doi: 10.1182/blood-2010-06-
  32. Wiernik P, Goldman J, Dutcher J. Neoplastic disease of the blood. Cambridge; 1216 p.
  33. Tubergen D, Krailo M, Meadows A, et al. Comparison of treatment regimens for pediatric lymphoblastic non-Hodgkin’s lymphoma: a Children’s Cancer Group study. J Clin Oncol Leuk. 1999;13(3):335–42.
  34. Amylon MD, Shuster J, Pullen J, et al. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma; Pediatr Oncol Group study. Leukemia. 1999;13(3):335–42. doi: 1038/sj.leu.2401310.
  35. Patte C, Philip T, Rodary C, et al. Improved survival rate in children with stage III-IV B-cell non-Hodgkin lymphoma and leukemia using multiagent chemotherapy: results of a study of 114 children from the French Pediatric Oncology Society. J Clin Oncol. 1986;4(8):1219–26.
  36. Reiter A, Schrappe M, Ludwig WD, et al. Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood. 1992;80(10):2471–8.
  37. Reiter A, Schrappe M, Parwaresch R, et al. Non-Hodgkin’s lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage – a report of the Berlin-Frankfurt-Munster Group. J Clin Oncol. 1995;13(2):359–72.
  38. Nachman J, Sather HN, Cherlow JM, et al. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children’s Cancer Group. J Clin Oncol. 1998;16(3):920–30.
  39. Tang JY, Xue HL, Chen J, et al. Multi-center trial based on SCMC-ALL-2005 for children’s acute lymphoblastic leukemia. Zhonghua Er Ke Za Zhi. 2013;51(7):495–501.
  40. Tallen G, Ratei R, Mann G, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010;28(14):2339–47. doi: 10.1200/jco.2009.25.1983.
  41. Dunsmore KP, Devidas M, Linda SB, et al. Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(22):2753–9. doi: 10.1200/jco.2011.40.8724.
  42. Lambe CU, Averett DR, Paff MT, et al. 2-Amino-6-methoxypurine arabinoside: an agent for T-cell malignancies. Cancer Res. 1995;55(15):3352–6.
  43. Cooper TM, Razzouk BI, Gerbing R, et al. Phase I/II trial of clofarabine and cytarabine in children with relapsed/refractory acute lymphoblastic leukemia (AAML0523): a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2013;60(7):1141–7. doi: 10.1002/pbc.24398.
  44. Schroeder H, Garwicz S, Kristinsson J, et al. Outcome after first relapse in children with acute lymphoblastic leukemia: a population-based study of 315 patients from the Nordic Society of Pediatric Hematology and Oncology (NOPHO). Med Pediatr Oncol. 1995;25(5):372–8. doi: 10.1002/mpo.2950250503.
  45. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favourable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–62. doi: 10.1084/jem.20031074.
  46. Borgmann A, von Stackelberg A, Hartmann R, et al. Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. 2003;101(10):3835–9. doi: 10.1182/blood.v101.10.3835.
  47. Wheeler K, Richards S, Bailey C, et al. Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia. Br J Haematol. 1998;101(1):94–103. doi: 10.1046/j.1365-2141.1998.00676.x.
  48. Stein H, Mason DY, Gerdes J, et al. The expression of Hodgkin’s disease associated antigen Ki-1 in reactive and neoplasic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from avtivated lymphoid cells. Blood. 1985;66(4):848–58.
  49. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-negative. Crit Rev Oncol Hematol. 2013;85(2):206–15. doi: 10.1016/j.critrevonc.2012.06.004.
  50. Sibon D, Fournier M, Briere J, et al. Prognostic Factors and Long Term Outcome of 138 Adults with Systemic Anaplastic Large-Cell Lymphoma: a Retrospective Study by the Groupe d’Etude Des Lymphomes De l’Adulte (GELA). Blood. 2010;116: Abstract 322.
  51. Park SJ, Kim S, Lee DH, et al. Primary Systemic Anaplastic Large Cell Lymphoma in Korean Adults: 11 Years’ Experience at Asan Medical Center. Yonsei Med J. 2008;49(4):601–9. doi: 10.3349/ymj.2008.49.4.601.
  52. Wang YF, Yang YL, Gao ZF, et al. Clinical and laboratory characteristics of systemic anaplastic large cell lymphoma in Chinese patients. J Hematol Oncol. 2012;5(1):38. doi: 10.1186/1756-8722-5-38.
  53. Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood. 2007;110(7):2259–67. doi: 10.1182/blood-2007-04-060715.
  54. Moreno L, Garzon L, Bautista FJ, et al. Diagnosis of paediatric anaplastic large-cell lymphoma: a historical perspective from a single institution. Clin Transl Oncol. 2009;11(5):318–21. doi: 10.1007/s12094-009-0360-
  55. Le Deley MC, Reiter A, Williams D, et al. Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood. 2008;111(3):1560–6. doi: 10.1182/blood-2007-07-
  56. Pillon M, Gregucci F, Lombardi A, et al. Results of AIEOP LNH-97 protocol for the treatment of anaplastic large cell lymphoma of childhood. Pediatr Blood Cancer. 2012;59(5):828–33. doi: 10.1002/pbc.24125.
  57. Gascoyne RD, Aoun P, Wu D, et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood. 1999;93(11):3913–21.
  58. Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral Tcell Lymphoma Project. Blood. 2008;111(12):5496–504. doi: 10.1182/blood-2008-01-
  59. Abramov D, Oschlies I, Zimmermann M, et al. Expression of CD8 is associated with non-common type morphology and outcome in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Haematologica. 2013;98(10):1547–53. doi: 10.3324/haematol.2013.085837.
  60. Damm-Welk C, Mussolin L, Zimmermann M, et al. Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma. Blood. 2014;123(3):334–7. doi: 10.1182/blood-2013-09-
  61. Bonvini P, Gastaldi T, Falini B, et al. Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK+ CD30+ lymphoma cells by Hsp90 antagonist 17-allylamino, 17-demethoxygeldanamycin. Cancer Res. 2002;62(5):1559–66.
  62. Ergin M, Denning MF, Izban KF, et al. Inhibition of tyrosine kinase activity induces caspase-dependent apoptosis in anaplastic large cell lymphoma with NPM-ALK (p80) fusion protein. Exp Hematol. 2001;29(9):1082–90. doi: 10.1016/s0301-472x(01)00688-
  63. Han Y, Amin HM, Franko B, et al. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteasome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. Blood. 2006;108(8):2796–803. doi: 10.1182/blood-2006-04-
  64. Ogura M, Tobinai K, Hatake K, et al. Phase I/II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin’s lymphoma or systemic anaplastic large-cell lymphoma. Cancer Sci. 2014;105(7):840–6. doi: 10.1111/cas.12435.
  65. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472–80. doi: 10.1016/s1470-2045(13)70095-
  66. Brugieres L, Le Deley MC, Rosolen A, et al. Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: a results of a randomized trial of the EICNHL Group. J Clin Oncol. 2009;27(6):897–903. doi: 10.1200/jco.2008.18.1487.
  67. Seidemann K, Tiemann M, Schrappe M, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM 90. Blood. 2001;97(12):3699–706. doi: 10.1182/blood.v97.12.3699.
  68. Woessmann W, Zimmermann M, Lenhard M, et al. Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. J Clin Oncol. 2011;29(22):3065–71. doi: 10.1200/jco.2011.34.8417.
  69. Goldberg JD, Casulo C, Horwitz The role of hematopoietic stem cell transplantation in peripheral T-cell lymphomas. In: Non-Hodgkin Lymphoma Cancer Drug Discovery and Development. Springer; 2013. pp. 279–93. doi: 10.1007/978-1-4614-5851-7_16.
  70. Giulino-Roth L, Ricafort R, Kernan NA, et al. Ten-year follow-up of pediatric patients with non-Hodgkin lymphoma treated with allogeneic or autologous stem cell transplantation. Pediatr Blood Cancer. 2013;60(12):2018–24. doi: 10.1002/pbc.24722.
  71. Woessmann W, Peters C, Lenhard M. Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents – a Berlin-Frankfurt-Munster group report. Br J Haematol. 2006;133(2):176–82. doi: 10.1111/j.1365-2141.2006.06004.x.
  72. Mori T, Takimoto T, Katano N, et al. Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan. Br J Haematol. 2006;132(5):594–7. doi: 10.1111/j.1365-2005.05910.x.
  73. Луговская С.А., Почтарь М.Е., Тупицын Н.Н. Иммунофенотипирование в диагностике гемобластозов. М.: Триада, 2005. 165 с. [Lugovskaya SA, Pochtar’ ME, Tupitsyn NN. Immunofenotipirovanie v diagnostike gemoblastozov. (Immunophenotyping in diagnosis of hemoblastoses.) Moscow: Triada Publ.; 2005. 165 p. (In Russ)]
  74. Курильников А.Я. Мабтера — первые моноклональные антитела в терапии неходжкинских лимфом. Современная онкология. 2002;4(1):25–8. [Kuril’nikov AYa. Mabtera: first monoclonal antibodies in therapy of non-Hodgkin’s lymphomas. Sovremennaya onkologiya. 2002;4(1):25–8. (In Russ)]
  75. Reff M, Carner C, Chambers K, et al. Depletion of B-cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435–45.
  76. Okur FV, Oguz A, Karadeniz C, et al. Refractoriness to rituximab monotherapy in a child with relapsed/refractory Burkitt non-Hodgkin lymphoma. Pediatr Hematol Oncol. 2006;23(1):25–31. doi: 10.1080/08880010500313298.
  77. Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin’s lymphoma. Eur J Haematol. 2007;78(s67):5–14. doi: 10.1111/j.1600-0609.2006.00789.x.
  78. Plosker GL, Figgitt DP. Rituximab. Drugs. 2003;63(8):803–43. doi: 10.2165/00003495-200363080-
  79. Михайлова Н.Б. Роль ритуксимаба в лечении неходжкинских лимфом (реферативный обзор рандомизированных клинических исследований). Современная онкология. 2009;11(3):28–31. [Mikhailova NB. Role of rituximab in treatment of non-Hodgkin’s lymphomas (abstract review of randomized clinical trials). Sovremennaya onkologiya. 2009;11(3):28–31. (In Russ)]
  80. Li X, Liu Z, Cao J, et al. Rituximab in combination with CHOP chemotherapy for the treatment of diffuse large B cell lymphoma in China: a 10-year retrospective follow-up analysis of 437 cases from Shanghai Lymphoma Research Group. Ann Hematol. 2012;91(6):837–45. doi: 10.1007/s00277-011-1375-
  81. Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. 2006;106(7):1569–80. doi: 10.1002/cncr.21776.
  82. Fayad L, Thomas D, Romaguera J. Update of the M. D. Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymph Myel. 2007;8(2):57–62. doi: 10.3816/clm.2007.s.034.
  83. Meinhardt A, Burkhardt B, Zimmermann M, et al. Phase II Window Study on Rituximab in Newly Diagnosed Pediatric Mature B-Cell Non-Hodgkin’s Lymphoma and Burkitt Leukemia. J Clin Oncol. 2010;28(19):3115–21. doi: 10.1200/jco.2009.26.6791.
  84. Bilic E, Femenic R, Conja J, et al. CD20-positive childhood B-non-Hodgkin lymphoma: morphology, immunophenotype and a novel treatment approach: a single center experience. Coll Antropol. 2010;34(1):171–5.
  85. Смирнова Н.В., Мякова Н.В., Белогурова М.Б. и др. Лечение зрелоклеточных В-клеточных неходжкинских лимфом с использованием комбинированной иммунохимиотерапии: возможности оптимизации терапевтической стратегии. Онкогематология. 2015;10(4):15–24. doi: 10.17650/1818-8346-2015-10-4-15-24. [Smirnova NV, Myakova NV, Belogurova MB, et al. Treatment of B-cells non-Hodgkin lymphomas with combined immunochemotherapy: ability to treatment optimization. Oncohematology. 2015;10(4):15–24. doi: 10.17650/1818-8346-2015-10-4-15-24. (In Russ)]
  86. Miyamoto KI, Kobayashi Y, Maeshima AM, et al. Clinicopathological prognostic factors of 24 patients with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Int J Hematol. 2016;103(6):693–702. doi: 1007/s12185-016-1989-z.
  87. Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPAD chemotherapy. Br J Haematol. 2008;141(6):840–7. doi: 10.1111/j.1365-2008.07144.x.
  88. Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood. 2007;109(7):2773–80. doi: 10.1182/blood-2006-07-
  89. Stary J, Zimmermann M, Campbell M, et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014;32(3):174–84. doi: 10.1200/jco.2013.48.6522.
 

Факторы, влияющие на течение и исход хронического лимфолейкоза: данные гематологических стационаров Красноярского края

В.И. Бахтина1,2, И.В. Демко2, А.Н. Наркевич2, Д.С. Гущин3

1 КГБУЗ «Краевая клиническая больница», ул. Партизана Железняка, д. 3, Красноярск, Российская Федерация, 660022

2 ГБОУ ВПО «КрасГМУ им. проф. В.Ф. Войно-Ясенецкого», ул. Партизана Железняка, д. 1, Красноярск, Российская Федерация, 660022

3 КГБУЗ «Норильская межрайонная больница № 1», Солнечный пр-д, д. 7а, Норильск, Российская Федерация, 663300

Для переписки: Варвара Ивановна Бахтина, ул. Партизана Железняка, д. 1, Красноярск, Российская Федерация, 660022; тел. +7(923)357-57-77; е-mail: doctor.gem@mail.ru

Для цитирования: Бахтина В.И., Демко И.В., Наркевич А.Н., Гущин Д.С. Факторы, влияющие на течение и исход хронического лимфолейкоза: данные гематологических стационаров Красноярского края. Клиническая онкогематология. 2016;9(4):413–19.

DOI: 10.21320/2500-2139-2016-9-4-413-419


РЕФЕРАТ

Актуальность и цели. В-клеточный хронический лимфолейкоз (ХЛЛ) — гетерогенное по клиническим проявлениям и биологическим особенностям заболевание. Ко времени первичной диагностики опухоли почти 70 % больных старше 65 лет, большинство из них имеют несколько сопутствующих заболеваний. Цель работы — выявить факторы, влияющие на выживаемость, причины летальности у пациентов с ХЛЛ, по данным гематологических стационаров Красноярского края.

Методы. Для выявления наиболее значимых факторов, влияющих на течение и исход ХЛЛ, проведен ретроспективный анализ данных пациентов, умерших в гематологических стационарах Красноярского края. В течение 6 лет зарегистрировано 45 случаев с летальным исходом. Все пациенты наблюдались у гематолога от времени диагностики заболевания, в течение всего периода лечения и вплоть до летального исхода.

Результаты. Показатели общей и выживаемости без прогрессирования определялись в первую очередь выбором и эффективностью терапии первой линии. Прогрессирование основного заболевания и инфекционные осложнения служили основной причиной летального исхода при ХЛЛ.

Заключение. Большинство больных в качестве терапии первой линии получали неадекватное лечение. Анализ сопутствующих заболеваний демонстрирует возможность проведения таким больным более эффективной противоопухолевой терапии, позволяющей добиться длительных полных ремиссий.


Ключевые слова: хронический лимфолейкоз, онкогематологические заболевания, сопутствующие заболевания, выживаемость, лечение.

Получено: 16 мая 2016 г.

Принято в печать: 17 июня 2016 г.

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ЛИТЕРАТУРА

  1. Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187– doi: 10.1182/blood-2009-08-207126.
  2. Lee JS, Dixon DO, Kantarjian H, et al. Prognosis of chronic lymphocytic leukemia: a multivariate regression analysis of 325 untreated patients. Blood. 1987;69(3):929–36.
  3. Molica S. Infections in chronic lymphocytic leukemia: risks factors and impact on survival and treatment. Leuk Lymphoma. 1994;13(3–4):203–14. doi: 10.3109/10428199409056283.
  4. Albertsen PC, Moore DF, Shih W, et al. Impact of comorbidity on survival among men with localized prostate cancer. J Clin Oncol. 2011;29(10):1335–41. doi: 10.1200/jco.2010.31.2330.
  5. Etienne A, Esterni B, Charbonnier A, et al. Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer. 2007;109(7):1376– doi: 10.1002/cncr.22537.
  6. Kos FT, Yazici O, Civelek B, et al. Evaluation of the effect of comorbidity on survival in pancreatic cancer by using “Charlson Comorbidity Index” and “Cumulative Illness Rating Scale”. Wien Klin Wochenschr. 2014;126(1–2):36– doi: 10.1007/s00508-013-0453-9.
  7. Della Porta MG, Malcovati L. Clinical relevance of extra-hematologic comorbidity in the management of patients with myelodysplastic syndrome. Haematologica. 2009;94(5):602– doi: 10.3324/haematol.2009.005702.
  8. Wang S, Wong ML, Hamilton N, et al. Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans. J Clin Oncol. 2012;30(13):1447–55. doi: 11200/jco.2011.39.5269.
  9. Strati P, Chaffe K, Achenbach S, et al. Comorbidity and cause of death in patients with chronic lymphocytic leukemia (CLL). Cancer Res. 2015;75(15): Abstract 5267. doi: 10.1158/1538-7445.am2015-5267.
  10. Goede V, Paula Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. 2014;99(6):1095–100. doi: 10.3324/haematol.2013.096792.
  11. Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocyticleukemia. Leuk Lymphoma. 2008;49(1):49–56. doi: 10.1080/10428190701724785.
  12. Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc. 1968;16(5):622–6. doi: 10.1111/j.1532-5415.1968.tbx.
  13. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. 2010;376(9747):1164–74. doi: 10.1016/S0140-6736.
  14. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83. doi: 10.1016/0021-9681(87)90171-8.
  15. Anaissie EJ, Kontoyiannis DP, O’Brien S, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129(7):559– doi: 10.7326/0003-4819-129-7-199810010-00010.
  16. Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. 2011;117(11):3016–24. doi: 10.1182/blood-2010-08-304683.
  17. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370(9583):230–9. doi: 10.1016/s0140-6736(07)61125-8.
  18. Bouvet E, Borel C, Oberic L, et al. Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia. 2013;98(1):65–70. doi: 10.3324/haematol.2012.070755.
  19. Miller MD, Paradis CF, Houck PR, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res. 1992;41(3):237–48. doi: 10.1016/0165-1781(92)90005-n.
  20. Parmlee PA, Thuras PD, Katz IR, et al. Validation of Cumulative Index Rating Scale in a geriatric residential population. J Am Geriatr Soc. 1995;43(2):130–7. doi: 10.1111/j.1532-5415.1995.tb06377.x.
  21. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373–83. doi: 1016/0021-9681(87)90171-8.
 

Брентуксимаб ведотин: новые возможности лечения рецидивов и рефрактерных форм лимфомы Ходжкина

Е.А. Демина

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: Елена Андреевна Демина, д-р мед. наук, профессор, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7 (499)324-90-89; e-mail: drdemina@yandex.ru

Для цитирования: Демина Е.А. Брентуксимаб ведотин: новые возможности лечения рецидивов и рефрактерных форм лимфомы Ходжкина. Клиническая онкогематология. 2016;9(4):390–405.

DOI: 10.21320/2500-2139-2016-9-4-398-405


РЕФЕРАТ

Концепция полной излечимости при лимфоме Ходжкина сформулирована еще в 70-е годы прошлого столетия. Тем не менее у 10–30 % больных развиваются рецидивы, кроме того, не исключается резистентное течение опухоли. Высокодозная химиотерапия с аутологичной трансплантацией гемопоэтических стволовых клеток — современный стандарт лечения при рецидивах и рефрактерных формах лимфомы Ходжкина. Однако длительные ремиссии достигаются только у половины этой категории больных. Токсичность эффективных программ терапии первой линии и недостаточная эффективность программ, применяемых при рецидивах и резистентных формах болезни, служат основанием для поиска новых методов лечения этой злокачественной опухоли. Одним из новых подходов к терапии лимфомы Ходжкина стало создание иммуноконъюгата брентуксимаба ведотина. В настоящем обзоре представлены сведения о фармакологии препарата, механизме противоопухолевого действия, а также результаты крупных международных рандомизированных клинических исследований.


Ключевые слова: брентуксимаб ведотин, лимфома Ходжкина, рецидив, лечение.

Получено: 14 июня 2016 г.

Принято в печать: 17 июня 2016 г.

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ЛИТЕРАТУРА

  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.

Современные аспекты диагностики и лечения анапластической крупноклеточной лимфомы у детей (обзор литературы)

А.С. Левашов1, Т.Т. Валиев1, А.М. Ковригина2, А.В. Попа1, Г.Л. Менткевич1

1 ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Москва, Российская Федерация, 115478

2 ФГБУ «Гематологический научный центр» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

Для переписки: Андрей Сергеевич Левашов, научный сотрудник, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(916)233-05-75; e-mail: andreyslevashov@mail.ru

Для цитирования: Левашов А.С., Валиев Т.Т., Ковригина А.М. и др. Современные аспекты диагностики и лечения анапластической крупноклеточной лимфомы у детей (обзор литературы). Клиническая онкогематология. 2016;9(2):199–207.

DOI: 10.21320/2500-2139-2016-9-2-199-207


РЕФЕРАТ

Анапластическая крупноклеточная лимфома (АККЛ) включает различные варианты заболевания, гетерогенные по клиническим, морфологическим, иммунологическим, цитогенетическим и молекулярно-биологическим параметрам. В обзоре не только приведены основные клинические и иммуноморфологические особенности АККЛ, но и представлены данные по экспрессии и прогностической роли STAT3, pSTAT3tyr705, survivin (транскрипционный фактор). Показано значение определения минимальной диссеминированной болезни (минимальная диссеминированная болезнь оценивается перед началом лечения методом ПЦР, минимальная остаточная болезнь — в процессе лечения и после его завершения), обозначены клинические и молекулярно-биологические факторы прогноза. Единой программы терапии АККЛ у детей в настоящее время нет. Однако наиболее эффективными признаются NHL-BFM 90/95, CCG5941, SFOP-LM 89/91, UKCCSG, ALCL99-Vinblastine, POG АРО 9315, AIEOP LNH-92/97. Результаты лечения по этим протоколам представлены в настоящей работе. Отдельное внимание уделяется изучению молекулярно-биологических маркеров, которые открывают путь к дальнейшему совершенствованию стратификации больных на группы риска и возможности применения таргетных препаратов (мультикиназных ингибиторов и моноклональных антител), улучшающих результаты терапии.


Ключевые слова: анапластическая крупноклеточная лимфома, диагностика, лечение, дети.

Получено: 3 февраля 2016 г.

Принято в печать: 10 февраля 2016 г.

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ЛИТЕРАТУРА
  1. Reiter A. Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma. 2007;2007(1):285–96. doi: 10.1182/asheducation-2007.1.285.
  2. Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. 1985;66(4):848–58.
  3. Piccaluga PP, Gazzola A, Mannu C, et al. Pathobiology of Anaplastic Large Cell Lymphoma. Adv Hematol. 2010:345053. doi:10.1155/2010/345053.
  4. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  5. Ковригина А.М., Пробатова Н.А. Лимфома Ходжкина и крупноклеточные лимфомы. М.: МИА, 2007. С. 212.[Kovrigina AM, Probatova NA. Limfoma Khodzhkina i krupnokletochnye limfomy. (Hodgkin’s lymphoma and large cell lymphomas.) Moscow: MIA Publ.; 2007. pp. 212. (In Russ)]
  6. Валиев Т.Т., Морозова О.В., Ковригина А.М. и др. Диагностика и лечение анапластических крупноклеточных лимфом у детей. Гематология и трансфузиология. 2012;51(1):3–9. [Valiev TT, Morozova OV, Kovrigina AM, et al. Diagnosis and treatment of anaplastic large-cell lymphomas in children. Gematologiya i transfuziologiya. 2012;51(1):3–9. (In Russ)]
  7. Lamant L, McCarthy K, d’Amore E, et al. Prognostic Impact of Morphologic and Phenotypic Features of Childhood ALK-Positive Anaplastic Large-Cell. Lymphoma: Results of the ALCL99 Study. J Clin Oncol. 2011;29(35):4669–76. doi: 10.1200/JCO.2011.36.5411.
  8. Calzado-Villarreal L, Polo-Rodriguez I, Ortiz-Romerob PL, et al. Primary Cutaneous CD30+ Lymphoproliferative Disorders. Actas Dermosifiliogr. 2010;101(2):119–28. doi: 10.1016/s1578-2190(10)70598-9.
  9. Brugieres L, Deley MC, Pacquement H, et al. CD30 Anaplastic Large-Cell Lymphoma in Children: Analysis of 82 Patients Enrolled in Two Consecutive Studies of the French Society of Pediatric Oncology. 1998;92(10):3591–8.
  10. Williams DM, Hobson R, Imeson J, et al. Anaplastic large cell lymphoma in childhood: analysis of 72 patients treated on The United Kingdom Children’s Cancer Study Group chemotherapy regimens. Br J Haematol. 2002;117(4):812–20. doi: 10.1046/j.1365-2141.2002.03482.x.
  11. Seidemann K, Tiemann M, Schrappe M, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM 90. 2001;97(12):3699–706. doi: 10.1182/blood.v97.12.3699.
  12. Burkhardt В., Oschlies I, Klapper W, et al. Non-Hodgkin’s lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. 2011;25(1):153–60. doi: 10.1038/leu.2010.245.
  13. Deley MC, Reiter A, Williams D, et al. Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. 2008;111(3):1560–6. doi: 10.1182/blood-2007-07-100958.
  14. Rosolen A, Pillon M, Garaventa A, et al. Anaplastic Large Cell Lymphoma Treated with a Leukemia-Like Therapy: Report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 Protocol. 2005;104(10):2133–40. doi: 10.1002/cncr.21438.
  15. Lowe EJ, Sposto R, Perkins SL, et al. Intensive Chemotherapy for Systemic Anaplastic Large Cell Lymphoma in Children and Adolescents: Final Results of Children’s Cancer Group Study 5941. Pediatr Blood Cancer. 2009;52(3):335–9. doi: 10.1002/pbc.21817.
  16. Laver JH, Kraveka JM, Hutchison RE, et al. Advanced-Stage Large-Cell Lymphoma in Children and Adolescents: Results of a Randomized Trial Incorporating intermediate-Dose Methotrexate and High-Dose Cytarabine in the Maintenance Phase of the APO Regimen: A Pediatric Oncology Group Phase III Trial. J Clin Oncol. 2005;23(3):541–7. doi: 10.1200/jco.2005.11.075.
  17. Pillon M, Gregucci F, Lombardi A, et al. Results of AIEOP LNH-97 Protocol for the Treatment of Anaplastic Large Cell Lymphoma of Childhood. Pediatr Blood Cancer. 2012;59(5):828–33. doi: 10.1002/pbc.24125.
  18. Jacobsen E. Anaplastic Large-Cell Lymphoma, T-/Null-Cell Type. The Oncologist. 2006;11(7):831–40. doi: 10.1634/theoncologist.11-7-831.
  19. Delsoll G, Brugieres L, Gaulard P, et al. Anaplastic large cell lymphoma, ALK-positive and anaplastic large cell lymphoma ALK-negative. Hematol Meet Rep. 2009;3(1):51–7.
  20. Zamo A, Chiarle R, Piva R, et al. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. 2002;21(7):1038–47. doi: 10.1038/sj.onc.1205152.
  21. Weinberg OK, Seo K, Arber DA. Prevalence of bone marrow involvement in systemic anaplastic large cell lymphoma: are immunohistochemical studies necessary? Hum Pathol. 2008;39(9):1331–40. doi: 10.1016/j.humpath.2008.01.005.
  22. Khoury JD, Medeiros LJ, Rassidakis GZ, et al. Differential expression and clinical significance of tyrosine-phosphorylated STAT3 in ALK+ and ALK- Anaplastic Large Cell Lymphoma. Clin Cancer Res. 2003;9:3692–9.
  23. Dourlat J, Liu W-Q, Florence S, et al. A novel non-phosphorylated potential antitumoral peptide inhibits STAT3 biological activity. 2009;91(8):996–1002. doi: 10.1016/j.biochi.2009.05.006.
  24. Schlette EJ, Medeiros LJ, Goy A, et al. Survivin Expression Predicts Poorer Prognosis in Anaplastic Large-Cell Lymphoma. J Clin Oncol. 2004;22(9):1682–8. doi: 10.1200/JCO.2004.10.172.
  25. Nasr MR, Laver JH, Chang M. Expression of Anaplastic Lymphoma Kinase, Tyrosine-Phosphorylated STAT3, and Associated Factors in Pediatric Anaplastic Large Cell Lymphoma. Am J Clin Pathol. 2007;127(5):770–8. doi: 10.1309/fny8y4h6pk1v2mge.
  26. Zhang J, Wang P, Wu F, et al. Aberrant expression of the transcriptional factor twist 1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma. Cell Signalling. 2012;24(4):852–8. doi: 10.1016/j.cellsig.2011.11.020.
  27. Huang W, Li X, Yao X, et al. Expression of ALK protein, mRNA and fusion transcripts in anaplastic large cell lymphoma. Exper Mol Pathol. 2009;86(2):121–6. doi:10.1016/j.yexmp.2008.11.012.
  28. Damm-Welk C, Klapper W, Oschlies I, et al. Distribution of NPM1-ALK and X-ALK fusion transcripts in paediatric anaplastic large cell lymphoma: a molecular-histological correlation. Br J Haematol. 2009;146(3):306–9. doi: 10.1111/j.1365-2141.2009.07754.x.
  29. Ait-Tahar K, Damm-Welk C, Burkhardt B, et al. Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. 2010;115(16):3314–9. doi: 10.1182/blood-2009-11-251892.
  30. Damm-Welk C, Busch K, Burkhardt B, et al. Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK–positive anaplastic large-cell lymphoma. 2007;110(2):670–7. doi: 10.1182/blood-2007-02-066852.
  31. Damm-Welk C, Mussolin L, Zimmermann M, et al. Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma. 2014;123(3):334–7. doi: 10.1182/blood-2013-09-526202.
  32. Jaffe ES. What’s new on the horizon in T-cell lymphoma. [Internet] Available from: http://www.ercongressi.it/t-cell-slide/April%2027,%202015/01.%20T-cell%20world/1%20-%20Jaffe.pdf. (accessed 18.04.2016).
  33. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. 2014;124(9):1473–80. doi: 10.1182/blood-2014-04-571091.
  34. Wrobel G, Mauguen A, Rosolen A, et al. Safety Assessment of Intensive Induction Therapy in Childhood Anaplastic Large Cell Lymphoma: Report of the ALCL99 Randomised Trial. Pediatr Blood Cancer. 2011;56(7):1071– doi: 10.1002/pbc.22940.
  35. Woessmann W, Seidemann K, Mann G, et al. The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM group study NHL-BFM95. 2005;105(3):948–58. doi: 10.1182/blood-2004-03-0973.
  36. Le Deley MC, Rosolen A, Williams DM, et al. Vinblastine in Children and Adolescents With High-Risk Anaplastic Large-Cell Lymphoma: Results of the Randomized ALCL99-Vinblastine Trial. J Clin Oncol. 2010;28(25):3987–93. doi: 10.1200/JCO.2010.28.5999.
  37. Alexander S, Kraveka JM, Weitzman S, et al. Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized Phase III Trial of APO versus a modified regimen with vinblastine: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2014;61(12):2236–42. doi: 10.1002/pbc.25187.
  38. Gross TG, Hale GA, He W, et al. Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant. 2010;16(2):223–30. doi: 10.1016/j.bbmt.2009.09.021.
  39. Brugieres L, Pacquement H, Le Deley MC, et al. Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large-cell lymphoma: a report from the French Society of Pediatric Oncology. J Clin Oncol. 2009;27(30):5056–61. doi: 10.1200/JCO.2008.20.1764.
  40. Mori T, Takimoto T, Katano N, et al. Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan. Br J Haematol. 2005;132(5):594–7. doi: 10.1111/j.1365-2141.2005.05910.x.
  41. Woessmann W, Zimmermann M, Lenhard M, et al. Relapsed or Refractory Anaplastic Large-Cell Lymphoma in Children and Adolescents After Berlin-Frankfurt-Muenster (BFM)-Type First-Line Therapy: A BFM-Group Study. J Clin Oncol. 2011;29(22):3065–71. doi: 10.1200/JCO.2011.34.8417.
  42. Forero-Torres A, Leonard JP, Younes A, et al. A phase II study of SGN30 (anti-CD30 mab) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009;146(2):171–9. doi: 10.1111/j.1365-2141.2009.07740.x.
  43. 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.
  44. Pro B., Advani R, Brice P, et al. Brentuximab Vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6. doi: 10.1200/JCO.2011.38.0402.
  45. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas. N Engl J Med. 2010;363(19):1812–21. doi: 10.1056/NEJMoa1002965.
  46. Mosse YP. Safety and activity of crizotinib for pediatric patients with refractory solid tumors or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472–80. doi: 10.1016/s1470-2045(13)70095-0.
  47. Passerini CG, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst. 2014;106(2):djt37 doi: 10.1093/jnci/djt378.
  48. National Cancer Insitute. A Randomized Phase II study of Brentuximab Vedotin (NSC# 749710) and Crizotinib (NSC# 749005) in Patients with Newly Diagnosed Anaplastic Large Cell Lymphoma (ALCL) IND #117117. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2016 April 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT01979536?term=NCT01979536&rank=1. NLM Identifier: NCT01979536.
  49. Greengard Е, Mosse Y, Liu X, et al. Safety and tolerability of crizotinib in combination with chemotherapy for relapsed or refractory solid tumors or anaplastic large cell lymphoma: a Children’s Oncology Group phase I consortium study. J Clin Oncol. 2015;33(Suppl): Abstract 10058.
  50. Geoerger B. Phase I study of ceritinib (Zycadia) in pediatric patients (Pts) with malignancies harboring a genetic alteration in ALK (ALK+): Safety, pharmacokinetic (PK), and efficacy J Clin Oncol. 2015;33(Suppl): Abstract 10005.
  51. Friboulet L, Li N, Katayama R, et al. The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung cancer. Cancer Discovery. 2014;4(6):662–73. doi: 10.1158/2159-8290.CD-13-0846.

Редкое заболевание — нодулярная лимфома Ходжкина с лимфоидным преобладанием: обзор литературы и собственные наблюдения

Е.А. Демина1, Г.С. Тумян1, А.А. Чекан1, М.Ю. Кичигина1, А.С. Антипова1, Н.А. Пробатова1, А.И. Павловская1, Н.В. Кокосадзе1, А.М. Ковригина2, О.П. Трофимова1, Е.А. Османов1

1 ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина», Каширское ш., д. 24, Москва, Российская Федерация, 115478

2 ФГБУ «Гематологический научный центр» МЗ РФ, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

Для переписки: Е.А. Демина, д-р мед. наук, профессор, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-90-89; e-mail: drdemina@yandex.ru

Для цитирования: Демина Е.А., Тумян Г.С., Чекан А.А., Кичигина М.Ю., Антипова А.С., Пробатова Н.А., Павловская А.И., Кокосадзе Н.В., Ковригина А.М., Трофимова О.П., Османов Е.А. Редкое заболевание — нодулярная лимфома Ходжкина с лимфоидным преобладанием: обзор литературы и собственные наблюдения. Клин. онкогематол. 2014; 7(4): 522–532.


РЕФЕРАТ

Нодулярная лимфома Ходжкина с лимфоидным преобладанием (НЛХЛП) встречается редко и составляет лишь 5 % всех случаев лимфомы Ходжкина (заболеваемость 1,5:1 000 000). От классической лимфомы Ходжкина (кЛХ) заболевание отличается как иммуноморфологическими (выраженная экспрессия CD20 на LP-клетках), так и клиническими характеристиками (значительное преобладание ранних стадий, индолентное течение с поздними рецидивами и тенденцией к трансформации в диффузную В-крупноклеточную лимфому). В связи с ограниченным числом больных во всех проспективных исследованиях НЛХЛП алгоритмы лечения исторически базируются, как правило, на ретроспективных данных, часто заимствованных из программ лечения кЛХ или индолентных В-клеточных лимфом. Больные редко умирают от НЛХЛП, общую смертность определяют преимущественно вторые опухоли и токсичность, связанная с лечением. В последнее десятилетие в целой серии публикаций показано значение ритуксимаба в лечении НЛХЛП как у первичных больных, так и при рецидиве, в т. ч. и в группе с высоким риском трансформации. Кроме того, обсуждается место тактики «наблюдай и жди», лучевой и химиотерапии. Собственный опыт использования ритуксимаба у больных НЛХЛП показал его эффективность при различных стадиях и на разных этапах течения заболевания.


Ключевые слова: нодулярная лимфома Ходжкина с лимфоидным преобладанием, диагностика, клиника, лечение, ритуксимаб.

Принято в печать: 8 сентября 2014 г.

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ЛИТЕРАТУРА

  1. Jackson H., Parker F. Hodgkin’s disease II. Pathology. N. Engl. J. Med. 1944; 231: 35–44.
  2. Lukes R., Butler J., Hicks E. Natural history of Hodgkin’s disease as related to its pathological picture. Cancer. 1966; 19: 317–44.
  3. Harris N.L., Jaffe E.S., Stein H. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994; 84: 1361–92.
  4. Jaffe E.S., Harris N.L., Stein H. et al. Pathology and genetics of tumors of hematopoietic and lymphoid tissues. Lyon: IARC Press, 2001: 240–3.
  5. Swerdlow S.H., Campo E., Harris N.L. et al. (eds.) WHO classification of tumors of hematopoietic and lymphoid tissues. Lyon: IARC Press, 2008.
  6. Diehl V., Sextro M., Franclin J. et al. Clinical presentation, course, and prognostic factors in lymphocyte predominant Hodgkin’s disease: report from European Task Force on Lymphoma (ETFL) Project on lymphocyte-predominant Hodgkin’s disease. J. Clin. Oncol. 1999; 17: 776–83.
  7. Saarinen S., Pukkala E., Vahteristo P. et al. High Familial Risk in Nodular Lymphocyte-Predominant Hodgkin Lymphoma. JCO. 2013; 31(7): 938–43.
  8. Mason D.Y., Banks P.M., Chan J. et al. Nodular lymphocyte-predominant Hodgkin’s disease. A distinct clinicopathological entity. Am. J. Surg. Pathol. 1994; 18: 526–30.
  9. Engert A., Horning S.J. (eds.) Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics (Hematologic Malignancies). Springer, 2011.
  10. Ковригина А.М., Пробатова Н.А. Лимфома Ходжкина и крупнокле- точные лимфомы. Медицинское информационное агентство, 2007. [Kovrigina A.M., Probatova N.A. Limfoma Khodzhkina i krupnokletochnye limfomy. (Hodgkin’s lymphoma and larg cell lymphomas.) Meditsinskoe informatsionnoe agentstvo Publ.; 2007.]
  11. Nogova L., Reineke T., Brillant C. et al. Lymphocyte-predominant and classical Hodgkin’s lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J. Clin. Oncol. 2008; 26: 434–9.
  12. Лимфома Ходжкина. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. Современная онкология. Экстравыпуск. 2013: 11–5. [Poddubnaya I.V., Savchenko V.G., eds. Limfoma Khodzhkina. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Hodgkin’s lymphoma. Russian clinical guidelines in diagnosis and treatment of lymphoproliferative disorders.) Sovremennaya onkologiya. Additional release; 2013. pр. 11–5.]
  13. Fanale M. Lymphocyte-predominant Hodgkin lymphoma: what is the optimal treatment? Hematology (EHA 2013 Education book). 2013: 406–16.
  14. 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: 10962–6.
  15. Marafioti T., Hummel M., Anagnostopoulos I. et al. Origin of nodular lymphocyte-predominant Hodgkin’s disease from a clonal expansion of highly mutated germinal center B-cells. N. Engl. J. Med. 1997; 337(7): 453–8.
  16. Isaacson P.G. Malignant lymphomas with a follicular growth pattern. Histopathology. 1996; 28(6): 487–95.
  17. Brune V., Tiacci E., Pfeil I. et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J. Exp. Med. 2008; 205(10): 2251–68.
  18. Mottok A., Renne C., Willenbrock K. et al. Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAC2 expression and activation of STAT6. Blood. 2007; 110(9): 3387–90.
  19. Schumacher A.M., Schmitz R., Brune V. et al. Mutations in the genes coding for den NJ-kB regulation factors IkBa and A20 are uncommon in nodular lymphocyte-predominant Hodgkin lymphoma. Haematologica. 2010; 95: 153–7.
  20. Liso A., Capello D., Marafiotti T. et al. Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma. Blood. 2006; 108(3): 1013–20.
  21. Rahemtullah A., Reichard K.K., Preffer F.I. et al. A double-positive CD4+CD8+ T-cells population is commonly found in nodular lymphocyte predominant Hodgkin lymphoma. Am. J. Clin. Pathol. 2006; 125(5): 153–7.
  22. Henry-Amar M. Second cancer after treatment for Hodgkin’s disease: a report from the International Database on Hodgkin’s disease. Ann. Oncol. 1992; 3(Suppl. 4): 117.
  23. Saad J., Sirop S.J., Habermann T.M. et al. Diffuse Large B-Cell Transformation in Nodular Lymphocyte Predominant Hodgkin Lymphoma: Incidence, Risk Factors and Outcomes After a Forty-Year Experience From a Single Institution. Blood (ASH Annual Meeting Abstracts). 2012; 120: 1525.
  24. Al-Mansour M., Connors J.M., Gascoyne R.D. et al. Transformation to Aggressive Lymphoma in Nodular Lymphocyte-Predominant Hodgkin’s Lymphoma. J. Clin. Oncol. 2010; 28: 793–9.
  25. Bennett M.H., MacLennan K.A., Vaughan Hudson G. et al. Non-Hodgkin’s lymphoma arising in patients treated for Hodgkin’s disease in the BNLI: A 20- year experience—British National Lymphoma Investigation. Ann. Oncol. 1991; 2(Suppl. 2): 83–92.
  26. Orlandi E., Lazzarino M., Brusamolino E. et al. Nodular lymphocyte predominance Hodgkin’s disease: Long-term observation reveals a continuous pattern of recurrence. Leuk. Lymphoma. 1997; 26: 359–68.
  27. Wickert R.S., Weisenburger D.D., Tierens A. et al. Clonal relationship between lymphocytic predominance Hodgkin’s disease and concurrent or subsequent large-cell lymphoma of B lineage. Blood. 1995; 86: 2312–20.
  28. Hell K., Hansmann M.L., Pringle J.H. et al. Combination of Hodgkin’s disease and diffuse large cell lymphoma: An in situ hybridization study for immunoglobulin light chain messenger RNA. Histopathology. 1995; 27: 491–9.
  29. Greiner T.C., Gascoyne R.D., Anderson M.E. et al. Nodular lymphocytepredominant Hodgkin’s disease associated with large-cell lymphoma: Analysis of Ig gene rearrangements by V-J polymerase chain reaction. Blood. 1996; 88: 657–66.
  30. Sirop S.J., Habermann T.M., Macon W.R. et al. Diffuse Large B-Cell Transformation in Nodular Lymphocyte Predominant Hodgkin Lymphoma: Incidence, Risk Factors and Outcomes After a Forty-Year Experience From a Single Institution. Blood (ASH Annual Meeting Abstracts). 2012; 120(21): Abstract 1525.
  31. Farrell K., Mckay P., Leach M. Nodular Lymphocyte Predominant Hodgkin Lymphoma behaves as a Distinct Clinical Entity with Good Outcome: Evidence from 14 year Follow-up from the West of Scotland Cancer Network. Ann. Oncol. 2011; 22(Suppl. 4): Abstract 291.
  32. Pappa V.I., Norton A.J., Gupta R.K. et al. Nodular type of lymphocyte predominant Hodgkin’s disease. A clinical study of 50 cases. Ann. Oncol. 1995; 6(6): 559–65.
  33. Connors J.M. Lymphocyte predominant Hodgkin’s lymphoma. ASH (Education Program Book). 2001: 1: 187–90.
  34. Borg-Grech A., Radford J.A., Crowther D., Swindell R., Harris M. A comparative study of the nodular and diffuse variants of lymphocytepredominant Hodgkin’s disease. J. Clin. Oncol. 1989; 7(9): 1303–9.
  35. Regula D.P. Jr., Hoppe R.T., Weiss L.M. Nodular and diffuse types of lymphocyte predominance Hodgkin’s disease. N. Engl. J. Med. 1988; 318(4): 214–9.
  36. Crennan E., D’Costa I., Liew K.H. et al. Lymphocyte predominant Hodgkin’s disease: a clinicopathologic comparative study of histologic and immunophenotypic subtypes. Int. J. Radiat. Oncol. Biol. Phys. 1995; 31(2): 333–7.
  37. Hansmann M.L., Zwingers T., Boske A., Loffler H., Lennert K. Clinical features of nodular paragranuloma (Hodgkin’s disease, lymphocyte predominance type, nodular). J. Cancer Res. Clin. Oncol. 1984; 108(3): 321–30.
  38. Bodis S., Kraus M.D., Pinkus G. et al. Clinical presentation and outcome in lymphocyte-predominant Hodgkin’s disease. J. Clin. Oncol. 1997; 15(9): 3060–6.
  39. Pellegrino B., Terrier-Lacombe M.J., Oberlin O. et al. Lymphocytepredominant Hodgkin’s lymphoma in children: therapeutic abstention after initial lymph node resection — a study of the French Society of Pediatric Oncology. J. Clin. Oncol. 2003; 21: 2948–52.
  40. Murphy S.B., Morgan E.R., Katzenstein H.M. et al. Results of little for not treatment for lymphocyte-predominant Hodgkin disease in children and adolescents. J. Pediatr. Hematol. Oncol. 2003; 25: 684–7.
  41. Mauz-Koerholz С., Hasenclever D., Gorde-Grosjean S. et al. Surgical resection alone in children with limited stage lymphocyte predominant Hodgkin’s lymphoma — the experience of the EuroNet-PHL group [abstract]. Blood (ASH Annual Meeting Abstracts). 2006; 108(11): 2470.
  42. Appel B., Ehrich P., Chen L. et al. Treatment of pediatric stage IA lymphocyte-predominant Hodgkin’s lymphoma with surgical resection alone: A report from the Children’s Oncology Group. J. Clin. Oncol. 2012; 30: 9524.
  43. Biasoli I., Stamatoullas A., Meignin V. et al. Nodular, LymphocytePredominant Hodgkin’s Lymphoma. Cancer. 2010; 116: 631–9.
  44. Schlembach P., Wilder R., Jones D. et al. Radiotherapy alone for lymphocyte-predominant Hodgkin’s disease. Cancer J. 2002; 8(5): 377–83.
  45. Wirth A., Yuen K., Barton M. et al. Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: a retrospective multicenter study of the Australian Radiation Oncology Lymphoma Group. Cancer. 2005; 104(6): 1221–9.
  46. Chen R.C., Chin M.S., Ng A.K. et al. Early stage, lymphocyte-predominant Hodgkin’s lymphoma: patient outcomes from a large, single-institution series with long follow-up. J. Clin. Oncol. 2010; 28(1): 136–41.
  47. Nogova L., Reineke T., Eich H.T. et al. Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patient with stage IA lymphocyte-predominant Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG). Ann. Oncol. 2005; 16(10): 1683–7.
  48. Eichenauer D.A., Fuchs M., Pluetschow A. et al. Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2011; 118(16): 4363–5.
  49. Canellos G.P., Mauch P. What Is the Appropriate Systemic Chemotherapy for Lymphocyte-Predominant Hodgkin’s Lymphoma? J. Clin. Oncol. 2010; 28(1): е8.
  50. Fanale M.A., Lai C.M., McLaughlin P. et al. Outcomes of Nodular Lymphocyte Predominant Hodgkin’s Lymphoma (NLPHL) Patients Treated with R-CHOP. Blood (ASH Annual Meeting Abstracts). 2010; 116(21): Abstract 2812.
  51. Advani R.H., Hope R.T. How I treat lymphocyte predominant Hodgkin Lymphoma. Blood. 2013; 122(26): 4182–8.
  52. Karuturi M., Hosing C., Fanale M. et al. High-dose chemotherapy and autologous stem cell transplantation for nodular lymphocyte-predominant Hodgkin lymphoma. Biol. Blood Marrow Transplant. 2013; 19(6): 991–4.
  53. Bierman P., Naushad H., Loberiza F. et al. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) for lymphocyte predominant Hodgkin’s disease [abstract]. Blood. 2006; 108(11): Abstract 3061.
  54. Jackson C., Sirohi B., Cunningham D. et al. Lymphocyte-predominant Hodgkin lymphoma — clinical features and treatment outcomes from a 30-year experience. Ann. Oncol. 2010; 21(10): 2061–8.
  55. Eichenauer D.A., Fuchs M., Pluetschow A. et al. Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2011; 118(16): 4363–5.
  56. Park H.C., Jung S.H., Ahn J.S. et al. Rituximab plus ifosfamide, carboplatin and etoposide for T-cell/histiocyte-rich B-cell lymphoma arising in nodular lymphocyte-predominant Hodgkin’s lymphoma. Case Rep. Oncol. 2012; 5(2): 413–9.
  57. Ekstrand B.C., Lucas J.B., Horwitz S.M. et al. Rituximab in lymphocytepredominant Hodgkin disease: results of a phase 2 trial. Blood. 2003; 101(11): 4285–9.
  58. Schulz H., Rehwald U., Morschhauser F. et al. Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood. 2008; 111(1): 109–11.
  59. Advani R.H., Buggy J.J., Sharman J.P. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/ refractory B-cell malignancies. J. Clin. Oncol. 2013; 31(1): 88–94.
  60. Advani R.H., Horning S.J., Hope RT. et al. Mature results of a Phase II Study of Rituximab Therapy for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. J. Clin. Oncol. 2014; 32(9): 912–8.

Оптимизация диагностики и лечения лимфомы Беркитта у детей, подростков и молодых взрослых

Т.Т. Валиев1, Е.А. Барях2, П.А. Зейналова3, А.М. Ковригина2, С.К. Кравченко2, Т.Н. Обухова2, Н.А. Фалалеева3, А.И. Сендерович3, И.Н. Серебрякова3, И.В. Каминская1, А.C. Левашов1, Г.Л. Менткевич1

1 НИИ детской онкологии и гематологии ФГБУ «РОНЦ им. Н.Н. Блохина» РАМН, Москва, Российская Федерация

2 ФГБУ «Гематологический научный центр» МЗ РФ, Москва, Российская Федерация

3 НИИ клинической онкологии ФГБУ «РОНЦ им. Н.Н. Блохина» РАМН, Москва, Российская Федерация


РЕФЕРАТ

В работе представлен и обобщен опыт ведущих российских онкогематологических клиник. В статье приводятся иммуноморфологические и цитогенетические критерии диагностики лимфомы Беркитта (ЛБ) у детей, подростков и молодых взрослых. Описаны клинические особенности ЛБ в разных возрастных группах. Освещены вопросы лечения ЛБ по современным программами B-NHL-BFM 90/95 и CODOX-M/IVAC. Приводятся результаты лечения по оригинальному отечественному протоколу ЛБ-М-04. Обсуждается место ритуксимаба в терапии ЛБ.


Ключевые слова: лимфома Беркитта, дети, подростки, молодые взрослые, клиника, диагностика, лечение

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ЛИТЕРАТУРА

  1. Kasili E.G. Paediatric malignancy in tropical Africa — a growing concern. East. Afr. Med. J. 1986; 63: 685–6.
  2. Thomas D., Cortes J., O’Brien S. et al. Hyper-CVAD program in Burkitt’s type adult acute lymphoblastic leukemia. J. Clin. Oncol. 1999; 17(8): 2461–70.
  3. Ferry J.A. Burkitt’s Lymphoma: Clinicopathologic Features and Differential Diagnosis. Oncologist 2006; 11: 375–83.
  4. Swerdlow S.H., Campo E., Lee H.N. et al. WHO Classification of Tumours of Haematopoetic and Lymphoid tissues, 4th edn. Lyon: IARC Press, 2008: 439.
  5. Agugua N.E., Okeahialam T. Malignant diseases of childhood seen at the University of Nigeria Teaching Hospital, Enugu, Nigeria. East. Afr. Med. J. 1986; 63: 717–23.
  6. Oguonu T., Emodi E., Kaine W. Epidemiologie of Burkitt’s lymphoma in Enugu, Nigeria. Ann. Trop. Paediatr. 2002; 22: 369–74.
  7. Amusa Y.B., Adediran I.A., Akinpelu V.O. et al. Burkitt’s lymphoma of the head and neck region in a Nigeria tertiary hospital. East. Afr. J. Med. 2005; 24(3): 139–42.
  8. Kittivorapart J., Chinthammitr Y. Incidence and risk factors of bone marrow involvement by non-Hodgkin lymphoma. J. Med. Assoc. Thai. 2011; 94(Suppl. 1): S239–45.
  9. Барях Е.А., Кравченко С.К., Обухова Т.Н. и др. Лимфома Беркитта: клиника, диагностика, лечение. Клин. онкогематол. 2009; 2(2): 137–46. [Baryakh Ye.A., Kravchenko S.K., Obukhova T.N., et al. Burkitt’s lymphoma: clinical presentation, diagnosis, management. Klin. onkogematol. 2009; 2(2): 137–47. (In Russ.)].
  10. Blum K.A., Lozansky G., Byrd J. Adult Burkitt’s leukemia and lymphoma. Blood 2004; 20: 32–7.
  11. Braziel R.M., Arber D.A., Slovac M.L. et al. The Burkitt-like lymphoma: a Southwest Oncologie Group study delineating phenotypic, genotypic and clinical features. Blood 2001; 97(12): 3713–20.
  12. Martinez-Maza O., Breen E.C. B-cell activation and lymphoma in patients with HIV. Curr. Opin. Oncol. 2002; 14: 528–32.
  13. Magrath I.T. Malignant Non-Hodgkin’s Lymphomas in Children. Pediatr. Oncol. 2002; 119: 661–705.
  14. Zeigler J. Burkitt’s lymphoma. N. Engl. J. Med. 1981; 305: 735–45.
  15. Kelly G., Bell A., Rickinson A. Epstein-Barr virus-associated Burkitt lymphoma genesis selects for down-regulation of the nuclear antigen EBNA2. Nat. Med. 2002; 8(10): 1098–104.
  16. Гурцевич В.Э. Роль вируса Эпштейна—Барр в онкогематологиче- ских заболеваниях человека. Клин. онкогематол. 2010; 3(3): 222–35. [Gurtsevich V.E. Role of Epstein—Barr virus in human hematological malignancies. Klin. onkogematol. 2010; 3(3): 222–35. (In Russ.)].
  17. Magrath I. Epidemiology: clues to the pathogenesis of Burkitt lymphoma. Br. J. Haematol. 2012; 156(6): 744–56.
  18. Croce C. Role of chromosome translocations in human neoplasia. Cell 1987; 49(2): 155–6.
  19. Zech L., Haglund U., Nilsson K., Klein G. Characteristic chromosomal abnormalities in biopsies and lymphoid-cell lines from patients with Butkitt and non-Burkitt lymphomas. Int. J. Cancer 1976; 17: 47–56.
  20. Обухова Т.Н., Барях Е.А., Капланская И.Б. и др. Выявление диагности- ческих для лимфомы Беркитта транслокаций методом флюоресцентной in situ гибридизации на гистологических срезах парафиновых блоков. Тер. арх. 2007; 79(7): 80–3. [Obukhova T.N., Baryakh Ye.A., Kaplanskaya I.B., et al. Detection of translocations typical for Burkitt’s lymphoma using fluorescent hydrydization in situ in histological slices from paraffin blocks. Ter. arkh. 2007; 79(7): 80–3. (In Russ.)]
  21. Green T.M., Nielsen O., de Stricker K. et al. High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma. Am. J. Surg. Pathol. 2012; 36(4): 612–9.
  22. Ben-Neriah S., Woods R., Steidl C. et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009; 114: 2273–9.
  23. Tagawa H., Ikeda S., Sawada K. Role of microRNA in the pathogenesis of malignant lymphoma. Cancer Sci. 2013; 10; 121–6.
  24. Mead G.M., Sydes M.R., Walewski J. et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann. Oncol. 2002; 13(8): 1264–74.
  25. Costa L.J., Xavier A.C., Wahlquist A.E. еt al. Trends in survival of patients with Burkitt lymphoma/leukemia in the USA: an analysis of 3691 cases. Blood 2013; 121(24): 4861–6.
  26. Fayad L., Thomas D., Romaguera J. Update of the M.D.Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin. Lymph. Myel. 2007; 8(2): 57–62.
  27. Rizzieri D.A., Johnson J.L., Byrd J.C. et al. Efficacy and toxicity of rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or Burkitt-like leukemia/lymphoma: Cancer and Leukemia Group B (CALGB) Study 10002 (abstract). Blood 2010; 116: Abstract 858.
  28. Dunleavy K., Pittaluga S., Wayne A.S. et al. MYC+ aggressive B-cell lymphomas: A novel therapy of untreated Burkitt lymphoma (BL) and MYC+ diffuse large B-cell lymphoma (DLBCL) with DA-EPOCH-R (abstract). Ann. Oncol. 2011; 22(4): Abstract 71.
  29. Griffin T.C., Weitzman S., Weinstein H. et al. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/ refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: A report from the Childrens Oncology Group. Pediatr. Blood Cancer 2009; 52: 177–81.
  30. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Медиа Медика, 2013: 102. [Rossiyskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevaniy. Pod red. I.V. Poddubnoy, V.G. Savchenko (Russian clinical guidelines for diagnosis and treatment of lymphoproliferative disorders. Ed. by: I.V. Poddubnaya, V.G. Savchenko) M.: Media Medika, 2013: 102.]
  31. Барях Е.А., Валиев Т.Т., Яцков К.В. и др. Интенсивная терапия лимфомы Беркитта: описание двух клинических случаев. Гематол. и транс- фузиол. 2007; 52(1): 41–3. [Baryakh Ye.A., Valiyev T.T., Yatskov K.V., et al. Intensive therapy for Burkitt’s lymphoma: presentation of two clinical cases. Gematol. i transfuziol. 2007; 1: 41–3. (In Russ.)].
  32. Барях Е.А., Звонков Е.Е., Кременецкая А.М. Лечение беркиттопо- добной лимфомы взрослых. Тер. арх. 2006; 7: 53. [Baryakh Ye.A., Zvonkov Ye.Ye., Kremenetskaya A.M. Management of adult Burkitt-like lymphoma. Ter. arkh. 2006; 7: 53. (In Russ.)].
  33. Rosenfeld A., Arrington D., Miller J. et al. A review of childhood and adolescent craniopharyngiomas with particular attention to hypothalamic obesity. Pediatr. Neurol. 2014; 50(1): 4–10. doi: 10.1016/j.pediatrneurol.2013.09.003. Epub 2013 Nov 1.
  34. Senerchia A.A., Ribeiro K.B., Rodriguez-Galindo C. Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: A population-based study. Pediatr. Blood Cancer 2014; 61(2): 211–6. doi: 10.1002/pbc.24639. Epub 2013 Oct 30.
  35. Тур А.Ф., Тарасов О.Ф., Шабалов Н.П. и др. Детские болезни, 2-е изд. М.: Медицина, 1985. [Tur A.F., Tarasov O.F., Shabalov N.P., et al. Detskiye bolezni, 2-e izd. (Pediatric disorders. 2nd ed.) M.: Meditsina, 1985]
  36. Bleyer A., Viny A., Barr R. Cancer in 15- to 29-year-olds by primary site. Oncologist 2006; 11(6): 590–601.
  37. Bleyer A. Young adult oncology: the patients and their survival challenges. СА Cancer J. Clin. 2007; 57(4): 242–55.
  38. Wood W.A., Lee S.J. Malignant hematologic diseases in adolescents and young adults. Blood 2011; 117: 5803–15.
  39. Sandlund J.T. Should adolescents with NHL be treated as old children or young adults? Hematol. Am. Soc. Hematol. Educ. Progr. 2007; 2007(1): 297–303.
  40. Cairo M.S., Sposto R., Gerrard M. et al. Advanced stage, increased, lactate dehydrogenase, and primary site, but not adolescent age (³ 15 years)are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkins lymphoma: results of FAB LMB 96 Study. J. Clin. Oncol. 2012; 30(4): 387–93.
  41. Coiffier B. State-of-the-art therapeutics: diffuse large B-cell lymphoma. J. Clin. Oncol. 2005; 23(26): 6387–93.
  42. Pfreundschuh M., Trumper L., Osterborg A. et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good prognosis diffuse large B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MinT). Lancet Oncol. 2006; 7(5): 379–91.

Множественная миелома (лечение рецидивов и рефрактерных форм): обзор литературы и собственные данные. Часть III

С.С. Бессмельцев

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург, Российская Федерация


РЕФЕРАТ

Использование новых подходов в лечении рецидивов/рефрактерных форм множественной миеломы (ММ) привело к существенному увеличению общей выживаемости больных, достижению качественного ответа и более длительной ремиссии по сравнению с пациентами, получавшими стандартную химиотерапию. Эти изменения связаны главным образом с применением новых препаратов: бортезомиба, талидомида, леналидомида, каждый из которых обладает выраженной противомиеломной активностью. Бортезомиб, талидомид и леналидомид используются в комбинации как с химиотерапевтическими препаратами, так и друг с другом, что существенно повышает эффективность лечения больных ММ. Однако, если больные не отвечают на бортезомиб и иммуномодуляторы, прогноз ухудшается. В настоящее время число препаратов, которые используются при ММ, достаточно большое, причем спектр их все более расширяется. Тем не менее результаты лечения больных с рецидивами/рефрактерными формами ММ не вполне удовлетворительные, что свидетельствует о трудностях разработки эффективных лекарственных средств. Появилось большое количество препаратов второго и третьего поколений, которые становятся все более доступными для клинического применения. Проводятся клинические исследования I, II и III фаз по оценке эффективности карфилзомиба, помалидомида, вориностата, панобиностата, ромидепсина, перифосина, танеспимицина, бендамустина и элотузумаба при рецидивах/рефрактерных формах ММ. В обзоре представлены современные подходы к ведению пациентов с рецидивами и рефрактерным течением ММ, основанные на результатах клинических исследований и собственных данных, целью которых было оптимизировать результаты лечения. Представлена эффективность различных классов новых лекарственных средств, обсуждены все «за» и «против», полученные в доклинических и клинических исследованиях. Подробно освещены побочные эффекты новых препаратов.


Ключевые слова: множественная миелома, рецидив, рефрактерное течение, бортезомиб, талидомид, леналидомид, карфилзомиб, помалидомид, лечение, полная ремиссия, общая выживаемость, нейропатия.

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ЛИТЕРАТУРА

  1. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома. Современный взгляд на проблему. Алматы: Коста, 2007. [Bessmeltsev S.S., Abdulkadyrov K.M. Mnozhestvennaya miyeloma. Sovremennyy vzglyad na problemu (Multiple myeloma. Current view of the problem). Almaty: Kosta, 2007.]
  2. Harousseau J.L., Shaughnessy J.Jr., Richardson P. Multiple myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2004: 237–56.
  3. Stewart A.K. Novel therapies for relapsed myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2009: 555–65.
  4. Podar K., Tai Y.T., Hideshima T. et al. Emerging therapies for multiple myeloma. Expert. Opin. Emerg. Drugs 2009; 14: 99–127.
  5. Ругаль В.И., Бессмельцев С.С., Семенова Н.Ю. и др. Структурные особенности паренхимы и стромы костного мозга больных множественной миеломой. Medline.ru. 2012; 13: 515–23. [Rugal V.I., Bessmeltsev S.S., Semenova N.Yu., et al. Structural features of bone marrow parenchyma and stroma in patients with multiple myeloma. Medline.ru. 2012; 13: 515–23. (In Russ.)].
  6. Morgan G.J., Kaiser M.F. How to use new biology to guide therapy in multiple myeloma. ASH Educ. Book 2012; 2012(1): 342–9.
  7. Morgan G.J., Gregory W.M., Davies F.E. et al.; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 2012; 119(1): 7–15.
  8. Fonseca R., Debes-Marun C.S., Picken E.B. et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 2003; 102(7): 2562–67.
  9. Hideshima T., Bergsagel P.L., Kuehl W.M., Anderson K.C. Advances in biology of multiple myeloma: clinical applications. Blood 2004; 104: 607–18.
  10. Rajkumar S.V., Harousseau J.-L., Durie B. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. Prepublished online Feb 3, 2011; doi: 10.1182/blood-2010-10-299487.
  11. Lonial S. Treatment of relapsed and refractory multiple myeloma. Hematol. Educ. Ann. Congr. Eur. Hematol. Assoc. 2013; 7: 216–26.
  12. Kumar S.K., Lee J.H., Lahuerta J.J. et al. Risk of progression and survival in multiple myeloma relapsed after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012; 26: 149–57.
  13. Durie B.G.M., Harousseau J.-L., Miguel J.S. et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 1467–73.
  14. Anderson K.C., Kyle R.A., Rajkumar S.V. et al. Clinically relevant end points and new drug approvals for myeloma. Leukemia 2008; 22(2): 231–9.
  15. Niesvizky R., Richardson P.G., Rajkumar S.V. et al. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br. J. Haematol. 2008; 143(1): 46–53.
  16. Dimopoulos M., Kyle R., Fermand J.-P. et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011; 117(18): 4701–5.
  17. Avet-Loiseau H. Ultra high-risk myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2010; 2010: 489–93.
  18. Mohty B., El-Cheikh J., Yakoub-Agha I. et al. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents. Leukemia 2012; 26: 73–85.
  19. Kumar S., Mahmood S.T., Lacy M.Q. et al. Impact of early relapse after auto-SCT for multiple myeloma. Bone Marrow Transplant. 2008; 42: 413–20.
  20. Kroger N., Perez-Simon J.A., Myint H. et al. Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose reduced allogeneic stem cell transplantation in patients multiple myeloma. Biol. Blood Marrow Transplant. 2004; 10: 698–708.
  21. Kroger N., Shimoni A., Schilling G. et al. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. Br. J. Haematol. 2009; 148: 323–31.
  22. Garban F., Attal M., Michaller M. et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in highrisk de novo multiple myeloma. Blood 2006; 107: 3474–80.
  23. Lonial S. Relapsed multiple myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2010: 303–9.
  24. Mikhael J.R., Goodwin J., Qi X. et al. p53 Deletion Yields High Response Rates but Rapid Progression and Poor Overall Survival in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation. ASH Ann. Meet. Abstr. 2007; 110: 953.
  25. Kaufman J., Nooka A., Muppidi S. et al. Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM). ASCO Ann. Meet. Abstr. 2012: 8100.
  26. Blade J., Samson D., Reece D. et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br. J. Haematol. 1998; 102(5): 1115–23.
  27. Alexanian R., Barlogie B., Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann. Intern. Med. 1986; 105: 8–11.
  28. Gertz M.A., Garton J.P., Greipp P.R., Witzig T.E., Kyle R.A. A phase II study of high-dose methylprednisolone in refractory or relapsed multiple myeloma. Leukemia 1995; 9: 2115–8.
  29. Barlogie B., Smith L., Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N. Engl. J. Med. 1984; 310: 1353–6.
  30. Anderson H., Scarffe J.H., Ranson M. et al. VAD chemotherapies remission induction for multiple myeloma. Br. J. Cancer 1995; 71: 326–30.
  31. Phillips J.K., Sherlaw-Johnson C., Pearce R. et al. A randomized study of MOD versus VAD in the treatment of relapsed and resistant multiple myeloma. Leuk. Lymphoma 1995; 17: 465–72.
  32. Durie B.G., Dixon D.O., Carter S. et al. Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study. J. Clin. Oncol. 1986; 4: 1227–37.
  33. Giles F.J., Wickham N.R., Rapoport B.L. et al. Cyclophosphamide, etoposide, vincristine, adriamycin, and dexamethasone (CEVAD) regimen in refractory multiple myeloma: an International Oncology Study Group (IOSG) phase II protocol. Am. J. Hematol. 2000; 63: 125–30.
  34. Munshi N., Desikan K., Jagannath S. et al. Dexamethasone, cyclophosphamide, etoposide and cisplatinum (DCEP), an effective regimen for relapse after high-dose chemotherapy and autologous transplantation. Blood 1996; 88: Abstract 586a.
  35. Passweg J.R., Baldomero H., Bregni M. et al. Hematopoietic SCT in Europe: date and trends in 2011. Bone Marrow Transplant. Advance online publication 15 April 2013; doi: 10.1038/bmt.2013.51.
  36. Бессмельцев С.С., Абдулкадыров К.М. Возможности применения производных нитрозометилмочевины и вепезида в химиотерапии множе- ственной миеломы и злокачественных лимфом. Совр. онкол. 2002; 1: 25–9.  [Bessmeltsev S.S., Abdulkadyrov K.M. Potentials use of nitrosourea derivatives and VePesid in chemotherapy for multiple myeloma and malignant lymphomas. Sovr. onkol., 2002; 1: 25–9. (In Russ.)].
  37. Parameswaran R., Giles C., Boots M. et al. CCNU (lomustin), idsrubicin and dexamethasone (CIDEX): an effective oral regimen for the treatments of refractory or relapsed myeloma. Br. J. Haematol. 2000; 109: 571–5.
  38. Abdulkadyrov K.M., Bessmeltsev S.S. Use of VCAP, ARA-COP and VAD schedules in treatment of patients with multiple myeloma (MM). XVI International Cancer Congress. New Delhi (India), 1994: Abstract NA-02807.
  39. Бессмельцев С.С., Абдулкадыров К.М., Рукавицын О.А. Эффектив- ность некоторых программ полихимиотерапии при лечении больных множественной миеломой. Tер. арх. 1998; 3: 46–9. [Bessmeltsev S.S., Abdulkadyrov K.M., Rukavitsyn O.A. Efficacy of some polychemotherapy programs in management of patient with multiple myeloma. Ter. arkh., 1998; 3: 46–9. (In Russ.)].
  40. Бессмельцев С.С., Стельмашенко Л.В. Сравнительная оценка раз- личных методов лечения больных с множественной миеломой. Эфферент. тер. 2000; 2: 54–63. [Bessmeltsev S.S., Stelmashenko L.V. Comparative evaluation of various therapeutic methods in patients with multiple myeloma. Efferent. ter. 2000; 2: 54–63. (In Russ.)].
  41. Mohrbacher A.F., Gregory S.A., Gabriel D.A. et al. Liposomal daunorubicin (DaunoXome) plus dexamethasone for patients with multiple myeloma. A phase II International Oncology Study Group study. Cancer 2002; 94: 2645–52.
  42. Alexanian R., Dimopoulos M.A., Hester I. et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84(12): 4278–82.
  43. Pulsoni A., Villiva N., Cavalieri E. et al. Continuous low dose of melphalan and prednisone in patients with multiple myeloma of very old age or severe associated disease. Drugs Aging 2002; 19: 947–53.
  44. Бессмельцев С.С., Абдулкадыров К.М. a-2а-интерферон (Реаферон) в лечении больных множественной миеломой. Вопр. онкол. 1999; 4: 393–7. [Bessmeltsev S.S., Abdulkadyrov K.M. a-2a-interferon (Reaferon) in management of patients with multiple myeloma. Vopr. onkol., 1999; 4: 393–7. (In Russ.)].
  45. Joshua D.E., Penny R., Matthews J.P. et al. Australian Leukemia Study Group myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma. Br. J. Haematol. 1997; 97: 38–45.
  46. Gertz M.A., Kalish L.A., Kyle R.A. et al. Phase III study comparing vincristine, doxorubicine (Adriamycin), and dexamethasone (VAD) chemotherapy with VAD plus recombinant interferon alfa-2 in refractory or relapsed multiple myeloma. An Eastern Cooperative Oncology Group study. Am. J Clin. Oncol. 1995; 18: 475–80.
  47. Peest D. The role of alpha-interferon in multiple myeloma. Pathol. Biol. (Paris) 1999; 47(2): 172–7.
  48. Бессмельцев С.С., Абдулкадыров К.М. Эффективность циклоспорина А при рефрактерных формах множественной миеломы и рецидиве заболевания. Актуальные вопросы гематологии и трансфузиологии. Мат-лы Рос. науч.-практ. конф., посвященной 70-летию Российского НИИ гематологии и трансфузиологии, Санкт-Петербург, 18–20 июня 2002 г. СПб., 2002: 98. [Bessmeltsev S.S., Abdulkadyrov K.M. Effektivnost tsiklosporina A pri refrakternykh formakh mnozhestvennoy mielomy i retsidive zabolevaniya. Aktualnye voprosy gematologii i transfuziologii. Mat-ly Ros. nauch.-prakt. konf., posvyashchennoy 70-letiyu Rossiyskogo NII gematologii i transfuziologii, (Efficacy of cyclosporine A in refractory forms and relapses of multiple myeloma. Current issues in hematology and transfusiology. In: Materials of Rus. scient.-pract. conference dedicated to 70th anniversary of the Russian Research Institute of Hematology and Transfusiology. Saint Petersburg, June 18-20, 2002, St. Petersburg, 2002: 98.]
  49. Бессмельцев С.С., Абдулкадыров К.М. Современные принципы лечения больных множественной миеломой. Гематол. i трансфузiол.: фунд. та приклад. пит. Мат-лы науч.-практ. конф., Киев, 13–14 октября 2005 г. Киев, 2005: 21–3. [Bessmeltsev S.S., Abdulkadyrov K.M. Sovremennye printsipy lecheniya bolnykh mnozhestvennoy mielomoy. Gematol. i transfuziol.: fund. ta priklad. pit. Mat-ly nauch.-prakt. konf. (Current principles of management of patients with multiple myeloma. Hematol. and transfuiol.: fund. and pract. issues. In: Material of scient.-pract. conference, Kiev, October 13-14, 2005), Kiev, 2005: 21–3.]
  50. Schwarzenbach H. Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. Med. Oncol. 2002; 19: 87–104.
  51. Uchiyama-Kokubu N., Watanabe T., Nakajima M. A bioassay for the activity of PSC 833 in human serum for modulation of P-glycoprotein-mediated multidrug resistance. Anticancer Drugs 2000; 11: 583–90.
  52. Koskela K., Pelliniemi T.T., Pulkki K., Remes K. Treatment of multiple myeloma with all-trans retinoic acid alone and in combination with chemotherapy: a phase I/II trial. Leuk. Lymphoma 2004; 45: 749–54.
  53. Singhal S., Mehta J., Desikan R. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 1999; 341: 1565–71.
  54. Barlogie B., Desikan R., Eddlemon P. et al. Extended survival in advanced and refractory multiple myeloma after single agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98: 492–4.
  55. Kumar S., Gertz M.A., Dispenzieri A. et al. Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin. Proc. 2003; 78: 34–9.
  56. Yakoub-Agha I., Mary J., Hulin C. et al. Low-dose vs. high-dose thalidomide for advanced multiple myeloma: A prospective trial from the Intergroupe Francophone du Myelome. Eur. J. Haematol. 2012; 88: 249–5.
  57. Neben K., Moehler T., Benner A. et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin. Cancer Res. 202; 8: 3377–80.
  58. Glasmacher A., Hahn C., Hoffmann F. et al. A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br. J. Haematol. 2006; 132: 584–93.
  59. Kropff M., Baylon H.G., Hillengass J. et al. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial. Haematologica 2012; 97(5): 784–91.
  60. Mileshkin L., Stark R., Day B. et al. Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J. Clin. Oncol. 2006; 24: 4507–14.
  61. Richardson P., Schlossman R., Jagannath S. et al. Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin. Proc. 2004; 79: 875–82.
  62. Dimopoulos M.A., Zervas K., Kouvatseas G. et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann. Oncol. 2001; 12: 991–5.
  63. Weber D. Thalidomide: a wide spectrum of activity. Myeloma Focus. Newslett. Multiple Myel. Res. Found. 2002; IV: 4.
  64. Palumbo A., Bertola A., Falco P. et al. Efficacy of low dose thalidomide as first salvage regimen in multiple myeloma. Hemat. J. 2004; 5: 318–24.
  65. Fermand J.P., Jaccard A., Macro M. et al. A randomized comparison of dexamethasone + thalidomide (Dex/Tal) vs Dex + Placebo (Dex/P) in patients (pts) with relapsing multiple myeloma (MM). Blood 2006; 108: Abstract 3563.
  66. Offidani M., Corvatta L., Marconi M. et al. Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma. Hematol. J. 2004; 5: 312–7.
  67. Palumbo A., Avonto I., Bruno B. et al. Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur. J. Hematol. 2006; 76: 273–7.
  68. Srakovic G., Elson P., Trebisky B. et al. Use of melphalan, thalidomide and dexamethasone in treatment of refractory and relapsed multiple myeloma. Med. Oncol. 2002; 19: 219–26.
  69. Kyriakou C., Thomson K., D’Sa S. et al. Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br. J. Haematol. 2005; 29: 763–5.
  70. Dimopoulos M.A., Hamilos G., Zomas A. et al. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regiment for previously treated patients with multiple myeloma. Hematol. J. 2004; 5: 112–7.
  71. Kropff M.N., Lang N., Bisping G. et al. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCTD) in primary refractory or relapsed multiple myeloma. Br. J. Haematol. 2003; 122: 607–16.
  72. Garcia-Sanz R., Gonzales-Porras H.R., Hermandez J.M. et al. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004; 18: 856–63.
  73. Offidani M., Corvatta L., Marconi M. et al. Low dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/ refractory multiple myeloma: a prospective, multicenter, phase II study. Haematologica 2006; 91: 133–6.
  74. Hussein M.A., Baz R., Srkalovic G. et al. Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin. Proc. 2006; 81: 889–95.
  75. Husseun M.A. Thromboembalism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations. Tromb. Haemost. 2006; 95: 924–30.
  76. Pineda-Roman M., Zangari M., van Rhee F. et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia 2008; 22: 1419–27.
  77. Biehn S.E., Moore D.T., Voorhees P.M. et al. Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin. Ann. Hematol. 2007; 86: 211–6.
  78. Reece D.E., Rodriguez G.P., Chen C. et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J. Clin. Oncol. 2008; 26(29): 4777–83.
  79. Garderet L., Iacobelli S., Moreau P. et al. Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J. Clin. Oncol. 2012; 30: 2475–82.
  80. Richardson P.G., Schlossman R.L., Weller E. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100(9): 3063–7.
  81. Richardson P.G., Blood E., Mitsiades C.S. et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006; 108: 3458–64.
  82. Weber D., Knight R., Chen C. et al. Prolonged Overall Survival with Lenalidomide Plus Dexamethasone Compared with Dexamethasone Alone in Patients with Relapsed or Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2007; 110: 412.
  83. Dimopoulos M., Spencer A., Attal M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 2007; 357: 2123–32.
  84. Reece D.E., Masih-Khan E., Chen C. et al. Lenalidomide (Revlimid) +/- corticosteroids in elderly patients with relapsed/refractory multiple myeloma. Blood (ASH Ann. Meet. Abstr.); 2006; 108: Abstract 3550.
  85. Dimopoulos M.A., Chen C., Spencer A. et al. Long-term follow-up on overall survival from the MM-009 and MM-010 Phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009; 23(11): 2147–52.
  86. Wang M., Dimopoulos M.A., Chen C. et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 2008; 112(12): 4445–51.
  87. Stadtmauer E., Weber D., Dimopoulos M. et al. Lenalidomide in combination with dexamethasone is more effective than dexamethasone at first relapse in relapsed multiple myeloma. Blood (ASH Ann. Meet. Abstr.). 2006; 108: Abstract 3552.
  88. Chanan-Khan A.A., Yu Z., Weber D. et al. Lenalidomide (L) in combination with dexamethasone (D) improves time to progression (TTP) in non-stem cell transplant patients (pts) with relapsed or refractory (rel/ref) multiple myeloma (MM): analysis from MM-009 and MM-010 randomized phase III clinical trials. Blood (ASH Ann. Meet. Abstr.). 2006; 108: Abstract 3554.
  89. Kyle R.A., Gertz M.A., Witzig T.E. et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin. Proc. 2003; 78: 21–33.
  90. Chen N., Lau H., Kong L. et al. Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J. Clin. Pharmacol. 2007; 47(12): 1466–75.
  91. Weber D., Wang M., Chen C. et al. Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): results of 2 phase III studies (MM-009, MM-010) and subgroup analysis of patients with impaired renal function. Blood (ASH Ann. Meet. Abstr.). 2006; 108: Abstract 3547.
  92. Bahlis N.J., Song K., Trieu Y. et al. Lenalidomide overcomes poor prognosis conferred by del13q and t(4; 14) but not del17p13 in multiple myeloma: results of the Canadian MM016 trial. Blood 2007; 110: Abstract 3597.
  93. Knight R., De Lap R.J., Zeldis J.B. Lenalidomide and venous thrombosis in multiple myeloma. N. Engl. J. Med. 2006; 354: 2079–80.
  94. Nooka A.K., Kaufman J.L., Heffner L.T. et al. Thromboembolic Events (TEE) with Lenalidomide-Based Therapies for Multiple Myeloma (MM): Emory Experience. ASH Ann. Meet. Abstr. 2009; 114: Abstract 3888.
  95. Reece D.E., Masih-Khan E., Chen C. et al. Use of Lenalidomide (Revlimid(R) +/- Corticosteroids in Relapsed/Refractory Multiple Myeloma Patients with Elevated Baseline Serum Creatinine Levels. ASH Ann. Meet. Abstr. 2006; 108: Abstract 3548.
  96. Baz R., Walker E., Karam M.A. et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann. Oncol. 2006; 17: 1766–71.
  97. Knop S., Gerecke C., Topp M.S. et al. Lеnalidomide (revlimidTM), adriamicin and dexamethasone chemotherapy (RAD) is safe and effective in treatment of relapsed multiple myeloma — first results of a German multicentre phase I/II trial. ASH Ann. Meet. Abstr. 2006; 108: 408.
  98. Knop S., Gerecke C., Topp M.S. et al. RAD (Revlimid, Adriamycin, Dex) is a new treatment regimen for relapsed multiple myeloma. Haematologica 2007; 92(s2): Abstract PO-658.
  99. Morgan G.J., Schey S.A., Wu P. et al. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients. Br. J. Haematol. 2007; 137: 268–9.
  100. Reece D.E., Masin-Khan E., Khan A. et al. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide (revlimid (R) (CPR) for treatment of patients with relapsed and refractory multiple myeloma. ASH Ann. Meet. Abstr. 2009; 114: 1874.
  101. Richardson P.G., Weller E., Jagannath S. et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/ refractory multiple myeloma. J. Clin. Oncol. 2009; 27: 5713–9.
  102. Anderson K., Jagannath S., Jakubowiak A. et al. Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma: Encouraging outcomes and tolerability in a phase II study. ASCO Annual Meeting Proceedings (Post-Meeting Edition). J. Clin. Oncol. 2009; 27(15S): 8536.
  103. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Эффективность леналидомида при рефрактерных/рецидивирующих формах множественной миеломы. Онкогематология 2012; 1: 6–14. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. et al. Lenalidomide efficacy in refractory/relapsing forms of multiple myeloma. Onkogematologiya 2012; 1: 6–14. (In Russ.)].
  104. Orlowski R.Z., Stinchcombe T.E., Mitchell B.S. et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J. Clin. Oncol. 2002; 20: 4420–7.
  105. Richardson P.G., Barlogie B., Berenson J. et al. A phase 2 study f bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 2003; 348(26): 2609–17.
  106. Jagannath S., Barlogie B., Berenson J. et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br. J. Haematol. 2004; 127(2): 165–72.
  107. Jagannath S., Barlogie B., Berenson J.R. et al. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br. J. Haematol. 2008; 143(4): 537–40.
  108. Richardson P.G., Sonneveld P., Schuster M.W. et al. Bortezomib or highdose dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 2005; 352(24): 2487–98.
  109. Richardson P.G., Sonneveld P., Schuster M. et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110(10): 3557–60.
  110. Richardson P., Sonneveld P., Schuster M. et al. Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed myeloma. Program and abstracts of the American Society of Clinical Oncology Annual Meeting, May 13–17, 2005; Orlando, Florida. Abstract 6533.
  111. Horton T.M., Gannavarapu A., Blaney S.M. et al. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother. Pharmacol. 2006; 58(1): 13–23.
  112. Jagannath S., Richardson P.G., Barlogie B. et al. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/ or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica 2006; 91: 929–34.
  113. Kropff M.H., Bisping G., Wenning D. et al. Bortezomib in combination with dexamethasone for relapsed multiple myeloma. Leuk. Res. 2005; 29: 587–90.
  114. Mikhael J.R., Belch A.R., Prince H.M. et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br. J. Haematol. 2009; 144: 169–75.
  115. Chou T. Multiple Myeloma: Recent Progress in Diagnosis and Treatment. J. Clin. Exp. Hematopathol. 2012; 52(3): 149–59.
  116. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Бортезомиб (Велкейд) в комбинации с дексаметазоном в лечении рефрактерных/рецидивирующих форм множественной миеломы. Результаты заключительного анализа. Клин. онкогематол. 2009; 2(3): 236–44. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V., et al. Bortezomib (Velcade) in combination with dexamethasone in therapy for refractory/relapsing forms of multiple myeloma (final analysis results). Klin. onkogematol. 2009; 2(3): 236–44. (In Russ.)].
  117. Richardson P.G., Briemberg H., Jagannath S. et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J. Clin. Oncol. 2006; 24: 3113–20.
  118. Moreau P., Richardson P.G., Cavo M. et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012; 120(5): 947–59.
  119. Moreau P., Coiteux V., Hulin C. et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 2008; 93(12): 1908–11.
  120. Moreau P., Pylypenko H., Grosicki S. et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011; 12(5): 431–40.
  121. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Бортезомиб (велкейд) и дексаметазон в лечении рефрактерных/рецидивирующих форм множественной миеломы (результаты промежуточного анализа). Вестн. гематол. 2008; 4: 14–22. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V., et al. Bortezomib (Velcade) in combination with dexamethasone in therapy for refractory/relapsing forms of multiple myeloma (interim analysis results). Vest. gematol. 2008; 4: 14–22. (In Russ.)].
  122. Mitsiades N., Mitsiades C.S., Richardson P.G. et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003; 101(6): 2377–80.
  123. Orlowski R.Z., Voorhees P.M., Garcia R.A. et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005; 105(8): 3058–65.
  124. Orlowski R.Z., Nagler A., Sonneveld P. et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J. Clin. Oncol. 2007; 25(25): 3892–901.
  125. Spencer A., Hajek R., Nagler A. et al. Doxil + velcade in previously treated high risk myeloma. Haematologica 2007; 92: 162. 126. San Miguel J., Hajek R., Nagler A. et al. Doxil + velcade in previously treated ³ 65y myeloma pts. Haematologica 2007; 92: 159.
  126. Palumbo A., Gay F., Bringhen S. et al. Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann. Oncol. 2008; 19(6): 1160–5.
  127. Pineda-Roman M., Zangari M., van Rhee F. et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia 2008; 22: 1419–27.
  128. Cioli S., Leoni F., Gigli F. et al. Low dose velcade, thalidomide and dexamethasone (LD-VTD): An effective regimen for relapsed and refractory multiple myeloma patients. Leuk. Lymphoma 2006; 47: 171–3.
  129. Garderet L., Iacobelli S., Moreau P. et al. Bortezomib (VELCADE)-thalidomide-dexamethasone (VTD) is superior to thalidomide-dexamethasone (TD) in patients with multiple myeloma (MM) progressing or relapsing after autologous transplantation [abstract]. Haematologica 2011; 96(s2): 420–1. Abstract 1008.
  130. Reece D.E., Rodriguez G.P., Chen C. et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J. Clin. Oncol. 2008; 26(29): 4777–83.
  131. Kropff M., Bisping G., Liebisch P. et al. Bortezomib in combination with high dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Blood (ASH Ann. Meet. Abstr.) 2005; 106: 2549.
  132. Berenson J., Yang H., Swift R. et al. Bortezomib in Combination with Melphalan in the Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study. Blood (ASH Ann. Meet. Abstr.) 2004; 104: Abstract 209.
  133. Terpos E., Anagnostopoulos A., Kastritis E. et al. The Combination of Bortezomib, Melphalan, Dexamethasone and Intermittent Thalidomide (VMDT) Is an Effective Treatment for Relapsed/Refractory Myeloma: Results of a Phase II Clinical Trial. ASH Ann. Meet. Abstr. 2005; 106: 363.
  134. Terpos E., Kastritis E., Roussou M. et al. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis. Leukemia 2008; 22: 2247–56.
  135. Palumbo A., Ambrosini M.T., Pregno P. et al. Velcade plus Melphalan, Prednisone and Thalidomide (V-MPT) for advanced multiple myeloma. Blood (ASH Ann. Meet. Abstr.) 2005; 106: 2553.
  136. Mitsiades N., Mitsiades C.S., Poulaki V. et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc. Natl. Acad. Sci. U S A 2002; 99(22): 14374–9.
  137. Richardson P., Jagannath S., Jakubowiak A. et al. Lenalidomide, bortezomib, and dexamethasone in patients with relapsed or relapsed/ refractory multiple myeloma (MM): encouraging response rates and tolerability with correlation of outcome and adverse cytogenetics in a phase II study. ASH Ann. Meet. Abstr. 2008; 112: Abstract 1742.
  138. Wolf J., Richardson P.G., Schuster M. et al. Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin. Adv. Hematol. Oncol. 2008; 6: 755–9.
  139. Hrusovsky I., Emmerich B., Enhgelhardt M. et al. Response to bortezomib retreatment is determined by duration of preceding treatment free interval — results from a retrospective multicenter survey. Haematologica 2008; 93(Suppl. 1): 259. Abstract 0645.
  140. Richardson P.G., Sonneveld P., Schuster M. et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110: 3557–60.
  141. Conner Th.M., Doan Q.Ch.D., Walters I.B. et al. An Observational, Retrospective Analysis of Retreatment with Bortezomib for Multiple Myeloma. Clin. Lymph. Myel. 2008; 8(3): 140–5.
  142. Hrusovsky I., Emmerich B., von Rohr A. et al. Bortezomib retreatment in relapsed multiple myeloma: results from a retrospective multicentre survey in Germany and Switzerland. Oncology 2010; 79(3–4): 247–54.
  143. Petrucci M.T., Blau I., Corradini P. et al. Efficacy and safety of retreatment with bortezomib in patients with multiple myeloma: interim results from RETRIEVE, a prospective international phase 2 study. Haematologica 2010; 95(s2): 152. Abstract 0377.
  144. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Лечение рефрактерных/рецидивирующих форм множественной миеломы. Medline. ru. 2011; 12: 763–80. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V., et al. Management of refractory/relapsing forms of multiple myeloma. Medline.ru. 2011; 12: 763–80. (In Russ.)].
  145. Verhelle D., Corral L.G., Wong K. et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res. 2007; 67(2): 746–55.
  146. Mitsiades N., Mitsiades C.S., Poulaki V. et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99(12): 4525–30.
  147. Schey S., Ramasamy K. Pomalidomide therapy for myeloma. Expert. Opin. Investig. Drugs 2011; 20: 691–700.
  148. Terpos E., Kanellias N., Christoulas D. et al. Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma. Oncol. Targ. Ther. 2013; 6: 531–8.
  149. Schey S.A., Fields P., Bartlett J.B. et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J. Clin. Oncol. 2004; 22: 3269–76.
  150. Streetly M.J., Gyertson K., Daniel Y. et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br. J. Haematol. 2008; 141(1): 41–51.
  151. Richardson P.G., Siegel D.S., Vij R. et al. Randomized, Open Label Phase 1/2 Study of Pomalidomide (POM) Alone or in Combination with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide (LEN) and Bortezomib (BORT): Phase 2 Results. ASH Ann. Meet. Abstr. 2011; 118: 634.
  152. Richardson P.G., Siegel D., Baz R. et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 2013; 121(11): 1961–7.
  153. Leleu X., Attal M., Arnulf B. et al. High Response Rates to Pomalidomide and Dexamethasone in Patients with Refractory Myeloma, Final Analysis of IFM 2009-02. ASH Ann. Meet. Abstr. 2011; 118: 812.
  154. Leleu X., Attal M., Arnulf B. et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide– refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02. Published online before print January 14, 2013, doi: 10.1182/blood-2012-09- 452375. Blood 2013; 121(11): 1968–75.
  155. Lacy M.Q., Kumar S.K., LaPlant B.R. et al. Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma: Long Term Follow up and Factors Predicting Outcome in 345 Patients. ASH Ann. Meet. Abstr. 2012; 120: 201.
  156. Vij R., Richardson P.G., Jagannath S. et al. Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). J. Clin. Oncol. 2012; 30(Suppl.): Abstract 8016.
  157. Dimopoulos M.A., Lacy M.Q., Moreau P. et al. Pomalidomide in combination with low-dose dexamethasone: demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory ММ: a phase 3, multicenter, randomized, open-label study. Blood (ASH Ann. Meet. Abstr.) 2012; 120: Abstract LBA-6.
  158. San-Miguel J.F., Weisel K.C., Moreau Ph. et al. MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide (POM) plus lowdose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM). 2013 ASCO Annual Meeting. J. Clin. Oncol. 2013; 31(Suppl.): Abstract 8510.
  159. Palumbo A., Larocca A., Montefusco V. et al. Pomalidomide Cyclophosphamide and Prednisone (PCP) Treatment for Relapsed/Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2012; 120: 446.
  160. Shah J.J., Stadtmauer E.A., Abonour R. et al. A Multi-Center Phase I/ II Trial of Carfilzomib and Pomalidomide with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2012; 120: 74.
  161. Richardson P.G., Hofmeister C.C., Siegel D. et al. MM-005: A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose for the Combination of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2012; 120: 727.
  162. Mark T.M., Boyer A., Rossi A.C. et al. ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma. Blood (ASH Ann. Meet. Abstr.) 2012; 120: Abstract 77.
  163. Jain S., Diefenbach C., Zain J., O’Connor O.A. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid. 2011; 6: 43–57.
  164. Reece D.E. Carfilzomib in multiple myeloma: gold, silver, or bronze? Blood 2012; 120(14): 2776–7.
  165. Badros A.Z., Vij R., Martin T. et al. Phase I study of carfilzomib in patients (pts) with relapsed and refractory multiple myeloma (MM) and varying degrees of renal insufficiency [ASH abstract]. Blood 2009; 114: 3877.
  166. Jagannath S., Vij R., Stewart A.K. et al. An open-label single arm pilot phase II study (PX-171-003-A0) of low-dose, single agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin. Lymph. Myel. Leuk. 2012; 12: 310–8.
  167. Vij R., Wang M., Kaufman J.L. et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012; 119: 5661–70.
  168. Siegel D.S., Martin T., Wang M. et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 (ph 2) study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood (ASH Ann. Meet. Abstr.) 2010; 116(21): 433. Abstract 985.
  169. Siegel D.S., Martin T., Wang M. et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120(14): 2817–25.
  170. Vij R., Siegel D.S., Kaufman J.L. et al. Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). J. Clin. Oncol. 2010; 28(15s): 573s. Abstract 8000.
  171. Vij R., Wang M., Kaufman J.L. et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma [published online ahead of print May 3, 2012]. Blood. doi: 10.1182/blood-2012-03-414359.
  172. Jakubowiak A.J., Martin T., Singhal S. et al. Responses to single-agent carfilzomib (CFZ) are not affected by cytogenetics in patients (pts) with relapsed and refractory multiple myeloma. Ann. Oncol. 2011; 22(Suppl. 4): iv122. Abstract 117.
  173. Singhal S., Siegel D.S., Martin T. et al. Integrated safety from phase 2 studies of monotherapy carfilzomib in patients with relapsed and refractory multiple myeloma (MM): an updated analysis [abstract]. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 819. Abstract 1876.
  174. Badros A.Z., Vij R., Martin T. et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia 2013; 27: 1707–14.
  175. Niesvizky R., Wang L., Orlowski R.Z. et al. Phase Ib multicenter dose escalation study of carfilzomib plus lenalidomide and low dose dexamethasone (CRd) in relapsed and refractory multiple myeloma (MM) [abstract]. Blood (ASH Ann. Meet. Abstr.) 2009; 114(22): 128–9. Abstract 304.
  176. Wang M., Bensinger W., Martin T. et al. Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ = CRd), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM). ASCO Ann. Meet. 2011; 29(15): 8025.
  177. Hajek R., Bryce R., Ro S. et al. Design and rationale of FOCUS (PX- 171-011): a randomized, open-label, phase 3 study of carf lzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer 2012; 12: 415.
  178. Potts B.C., Albitar M.X., Anderson K.C. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr. Cancer Drug Targ. 2011; 11(3): 254–84.
  179. Richardson P.G., Spencer A., Cannell P. et al. Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM) [abstract]. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 140–1. Abstract 302.
  180. Richardson P.G., Baz R., Wang L. et al. Investigational agent MLN9708, an oral proteasome inhibitor, in patients (pts) with relapsed and/or refractory multiple myeloma (MM): results from the expansion cohorts of a phase 1 doseescalation study. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 140. Abstract 301.
  181. Kumar S., Bensinger W.I., Reeder C.B. et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/ or refractory multiple myeloma: results from a phase 1 dose-escalation study [abstract]. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 371–2. Abstract 816.
  182. Hideshima T., Catley L., Yasui H. et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006; 107: 4053–62.
  183. Mitsiades C.S., Mitsiades N., Poulaki V. et al. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 2002; 21: 5673–83.
  184. Jakubowiak A., Richardson P., Zimmerman T.M. et al. Phase I results of perifosine (KRX-0401) in combination with lenalidomide and dexamethasone in patients with relapse or refractory multiple myeloma (mm) [ASH abstract]. Blood 2008; 112: 3691.
  185. Richardson P., Lonial S., Jakubowiak A. et al. Multi-center phase II study of perifosine (KRX-0401) alone and in combination with dexamethasone (dex) for patients with relapsed or relapsed/refractory multiple myeloma: promising activity as combination therapy with manageable toxicity [ASH abstract]. Blood 2007; 110: 1164.
  186. Richardson P., Wolf J.L., Jakubowiak A. et al. Perifosine in combination with bortezomib and dexamethasone extends progression-free survival and overall survival in relapsed/refractory multiple myeloma patients previously treated with bortezomib: updated phase I/II trial results [ASH abstract]. Blood 2009; 114: 1869.
  187. Khan N., Jeffers M., Kumar S. et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem. J. 2008; 409: 581–9.
  188. Wolf J.L., Siegel D., Matous J. et al. A phase II study of oral panobinostat (LBH589) in adult patients with advanced refractory multiple myeloma [ASH abstract]. Blood 2008; 112: 2774.
  189. Spencer A., Taylor K.M., Lonial S. et al. Panobinostat plus lenalidomide and dexamethasone phase I trial in multiple myeloma (MM) [ASCO abstract]. J. Clin. Oncol. 2009; 27: 8542.
  190. Berenson J.R., Yellin O., Boccia R.V. et al. A phase I study of oral melphalan combined with LBH589 for patients with relapsed or refractory multiple myeloma (MM) [ASH abstract]. Blood 2009; 114: 1855.
  191. Siegel D., Sezer O., San Miguel J. et al. A phase IB, multicenter, openlabel, dose-escalation study of oral panobinostat (LBH589) and I.V. bortezomib in patients with relapsed multiple myeloma [ASH abstract]. Blood 2008; 112: 2781.
  192. San Miguel J., Sezer O., Siegel D. et al. A phase IB, multi-center, openlabel dose-escalation study of oral panobinostat (LBH589) and I.V. bortezomib in patients with relapsed multiple myeloma [ASH abstract]. Blood 2009; 114: 3852.
  193. Alsina M., Schlossman R., Weber D.M. et al. PANORAMA 2: a phase II study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma. J. Clin. Oncol. 2012; 30(Suppl.): Abstract 8012.
  194. Richardson P.G., Schlossman R.L., Alsina M. et al. PANORAMA 2: Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and Bortezomib-Refractory Myeloma. Blood 2013. doi: 10.1182/blood- 2013-01-481325 (Epub Ahead of Print: bloodjournal.hematologylibrary.org).
  195. Prince M., Quach H., Neeson P. et al. Safety and efficacy of the combination of bortezomib with the deacetylase inhibitor romidepsin in patients with relapsed or refractory multiple myeloma: preliminary results of a phase I trial [ASH abstract]. Blood 2007; 110: 1167.
  196. Berenson J.R., Yellin O., Mapes R. et al. A phase II study of a 1-hour infusion of romidepsin combined with bortezomib for multiple myeloma (MM) patients with relapsed or refractory disease. [ASCO abstract]. J. Clin. Oncol 2009; 27: e19508.
  197. Harrison S.J., Quach H., Yuen K. et al. High response rates with the combination of bortezomib, dexamethasone and the pan-histone deacetylase inhibitor romidepsin in patients with relapsed or refractory multiple myeloma in a phase I/II clinical trial [ASH abstract]. Blood 2008; 112: 3698.
  198. Mann B.S., Johnson J.R., Cohen M.H. et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12: 1247–52.
  199. Badros A., Burger A.M., Philip S. et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin. Cancer Res. 2009; 15: 5250–7.
  200. Jagannath S., Weber D., Sobecks R. et al. The combination of vorinostat and bortezomib provides long-term responses in patients with relapsed or refractory multiple myeloma [ASH abstract]. Blood 2009; 114: 3886.
  201. Siegel D., Jagannath S., Lonial S. et al. Update on the phase IIb, openlabel study of vorinostat in combination with bortezomib in patients with relapsed and refractory multiple myeloma [ASH abstract]. Blood 2009; 114: 3890.
  202. Siegel D., Weber D.M., Mitsiades C. et al. Combined vorinostat, lenalidomide and dexamethasone therapy in patients with relapsed or refractory multiple myeloma: a phase I study [ASH abstract]. Blood 2009; 114: 305.
  203. Voorhees P.M., Gasparetto C., Richards K.L. et al. Vorinostat in combination with pegylated liposomal doxorubicin and bortezomib for patients with relapsed/refractory multiple myeloma: results of a phase I study [ASH abstract]. Blood 2009; 114: 306.
  204. Siegel D.S., Dimopoulos M.A., Yoon S.-S. et al. VANTAGE 095: vorinostat in combination with bortezomib in salvage multiple myeloma patients: final study results of a global phase 2b trial. ASH Ann. Meet. Abstr. 2011; 118: 480.
  205. Siegel D., Munster P.N., Rubin E.H. et al. The combined safety and tolerability profile of vorinostat-based therapy for solid or hematologic malignancies [ASH abstract]. Blood 2009; 114: 1710.
  206. Raje N., Hari P.N., Vogl D.T. et al. Rocilinostat (ACY-1215), a selective HDAC6 inhibitor, alone and in combination with bortezomib in multiple myeloma: preliminary results from the first-in-humans phase I/II study. ASH Ann. Meet. Abstr. 2012; 120: 4061.
  207. Kapoor T.M., Mayer T.U., Coughlin M.L. et al. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J. Cell Biol. 2000; 150: 975–88.
  208. Sawin K.E., LeGuellec K., Philippe M. et al. Mitotic spindle organization by a plus-end-directed microtubule motor. Nature 1992; 359: 540–3.
  209. Shah J.J., Zonder J., Cohen A. et al. ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study. ASH Ann. Meet. Abstr. 2011; 118: 1860.
  210. Shah J.J., Zonder J.A., Cohen A. et al. The Novel KSP Inhibitor ARRY- 520 Is Active Both with and without Low-Dose Dexamethasone in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide: Results From a Phase 2 Study. ASH Ann. Meet. Abstr. 2012; 120: 449.
  211. Leoni L.M., Bailey B., Reifert J. et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin. Cancer Res. 2008; 14: 309–17.
  212. Michael M., Bruns I., Bolke E. et al. Bendamustine in patients with relapsed or refractory multiple myeloma. Eur. J. Med. Res. 2010; 15: 13–9.
  213. Knop S., Straka C., Haen M. et al. The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. Haematologica 2005; 90: 1287–8.
  214. Ponisch W., Rozanski M., Goldschmidt H. et al. Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial. Br. J. Haematol. 2008; 143: 191–200.
  215. Fenk R., Michael M., Zohren F. et al. Escalation therapy with bortezomib, dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma. Leuk. Lymphoma 2007; 48: 2345–51.
  216. Havasi A., Li Z., Wang Z. et al. Hsp27 inhibits Bax activation and apoptosis via a phosphatidylinositol 3-kinase-dependent mechanism. J. Biol. Chem. 2008; 283: 12305–13.
  217. Ciocca D.R., Calderwood S.K. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 2005; 10: 86–103.
  218. Chauhan D., Li G., Hideshima T. et al. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Blood 2003; 102: 3379–86.
  219. Chauhan D., Li G., Shringarpure R. et al. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003; 63: 6174–7.
  220. Badros A.Z., Richardson P.G., Albitar M. et al. Tanespimycin + bortezomib in relapsed/refractory myeloma patients: results from the Time-2 study. Blood 2009; 114: 1871 (ASH abstract).
  221. Richardson P., Chanan-Khan A.A., Lonial S. et al. Tanespimycin + bortezomib demonstrates safety, activity, and effective target inhibition in relapsed/refractory myeloma patients: updated results of a phase 1/2 study [ASH abstract]. Blood 2009; 114: 2890.
  222. Badros A.Z., Richardson P.G., Albitar M. et al. Tanespimycin + bortezomib in relapsed/refractory myeloma patients: results from the Time-2 study (ASH abstract). Blood 2009; 114: 1871.
  223. Lonial S., Jagannath S. Monoclonal antibodies in the treatment of multiple myeloma. Haematologica. 13th International Myeloma Workshop, Paris, France, May 3–6, 2011; Abstract Book: S22–3.
  224. Plesner T., Lokhorst H.M., Gimsing P. et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma — date from a doseescalation phase I/II study. 54th American Society Hematology Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.
  225. Харченко М.Ф., Бессмельцев С.С. Значение протеогликанов в патогенезе множественной миеломы. Medline.ru. 2010; 11: 404–23. [Kharchenko M.F., Bessmeltsev S.S. Significance of proteoglycans in pathogenesis of multiple myeloma. Medline.ru. 2010; 11: 404–23. (In Russ.)].
  226. Dimopoulos M.A., San-Miguel J.F., Anderson K.C. Emerging therapies for the treatment of relapsed or refractory multiple myeloma. Eur. J. Haematol. 2010; 86: 1–15.
  227. Tai Y.T., Dillon M., Song W. et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 2008; 112: 1329–37.
  228. Hsi E.D., Steinle R., Balasa B. et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin. Cancer Res. 2008; 14: 2775–84.
  229. Van Rhee F., Szmania S.M., Dillon M. et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol. Cancer Ther. 2009; 8: 2616–24.
  230. Lonial S., Vij R., Harousseau J. et al. Multiple Myeloma Research Consortium. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma: a phase I/II study. J. Clin. Oncol. 2010; 28: 8020.
  231. Richardson P.G., Jagannath S., Moreau P. et al. A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma: update results: 54th American Society of Hematology Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.