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ОПЫТ ПРИМЕНЕНИЯ ИБРУТИНИБА У БОЛЬНЫХ РЕФРАКТЕРНЫМИ ФОРМАМИ И РЕЦИДИВАМИ В-КЛЕТОЧНОГО ХРОНИЧЕСКОГО ЛИМФОЛЕЙКОЗА

https://doi.org/10.21518/2079-701X-2017-6-132-138

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Аннотация

Цель исследования. Получение опыта применения ибрутиниба у пациентов с хроническим лимфолейкозом (ХЛЛ) в повседневной клинической практике.

Материалы и методы. С октября 2015 г. по январь 2016 г. в исследование было включено 20 больных с рефрактерными формами и рецидивами ХЛЛ. Всем пациентам было выполнено иммунофенотипическое, цитогенетическое и молекулярное исследования образцов периферической крови. Пациенты принимали ибрутиниб в суточной дозе 420 мг однократно ежедневно в течение года или до прогрессирования. Эффективность лечения оценивали по показателям общей частоты ответов, частоты полных ответов, общей выживаемости.

Результаты. Общая частота ответов составила 100%. Показатель общей выживаемости к сроку в 14 месяцев терапии составил 80%. Частота полных ответов на сроке наблюдения в 14 месяцев после начала терапии составила 60%. Первый эффект наблюдается со стороны лимфоузлов, тогда как изменения гемограммы происходят позднее. Препарат хорошо переносился. Пациентам, которым терапия ибрутинибом была временно приостановлена из-за развившихся осложнений, после их разрешения она была возобновлена в полной дозе.

Заключение. Ибрутиниб является высокоэффективным препаратом для пациентов с рефрактерными формами и рецидивами ХЛЛ, в том числе из группы высокого риска, однако он не является «терапией спасения» и не обладает эффективностью при терминальных состояниях. Ибрутиниб может рассматриваться в качестве «мостика» для молодых пациентов, которым планируется выполнение трансплантации аллогенного костного мозга.

Об авторах

Т. В. СОРОКИНА
Гематологический научный центр Минздрава России
Россия
к.м.н.


С. Р. ГОРЯЧЕВА
Гематологический научный центр Минздрава России
Россия
к.м.н.


В. А. СПИРИНА
Гематологический научный центр Минздрава России
Россия


Л. С. АЛЬ-РАДИ
Гематологический научный центр Минздрава России
Россия
к.м.н.


Т. Н. ОБУХОВА
Гематологический научный центр Минздрава России
Россия
к.м.н.


Б. В. БИДЕРМАН
Гематологический научный центр Минздрава России
Россия
к.б.н.


Т. Н. МОИСЕЕВА
Гематологический научный центр Минздрава России
Россия
к.м.н.


Список литературы

1. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood, 2006 Jan, 107(1): 265–76.

2. Watson L, Wyld P, Catovsky D. Disease burden of chronic lymphocytic leukaemia within the Euro pean Union. Eur J Haematol, 2008 Oct, 81(4): 253–8.

3. Molica S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk Lymphoma, 2006 Aug, 47(8): 1477–80.

4. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Work shop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 2008 Jun, 111(12): 5446–56.

5. Mauro FR, Foa R, Giannarelli D, Cordone I, Crescenzi S, Pescarmona E, et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood, 1999 Jul, 94(2): 448–54.

6. Rawstron AC, Bennett FL, O’Connor SJM, Kwok M, Fenton JAL, Plummer M, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med, 2008 Aug, 359(6): 575–83.

7. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med, 2000 Dec, 343(26): 1910–6.

8. Malcikova J, Smardova J, Rocnova L, Tichy B, Kuglik P, Vranova V, et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood, 2009 Dec, 114(26): 5307–14.

9. Zenz T, Benner A, Döhner H, Stilgenbauer S. Chronic lymphocytic leukemia and treatment resistance in cancer: the role of the p53 pathway. Cell Cycle, 2008 Dec, 7(24): 3810–4.

10. Fischer K et al. Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012; 30:3209-3216

11. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood, 2016 Jan, 127(2): 208–15.

12. Tam CS, O’Brien S, Lerner S, Khouri I, Ferrajoli A, Faderl S, et al. The natural history of fludarabinerefractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leuk Lymphoma, 2007 Oct, 48(10): 1931–9.

13. Panovská A, Smolej L, Lysák D, Brychtová Y, Šimkovič M, Motyčková M, et al. The outcome of chronic lymphocytic leukemia patients who relapsed after fludarabine, cyclophosphamide, and rituximab. Eur J Haematol, 2013 Jun, 90(6): 479–85.

14. Tam CS, O’Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, et al. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood, 2014 Nov, 124(20): 3059–64.

15. Fornecker L-M, Aurran-Schleinitz T, Michallet A-S, Cazin B, Guieze R, Dilhuydy M-S, et al. Salvage outcomes in patients with first relapse after fludarabine, cyclophosphamide, and rituximab for chronic lymphocytic leukemia: the French intergroup experience. Am J Hematol, 2015 Jun, 90(6): 511–4.

16. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol, 2016; 17: 928–42.

17. Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stil genbauer S, Mayer J, et al. Chemoimmuno therapy with O-FC in previously untreated pati ents with chronic lymphocytic leukemia. Blood, 2011 Jun, 117(24): 6450–8.

18. Shanafelt T, Lanasa MC, Call TG, Beaven AW, Leis JF, LaPlant B, et al. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in pati ents with previously untreated chronic lymphocytic leukemia (CLL). Cancer, 2013 Nov, 119(21): 3788–96.

19. Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol, 2009 Sep, 27(27): 4578–84.

20. Faderl S, Wierda W, O’Brien S, Ferrajoli A, Lerner S, Keating MJ. Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL. Leuk Res, 2010 Mar, 34(3): 284–8.

21. Brown JR, Abramson J, Hochberg E, Mikler E, Dalton V, Werner L, et al. A phase I study of lenalidomide in combination with fludarabine and rituximab in previously untreated CLL/SLL. Leukemia, 2010 Nov, 24(11): 1972–5.

22. Mato AR, Foon KA, Feldman T, Schuster SJ, Svoboda J, Chow KF, et al. Reduced-dose fludarabine, cyclophosphamide, and rituximab (FCR-Lite) plus lenalidomide, followed by lenalidomide consolidation/maintenance, in previously untreated chronic lymphocytic leukemia. Am J Hematol, 2015 Jun, 90(6): 487–92.

23. Parikh SA, Keating MJ, O’Brien S, Wang X, Ferrajoli A, Faderl S, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood, 2011 Aug, 118(8): 2062–8.

24. Geisler CH, van T’ Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, et al. Frontline lowdose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood, 2014 May, 123(21): 3255–62.

25. Lepretre S, Aurran T, Mahé B, Cazin B, Tournil hac O, Maisonneuve H, et al. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood, 2012 May, 119(22): 5104–10.

26. Stilgenbauer S, Sander S, Bullinger L, Benner A, Leupolt E, Winkler D, et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of highrisk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica, 2007 Sep, 92(9): 1242–5.

27. Osterborg A, Foà R, Bezares RF, Dearden C, Dyer MJS, Geisler C, et al. Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia. Leukemia, 2009 Nov, 23(11): 1980–8.

28. Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, et al. The phosphoinositide 3’-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood, 2011 Sep, 118(13): 3603–12.

29. Herman SEM, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood, 2011 Jun, 117(23): 6287–96.

30. Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol, 2013 Aug, 13(8): 578–91.

31. Burger JA, Gribben JG. The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin Cancer Biol, 2014 Feb, 24: 71–81.

32. Ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment. Biochim Biophys Acta, 2016 Mar, 1863(3): 401–13.

33. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood, 2012 Aug, 120(6): 1175–84.

34. Dühren-von Minden M, Übelhart R, Schneider D, Wossning T, Bach MP, Buchner M, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature, 2012 Sep, 489(7415): 309–12.

35. Bernal A, Pastore RD, Asgary Z, Keller SA, Cesarman E, Liou HC, et al. Survival of leukemic B cells promoted by engagement of the antigen receptor. Blood, 2001 Nov, 98(10): 3050–7.

36. Herishanu Y, Pérez-Galán P, Liu D, Biancotto A, Pittaluga S, Vire B, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood, 2011 Jan, 117(2): 563–74.

37. Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan X-J, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood, 2012 May, 119(19): 4467–75.

38. O’Brien S, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Blood, 2016 128(22): 233

39. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med [Internet], 2014 Jul 17 [cited 2017 Feb 16], 371(3): 213–23. Available from: http: //www.ncbi.nlm.nih.gov/pubmed/24881631

40. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, et al. Three-year follow-up of treatment- naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood, 2015 Apr, 125(16): 2497–506.

41. Farooqui MZH, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, singlearm trial. Lancet Oncol [Internet], 2015 Feb [cited 2017 Feb 16], 16(2): 169–76. Available from: http: //www.ncbi.nlm.nih.gov/pubmed/25555420.

42. Woyach JA, Smucker K, Smith LL, Lozanski A, Zhong Y, Ruppert AS, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood, 2014 Mar, 123(12): 1810–7.

43. Kamel S, Horton L, Ysebaert L, Levade M, Burbury K, Tan S, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia, 2015 Apr, 29(4): 783–7.

44. McMullen JR, Boey EJH, Ooi JYY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood, 2014 Dec, 124(25): 3829–30.

45. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single- arm, phase 2 study. Lancet Oncol [Internet], 2014 Sep [cited 2017 Feb 16], 15(10): 1090–9. Available from: http: //www.ncbi.nlm.nih.gov/pubmed/25150798.

46. Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andrit sos LA, Maddocks KJ, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood, 2015 Aug, 126(7): 842–50.

47. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1- selective pressure in T lymphocytes. Blood, 2013 Oct, 122(15): 2539–49.

48. Byrd JC, Pagel JM, Awan FT, Forero A, Flinn IW, Deauna-Limayo DP, et al. A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia. Blood, 2014 Feb, 123(9): 1302–8.

49. Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood, 2015 May, 125(19): 2915–22.

50. Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol, 2011 Sep, 29(26): 3559–66.

51. Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol, 2016 Feb, 17(2): 200–11.


Для цитирования:


СОРОКИНА Т.В., ГОРЯЧЕВА С.Р., СПИРИНА В.А., АЛЬ-РАДИ Л.С., ОБУХОВА Т.Н., БИДЕРМАН Б.В., МОИСЕЕВА Т.Н. ОПЫТ ПРИМЕНЕНИЯ ИБРУТИНИБА У БОЛЬНЫХ РЕФРАКТЕРНЫМИ ФОРМАМИ И РЕЦИДИВАМИ В-КЛЕТОЧНОГО ХРОНИЧЕСКОГО ЛИМФОЛЕЙКОЗА. Медицинский Совет. 2017;(6):132-138. https://doi.org/10.21518/2079-701X-2017-6-132-138

For citation:


SOROKINA T.V., GORYACHEVA S.R., SPIRINA V.A., AL-RADI L.S., OBUKHOVA T.N., BIDERMAN B.V., MOISEEVA T.N. EXPERIENCE WITH IBRUTINIB IN PATIENTS WITH REFRACTORY AND RECURRENT B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA. Medical Council. 2017;(6):132-138. (In Russ.) https://doi.org/10.21518/2079-701X-2017-6-132-138

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ISSN 2079-701X (Print)
ISSN 2658-5790 (Online)