NOVEL DRUGS

Practical Aspects of the Use of Carfilzomib in Multiple Myeloma

NOVEL DRUGS , , , , ,

SV Semochkin1,2, GN Salogub3, SS Bessmeltsev4, KD Kaplanov5

1 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

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

3 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

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

5 Volgograd Regional Clinical Oncology Dispensary No. 1, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

For correspondence: Prof. Sergei Vyacheslavovich Semochkin, MD, PhD, 3 Pekhotnaya str., Moscow, Russian Federation, 123182; Tel./fax: +7(495)369-00-36; e-mail: semochkin_sv@rsmu.ru

For citation: Semochkin SV, Salogub GN, Bessmeltsev SS, Kaplanov KD. Practical Aspects of the Use of Carfilzomib in Multiple Myeloma. Clinical oncohematology. 2019;12(1):21–31.

DOI: 10.21320/2500-2139-2019-12-1-21-31

ABSTRACT

Carfilzomib (Kyprolis®, Amgen), a second-generation proteasome inhibitor, is capable of covalent bonding and irreversible inhibition of the 20S proteasome chymotrypsin-like activity. In 2016 this drug was approved in Russia for monotherapy of relapsed refractory multiple myeloma (MM) and in combination with lenalidomide and dexamethasone (KRd) or only with dexamethasone (Kd) for treatment of patients with relapsed MM after at least one line of prior therapy. The present review outlines mechanism, clinical efficacy, and adverse effects of carfilzomib according to the data of a phase II (monotherapy) trial and two key randomized phase III (carfilzomib combined with other drugs) trials. The ASPIRE trial demonstrated that adding carfilzomib to the combination of lenalidomide and dexamethasone (KRd) significantly improves progression-free survival (PFS) compared with the Rd original regimen (median 26.3 vs. 17.6 months; hazard ratio [HR] 0.69; p = 0.0001). Median overall survival (OS) was 48.3 months (95% confidence interval [95% CI] 42.4–52.8 months) for KRd vs. 40.4 months (95% CI 33.6–44.4 months) for Rd (HR 0.79; p = 0.0045). The ENDEAVOR trial showed that as compared with combination of bortezomib and dexamethasone (Vd) the carfilzomib + dexamethasone (Kd) regimen significantly improves PFS (median 18.7 vs. 9.4 months; HR 0.53; p < 0.0001) and OS (47.6 vs. 40.0 months; HR 0.79; p = 0.010) as well. The present review also discusses how carfilzomib is to be used in special patient groups (with renal failure and high cytogenetic risk).

Keywords: carfilzomib, proteasome inhibitor, lenalidomide, bortezomib, multiple myeloma, renal failure, cytogenetic risk.

Received: May 12, 2018

Accepted: December 28, 2018

Read in PDF 

REFERENCES

  1. Siegel D, 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. doi: 10.1182/blood-2012-05-425934.

  2. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753–61. doi: 10.3324/haematol.2013.089334.

  3. Badros AZ, Vij R, Martin T, et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013;27(8):1707–14. doi: 10.1038/leu.2013.29.

  4. Wang TF, Ahluwalia R, Fiala MA, et al. The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide. Leuk Lymphoma. 2014;55(2):337–41. doi: 10.3109/10428194.2013.803547.

  5. Moreau P. How I treat myeloma with new agents. Blood. 2017;130(13):1507–13. doi: 10.1182/blood-2017-05-743203.

  6. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27–38. doi: 10.1016/S1470-2045(15)00464-7.

  7. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52. doi: 10.1056/NEJMoa1411321.

  8. Gea J, Agusti A, Roca J. Pathophysiology of muscle dysfunction in COPD. J Appl Physiol. 2013;114(9):1222–34. doi: 10.1152/japplphysiol.00981.2012.

  9. Ciehanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun. 2012;425(3):565–70. doi: 10.1016/j.bbrc.2012.08.025.

  10. Nobel Prize in Chemistry 2004. Nobelprize.org. Nobel Media AB 2014. Available from: http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2004/ (accessed 10.01.2018).

  11. Vincenz L, Jager R, O’Dwyer M, Samali A. Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma. Mol Cancer Ther. 2013;12(6):831–43. doi: 10.1158/1535-7163.MCT-12-0782.

  12. Hasinoff BB. Progress curve analysis of the kinetics of slow-binding anticancer drug inhibitors of the 20S proteasome. Arch Biochem Biophys. 2018;639:52–8. doi: 10.1016/j.abb.2017.12.020.

  13. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110(9):3281–90. doi: 10.1182/blood-2007-01-065888.

  14. Accardi F, Toscani D, Bolzoni M, et al. Mechanism of action of bortezomib and the new proteasome inhibitors on myeloma cells and the bone microenvironment: impact on myeloma-induced alterations of bone remodeling. Biomed Res Int. 2015;2015:1–13. doi: 10.1155/2015/172458.

  15. Wang Z, Yang J, Kirk C, et al. Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib. Drug Metab Dispos. 2013;41(1):230–7. doi: 10.1124/dmd.112.047662.

  16. Alsina M, Trudel S, Furman RR, et al. A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012;18(17):4830–40. doi: 10.1158/1078-0432.ccr-11-3007.

  17. Squifflet P, Michiels S, Siegel D, et al. Relationship between carfilzomib dose and efficacy outcomes in patients with relapsed and/or refractory multiple myeloma. Clin Lymph Myel Leuk. 2015;15(11):680–6. doi: 10.1016/j.clml.2015.09.005.

  18. Papadopoulos KP, Siegel DS, Vesole DH, et al. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015;33(7):732–9. doi: 10.1200/JCO.2013.52.3522.

  19. Hajek R, Masszi T, Petrucci MT, et al. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017;31(1):107–14. doi: 10.1038/leu.2016.176.

  20. Dimopoulos MA, Stewart AK, Masszi T, et al. Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment. Blood Cancer J. 2017;7(4):e554. doi: 10.1038/bcj.2017.31.

  21. Stewart KA, Siegel D, Ludwig H, et al. Overall Survival (OS) of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide and Dexamethasone (Rd): Final Analysis from the Randomized Phase 3 Aspire Trial. Blood (ASH Annual Meeting Abstracts). 2017;130(Suppl 1): Abstract 743.

  22. Stewart AK, Dimopoulos MA, Masszi T, et al. Health-Related Quality of Life Results From the Open-Label, Randomized, Phase III ASPIRE Trial Evaluating Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma. J Clin Oncol. 2016;34(32):3921–30. doi: 10.1200/JCO.2016.66.9648.

  23. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(10):1327–37. doi: 10.1016/S1470-2045(17)30578-8.

  24. Gavriatopoulou M, Terpos E, Kastritis E, Dimopoulos MA. Current treatments for renal failure due to multiple myeloma. Expert Opin Pharmacother. 2016;17(16):2165–77. doi: 10.1080/14656566.2016.1236915.

  25. Yadav P, Cook M, Cockwell P. Current Trends of Renal Impairment in Multiple Myeloma. Kidney Dis. 2016;1(4):241–57. doi: 10.1159/000442511.

  26. Рехтина И.Г., Менделеева Л.П., Бирюкова Л.С. Диализзависимая почечная недостаточность у больных множественной миеломой: факторы обратимости. Терапевтический архив. 2015;87(7):72–6. doi: 10.17116/terarkh201587772-76.

    [Rekhtina IG, Mendeleeva LP, Biryukova LS. Dialysis-dependent renal failure in patients with multiple myeloma: Reversibility factors. Terapevticheskii arkhiv. 2015;87(7):72–6. doi: 10.17116/terarkh201587772-76. (In Russ)]

  27. Dimopoulos MA, Sonneveld P, Leung N, et al. International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. J Clin Oncol. 2016;34(13):1544–57. doi: 10.1200/JCO.2015.65.0044.

  28. Stansfield LC, Gonsalves WI, Buadi FK. The use of novel agents in multiple myeloma patients with hepatic impairment. Fut Oncol. 2015;11(3):501–10. doi: 10.2217/fon.14.270.

  29. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–57. doi: 10.1038/leu.2011.196.

  30. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62. doi: 10.1182/blood-2016-01-631200.

  31. Jakubowiak AJ, Siegel DS, Martin T, et al. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013;27(12):2351–6. doi: 10.1038/leu.2013.152.

  32. Avet-Loiseau H, Fonseca R, Siegel D, et al. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016;128(9):1174–80. doi: 10.1182/blood-2016-03-707596.

  33. Stessman HA, Baughn LB, Sarver A, et al. Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol Cancer Ther. 2013;12(6):1140–50. doi: 10.1158/1535-7163.MCT-12-1151.

  34. Berenson JR, Hilger JD, Yellin O, et al. Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy. Leukemia. 2014;28(7):1529–36. doi: 10.1038/leu.2014.27.

  35. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754–66. doi: 10.1056/NEJMoa1606038.

  36. Moreau Ph, Oriol A, Kaufman JL, et al. Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Lenalidomide and Dexamethasone (Rd) in Relapsed or Refractory Multiple Myeloma (RRMM) Based on Prior Treatment History, Renal Function, and Cytogenetic Risk: Subgroup Analyses of Pollux. Blood (ASH Annual Meeting Abstracts). 2017;130(Suppl 1): Abstract 1883.

  37. Dimopoulos MA, Lonial S, White D, et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017;178(6):896–905. doi: 10.1111/bjh.14787.

  38. Grandin EW, Ky B, Cornell RF, et al. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. J Card Fail. 2015;21(2):138–44. doi: 10.1016/j.cardfail.2014.11.008.

  39. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Частота, характеристика и методы лечения периферической нейропатии у больных множественной миеломой, получающих бортезомиб (велкейд). Онкогематология. 2008;3(3):52–62.

    [Bessmeltsev SS, Karyagina EV, Stelmashenko LV, et al. Incidence, characteristics, and treatments of peripheral neuropathy in multiple myeloma patients receiving bortezomib (velcade). Onkogematologiya. 2008;3(3):52–62. (In Russ)]

  40. Скворцова Н.В., Поспелова Т.И., Нечунаева И.Н. и др. Эффективность повторной терапии бортезомибом у пациентов с рефрактерными и рецидивирующими формами множественной миеломы. Сибирский научный медицинский журнал. 2013;33(1):76–81.

    [Skvortsova NV, Pospelova TI, Nechunaeva IN, et al. Antitumor activity of bortezomib retreatment in relapsed or refractory multiple myeloma patients. Sibirskii nauchnyi meditsinskii zhurnal. 2013;33(1):76–81. (In Russ)]

  41. Rosenthal A, Luthi J, Belohlavek M, et al. Carfilzomib and the cardiorenal system in myeloma: an endothelial effect? Blood Cancer J. 2016;6(1):e384. doi: 10.1038/bcj.2015.112.

  42. Atrash S, Tullos A, Panozzo S, et al. Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib. Blood Cancer J. 2015;5(1):e272. doi: 10.1038/bcj.2014.93.

  43. Danhof S, Schreder M, Rasche L, et al. ‘Real-life’ experience of preapproval carfilzomib-based therapy in myeloma – analysis of cardiac toxicity and predisposing factors. Eur J Haematol. 2016;97(1):25–32. doi: 10.1111/ejh.12677.

  44. Berenson JR, Cartmell A, Bessudo A, et al. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016;127(26):3360–8. doi: 10.1182/blood-2015-11-683854.

  45. Chari A, Hajje D. Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring. BMC Cancer. 2014;14(1):915. doi: 10.1186/1471-2407-14-915.

  46. Sullivan MR, Danilov AV, Lansigan F, Dunbar NM. Carfilzomib associated thrombotic microangiopathy initially treated with therapeutic plasma exchange. J Clin Apher. 2015;30(5):308–10. doi: 10.1002/jca.21371.

  47. Yui JC, Van Keer J, Weiss BM, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol. 2016;91(9):E348–52. doi: 10.1002/ajh.24447.

  48. Григорьева В.Н., Стамо А.П., Авдонина Ю.Д., Беляков К.М. Особенности поражения периферической нервной системы при множественной миеломе. Неврологический журнал. 2013;18(2):4–10.

    [Grigor’eva VN, Stamo AP, Avdonina YuD, Belyakov KM. Characteristics of lesions in the peripheral nervous system in multiple myeloma. Nevrologicheskii zhurnal. 2013;18(2):4–10. (In Russ)]

  49. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2).

    [Mendeleeva LP, Votyakova OM, Pokrovskaya OS, et al. National clinical guidelines on diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). (In Russ)]

  50. Lataifeh AR, Nusair A. Fatal pulmonary toxicity due to carfilzomib (Kyprolis). J Oncol Pharm Pract. 2016;22(5):720–4. doi: 10.1177/1078155215588630.

  51. Cai X, Bhattacharyya S, Plitt A, et al. Management of posterior reversible encephalopathy syndrome induced by carfilzomib in a patient with multiple myeloma. J Clin Oncol. 2016;34(2):e1–5. doi: 10.1200/JCO.2013.49.6166.

  52. Скворцова В.И., Губский Л.В., Мельникова Е.А. Синдром задней обратимой энцефалопатии. Журнал неврологии и психиатрии им. C.C. Корсакова. 2010;110(5):104–9.

    [Skvortsova VI, Gubskii LV, Mel’nikova EA. Posterior reversible encephalopathy syndrome. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2010;110(5):104–9. (In Russ)]

Erythrodermic Mycosis Fungoides: The Algorithm of Diagnosis and Treatment

NOVEL DRUGS , ,

OYu Olisova1, AA Sydikov2, IN Chuprov3, LG Gorenkova4, SA Chernysh5, VA Doronin6, EV Grekova1

1 IM Sechenov First Moscow State Medical University, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991

2 Saint-Petersburg State Pediatric Medical University, 2 Litovskaya str., Saint Petersburg, Russian Federation, 194100

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

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

5 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

6 Municipal Clinical Hospital No. 40, 7 Kasatkina str., Moscow, Russian Federation, 129301

For correspondence: Ekaterina Vladimirovna Grekova, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991; e-mail: grekova_kate@mail.ru

For citation: Olisova OYu, Sydikov AA, Chuprov IN, et al. Erythrodermic Mycosis Fungoides: The Algorithm of Diagnosis and Treatment. Clinical oncohematology. 2018;11(4):295–302.

DOI: 10.21320/2500-2139-2018-11-4-295-302

ABSTRACT

Erythrodermic mycosis fungoides (eMF) is an atypical severe form of mycosis fungoides resulting from persistent and treatment-resistant disease. eMF manifests as generalized skin bluish lesions, intense itching, secondary lymphadenopathy, and significant deterioration of quality of life. A differential diagnostic algorithm for various forms of erythrodermia is suggested. The paper presents a clinical case of eMF with spots and plaques that skipped the tumor stage. Experience of eMF treatment using vorinostat, gemcitabine, doxorubicin, and alemtuzumab is described.

Keywords: erythrodermic mycosis fungoides, cutaneous lymphoma, diagnostic algorithms, vorinostat.

Received: May 8, 2018

Accepted: August 15, 2018

Read in PDF 

REFERENCES

  1. Willemze R, Meijer CJ. Classification of cutaneous T-cell lymphoma: from Alibert to WHO-EORTC. J Cutan Pathol. 2006;33(Suppl 1):18–26. doi: 10.1111/j.0303-6987.2006.00494.x.

  2. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(1):3768–85. doi: 10.1182/blood-2004-09-3502.

  3. Ястребов В.В., Разнатовский И.М. Лимфомы кожи. Урогенитальная герпесвирусная инфекция. СПб.: Сотис, 2000. 185 c.

    [Yastrebov VV, Raznatovskii IM. Limfomy kozhi. Urogenital’naya gerpesvirusnaya infektsiya. (Cutaneous lymphomas. Urogenital herpes virus infection.) Saint Petersburg: Sotis Publ.; 2000. 185 p. (In Russ)]

  4. Заславский Д.В., Раводин Р.А., Татарская О.Б. и др. Эритродермия: современные вопросы диагностики и лечения. Педиатр. 2014;5(1):97–102.

    [Zaslavskii DV, Ravodin RA, Tatarskaya OB, et al. Erythrodermia: Current issues of diagnosis and treatment. Pediatr. 2014;5(1):97–102. (In Russ)]

  5. Calonje E, Brenn T, Lazar A, McKee PH. McKee’s pathology of the skin with clinical correlations. 4th edition. Elsevier/Saunders; 2012. pp. 1311–420.

  6. Vidulich KA, Talpur R, Bassett RL, Duvic M. Overall survival in erythrodermic cutaneous T-cell lymphoma: an analysis of prognostic factors in a cohort of patients with erythrodermic cutaneous T-cell lymphoma. Int J Dermatol. 2009;48(3):243–52. doi: 10.1111/j.1365-4632.2009.03771.x.

  7. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2016. С. 84–113.

    [Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines on diagnosis and treatment of lymphoproliferative disorders). Moscow: Buki Vedi Publ.; 2016. pp. 84–113. (In Russ)]

  8. Белоусова И.Э., Самцов А.В. Федеральные клинические рекомендации по ведению больных лимфомами кожи [электронный документ]. Доступно по: https://mzdrav.rk.gov.ru/file/Limfomy_kozhi_05052014_Klinicheskie_rekomendacii.pdf. Ссылка активна на 29.05.2018.

    [Federal clinical guidelines on management of patients with cutaneous lymphomas [Internet]. Available from: https://mzdrav.rk.gov.ru/file/Limfomy_kozhi_05052014_Klinicheskie_rekomendacii.pdf. (accessed 29.05.2018) (In Russ)]

  9. Кунгуров Н.В.,Куклин И.А., Кохан М.М., Сазонов С.В. Дифференциальная диагностика эритродермической формы грибовидного микоза и других эритродермий. Вестник дерматологии и венерологии. 2009;1:27–32.

    [Kungurov NV, Kuklin IA, Kokhan MM, Sazonov SV. Differential diagnosis of erythrodermic mycosis fungoides and other erythrodermias. Vestnik dermatologii i venerologii. 2009;1:27–32. (In Russ)]

  10. Trautingera F, Knobler R, Willemzeb R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer. 2006;42(8):1014–30. doi: 10.1016/j.ejca.2006.01.025.

  11. Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29(18):2598–607. doi: 10.1200/jco.2010.32.0630.

  12. Заславский Д.В., Родионов А.Н., Чупров И.Н. и др. Эволюция взглядов на эритродермию. Российский журнал кожных и венерических болезней. 2017;20(1):10–4. doi: 10.18821/1560-9588-2017-20-1-10-14.

    [Zaslavsky DV, Rodionov AN, Chuprov IN, et al. The evolution of views on the erythroderma. Rossiiskii zhurnal kozhnykh i venericheskikh boleznei. 2017;20(1):10–4. doi: 10.18821/1560-9588-2017-20-1-10-14. (In Russ)]

  13. Сыдиков А.А., Заславский Д.В., Зайцев В.С., Насыров Р.А. Об эволюции взглядов на группы парапсориазов Брока. Современные проблемы науки и образования. 2013;5:317.

    [Sydikov AA, Zaslavskii DV, Zaitsev VS, Nasyrov RA. The evolution of views on the group parapsoriasis of Brocq. Sovremennye problemy nauki i obrazovaniya. 2013;5:317. (In Russ)]

  14. Олисова О.Ю., Смирнов К.В., Грекова Е.В. Комбинация ПУВА-терапии с интерфероном А у больных грибовидным микозом. Российский журнал кожных и венерических болезней. 2017;20(3):132–9. doi: 10.18821/1560-9588-2017-20-3-132-139.

    [Olisova OYu, Smirnov KV, Grekova EV. PUVA and interferon Α combined therapy in patients with mycosis fungoides. Rossiiskii zhurnal kozhnykh i venericheskikh boleznei. 2017;20(3):132–9. doi: 10.18821/1560-9588-2017-20-3-132-139. (In Russ)]

  15. Заславский Д.В., Юновидова А.А., Волькенштейн П. и др. Комплексная терапия синдрома Сезари. Иммунопатология, аллергология, инфектология. 2016;1:6–13. doi: 10.14427/jipai.2016.1.6.

    [Zaslavsky DV, Yunovidova AA, Wolkenstein P, et al. Combined therapy Sezary syndrome. Immunopathology, allergology, infectology. 2016;1:6–13. doi: 10.14427/jipai.2016.1.6. (In Russ)]

  16. Горенкова Л.Г., Пенская Е.А., Кравченко С.К. и др. Лечение резистентных форм грибовидного микоза и синдрома Сезари. Клиническая онкогематология. 2017;10(3):366–71. doi: 10.21320/2500-2139-2017-10-3-366-371.

    [Gorenkova LG, Penskaya EA, Kravchenko SK, et al. Treatment of Drug-Resistant Mycosis Fungoides and Sezary Syndrome. Clinical oncohematology. 2017;10(3):366–71. doi: 10.21320/2500-2139-2017-10-3-366-371. (In Russ)]

  17. Доронин В.А. Т-клеточные лимфомы: возможности терапии при ограниченном выборе. Клиническая онкогематология. 2013;6(2):127–38.

    [Doronin VA. T­cell lymphomas: therapeutic possibilities for a limited choice. Klinicheskaya onkogematologiya. 2013;6(2):127–38. (In Russ)]

  18. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment Refractory Cutaneous T-Cell Lymphoma. J Clin Oncol. 2007;25(21):3009–15. doi: 10.1200/jco.2006.10.2434.

Clinical Experience and Perspectives of Bosutinib Use in Patients with Chronic Myeloid Leukemia

NOVEL DRUGS , , , ,

VA Shuvaev1, OYu Vinogradova2,3,4, IS Martynkevich1, NV Novitskaya2, MS Fominykh1, SN Tsareva2, DI Shikhbabaeva2, MM Pankrashkina2,3, MV Chernikov2, NN Sharkunov2, II Zotova1, VYu Udal’eva1, EV Motyko1, SV Voloshin1,5,6

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

2 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

3 Dmitrii Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117198

4 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

5 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

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

For correspondence: Ol’ga Yur’evna Vinogradova, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(495)945-97-61; e-mail: olgavinz@mail.ru.

For citation: Shuvaev VA, Vinogradova OYu, Martynkevich IS, et al. Clinical Experience and Perspectives of Bosutinib Use in Patients with Chronic Myeloid Leukemia. Clinical oncohematology. 2018;11(4):288–94.

DOI: 10.21320/2500-2139-2018-11-4-288-294

ABSTRACT

Aim. To evaluate the clinical experience of bosutinib use for treatment of chronic myeloid leukemia (CML) patients with intolerance and resistance to other tyrosine kinase inhibitors (TKI), as well as to compare the obtained results with the data of clinical trials.

Materials & Methods. The analysis was conducted on case history records of 51 CML patients (25 men and 26 women; median age was 56 years, range 28–86). By the beginning of bosutinib therapy 37 chronic phase, 8 acceleration phase, and 6 blast crisis patients were included in the study. Bosutinib was administered as second–line TKI treatment in 10 patients, as third–line treatment in 18 patients, and as fourth–line treatment in 23 patients. The causes for switching to bosutinib were poor tolerance of previous TKI therapy in 21 patients and resistance to previous TKI therapy in 30 patients.

Results. The median duration of bosutinib treatment was 6 months (range 1–50). Bosutinib toxicity profile and its tolerance in common clinical practice corresponded to the data of clinical trials. Because of adverse events the therapy was discontinued only in 5 (10 %) patients. Complete hematological response was 88 % (persistent response was maintained in 76 % of patients); complete cytogenetic response (CCyR) was 39 %, (persistent response in 37 % of cases); major molecular response (MMR) was 31 % (it was confirmed in 25 % of patients during the last follow-up visit). The efficacy of bosutinib in the real clinical setting was slightly higher compared to the results of clinical trials. This difference was associated with a disease phase, a reason for withdrawal of the previous TKI, line of treatment, BCR–ABL mutations, and the form of them. The therapy was continued in 22 (43 %) patients, most of them reached stable optimal response, both CCyR and MMR.

Conclusion. Bosutinib appears to be an acceptable alternative to other TKIs having its specific mechanisms of action and adverse events. The efficacy and safety of bosutinib proved in routine clinical practice are sufficient to recommend it for use in national hematology.

Keywords: chronic myeloid leukemia, bosutinib, target therapy, tyrosine kinase inhibitors, clinical practice.

Received: May 9, 2018

Accepted: August 10, 2018

Read in PDF 

REFERENCES

  1. Hehlmann R, Lauseker M, Saussele S, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31(11):2398–406. doi: 10.1038/leu.2017.253.

  2. Deininger M, O’Brien SG, Guilhot F, et al. International Randomized Study of Interferon Vs STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. Blood. 2009;114(22):1126.

  3. Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. и др. Хронический миелолейкоз: многолетний опыт таргетной терапии. Клиническая онкогематология. 2016;9(1):54–60. doi: 10.21320/2500-2139-2016-9-1-54-60.

    [Abdulkadyrov KM, Shuvaev VA, Martynkevich IS, et al. Chronic Myeloid Leukemia: Long-Term Experience of Target Therapy. Clinical oncohematology. 2016;9(1):54–60. doi: 10.21320/2500-2139-2016-9-1-54-60. (In Russ)]

  4. Шухов О.А., Туркина А.Г., Челышева Е.Ю. и др. Отдаленные результаты терапии ингибиторами тирозинкиназ у больных хроническим миелолейкозом в ранней и поздней хронической фазе. Клиническая онкогематология. 2016;9(3):368.

    [Shukhov OA, Turkina AG, Chelysheva EYu, et al. Long-Term Results of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients in Early and Late Chronic Phase. Clinical oncohematology. 2016;9(3):368, abstract. (In Russ)]

  5. Steegmann JL, Michallet M, Morra E, et al. Imatinib use in chronic phase CML in clinical practice: the UNIC study. J Clin Oncol. 2008;26(15 Suppl):7077. doi: 10.1200/jco.2008.26.15_suppl.7077.

  6. Michallet M, Tulliez M, Corm S, et al. Management of chronic myeloid leukaemia in clinical practice in France: results of the French subset of patients from the UNIC study. Curr Med Res Opin. 2010;26(2):307–17. doi: 10.1185/03007990903479299.

  7. Goldberg SL, Cortes JE, Gambacorti‐Passerini C, et al. First‐line treatment selection and early monitoring patterns in chronic phase‐chronic myeloid leukemia in routine clinical practice: SIMPLICITY. Am J Hematol. 2017;92(11):1214–23. doi: 10.1002/ajh.24887.

  8. Туркина А.Г., Зарицкий А.Ю., Шуваев В.А. и др. Клинические рекомендации по диагностике и лечению хронического миелолейкоза. Клиническая онкогематология. 2017;10(3):294–316. doi: 10.21320/2500-2139-2017-10-3-294-316.

    [Turkina AG, Zaritskii AYu, Shuvaev VA, et al. Clinical Recommendations for the Diagnosis and Treatment of Chronic Myeloid Leukemia. Clinical oncohematology. 2017;10(3):294–316. doi: 10.21320/2500-2139-2017-10-3-294-316. (In Russ)]

  9. Стахина О.В., Туркина А.Г., Гусарова Г.А. и др. Отдаленные результаты выживаемости больных в поздней хронической фазе Ph+ хронического миелолейкоза при лечении иматиниб мезилатом (Гливек®). Вестник гематологии. 2009;5(2):42.

    [Stakhina OV, Turkina AG, Gusarova GA, et al. Long-term results of survival rates of patients in late chronic phase of Ph+ chronic myeloid leukemia treated with imatinib mesylate (Glivec®). Vestnik gematologii. 2009;5(2):42. (In Russ)]

  10. Туркина А.Г., Челышева Е.Ю. Стратегия терапии хронического миелолейкоза: возможности и перспективы. Терапевтический архив. 2013;85(7):4–9.

    [Turkina AG, Chelysheva EYu. Therapeutic strategy for chronic myeloid leukemia: possibilities and prospects. Terapevticheskii arkhiv. 2013;85(7):4–9. (In Russ)]

  11. Branford S, Lawrence R, Grigg A, et al. Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response. Blood. 2008;112(11):2113.

  12. Hasford J, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118(3):686–92. doi: 10.1182/blood-2010-12-319038.

  13. Kantarjian H, Cortes JE. Complete Cytogenetic Response, Not Deep Molecular Response, Is Associated With Survival in Chronic Myeloid Leukemia. J Clin Oncol. 2014;32(27):3077. doi: 10.1200/jco.2014.56.0904.

  14. Hughes TP, Hochhaus A, Branford S, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010;116(19):3758–65. doi: 10.1182/blood-2010-03-273979.

  15. Smith AG, Painter D, Howell DA, et al. Determinants of survival in patients with chronic myeloid leukaemia treated in the new era of oral therapy: findings from a UK population-based patient cohort. BMJ Open. 2014;4(1):e004266. doi: 10.1136/bmjopen-2013-004266.

  16. Шуваев В.А., Абдулкадырова А.С., Мартынкевич И.С. и др. Опыт лечения хронического миелолейкоза в Санкт-Петербурге. Вестник гематологии. 2011;7(1):43.

    [Shuvaev VA, Abdulkadyrova AS, Martynkevich IS, et al. Experience of chronic myeloid leukemia treatment in Saint Petersburg. Vestnik gematologii. 2011;7(1):43. (In Russ)]

  17. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84. doi: 10.1182/blood-2013-05-501569.

  18. NCCN Guidelines. Chronic Myelogenous Leukemia Version 4.2018. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. (accessed 10.05.2018).

  19. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303–9. doi: 10.1182/blood-2006-09-047266.

  20. Mauro MJ, Baccarani M, Cervantes F, et al. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C). J Clin Oncol. 2008;26(15 Suppl):1. doi: 10.1200/jco.2008.26.15_suppl.7009.

  21. Nicolini FE, Turkina A, Shen Z-X, et al. Expanding Nilotinib Access in Clinical Trials (ENACT). Cancer. 2012;118(1):118–26. doi: 10.1002/cncr.26249.

  22. Tefferi A, Letendre L. Nilotinib treatment-associated peripheral artery disease and sudden death: Yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am J Hematol. 2011;86(7):610–1. doi: 10.1002/ajh.22051.

  23. Valent P, Hadzijusufovic E, Schernthaner G-H, et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2014;125(6):901–6. doi: 10.1182/blood-2014-09-594432.

  24. Quintas-Cardama A, Han X, Kantarjian H, et al. Tyrosine kinase inhibitor–induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114(2):261–3. doi: 10.1182/blood-2008-09-180604.

  25. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure. J Clin Oncol. 2007;25(25):3908–14. doi: 10.1200/jco.2007.12.0329.

  26. Krauth M-T, Herndlhofer S, Schmook M-T, et al. Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily. Haematologica. 2011;96(1):163–6. doi: 10.3324/haematol.2010.030494.

  27. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118(17):4567–76. doi: 10.1182/blood-2011-05-355594.

  28. Puttini M, Coluccia AML, Boschelli F, et al. In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells. Cancer Res. 2006;66(23):11314–22. doi: 10.1158/0008-5472.CAN-06-1199.

  29. Redaelli S, Piazza R, Rostagno R, et al. Activity of Bosutinib, Dasatinib, and Nilotinib Against 18 Imatinib-Resistant BCR/ABL Mutants. J Clin Oncol. 2009;27(3):469–71. doi: 10.1200/jco.2008.19.8853.

  30. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119(15):3403–12. doi: 10.1182/blood-2011-11-390120.

  31. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 2017;36(3):231–7. doi: 10.1200/jco.2017.74.7162.

  32. Бозулиф® (инструкция по медицинскому применению). Pfizer, США. Доступно по: https://www.24farm.ru/preparats/bozulif_pfizer/. Ссылка активна на 30.05.2018.

    [Bosulif® (package insert). Pfizer, USA. Available from: https://www.24farm.ru/preparats/bozulif_pfizer/. (accessed 30.05.2018) (In Russ)]

  33. National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Available from: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. (accessed 29.04.2018).

The Use of Pomalidomide in the Treatment of Relapsed/Refractory Multiple Myeloma in Patients with Renal Failure

NOVEL DRUGS , ,

IG Rekhtina, MV Nareiko, LP Mendeleeva

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

For correspondence: Irina Germanovna Rekhtina, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-49-66; e-mail: rekhtina.i@blood.ru

For correspondence: Rekhtina IG, Nareiko MV, Mendeleeva LP. The Use of Pomalidomide in the Treatment of Relapsed/Refractory Multiple Myeloma in Patients with Renal Failure. Clinical oncohematology. 2018;11(4):283–7.

DOI: 10.21320/2500-2139-2018-11-4-283-287

ABSTRACT

The present review includes data on efficacy and safety of pomalidomide, an immunomodulating 3rd generation drug used for treatment of relapsed and refractory multiple myeloma patients with renal failure. The results of multicenter randomized trials proved similar efficacy and comparable safety profile in patients with normal renal function and patients with moderate and/or severe renal failure. All patients received the standard starting dose. Pomalidomide dose needs to be reduced in response to hematological toxicity. The paper provides practical guidelines on the use of pomalidomide and treatment of adverse events adopted by consensus of international experts. Current approaches to multiple myeloma with renal failure, and the use of pomalidomide in particular, are demonstrated by means of a clinical case.

Keywords: multiple myeloma, pomalidomide, renal failure.

Received: March 28, 2018

Accepted: July 16, 2018

Read in PDF 

REFERENCES

  1. Qian Y, Bhowmik D, Bond C, et al. Renal impairment and use of nephrotoxic agents in patients with multiple myeloma in the clinical practice setting in the United States. Cancer Med. 2017;6(7):1523–30. doi: 10.1002/cam4.1075.

  2. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2).

    [Mendeleeva LP, Votyakova OM, Pokrovskaya OS, et al. National clinical guidelines on diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). (In Russ)]

  3. Имновид® (инструкция по медицинскому применению). Будри, Швейцария: Celgene International, Sarl. Доступно по: https://www.vidal.ru/drugs/imnovid__44356. Ссылка активна на 30.06.2018.

    [Imnovid® (package insert). Boudry, Switzerland: Celgene International, Sarl. Available from: https://www.vidal.ru/drugs/imnovid__44356. (accessed 30.06.2018) (In Russ)]

  4. Dimopoulos MA, Palumbo A, Corradini P, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016;128(4):497–503. doi: 10.1182/blood-2016-02-700872.

  5. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826–32. doi: 10.1182/blood-2014-04-566661.

  6. Miguel JS, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomized, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055–66. doi: 10.1016/S1470-2045(13)70380-2.

  7. Siegel DS, Weisel KC, Dimopoulosc MA, et al. Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials. Leuk Lymphoma. 2016:57(12):2833–8. doi: 10.1080/10428194.2016.1177181.

  8. Matous J, Siegel DS, Lonial S, et al. A Phase 1 Study of the Pharmacokinetics (PK) and Safety of Pomalidomide + Low Dose Dexamethasone (POM+LODEX) in Patients (PTS) With Relapsed or Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI). Clin Lymph Myel Leuk. 2015;15:e265. doi: 10.1016/j.clml.2015.07.557.

  9. Sonneveld P, Dimopoulos M, Ramasamy K, et al. Treatment (Tx) With Pomalidomide (POM) and Low-Dose Dexamethasone (LoDEX) in Patients (Pts) With Relapsed or Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI) Including Those on Dialysis. Clin Lymph Myel Leuk. 2015;15:e265. doi: 10.1016/j.clml.2015.07.556.

  10. Weisel K, Dimopoulos M, Van de Donk N, et al. Phase 2 Multicenter Study of Pomalidomide (POM) Plus Low-Dose Dexamethasone (LoDEX) in Patients (Pts) With Relapsed/Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI): An Updated Safety Analysis. Clin Lymph Myel Leuk. 2017;17(1):e145. doi: 10.1016/j.clml.2017.03.261.

  11. Sonneveld P, Weisel K, Van de Donk N et al. MM-013 phase 2 multicenter study of pomalidomide plus low-dose dexamethasone in patients with RRMM and renal impairment. 22nd Congress of the European Hematology Association (EHA). 2017. Abstract P343.

  12. Li Y, Wang X, O’Mara E, et al. Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function. Clin Pharmacol Adv Appl. 2017;9:133–45. doi: 10.2147/CPAA.S144606.

  13. Dimopoulos M, Leleu X, Palumbo A, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573–85. doi: 10.1038/leu.2014.60.

PD-1 Blockade with Nivolumab as a New Immunotherapy for Classical Hodgkin’s Lymphoma

NOVEL DRUGS , , ,

EA Demina

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

For correspondence: Prof. Elena Andreevna Demina, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: drdemina@yandex.ru

For citation: Demina EA. PD-1 Blockade with Nivolumab as a New Immunotherapy for Classical Hodgkin’s Lymphoma. Clinical oncohematology. 2018;11(3):213–19.

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

ABSTRACT

During the last two decades individualization of programmed treatment combined with intensified chemotherapy has proven to be effective treatment for the majority of classical Hodgkin’s lymphoma (cHL) patients. However, in 10–30 % of cases relapses and resistance to therapy still occur. Further intensification of therapy induces toxicity that leads to decrease in overall survival and quality of life. The standard second-line treatment with high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (auto-HSCT) allows for the achievement of long-term 5-year progression-free survival only in 50–60 % of patients with relapsed disease and not more than 40–45 % of patients with refractory disease. Approximately 50 % of patients relapse after HDCT and auto-HSCT. The median overall survival of relapsed patients does not exceed 2 years. Allogeneic HSCT improves treatment results to some extent, but is not an optimal strategy in all patients. A search for new treatment options has been made to improve effectiveness of relapsed and refractory cHL treatment and to reduce toxicity of highly effective programs. А new CD30-targeted conjugate brentuximab vedotin was developed to use anti-CD30 monoclonal antibodies against a specific marker of tumor Reed-Sternberg cells allowing for the transfer of the highly effective antitumor compound of monomethyl auristatin E directly to tumor cells. This drug showed high effectiveness, although failed to provide a complete solution to the problem. The development of anti-PD1 antibody nivolumab opened up new opportunities for cHL treatment. This paper reviews literature information on pharmacological data and antitumor mechanisms of the drug as well as the results of significant international randomised studies.

Keywords: nivolumab, Hodgkin’s lymphoma, relapse, resistance, treatment.

Received: February 5, 2018

Accepted: April 30, 2018

Read in PDF 

REFERENCES

  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

The Use of Brentuximab Vedotin in Relapsed/Refractory Hodgkin’s Lymphoma in the Kransnodar Region

NOVEL DRUGS , , ,

OD Serdyuk, DA Yaskul’skii

Clinical Oncology Dispensary No. 1 of the Krasnodar region, 146 Dimitrova str., Krasnodar, Russian Federation, 350040

For correspondence: Ol’ga Dmitrievna Serdyuk, 146 Dimitrova str., Krasnodar, Russian Federation, 350040; Tel.: +7(918)441-08-33; e-mail: 7-18@mail.ru

For citation: Serdyuk OD, Yaskul’skii DA. The Use of Brentuximab Vedotin in Relapsed/Refractory Hodgkin’s Lymphoma in the Kransnodar Region. Clinical oncohematology. 2018;11(1):50-3.

DOI: 10.21320/2500-2139-2018-11-1-50-53

ABSTRACT

The treatment of relapsed/refractory Hodgkin’s lymphoma (HL) remains to be a challenging issue. The morbidity of HL is reported to increase in the Krasnodar region. While considerable progress in the treatment of HL has been achieved, the relapse rate still remains high. The standard second-line treatment allows for the disease control in only half of cases of relapsed HL. Until recently, however, relapses after autologous hematopoietic stem cell transplantation (autoHSCT) could be treated only by polychemotherapy aimed at slowing the tumor growth. The use of anti-CD30 conjugated monoclonal antibodies and cytotoxic agent was shown to control the relapsed disease after high dose chemotherapy followed by autoHSCT. The present study provides pharmacological characteristics of brentuximab vedotin, its antineoplastic mechanism as well as the author’s own clinical experience in the management of a female patient with HL after autoHSCT.

Keywords: Hodgkin’s lymphoma, brentuximab vedotin, targeted therapy, relapse.

Received: November 25, 2017

Accepted: January 8, 2018

Read in PDF 

REFERENCES

  1. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2016. С. 9, 22. [Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines in diagnosis and treatment of lymphoproliferative disorders.) Moscow: Buki Vedi Publ.; 2016. pp. 9, 22. (In Russ)]
  2. Злокачественные новообразования в России в 2013 г. (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Стравинского, Г.В. Петровой. М., 2017. С. 113, 212. [Kaprina AD, Stravinskii VV, Petrova GV, eds. Zlokachestvennye novoobrazovaniya v Rossii v 2013 godu (zabolevaemost’ i smertnost’). (Malignant Tumors in Russia 2013 (Morbidity and Mortality.) Moscow; 2015. pp. 113, 212. (In Russ)]
  3. Казанцева М.В., Тесленко Л.Г., Бондарева И.С. и др. Злокачественные новообразования в Краснодарском крае (2010–2014 годы). Состояние онкологической помощи населению. Краснодар, 2015. С. 262. [Kazantseva MV, Teslenko LG, Bondareva IS, et al. Zlokachestvennye novoobrazovaniya v Krasnodarskom krae (2010–2014 gody). Sostoyanie onkologicheskoi pomoshchi naseleniyu. (Malignant tumors in the Krasnodar region (2010–2014). The state of cancer care.) Krasnodar; 2015. pp. 262. (In Russ)]
  4. Ferrero S, Drandi D, Mantoan B, et al. Minimal residual disease detection in lymphoma and multiple myeloma: impact on therapeutic paradigms. Hematol Oncol. 2011;29(4):167–76. doi: 10.1002/hon.989.
  5. Демина Е.А. Брентуксимаб ведотин: новые возможности лечения рецидивов и рефрактерных форм лимфомы Ходжкина. Клиническая онкогематология. 2016;9(4):398–405. doi: 10.21320/2500-2139-2016-9-4-398-405. [Demina EA. Brentuximab Vedotin: New Possibilities for Treatment of Relapses and Refractory Hodgkin’s Lymphomas. Clinical oncohematology. 2016;9(4):398–405. doi: 10.21320/2500-2139-2016-9-4-398-405. (In Russ)]
  6. 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.
  7. Chen R, Gopal AK, Smith SE, et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016;128(12):1562–6. doi: 10.1182/blood-2016-02-699850.
  8. 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.
  9. 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.

Ibrutinib in the Treatment of Relapsed Chronic Lymphocytic Leukemia

NOVEL DRUGS , , ,

EA Stadnik, NS Timofeeva, VV Strugov, AYu Zaritskey

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

For correspondence: Elena Aleksandrovna Stadnik, PhD, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(921)575-54-55; e-mail: elena_stadnik@mail.ru

For citation: Stadnik EA, Timofeeva NS, Strugov VV, Zaritskey AYu. Ibrutinib in the Treatment of Relapsed Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(1):42–9.

DOI: 10.21320/2500-2139-2018-11-1-42-49

ABSTRACT

Aim. To estimate ibrutinib efficacy in the treatment of first early CLL relapses and in patients with ≥ 2 lines of preceding therapy. Analysis of treatment results in patients with del(17p) and monitoring of minimal residual disease (MRD) and ibrutinib safety profile.

Materials & Methods. The analysis included the results of ibrutinib treatment in 31 patients with CLL. Twenty eight patients were treated by bendamustine and fludarabine containing regimens. The median prior treatment lines were 2 (range 1–10). The indications for the treatment initiation were the first early relapse in 51 % of cases (n = 16) and a relapse after 2 and more lines of therapy in 49 % of cases (n = 15). Ibrutinib was administered in mono- (n = 15) and combined therapy (n = 14) as well as in the R-BAC scheme (n = 2). Using FISH analysis del(17p) was found in 9 patients (34 %).

Results. Within the median follow up of 18 months (range 7–42+) the overall survival (OS) rate was reported to be 87 %, and the progression-free survival (PFS) rate was 77 %. The maximum MRD after a year of ibrutinib treatment was observed in case of combination with immunochemotherapy (e.g., R-BAC). Within the period of 18 months OS rate was 100 %, in the patient group with first early relapses and 66 % in the group with a relapse after 2 and more therapy lines (p = 0.02). Within the same examination period PFS was significantly higher (94 %) in the patient group with first early relapses compared to the previously treated patients (60 %) (p = 0.034). The most common adverse events were grade 1–2 purpura (30 %), grade 1–2 diarrhea (10 %), atrial fibrillation paroxysms (10 %) and arterial hypertension (10 %). Severe infectious complications registered in 6 % (n = 3) patients were successfully solved in the course of combined antibacterial and antimycotic treatment.

Conclusion. Ibrutinib was shown to be effective drug for treatment of relapsed CLL. The OS and PFS values were more favourable in patients with first early relapses compared to the patients with relapses after ≥ 2 lines of therapy prior to ibrutinib treatment. The maximum elimination of the tumor clone was observed after combined ibrutinib/immunochemotherapy treatment. The tolerance of ibrutinib was reported to be satisfactory with acceptable toxicity profile. No mortality due to infection complications was observed.

Keywords: chronic lymphocytic leukemia, first early relapse, del(17p), ibrutinib, minimal residual disease.

Received: August 20, 2017

Accepted: November 16, 2017

Read in PDF 

REFERENCES

  1. Fornecker LM, Aurran-Schleinitz T, Michallet AS, 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;90(6):511–4. doi: 10.1002/ajh.23999.
  2. Стадник Е.А., Стругов В.В., Андреева Т.О. и др. Эффективность комбинации бендамустина ритуксимаба в первой линии терапии ХЛЛ: результаты исследования BEN-001. Терапевтический архив. 2017;89(7):57–64. doi: 10.17116/terarkh201789757-64. [Stadnik EA, Strugov VV, Andreeva TO, et al. Efficacy of a bendamustine and rituximab combination in first-line therapy for chronic lymphocytic leukemia: Results of the BEN-001 study. Terapevticheskii arkhiv. 2017;89(7):57–64. doi: 10.17116/terarkh201789757-64. (In Russ)]
  3. Стругов В.В., Стадник Е.А., Вирц Ю.В. и др. Значение возраста и сопутствующих заболеваний в терапии хронического лимфолейкоза. Клиническая онкогематология. 2016;9(2):162–75. doi: 10.21320/2500-2139-2016-9-2-162-175. [Strugov VV, Stadnik EA, Virts YuV, et al. Role of Patient’s Age and Comorbidities in Therapy of Chronic Lymphocytic Leukemia. Clinical oncohematology. 2016;9(2):162–75. doi: 10.21320/2500-2139-2016-9-2-162-175. (In Russ)]
  4. Никитин Е.А., Стадник Е.А., Лорие Ю.Ю. и др. Прогностическое значение мутационного статуса генов вариабельного региона иммуноглобулинов у больных хроническим лимфолейкозом, получавших комбинированную терапию флударабином и циклофосфаном. Терапевтический архив. 2007;79(7):66–70. [Nikitin EA., Stadnik EA, Lorie YuYu, et al. Prognostic significance of immunoglobulin variable region mutations in B-CLL patients treated with combination therapy fludarabine plus cyclophosphamide. Terapevticheskii arkhiv. 2007;79(7):66–70. (In Russ)]
  5. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303–9. doi: 10.1182/blood-2015-09-667675.
  6. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208–15. doi: 10.1182/blood-2015-06-651125.
  7. Robbe P, Ridout K, Becq J, et al. Identifying High-Risk CLL to Predict Early Relapse after FCR Based Treatment Using Whole Genome Sequencing: First Results from the Genomics England CLL Pilot. Blood. 2016;128:2022.
  8. Castro JE, James DF, Sandoval-Sus JD, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009;23(10):1779–89. doi: 10.1038/leu.2009.133.
  9. Cramer P, Fink A-M, Busch R, et al. Second-line therapies of patients initially treated with fludarabine and cyclophosphamide or fludarabine, cyclophosphamide and rituximab for chronic lymphocytic leukemia within the CLL8 protocol of the German CLL Study Group. Leuk Lymphoma. 2013;54(8):1821–2. doi: 10.3109/10428194.2013.796050.
  10. Brown JR. The Treatment of Relapsed Refractory Chronic Lymphocytic Leukemia. Hematology. 2011;2011(1):110–8. doi: 10.1182/asheducation-2011.1.110.
  11. Tam CS, O’Brien S, Plunkett W. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood. 2014;124(20):3059–64. doi: 10.1182/blood-2014-06-583765.
  12. Zenz T, Busch R, Fink A, et al. Genetics of patients with F-refractory CLL or early relapse after FC or FCR: Results from the CLL8 trial of the GCLLSG [Abstract]. Blood (ASH Annual Meeting Abstracts) 2010;116(21):2427.
  13. Stilgenbauer S, Zenz T, Winkler D, et al. Genomic Aberrations, VH Mutation Status and Outcome after Fludarabine and Cyclophosphamide (FC) or FC Plus Rituximab (FCR) in the CLL8 Trial. Blood. 2008;112(11): Abstract 781.
  14. Montserrat E, Dreger P. Treatment of Chronic Lymphocytic Leukemia With del(17p)/TP53 Mutation: Allogeneic Hematopoietic Stem Cell Transplantation or BCR-Signaling Inhibitors? Clin Lymph Myel Leuk. 2016;16:S74–S81. doi: 10.1016/j.clml.2016.02.013.
  15. Gladstone DE, Blackford A, Cho E, et al. The Importance of IGHV Mutational Status in del(11q) and del(17p) Chronic Lymphocytic Leukemia. Clin Lymph Myel Leuk. 2012;12(2):132–7. doi: 10.1016/j.clml.2011.12.005.
  16. The International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779–90. doi: 10.1016/S1470-2045(16)30029-8.
  17. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23. doi: 10.1056/nejmoa1400376.
  18. O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17(10):1409–18. doi: 10.1016/s1470-2045(16)30212-1.
  19. Visco C, Finotto S, Pomponi F, et al. The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia. Am J Hematol. 2013;88(4):289–93. doi: 10.1002/ajh.23391.
  20. Castegnaro S, Visco C, Chieregato K. et al. Cytosine arabinoside potentiates the apoptotic effect of bendamustine on several B- and T-cell leukemia/lymphoma cells and cell lines. Leuk Lymphoma. 2012;53(11):2262–8. doi: 10.3109/10428194.2012.688200.
  21. Brown JR, Hillmen P, O’Brien S, et al. Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATE TM Trial of Ibrutinib Versus Ofatumumab. Blood. 2014;124(21): Abstract 3331.
  22. Jones J, Coutr S, Byrd JC, et al. Evaluation of 243 patients with deletion 17p chronic lymphocytic leukemia treated with ibrutinib: a cross-study analysis of treatment outcomes. EHA Learning Center. 2016;135185: Abstract S429.
  23. Burger JA, Keating MJ, Wierda WG. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15(10):1090–9. doi: 10.1016/S1470-2045(14)70335-3.
  24. Fraser G, Cramer P, Hallek M, et al. Three-Year Follow-up of Patients With Previously Treated Chronic Lymphocytic Lymphoma (CLL) Receiving Ibrutinib Plus Bendamustine and Rituximab (BR) Versus Placebo Plus BR. An Update of the HELIOS Study. XVII iwCLL. 2017: Abstract 400.
  25. Burger JA, Tedeschi A, Bar PM. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425–37. doi: 10.1056/NEJMoa1509388.

Current Opportunities for Treatment Optimization of Mycosis Fungoides and Sezary Syndrome

NOVEL DRUGS , , ,

NG Chernova1, OA Kolomeitsev2

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

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

For correspondence: Natal’ya Gennad’evna Chernova, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-48-10; е-mail: ngchernova@mail.ru

For citation: Chernova NG, Kolomeitsev OA. Current Opportunities for Treatment Optimization of Mycosis Fungoides and Sezary Syndrome. Clinical oncohematology. 2018;11(1):34–41.

DOI: 10.21320/2500-2139-2018-11-1-34-41

ABSTRACT

Aim. To estimate vorinostat efficacy in patients with relapsed/refractory mycosis fungoides and Sezary syndrome.

Materials & Methods. The total of 21 patients with refractory and progressive mycosis fungoides and Sezary syndrome receiving vorinostat 400 mg once daily were followed up from 2014 to 2017. The median age was 62 years (range 34–79). The male to female ratio was 10/11. The median number of various regimens of pre-study systemic treatment was 4 (range 1–7). Progressive disease were observed in 85,7 % of patients before administration of vorinostat and after mono- and polychemotherapy.

Results. The study group included 15 patients with mycosis fungoides and 6 patients with Sezary syndrome. Early stages of primary cutaneous T-cell lymphoma were diagnosed in 4 patients, the advanced stages in 17 patients. Seventeen patients received vorinostat treatment in monoregime; 4 patients were administered with vorinostat in combination with methotrexate or α-interferon. The median duration of vorinostat therapy was 6 months (range 1–38). Stabilization of the disease was observed in 47.6 % of cases, response to treatment in 38.1 % of cases (with 5 cases of complete response and 3 cases of partial response), and 14.3 % of patients had progression of the disease. The decrease of skin itching was reported in 38.1 % of patients; skin itching completely resolved in 28.6 % of cases. The adverse events required the vorinostat dose adjustment in 3 cases and treatment discontinuation in 3 cases. The total of 9 patients continue to receive vorinostat.

Conclusion. Vorinostat treatment was shown to be effective in patients with refractory and advanced mycosis fungoides and Sezary syndrome not responding to various types of external, mono- and polychemotherapy. The therapy with vorinostat was associated with higher life expectancy and improved quality of life.

Keywords: vorinostat, mycosis fungoides, Sezary syndrome, refractory and advanced stages, primary cutaneous T-cell lymphoma.

Received: August 18, 2017

Accepted: December 1, 2017

Read in PDF 

REFERENCES

  1. Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med. 2004;350(19):1978–88. doi: 10.1056/NEJMra032810.
  2. Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  3. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124–30. doi: 10.1200/JCO.2008.16.4558.
  4. Виноградова Ю.Е., Луценко И.Н., Кременецкая А.М. и др. Структура T/NK-клеточных лимфатических опухолей в Гематологическом научном центре РАМН. Проблемы гематологии и переливания крови. 2005;4:30–4. [Vinogradova YuE, Lutsenko IN, Kremenetskaya AM, et al. Distribution of T/NK cell lymphoma types in Hematology Research Centre. Problemy gematologii i perelivaniya krovi. 2005;4:30–4. (In Russ)]
  5. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(10):3768–85. doi: 10.1182/blood-2004-09-3502.
  6. Gemmill R. Cutaneous T-cell lymphoma. Semin Oncol Nurs. 2006;22(2):90–6. doi: 10.1016/j.soncn.2006.01.005.
  7. Olsen EA, Rook AH, Zic J, et al. Sezary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol. 2011;64(2):352–404. doi: 10.1016/j.jaad.2010.08.037.
  8. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2016. С. 84–113. [Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines in diagnosis and treatment of lymphoproliferative disorders) Moscow: Buki Vedi Publ.; 2016. pp. 84–113. (In Russ)]
  9. Stowell JC, Huot RI, Van Voast L. The synthesis of N-hydroxy-N’-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells. J Med Chem. 1995;38(8):1411–3.
  10. Lai JP, Yu C, Moser CD, et al. SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma. Gastroenterology. 2006;130(7):2130–44. doi: 10.1053/j.gastro.2006.02.056.
  11. Marks PA. Discovery and development of SAHA as an anticancer agent. Oncogene. 2007;26(9)1351–6. doi: 10.1038/sj.onc.1210204.
  12. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31–9. doi: 10.1182/blood-2006-06-025999.
  13. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(21):3109–15. doi: 10.1200/JCO.2006.10.2434.
  14. Duvic M, Olsen EA, Breneman D, et al. Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma. Clin Lymph Myel. 2009;9(6):412–6. doi: 10.3816/CLM.2009.n.082.
  15. Mann BS, Johnson JR, He K, et al. Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clin Cancer Res. 2007;13:2318–22. doi: 10.1158/1078-0432.CCR-06-2672.