toxicity

Second Generation Tyrosine Kinase Inhibitors and Their Toxicity in Treatment of Patients in Chronic Phase of Chronic Myeloid Leukemia

MYELOID TUMORS , ,

N.S. Lazorko1, E.G. Lomaia1, E.G. Romanova1, E.I. Sbityakova1, E.R. Machyulaitene2, P.A. Butylin1,3, A.Yu. Zaritskii1,2

1 Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341

2 Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russia, 197022

3 Saint Petersburg State University of Information Technologies, Mechanics and Optics, Institute of Translational Medicine, 49 Kronverkskii pr-t, Saint Petersburg, Russia, 197101

For correspondence: Elza Galaktionovna Lomaia, PhD, 2 Akkuratova str., Saint Petersburg, Russia, 197341; Tel.: +7(812)702-37-65; e-mail: lomelza@gmail.com

For citation: Lazorko N.S., Lomaia E.G., Romanova E.G., Sbityakova E.I., Machyulaitene E.R., Butylin P.A., Zaritskii A.Yu. Second Generation Tyrosine Kinase Inhibitors and Their Toxicity in Treatment of Patients in Chronic Phase of Chronic Myeloid Leukemia. Klin. Onkogematol. 2015;8(3):302–8. (In Russ.)

ABSTRACT

Background & Aims. Certain experience in the use of new tyrosine kinase inhibitors (TKIs) in treatment of patients with chronic myeloid leukemia has been obtained over the last years. The article summarizes literature data on toxicity obtained in international clinical trials. The aim of the study is to evaluate adverse effects of second generation TKIs in the routine clinical practice and to assess their effect on patient future life.

Methods. We analyzed our own data obtained during routine clinical practice. 76 patients (36 men and 40 women) over 18 years of age (median age was 49 years, range 26–75) with chronic myeloid leukemia were enrolled in the retrospective trial. 48 patients were treated with nilotinib, 28 patients received dazatinib during the chronic phase of the disease as a second line therapy after withdrawal of imatinib mesylate. The toxicity degree was determined according to CTCAE 4.0 criteria.

Results. III–IV degree hematologic toxicity was registered in 36.8 % of patients. No significant difference in the incidence of complications between nilotinib and dazatinib groups was observed: 39.6 % and 32.1 %, respectively. II–IV degree non-hematologic toxicity was found in 35.4 % patients on nilotinib and in 25 % of patients on dazatinib. The incidence of individual types of toxicity did not exceed 15 %. A combination of different types of non-hematologic toxicity was observed in 9.2 % of patients. No TKI2 toxicity-related lethal outcomes were registered.

Conclusion. Hematologic and/or non-hematologic toxicity related to TKI2 was registered in more than 50 % of patients. In most cases, the complications were transient and eliminated after discontinuation of TKI2 or after dose reduction. TKI2-associated complications did not affect the possibility to achieve a complete cytogenetic response and its stability.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, toxicity.

Received: January 29, 2015

Accepted: June 1, 2015

Read in PDF (RUS)pdficon

REFERENCES

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

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

AUTOIMMUNE THROMBOCYTOPENIA, LYMPHOID TUMORS , , ,

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

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

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

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

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

ABSTRACT

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

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

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

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

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

Received: March 31, 2015

Accepted: May 31, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Diehl V, ed. 25 Years German Hodgkin Study Group. Medizin & Wissen; 2004.
  2. Демина Е.А. Лимфома Ходжкина: от Томаса Ходжкина до наших дней. Клиническая онкогематология. 2008;1(2):114–8.
    [Demina EA. Hodgkin’s lymphoma: from Thomas Hodgkin till present days. Klinicheskaya onkogematologiya. 2008;1(2):114–8. (In Russ)]
  3. Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386–95. doi: 10.1056/nejmoa022473.
  4. Федоренко З.П., Гайсенко А.В., Гулак Л.О. [та ін.] Рак в Украiні, 2009–2010. Захворюваність, смертність, показники діяльності онкологічноi служби. Бюл. Національного канцер-ре’стру Украiни. 2011;12:73–4.
    [Fedorenko ZP, Gaisenko AV, Gulak LO, et al. Cancer in Ukraine, 2009–2010. Morbidity and mortality rates and cancer service performance indicators. Byulleten’ Natsіonal’nogo kantser-re’stru Ukraini. 2011;12:73–4. (In Ukr.)]
  5. Engert A, Diehl V, Franklin J, et al. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 Study. J Clin Oncol. 2009;27(27):4548–54. doi: 10.1200/jco.2008.19.8820.
  6. Lister TA. Staging for Hodgkin’s disease. Semin Oncol. 1990;17(6):696–703.
  7. Aleman BM, Raemaekers JM, Tirelli U, et al. Involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med. 2003;348(24):2396–406. doi: 10.1056/nejmoa022628.
  8. Bonadonna G, Zucali R, Monfardini S, et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252–9. doi: 10.1002/1097-0142(197507)36:1<252::aid-cncr2820360128>3.0.co;2-7.
  9. Bonadonna G, Bonfante V, Viviani S, et al. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol. 2004;22(14):2835–41. doi: 10.1200/jco.2004.12.170.
  10. Engert A, Plutschow A, Eich HT, et al. Reduced Treatment Intensity in Patients with Early-Stage Hodgkin’s Lymphoma. N Engl J Med. 2010;363(7):640–52. doi: 10.1056/nejmoa1000067.
  11. Horning SJ. Risk, cure and complications in advanced Hodgkin disease. ASH Educ Program. 2007;1:197–203. doi: 10.1182/asheducation-2007.1.197.
  12. Horning SJ, Hoppe RT, Advani R, et al. Efficacy and late effects of Stanford V chemotherapy and radiotherapy in untreated Hodgkin’s disease: mature data in early and advanced stage patients. Blood. 2004;104:92a, abstract 308.
  13. Diehl V, Haverkamp H, Mueller RP, et al. Eight Cycles of BEACOPP escalated compared with 4 cycles of BEACOPP escalated followed by 4 cycles of BEACOPP baseline with or without radiotherapy in patients in advanced stage Hodgkin lymphoma (HL): final analysis of the randomised HD12 trial of the German Hodgkin Study Group (GHSG). Blood. 2008;112(11): Abstract 1558.
  14. Sieber M, Bredenfeld H, Josting А, et al. 14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced stage Hodgkin’s lymphoma: results of a pilot study of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2003;21(9):1734–9. doi: 10.1200/jco.2003.06.028.
  15. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trail): a randomised, open-label, phase 3 non-inferiority trail. The Lancet. 2012;379(9828):1791–9. doi: 10.1016/s0140-6736(11)61940-5.
  16. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86. doi: 10.1200/jco.2006.09.2403.
  17. Engert A, Franklin J, Eich HT, et al. Two cycles of ABVD plus extended field radiotherapy is superior to radiotherapy alone in early-favorable Hodgkin lymphoma: final results of the GHSG HD7 Trial. J Clin Oncol. 2007;10(10):3495–502. doi: 10.1200/jco.2006.07.0482.
  18. Engert A, Diehl V, Pluetschow A, et al. Two cycles of ABVD followed by involved field radiotherapy with 20 Gray (Gy) the new standard of care in the treatment of patients with early-stage Hodgkin lymphoma: final analysis of the randomized German Hodgkin Study Group (GHSG) HD10. Blood. 2009;114: Abstract 716.
  19. Diehl V, Franklin J, Pfistner B, Engert A. German Hodgkin Study Group. Ten-year results of a German Hodgkin Study Group randomized trial of standart and increased dose BEACOPP chemotherapy for advanced Hodgkin lymphoma (HD9). J Clin Oncol (Meeting Abstracts). 2007;25(Suppl 18):LBA8015.