№ 1 / 2015 / 90-97

The results of 12 years treatment of patients in late chronic phase of chronic myeloid leukemia by tyrosine kinase inhibitors after failure IFN-α

Author: Lazareva O.V.¹, Turkina A.G.², Gusarova G.A.³, Chelysheva E.Yu.⁴, Zakharova E.S.⁵, Shukhov O.A.⁶, Bykova A.V.⁷, Goryacheva S.R.⁸, Kolosheinova T.I.⁹, Ivanova T.V.¹⁰, Tishchenko I.A.¹¹, Kulikov S.M.¹²

Author Affiliations

Abstract

Expanding the range of tyrosine kinase inhibitors (TKI) from the 1st (imatinib) to 2nd generation (nilotinib, dasatinib, bosutinib) allows achieving the suppression of Ph′-positive leukemia clone in the treatment of patients with chronic myeloid leukemia (CML). The aim of our study was to evaluate the results of 12 years treatment by TKIs of the 1st and 2nd generation of patients in late chronic phase (CP) CML including the overall survival (OS) and progression-free survival, mortality in the group structure. Overall 12-year survival was 68 %, progression-free survival was 66 %. The annual mortality from progression of CML remains unchanged during the last 3 years – 1.3 % occurrences per year. The death main cause remains the progression of CML. Achieving of the complete cytogenetic response (CCyR) for various periods of therapy by TKIs of the 1st and 2nd generation was observed in 54 (68 %) patients, firstly CCyR was obtained in 10 (30 %) of 34 patients due to therapy change to the TKI of the 2nd generation. The OS in patients with CCyR at 12 months of TKI-1 was 90 % versus 67 % in patients without response to this term (p = 0.05). The mortality of patients without the CCyR was 80 %. The possibility of stable recovery of residual clone Ph′-negative cells has been revealed in the group of patients in late CP CML with poor prognosis (resistance and intolerance to IFN). It is associated with the increase in OS and progression-free survival. Considering the possibility of long-term molecular remission during therapy by TKIs, it is necessary to develop the program on conducting remission without maintenance treatment in patients with complete molecular response. The interruption of TKIs intake without deep stable molecular response is dangerous for patients and may lead to the progression of CML up to death.

Key words

imatinib, tyrosine kinase inhibitors, the characteristic of molecular response, overall survival, chronic myeloid leukemia, the prognostic value of a complete cytogenetic response, chronic myeloid leukemia

References

1. Druzhkova G.A. Inhibitor of bcr/abl- tyrosine kinase in the treatment of patients with chronic myeloid leukemia resistant to interferon-α: abstract of thesis…candidate of medical sciences. Moscow, 2005. (in Russian)

2. Lazareva O.V. Information technology for monitoring and analyzing long-term results of therapy in patients with chronic myeloid leukemia: abstract of thesis…candidate of medical sciences. Moscow, 2011. (in Russian)

3. Guidelines for the diagnosis and treatment of chronic myeloid leukemia. Saint-Petersburg; Moscow. 2013. 10 p. (in Russian)

4. Turkina A.G., Khoroshko N.D., Druzhkova G.A. et al. The effectiveness of therapy with imatinib mesylate (Gleevec) in patients with chronic-phase chronic myeloid leukemia // Therapevticheskiy arckhiv. 2003. 75. (8). 62–67. (in Russian)

5. Allan N., Richards S., Sheperd P. et al. UK Medical Research Council randomized multicenter trial of interferon-alpha in chronic myeloid leukemia: improved survival irreppective of cytogenetic response // Lancet. 1995. 345. 1392–1397.

6. Bonifazi F., De Vivo A., Rosti G. et al. Chronic myeloid leukemia and interferon-alpha: A study of complete cytogenetic responders // Blood. 2001. 98. 3074–3081.

7. Deininger M., O’Brien S.G., 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). 142.

8. Hochhaus A., Druker B.J., Larson R.A. et al. IRIS 6-year follow-up: sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib // Blood (ASH Annual Meeting Abstracts). 2007. 110. Abstr. 25.

9. Kantarjian H., Smith T., O’Brien S. et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy // Ann. Intern. Med. 1995. 122. 254–261.

10. National Cancer Institute, Bethesda. Common Terminology Criteria for Adverse Events, Version 3.0. March 31, 2003.

11. O’Brien S., Kantarjian H., Keating M. et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase // Blood. 1995. 86. 3322–3326.

12. Quintas-Cardama A., Kantarjian H.M., Cortes J.E. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia // Cancer Control. 2009. 16. 122–131.

13. Raanani P., Ben-Bassat I., Gann S. et al. Assessment of the response to imatinib in chronic myeloid leukemia patients: comparison between the FISH, multiplex and RT-PCR methods // Eur. J. Hematol. 2004. 73. 243–250.

14. Reinhold U., Henning E., Leiblein S. et al. FISH for BCR-ABL on interphases of peripheral blood neutrophils but not of unselected white bone marrow cells in CML patents treated with imatinib // Leulemia. 2003. 17. 1925–1929.

15. Rodriguez J., Cortes J., Smith T. et al. Determinants of prognosis in late chronic-phase chronic myelogenous leukemia // J. Clin. Oncol. 1998. 16. 3782–3787.

16. Sokal J.E. Prognosis in chronic myeloid leukemia; biology of the disease vs treatment // Baillieres Clin. Haematol. 1987. 1. 907–929.

17. SAS Institute Inc. 2004. SAS® 9.1.3, Cary, NC: SAS Institute Inc.

About Authors (Correspondence):

Lazareva O.V. – candidate of medical sciences, researcher of the scientific advisory department of chemotherapy myeloproliferative disorders, e-mail: stakhino@gmail.com

Turkina A.G. – doctor of medical sciences, professor, head of the scientific advisory department chemotherapy myeloproliferative disorders, e-mail: turkianna@yandex.ru

Gusarova G.A. – candidate of medical sciences, senior researcher of the scientific advisory department chemotherapy myeloproliferative disorders, e-mail: galina1966@bk.ru

Chelysheva E.Yu. – candidate of medical sciences, senior researcher of the scientific advisory department chemotherapy myeloproliferative disorders, e-mail: denve@bk.ru

Zakharova E.S. – candidate of medical sciences, doctor-hematologist

Full Text

17-1-2015.pdf

Received: 17/02/2015