Prognostic factors of the tyrosinkinase inhibitors therapy response in ukrainian cohort of patients with chronic myeloid leukemia

I. Dmytrenko, I. Dyagil, Zh. Minchenko, Z. Martina, V. Fedorenko, T. Shlyakhtychenko, V. Sholoyko, O. Dmytrenko
State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv; State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv; State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv; State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv; State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv; State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv; State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv; State institution "National Scientific Center for Radiation Medicine of NAMS of Ukraine", Kyiv

Abstract


To compare the dynamics of BCR/ABL-positive clone reduction in patients with chronic myeloid leukemia (CML) during long-term treatment with imatinib (IM) and nilotinib (NI) and to make a complex of initial prognostic factors that influence the reduction of leukemia clone and survival in CML patients.
The therapy efficacy by the level of BCR/ABL1 gene expression and survival rates was evaluated in 937 patients on IM and 72 patients on NI therapy from the total 1095 CML patients cohort examined during the period 2002–2018 years. The Cox regression was used to determine the prognostic factors associated with the best response to therapy and survival.
At 12 months of therapy the rate of patients who achieved reduction of tumor clone to the level of major molecular response (MMR) was significantly higher in the group of patients on NI than in the group of patients on IM (61.0 % vs 23.7 %, p <0.001). At 24 months of therapy the reduction of BCR/ABL1 gene expression to the level of deep molecular response (МR4) was revealed in 38.3 % of NI patients and only 12.4 % of IM patients (p <0.001). The median of the time to MMR and MR4 was less in patients treated with NI in comparison with patients with IM (p <0.001). It was proved that differences in the efficiency of IM and NI refered only to the dynamics of responses, but not to survival rate. The most significant factor of progression, overall and event free survival was the duration of the period between diagnosis and the initiation of IM and NI therapy.
Nilotinib causes deep and rapid reduction of the tumor clone. However, the delay with the timely appointment of tyrosinekinases inhibitors leads to decline of efficiency imatinib as well as nilotinib.


Keywords


CML, tyrosine kinases inhibitors, pretreatment, therapy efficiency

Full Text:

PDF>PDF

References


Hoffmann V., Baccarani M., Hasford J., Lindoerfer D., Burgstaller S., Sertic D. et al. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia. 2015;29(6):1336-43.

Novak V., Maslyak Z., Klymenko S., Voytsitskiy Y., Bereketa Y., Prymak S. et al. Pokaznyky diyalnosti gematologichnoyi sluzhby Ukrainy v 2016 rotsi. Lviv: TzOV "ZUKTS"; 2017. 44 p. Ukrainian.

Deininger M., O'Brien S., Guilhot F., Goldman J., Hochhaus A., Hughes T. 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;114:1126.

Druker B., Guilhot F., O'Brien S., Gathmann I., Kantarjian H., Gattermann N. et al. Five year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

Hochhaus A., Saglio G., Hughes T., Larson R., Kim D., Issaragrisil S. et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044-54.

Baccarani M., Deininger M., Rosti G., Hochhaus A., Soverini S., Apperley J., et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872–84.

O'Brien S., Radich J., Abboud C., Akhtari M., Altman J., Berman E. et al. Chronic myelogenous leukemia, version 1.2015. J Natl Compr Canc Netw. 2014;12:1590–610.

Pfirrmann M., Baccarani M., Saussele S., Guilhot J., Cervantes F., Ossenkoppele G. et al. Prognosis of long-term survival considering diseasespecific death in patients with chronic myeloid leukemia. Leukemia. 2016 Jan;30(1):48-56.

Sokal J., Cox E., Baccarani M., Tura S., Gomez G., Robertson J. et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 1984;63(4):789–99.

Hasford J., Pfirrmann M., Hehlmann R., Allan N., Baccarani M., Kluin-Nelemans J. et al. Writing Committee for the Collaborative CML Prognostic Factors Project Group. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer

Inst. 1998;90(11):850–8.

Sharashova E., Holmatova K., Gorbatova M., Grzhybovskiy A. Primenenie analiza vyzyvaemosti v zdravoohranenii s ispolzovaniem paketa statisticheskih program SPSS. Nauka I zdravoohranenie. 2017;5:5-28. Russian.

Sharashova E., Holmatova K., Gorbatova M., Grzhybovskiy A. Primenenie regressii Coksa v zdravoohranenii s ispolzovaniem paketastatisticheskih program SPSS. Nauka I zdravoohranenie. 2017;6:5-27.Russian.

Saglio G., Kim D., Issaragrisil S., Coutre P., Etienne G., Lobo C. et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 2010; 362(24):2251–9.

Marin D., Ibrahim A., Lucas C., Gerrard G., Wang L., Szydlo R. et al. Assessment of BCR-ABL1 Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors. J. Clin. Oncol. 2012; 30(3): 232–8.

Saglio G., Kantarjian H., Shah N., Jabbour E., Quintas-Cardama A., Steegmann J. et al. Early Response (Molecular and Cytogenetic) and Long-Term Outcomes in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Exploratory Analysis of DASISION 3-Year Data. ASH Annual Meeting Abstracts. 2012;120(21):1675.

Hochhaus A., Hughes T., Saglio G., Guilhot F., Al-Ali H., Rostiet G. et al. Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Based On Early Molecular Response and Factors Associated with Early Response: 4-Year Follow-up Data From Enestnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients). ASH Annual Meeting Abstracts. 2012;120(21):167.

Kantarjian H., O'Brien S., Jabbour E., Garcia-Manero G., Quintas-Cardama A., Shan J. et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood. 2012;119(9):1981–7.

***

Received: 26.03.2018

Revised: 30.04.2018

Signed for publication: 30.04.2018




DOI: http://dx.doi.org/10.17721/2616_6410.2018.24.17-23

Refbacks

  • There are currently no refbacks.


Лицензия Creative Commons
This journal is available according to the Creative Commons License «Attribution» («Атрибуція») 4.0 Global (CC-BY).