Unplanned discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia

Tsutsumi,Yutaka; Ito,Shinichi; Ohigashi,Hiroyuki; Shiratori,Souichi; Teshima,Takanori

doi:10.3892/mco.2015.653

Unplanned discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia

Authors:
- Yutaka Tsutsumi
- Shinichi Ito
- Hiroyuki Ohigashi
- Souichi Shiratori
- Takanori Teshima
View Affiliations

Affiliations: Department of Hematology, Hakodate Municipal Hospital, Hakodate, Hokkaido 041-8680, Japan, Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan
Published online on: October 15, 2015 https://doi.org/10.3892/mco.2015.653
Pages: 89-92

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

This study was conducted to investigate the outcomes of patients with chronic myeloid leukemia (CML) who discontinued tyrosine kinase inhibitor (TKI) treatment. A single‑center retrospective analysis was performed, including 46 chronic-phase (CP) CML patients who achieved complete molecular response (CMR) with TKIs. TKI treatment was discontinued in 13 patients based on their requests. The BCR-ABL transcript levels were monitored in the peripheral blood by quantitative polymerase chain reaction analysis following treatment discontinuation. of the 13 patients who discontinued TKI treatment, 7 remained in CMR, with a median follow-up of 26 months (range, 10-60 months). The remaining 6 patients lost CMR following TKI discontinuation; 2 of these patients achieved a second CMR following re-administration of TKIs, 2 patients spontaneously achieved CMR and 2 remained in complete hematological response (CHR) without TKI treatment with a median follow-up of 29.5 months (range, 10-52 months). In conclusion, the survival of patients who lost CMR following TKI discontinuation may not be affected, even without re-administration of TKIs. vigilant observation is recommended for such patients. The limitations of this study included the small patient sample, retrospective design and patient heterogeneity. Therefore, the results must be interpreted with caution.

View Figures

View References

1	Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J and Lydon NB: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 2:561–566. 1996. View Article : Google Scholar : PubMed/NCBI
2	Deininger MW, Goldman JM and Melo JV: The molecular biology of chronic myeloid leukemia. Blood. 96:3343–3356. 2000.PubMed/NCBI
3	O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, et al: IRIS Investigators: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 348:994–1004. 2003. View Article : Google Scholar : PubMed/NCBI
4	Colombat M, Fort MP, Chollet C, Marit G, Roche C, Preudhomme C, Reiffers J, Praloran V and Mahon FX: Molecular remission in chronic myeloid leukemia patients with sustained complete cytogenetic remission after imatinib mesylate treatment. Haematologica. 91:162–168. 2006.PubMed/NCBI
5	Branford S, Seymour JF, Grigg A, Arthur C, Rudzki Z, Lynch K and Hughes T: BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res. 13:7080–7085. 2007. View Article : Google Scholar : PubMed/NCBI
6	Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarajian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, et al: IRIS Investigators: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 355:2408–2417. 2006. View Article : Google Scholar : PubMed/NCBI
7	Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R, 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. 26:2197–2203. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Ipiña JJ, Kim DW, Ogura M, et al: Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 119:1123–1129. 2012. View Article : Google Scholar : PubMed/NCBI
9	Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O, Blanchet O, Marit G, Gluckman E, Reiffers J, et al: Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 109:58–60. 2007. View Article : Google Scholar : PubMed/NCBI
10	Ross DM, Grigg A, Schwarer A, Arthur C, Loftus K, Mills AK, et al: The majority of chronic myeloid leukemia patients who cease imatinib after achieving a sustained complete molecular response (CMR) remain in CMR, and any relapses occur early. Blood (ASH Annual Meeting abstracts). 112:402–403. 2008.
11	Mahon FX, Rea D, Guilhot F, Legros L, Guilhot J, Aton E, Dulucq S, Reiffers J and Rousselot P: Persistence of complete molecular remission in chronic myeloid leukemia after imatiib discontinuation: Interim analysis of the STIM trial. J Clin Oncol. May 20;Supplement. 27:2009.
12	Ross DM and Hughes TP: How I determine if and when to recommend stopping tyrosine kinase inhibitor treatment for chronic myeloid leukaemia. Br J Haematol. 166:3–11. 2014. View Article : Google Scholar : PubMed/NCBI
13	Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, et al: European LeukemiaNet: Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 27:6041–6051. 2009. View Article : Google Scholar : PubMed/NCBI
14	Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N, Barbany G, Cazzaniga G, Cayuela JM, Cavé H, et al: Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia-A Europe Against Cancer Program. Leukemia. 17:2318–2357. 2003. View Article : Google Scholar : PubMed/NCBI
15	Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, et al: Intergroupe Français des Leucémies Myéloïdes Chroniques: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 11:1029–1035. 2010. View Article : Google Scholar : PubMed/NCBI
16	Yhim HY, Lee NR, Song EK, Yim CY, Jeon SY, Shin S, Kim JA, Kim HS, Cho EH and Kwak JY: Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response. Leuk Res. 36:689–693. 2012. View Article : Google Scholar : PubMed/NCBI
17	Ross DM, Bartley PA, Goyne J, Morley AA, Seymour JF and Grigg AP: Durable complete molecular remission of chronic myeloid leukemia following dasatinib cessation, despite adverse disease features. Haematologica. 96:1720–1722. 2011. View Article : Google Scholar : PubMed/NCBI
18	Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Bartley PA, Slader C, Field C, Dang P, Filshie RJ, et al: Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia. 24:1719–1724. 2010. View Article : Google Scholar : PubMed/NCBI
19	Mahon FX, Nicolini FE, Noel MP, Escoffre M, Charbonnier A, Rea D, Dubruille V, Varet BR, Legros L, Guerci A, et al: Preliminary report of the STIM2 study: A multicenter stop imatinib trial for chronic phase chronic myeloid leukemia de novo patients on imatinib. Blood. 122:6542013.
20	Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, Gradembas M, Etienne G, Rea D, Roy L, et al: Loss of major molecular kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 32:424–430. 2014. View Article : Google Scholar : PubMed/NCBI