MCO Molecular and Clinical Oncology 2049-9450 2049-9469 D.A. Spandidos 10.3892/mco.2015.653 MCO-0-0-653 Articles Unplanned discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia TSUTSUMIYUTAKA 1 ITOSHINICHI 1 OHIGASHIHIROYUKI 1 SHIRATORISOUICHI 1 TESHIMATAKANORI 2 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 correspondence to: Dr Yutaka Tsutsumi, Department of Hematology, Hakodate Municipal Hospital, 1-10-1 Minato-cho, Hakodate, Hokkaido 041-8680, Japan, E-mail: yutsutsu@shore.ocn.ne.jp 01 2016 15 10 2015 4 1 89 92 31032015 18092015 Copyright © 2015, Spandidos Publications 2015

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.

 chronic myeloid leukemia tyrosine kinase inhibitors Introduction

The emergence of tyrosine kinase inhibitors (TKIs) has significantly changed chronic myeloid leukemia (CML) treatment (1–3). With imatinib, ~40% of chronic-phase (CP) CML patients achieve a complete molecular response (CMR) within 5 years, as determined by the sensitive reverse transcription quantitative polymerase chain reaction (qPCR) analysis (4,5). The estimated overall survival (OS) rate of CML patients treated with imatinib was reported to be 89 and 85% at 5 and 8 years, respectively (6). Next-generation TKIs have also been found to be effective for CML (7,8). Although CML patients primarily require lifelong treatment with TKIs, recent clinical studies demonstrated that approximately half of the patients in CMR who discontinued TKIs remained in CMR, whereas the remaining patients lost CMR (9–11).

The high cost of TKIs may be prohibitive for their administration (12). A significant proportion of patients have decided to discontinue TKI treatment, but their outcomes have not been reported. The aim of this study was to investigate the natural course of patients who voluntarily discontinue TKI treastment.

 Patients and methods <sec> <title>Patients

The medical records from the Hakodate Municipal Hospital were reviewed to identify all Philadelphia chromosome-positive CP-CML patients aged >18 years who achieved CMR with TKIs, such as imatinib, nilotinib and dasatinib, between August, 2002 and March, 2013. Certain patients had a history of prior treatment with interferon, hydroxycarbamide or busulfan. Our study protocol was approved by the Hakodate Municipal Hospital Institutional Review Board. Based on the Declaration of Helsinki, written informed consent was obtained from all participating patients.

 Treatment

The patients were treated according to the European LeukemiaNet recommendations (13). We monitored the BCR-ABL transcript levels in the peripheral blood based on the recommendations of the Europe Against Cancer Program (14). CMR was defined as no detection of BCR-ABL/ABL transcript. The limit of detection with this method was <2×105 copy/µgRl. A complete hematological response (CHR) was defined as a white blood cell count of <1.0×104/l, a platelet count of <45×104/l, a proportion of basophils <5%, with no blast cells in the peripheral blood and no splenomegaly. qPCR analysis of the peripheral blood was performed once a month for 2 years after the initiation of TKI therapy and once every 3 months thereafter. Following TKI discontinuation, qPCR analysis was performed once a month.

 Analysis

The OS was defined as the time from the initiation of TKI treatment until death from any cause or the date of the last follow-up. In patients who discontinued TKI treatment, event-free survival (EFS) was defined as the time from TKI discontinuation to molecular relapse (loss of CMR) or the date of the last molecular evaluation. These values were estimated using the Kaplan-Meier method. Statistical analysis was performed using a log-rank test. A P-value of ≤0.05 was considered to indicate statistically significant differences.

 Results <sec> <title>Patient characteristics

We evaluated a total of 46 newly diagnosed CML-CP patients who were treated with various TKIs and achieved CMR (Table I). The first-line TKI treatment was imatinib in 38, dasatinib in 6 and nilotinib in 2 patients. Prior to TKI treatment, additional cytogenetic abnormalities were detected by G-band analysis in 2 patients. With a median follow-up of 66 months, the 8-year OS rate of all the patients was 83% (Fig. 1). There was no significant difference in the OS rate between patients who continued (86%) and those who discontinued TKI treatment (100%).

 Characteristics of patients who discontinued TKI treatment

In patients who discontinued TKIs, the median duration of the treatment until discontinuation was 74 months (range, 27–158 months) (Table II). The reasons for treatment disconinuation were as follows: A total of 5 patients were unable to receive TKIs due to surgery (1 for a traffic accident and 4 for malignancy) and refused TKI treatment after recovery. The remaining 8 patients declined TKI treatment due to their high cost.

 Patient outcomes

The median follow-up of the patients after TKI discontinuation was 28 months (range, 10–60 months) (Table III). The 5-year EFS was 67% and the median duration of CMR was 20 months (range, 1–60 months) (Fig. 2).

Of the 13 patients who discontinued TKIs, 7 remained in CMR with a median follow-up of 26 months (range, 10–60 months) (Table III), whereas the remaining 6 patients lost CMR, with a median follow-up of 29.5 months (range, 10–52 months). The median time to CMR loss after TKI discontinuation was 6.5 months (range, 1–20 months). The BCR-ABL levels after TKI discontinuation are presented in Fig. 3. Of the 6 patients who lost CMR, 2 were re-treated with TKIs and attained a second CMR; 2 spontaneously attained a second CMR without TKI treatment; and the remaining 2 patients lost CMR but remained in CHR without any treatment for 43–126 months. A total of 4 patients on TKI treatment who succumbed to the disease were aged >75 years, of whom 2 patients had solid cancers (lung cancer, n=1; and uterine cancer, n=1); for these 2 patients, the spleen size was not measured at diagnosis, so the Sokal or Hasford scores could not be calculated. The remaining 2 patients were classified as a high-risk Sokal score group; in 1 patient, severe thrombocytosis was found at diagnosis and led to pulmonary infarction and death; the other patient was unresponsive to all types of TKIs, developed a blast crisis and succumbed to CML. There were no mortalities among patients who discontinued TKI treatment.

 Discussion

TKI discontinuation has been investigated in a number of clinical trials in CML patients who have been in CMR. In a study by Rousselot et al (9), where imatinib was discontinued in patients who had been in CMR for >2 years (range, 26–45 months), approximately half of the patients experienced a molecular relapse within 6 months following discontinuation. No late relapse was observed 4 years after TKI discontinuation. In the Stop Imatinib (STIM) study, 61% of the patients lost CMR, mostly within the first 6 months following treatment discontinuation (15). The predictive factors for treatment-free remission are the Sokal score and the length of the imatinib treatment (12,15–17). However, the Sokal score could not be analysed, as the spleen size on admission was not recorded for all the patients in this study.

In our study, the probability of CMR persistence was 41%. The OS in patients who discontinued TKI treatment in our study almost equaled that in prospective TKI stop studies (15,18–20). Interestingly, no statistical differences in OS were observed between patients who continued and those who discontinued TKI treatment in our analysis, suggesting that survival was not always compromised by molecular relapse following TKI discontinuation, even without TKI re-treatment.

A total of 2 patients spontaneously attained a second CMR without TKI treatment, and 2 patients remained in CHR without any treatment for 43 and 126 months. These findings suggest that immediate re-treatment with TKIs may not always be necessary for patients who had been in CMR for >2 years and lost CMR following TKI discontinuation. This study was conducted retrospectively using a single-center analysis, which raises the risk of bias; thus, additional investigation is required to elucidate this issue.

 References DrukerBJTamuraSBuchdungerEOhnoSSegalGMFanningSZimmermannJLydonNBEffects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cellsNat Med2561566199610.1038/nm0596-5618616716 DeiningerMWGoldmanJMMeloJVThe molecular biology of chronic myeloid leukemiaBlood9633433356200011071626 O'BrienSGGuilhotFLarsonRAGathmannIBaccaraniMCervantesFCornelissenJJFischerTHochhausAHughesTIRIS Investigators: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemiaN Engl J Med3489941004200310.1056/NEJMoa02245712637609 ColombatMFortMPCholletCMaritGRocheCPreudhommeCReiffersJPraloranVMahonFXMolecular remission in chronic myeloid leukemia patients with sustained complete cytogenetic remission after imatinib mesylate treatmentHaematologica91162168200616461299 BranfordSSeymourJFGriggAArthurCRudzkiZLynchKHughesTBCR-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 criteriaClin Cancer Res1370807085200710.1158/1078-0432.CCR-07-084418056186 DrukerBJGuilhotFO'BrienSGGathmannIKantarajianHGattermannNDeiningerMWSilverRTGoldmanJMStoneRMIRIS Investigators: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemiaN Engl J Med35524082417200610.1056/NEJMoa06286717151364 LarsonRAHochhausAHughesTPClarkREEtienneGKimDWFlinnIWKurokawaMMoiraghiBYuRNilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-upLeukemia2621972203201210.1038/leu.2012.13422699418 KantarjianHMShahNPCortesJEBaccaraniMAgarwalMBUndurragaMSWangJIpiñaJJKimDWOguraMDasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)Blood11911231129201210.1182/blood-2011-08-37608722160483 RousselotPHuguetFReaDLegrosLCayuelaJMMaarekOBlanchetOMaritGGluckmanEReiffersJImatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 yearsBlood1095860200710.1182/blood-2006-03-01123916973963 RossDMGriggASchwarerAArthurCLoftusKMillsAKThe majority of chronic myeloid leukemia patients who cease imatinib after achieving a sustained complete molecular response (CMR) remain in CMR, and any relapses occur earlyBlood (ASH Annual Meeting abstracts)1124024032008 MahonFXReaDGuilhotFLegrosLGuilhotJAtonEDulucqSReiffersJRousselotPPersistence of complete molecular remission in chronic myeloid leukemia after imatiib discontinuation: Interim analysis of the STIM trialJ Clin OncolMay20Supplement272009 RossDMHughesTPHow I determine if and when to recommend stopping tyrosine kinase inhibitor treatment for chronic myeloid leukaemiaBr J Haematol166311201410.1111/bjh.1289224754670 BaccaraniMCortesJPaneFNiederwieserDSaglioGApperleyJCervantesFDeiningerMGratwohlAGuilhotFEuropean LeukemiaNet: Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNetJ Clin Oncol2760416051200910.1200/JCO.2009.25.077919884523 GabertJBeillardEvan der VeldenVHJBiWGrimwadeDPallisgaardNBarbanyGCazzanigaGCayuelaJMCavéHStandardization 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 ProgramLeukemia1723182357200310.1038/sj.leu.240313514562125 MahonFXRéaDGuilhotJGuilhotFHuguetFNicoliniFLegrosLCharbonnierAGuerciAVaretBIntergroupe 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) trialLancet Oncol1110291035201010.1016/S1470-2045(10)70233-320965785 YhimHYLeeNRSongEKYimCYJeonSYShinSKimJAKimHSChoEHKwakJYImatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular responseLeuk Res36689693201210.1016/j.leukres.2012.02.01122398220 RossDMBartleyPAGoyneJMorleyAASeymourJFGriggAPDurable complete molecular remission of chronic myeloid leukemia following dasatinib cessation, despite adverse disease featuresHaematologica9617201722201110.3324/haematol.2011.04816521828123 RossDMBranfordSSeymourJFSchwarerAPArthurCBartleyPASladerCFieldCDangPFilshieRJPatients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCRLeukemia2417191724201010.1038/leu.2010.18520811403 MahonFXNicoliniFENoelMPEscoffreMCharbonnierAReaDDubruilleVVaretBRLegrosLGuerciAPreliminary report of the STIM2 study: A multicenter stop imatinib trial for chronic phase chronic myeloid leukemia de novo patients on imatinibBlood1226542013 RousselotPCharbonnierACony-MakhoulPAgapePNicoliniFEVaretBGradembasMEtienneGReaDRoyLLoss of major molecular kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable diseaseJ Clin Oncol32424430201410.1200/JCO.2012.48.579724323036

OS from initiation of TKI treatment in all patients, those who continued TKI treatment (on-TKI) and those who discontinued treatment (off-TKI). The 8-year OS rate of all the patients was 83%. OS, overall survival; TKI, tyrosine kinase inhibitor.

EFS following tyrosine kinase inhibitor treatment discontinuation. The 5-year EFS was 67% and the median duration of CMR was 20 months. EFS, event-free survival; CMR, complete molecular response.

Time course analysis of BCR-ABL levels in patients who discontinued TKI treatment. TKI treatment was resumed in 2 patients (arrows). A total of 6 patients lost CMR: 2 patients were re-administered TKIs, 2 spontaneously attained a second CMR without retreatment and 2 remained in CHR without retreatment. TKI, tyrosine kinase inhibitor.; CMR, complete molecular response.

Patient characteristics.

Characteristics On TKIs (n=33) Off TKIs (n=13) P-value
Median age, years (range) 64 (34–84) 56 (39–85) 0.6661a
Gender (male/female) 24/9 10/3 0.999b
First-line TKI 0.0226c
  Imatinib 25 13
  Dasatinib 6 0
  Nilotinib 6 0

Median test. Fisher's exact test.

G-test. TKI, tyrosine kinase inhibitor.

Characteristics of patients who discontinued TKI treatment.

Characteristics No.
Duration of TKI therapy, months 74 (27–158)
  Median (range)
Reasons for TKI discontinuation
  Surgery for accidents 1
  Surgery for malignancy 4
  High cost 8

TKI, tyrosine kinase inhibitor.

Patient outcome.

Outcome On TKIs (n=33) Off TKIs (n=13)
Median follow-up, months (range) 34 (1–143) 107 (44–177)
Median follow-up after TKI – 28 (10–60)
discontinuation, months (range)
Disease status
  First CMR 20 7
  Second CMR 1 4
  CHR 11 2
  Disease progression 1 0
Cause of death 4 0
  Lung cancer 1
  Pulmonary infarction 1
  Uterine cancer 1
  CML blast crisis 1

TKI, tyrosine kinase inhibitor; CMR, complete molecular response; CHR, complete hematological response; CML, chronic myeloid leukemia.