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Expert Review of Hematology
ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: https://www.tandfonline.com/loi/ierr20
An alternative way – tyrosine kinase inhibitor (TKI)
de-escalation – to discontinue TKIs in order to
achieve treatment-free remission
Ahmad Kunbaz & Ahmet Emre Eskazan
To cite this article: Ahmad Kunbaz & Ahmet Emre Eskazan (2019) An alternative way – tyrosine kinase inhibitor (TKI) de-escalation – to discontinue TKIs in order to achieve treatment-free remission, Expert Review of Hematology, 12:7, 477-480, DOI: 10.1080/17474086.2019.1623666
To link to this article: https://doi.org/10.1080/17474086.2019.1623666
Published online: 05 Jun 2019.
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EDITORIAL
An alternative way – tyrosine kinase inhibitor (TKI) de-escalation – to discontinue
TKIs in order to achieve treatment-free remission
Ahmad Kunbaz aand Ahmet Emre Eskazan b
aCerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey;bDivision of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
ARTICLE HISTORYReceived 2 February 2019; Accepted 22 May 2019
KEYWORDSChronic myeloid leukemia; deep molecular response; DESTINY trial; treatment-free remission; tyrosine kinase inhibitor 1. Introduction
Since the introduction of imatinib ‘the first tyrosine kinase inhibitor (TKI)’ that targets BCR-ABL1, chronic myeloid leuke-mia (CML) has become a controlled malignancy at which patients with optimal responses would expect similar life expectancies of normal population [1]. Second-generation TKIs (2GTKIs; dasatinib, nilotinib, and bosutinib) and third-generation TKI (ponatinib) were introduced as a salvage treat-ment option in patients with imatinib resistance or inadequate tolerability as well as a frontline alternative to imatinib [2,3]. Following a long-term TKI therapy, substantial portion of CML patients will achieve major molecular response (MMR); defined as aBCR-ABL1/ABL1 transcript ratio of ≤0.1%, also called MR3
[molecular response of three logs below an arbitrary standard baseline] expressed on international scale. A deep molecular response (DMR) is also defined as either MR4 (BCR-ABL1/ABL1
transcript ratio ≤0.01%) or MR4.5 (BCR-ABL1/ABL1 transcript ratio≤0.0032%) [4].
Final update of the DASISION trial showed higher MR4.5
rates within 5 years among patients treated with dasatinib (43%) in comparison to imatinib-treated group (33%), deter-mining the favorable outcomes of dasatinib as first-line treat-ment for CML [5]. Similarly, patients treated with nilotinib in ENESTnd trial had significant higher MR4.5rates (300 mg twice daily, 54%; 400 mg twice daily, 52%) in comparison to imatinib group (31%) at 5 years of follow-up [6]. Although with a shorter follow-up period, BFORE trial indicated significantly higher rates of MR4.5with bosutinib versus imatinib (8.1% vs.
3.3%) at 12 months [7].
2. The possibility of achieving treatment-free remission (TFR) among CML patients
As patients on TKI treatment achieve a sustained DMR, discus-sions regarding TFR have dominated CML researches in the recent years [8,9]. There have been a variety of criteria for TKI treatment cessation [10,11]. For example, evidence indicated a more favorable outcome with lower molecular relapses in patients that receive TKI treatment for more than 50 months [12]. In addition, Sokal risk score at the time of diagnosis has
been used as an effective prognostic factor to determine successful TFR, especially in imatinib discontinuation trials [13]. However, several long-term TKI discontinuation trials have shown different TFR relapse rates, as STIM1 trial reported that 57% of patients with sustained MR4.5may relapse within
the first 6 months of TFR in comparison to 39% of patients with sustained MR4in EURO-SKI trial [12,14]. In these studies,
none of the patients experienced CML progression and within a few months, all of them regained optimal response once TKI treatment is reinitiated [12].
Beside TKI cessation strategy, Russo et al. [15] investigated the outcomes of a novel method of intermittent imatinib treatment for 1 month on and 1 month off. They included CML patients who received imatinib for more than 2 years and achieved stable complete cytogenetic response (CCyR) for at least a year. With more than 4 years of follow-up, only 18% of patients lost MMR and none of them progressed to acceler-ated or blastic phase; and all of these patients regained MMR after resuming imatinib treatment [15]. This novel strategy requires further investigation in order to evaluate its efficacy with different TKI treatments and patient groups.
3. Possible mechanisms beyond successful TFR
The mechanisms beyond the efficacy of TKI cessation is still unclear. Theories suggest the possible role of long-term TKI therapy on the leukemic stem cells (LSCs) or/and host factors [10]. A study found that a significant circulating CD26+LSCs in
the peripheral blood of all newly diagnosed CML patients, using flow cytometry analysis, which as a result could be a potential biomarker for the early detection of CML [16]. Another study showed that patients with better TFR had higher levels of natural killer – (NK) cells in comparison to the relapsed patients [17]. Similarly, in the DADI trial, where dasatinib was discontinued after >1 year of sustained DMR, researchers found that significant high counts of three NK-cell phenotypes and low δγ+ T-cell and CD4+ regulatory T-cell (CD25 + CD127) were associated with more favorable TFR, suggesting the possible immunological role of innate NK-cell immune response to TKI in maintaining response after
CONTACTAhmet Emre Eskazan emreeskazan@hotmail.com;emre.eskazan@istanbul.edu.tr Cerrahpasa Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Istanbul University-Cerrahpasa, Istanbul, Turkey
https://doi.org/10.1080/17474086.2019.1623666
cessation [18]. Despite the favorable evidence, safety consid-erations of TFR require more clarifications as patients may not achieve an optimal response with TKIs resumption or may relapse with a progressed CML. Therefore, with the inclusive findings of the TKI discontinuation trials, efforts should be shifted toward different treatment strategies, discovering potential biomarkers and/or basic studies to determine the success or failure of TFR [10].
4. Criteria for TKI discontinuation
TKI discontinuation is still investigated in the clinical trials in order to find the optimal criteria to achieve TFR. In EURO-SKI study, Saussele et al. [14]. investigated the long-term outcome of TKI discontinuation in patients received TKI for more than 3 years and achieved DMR for at least a year, they demonstrated that longer treatment duration and longer DMR were asso-ciated with a better TFR. Similarly, Rea et al. [19]. recom-mended that adult patients with TKI intake for more than 5 years and in DMR for more than 2 years could be possible candidates for treatment cessation. In ISAV trial, researchers investigated the validity of digital PCR (dPCR) in detection of relapses following imatinib discontinuation in patients who achieved MR4.5under imatinib for at least 18 months, showed an inverse relationship between patients age and risk of relapse, they also detected a significant negative predictive value of dPCR ratio of 1.115 [95% CI: 1.013–1.227], they also showed a relapse rate of 48.1% in the first 9 months of treatment cessation [20]. In 2017, the Food and Drug Administration (FDA) approved the inclusion of TFR data in the nilotinib (Tasigna®) US product label, which is considered as the first approval for TFR in the daily practice following two clinical trials [21,22]. This approval allows chronic phase CML patients who were treated with upfront nilotinib for≥3 years and achieved DMR (MR4.5) in addition to patients who switched to nilotinib due to imatinib resistance or/and intol-erance and have DMR (MR4.5) to be a candidate for treatment cessation [21,22].
5. A novel strategy for inducing TFR among CML patients
Currently, in almost all clinical trials, patients tend to stop TKIs immediately, instead of the gradual decrease in treatment dose [12,14]. Clark et al. [23]. in a non-randomized DESTINY trial investigated the efficacy of a novel strategy characterized by de-escalation TKI dose to the half for 12 months (i.e. in a decrescendo fashion) followed by a complete cessation of TKI for 2 years. They investigated this concept not only in patients within stable MR4 but also MMR not MR4 patients that usually represent the gray zone of CML. The study enrolled 174 patients who had at least 3 years of TKI therapy; these patients were receiving a standard dose of imatinib, nilotinib, or dasatinib. At the end of the de-escalation phase of this trial, they reported a loss of MMR in 2% of MR4cohort group and 18% in MMR not MR4 group. However, MMR was restored in these patients after reinitiating a full dose of TKI within 4 months. In addition, these relapsed patients had a significant reduction in the treatment costs with 46% saving
of the expected budget for TKI therapy without serious adverse events (AEs). For this stage of the study, they impli-cated the feasibility of de-escalation strategy of TKI in 98% of stable MR4 patients and 81% of MMR not MR4 group, with a deep molecular restoration of MMR within few months, improved side effects and substantial financial savings [23].
In a recent study, a mathematical model was used to investigate the possible mechanisms and effectiveness of dif-ferent TKI doses in CML patients [24]. The authors included patients from different trials who received TKIs for more than 3 years in order to mimic DESTINY trial’s criteria. Similar to what was observed in the DESTINY study, their results determined that dose-halving preserved the long-term effect of standard dose of TKI treatment in patients who already achieved sus-tained remission [24].
The final results of DESTINY trial were presented in the European Hematology Association 2018 congress [25]. Patients who passed the de-escalation phase with sustained TFR were included in the 2-years complete cessation phase of TKI, including 36 patients (73%) in the MMR cohort and 117 (94%) in the MR4. They reported five recurrences in MR4group with overall TFR of 72% (90% CI: 65–79%) at 36 months follow-up, while for MMR not MR4 cohort, the overall TFR was 39% (90% CI: 29–52%); p< 0.001), though no new relapses were detected within the second year of the TKI cessation. These patients restored MMR within 4 months of full TKI dose with no CML progression reported [25]. However, although relapses were shown to be mostly transient, a closer patients’ monitor-ing would be more efficient than MMR values in order to distinguish transient from permanent BCR-ABL1 regrowth dynamics, especially within the aspect of dose de-escalation [24]. In DESTINY trial, a multivariable analysis confirmed that the median duration of TKI treatment could be used as a predictive value for TFR (p= 0.047; HR 0.93), which is con-sistent with earlier studies [10]. On the other hand, there was no significant difference in TFR among patients who had baseline MR4 or MR4.5status for 12 months prior to the start-ing date of the trial. Age, performance status and the type of TKI (imatinib vs 2GTKI) were unrelated to TFR as well [25].
6. TKI withdrawal syndrome
The term so-called ‘TKI withdrawal syndrome’, which is the musculoskeletal or joint pain following the discontinuation of TKIs, was first introduced in the EURO-SKI trial [14]. In this study, 224 (30%) of 758 patients reported a grade I–II and nine (1%) reported a grade III TKI withdrawal syndrome during the treatment period [14]. It usually starts, or worsens after 1–6 weeks from TKI discontinuation [12]. In addition, among 50 patients who were enrolled to this study from Sweden, 15 (30%) reported musculoskeletal pain after stopping imatinib [12]. During the follow-up, seven of these 15 patients lost MMR and restarted imatinib, and six of these seven cases had persistent musculoskeletal symptoms and these symp-toms completely resolved within 1–3 months after imatinib reinitiation in all six patients [12]. In a more recent Spanish nationwide study, where the authors evaluated TKI disconti-nuation in the real-life setting, there were 51 patients who developed musculoskeletal or joint pain after treatment
cessation [6]. In one patient, imatinib had to be reinitiated at low doses due to severe pain and joint deformities in both hands that did not respond to anti-inflammatory drugs [6].
On the other hand, in the DESTINY trial, 53 new musculos-keletal symptoms were reported in 36 patients (21%), at which 43 were grade I, 10 were grade II, and there were no≥ grade III events. In addition, no withdrawal symptoms were reported in all relapsed patients within the trial. Within the study per-iod, there were 16 AEs at which, none of them were related to TKIs nor CML [23].
The etiology of this TKI withdrawal syndrome remains unclear and further studies are needed to asses the impact of TKI withdrawal on patients before applying these strategies in the real clinical practice.
7. De-escalation strategy – is it a better way to achieve sustained TFR?
DESTINY trial results showed that de-escalation has a potential effect to further delay of relapsing, but the mechanism beyond that is still unclear, suggesting that de-escalation strategy may modulate LSC behavior and induce the anti-leukemic immune response at a time when TKI is still present but with a lower dose [25]. After reaching the sustained remission, the reduced dose could be enough to target pro-liferating LSCs with a lower cytotoxic activity [24]. However, Fassoni et al. [24]. suggested that longer de-escalation doses before stopping of TKI treatment would have better beneficial effects on patients.
Evidence shows that TKI discontinuation could be effective in maintaining TFR for a significant period in optimal patients. However, more studies are needed to clarify the best treat-ment strategy with less possible complications. On the other hand, de-escalation approach has shown high efficacy in delaying the recurrence, short interval restoration of MMR and high-cost saving with fewer side effects. Mechanisms of these effects need further clarification and more studies with different intervals for de-escalation are needed to determine the best strategy to achieve higher TFR.
Acknowledgements
AEE would like to thank Prof. Zafer Baslar for his continuous support and guidance during his internal medicine residency and hematology fellowship.
Funding
This paper was not funded.
Declaration of interest
AE Eskazan has received advisory board honorarium from Novartis, and has also received speaker bureau honoraria from Novartis, Bristol-Myers Squibb and Pfizer, outside the present study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.
Reviewer disclosures
A reviewer on this article has received personal fees from Incyte. They have also acted on advisory boards for Novartis, Pfizer, and Incyte and as a consultant for Bristol–Myers Squibb. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
ORCID
Ahmad Kunbaz http://orcid.org/0000-0003-2209-8187 Ahmet Emre Eskazan http://orcid.org/0000-0001-9568-0894
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