From lifelong therapy to intermittent treatment: the future of chronic myeloid leukemia management—commentary on interim results from DAstop2 trial

Before the discovery of imatinib, the first tyrosine kinase inhibitor (TKI), chronic myeloid leukemia (CML) was considered an unstoppable disease, slowly progressing over a few years with a fatal end, except for patients eligible for allogeneic stem cell transplant. Imatinib, later followed by newer generation TKIs, drastically changed the prognosis of patients with CML, promising a much better outcome with a lifelong therapy (1). Because of now-chronic nature of the disease, new topics have been brought into the spotlight i.e., adverse events (AEs) of different TKIs, setting the time-point criteria for the adequate treatment response, financial burden of potential decades of the therapy, and all-in-all, the quality of life now stands in the centre of the attention for most of patients with CML.

The revolution of CML therapy went further. Nowadays, the concept of treatment-free remission (TFR) is a part of everyday clinical practice. For some patients, TFR may now present the ultimate goal of their treatment strategy. Identification of those eligible to attempt TFR poses a challenge that has not yet been fully resolved, even though the guidelines for this approach are available (2). Total duration of the TKI therapy and the time spent in deep molecular response (DMR) were repeatedly shown to be the most important factors to predict stable TFR. In overwhelming majority of patients experiencing molecular recurrence, defined variously across the studies as a loss of major molecular response (MMR) or DMR, the treatment response is re-achieved shortly after restarting the TKI therapy, therefore attempts at TFR are considered safe (3,4).

Even with this confirmed knowledge, some patients who fulfil the eligibility criteria are not willing to try to achieve TFR. In the analysis related to the ongoing Czech nationwide TKI stopping trial HALF (NCT04147533), patients who refused participation in the trial were presented with a complementary survey called Anti-HALF to explore the reasons for their position. The HALF trial is designed to include stepwise TKI dose reduction (half of the standard dose for 6 months followed by every other day administration for another 6 months) before complete cessation. Out of total 246 eligible candidates for the HALF study, 56 (22.8%) declined to participate in the trial. Among nonparticipants, 45 (18.3%) agreed to participate in the Anti-HALF survey. In comparison with patients enrolled in the HALF trial, the Anti-HALF group included more females, elderly patients, patients with lower level of education, retired patients, unemployed patients, disabled patients. Moreover, patients from Anti-HALF group reported longer duration of their journey to specialized hematologic centre. All patients were informed about the possibility of TKI cessation by their attending hematologist who was also the study investigator at the same time. Most of the Anti-HALF patients (93.3%) felt highly satisfied with the information they had received and 86.7% felt motivation to participate in the HALF study. The decision about their participation in the study was hard for 53.3% of patients as they reported the fear of the disease recurrence (62.2%) and worries about less effective TKI retreatment (55.6%) as the main reasons for deciding not to stop the TKI treatment. Additionally, 15.6% of worried about feeling like a personal failure in case of confirmed disease recurrence (5).

As shown by Sharf et al. (6), patients reported negative psychological impacts even during their TFR attempts. Across 68 countries, questionnaires from 1,016 patients were collected. During the time when TFR was considered, patients reported worries of disease recurrence (57%), not feeling safe going off the treatment (20%), not having enough information (16%), fear of withdrawal symptoms (12%) and 7% said there is a lack of proper quality polymerase chain reaction (PCR) monitoring, while 26% of patients were not worried. During the stopping phase, 56% of patients said they felt fear or anxiety at some point and 55% of those happened around the time of their PCR testing. After experiencing molecular recurrence, 59% of patients felt scared/anxious, 91% felt disappointed, 56% felt depressed, 20% felt confused, and 4% felt relieved. After restarting the therapy, 35% of patients felt emotionally worse than before stopping treatment, and 30% felt emotionally worse than during TFR. Even in case of achieving long-term TFR, patients still demonstrated major concerns: 58% feared late recurrence, 34% was uncertain of future in terms of CML, 29% were concerned over the misunderstanding of people thinking that they were cured, 26% feared late detection of recurrence, 4% were concerned that they have more frequent PCR tests than before.

It is clear that even though the medical community considers TFR attempts safe, many patients are still uncertain and go through wide spectrum of negative emotions before and during their TFR phase, and also when they have to re-initiate TKI therapy in case of molecular recurrence, which also represents the notion of a definitive lifelong therapy with no further opportunity to attempt TFR. To address this issue, a few studies have focused on feasibility of repeated TFR attempts (7-11). In the interim analysis of the DAstop2 trial, which invoked this commentary, enrolled patients had previously experienced failed TFR attempt either in the EURO-SKI study or attempted TFR according to the EURO-SKI criteria. After the failed attempt, patients were retreated with any TKI for at least a year. After study inclusion, patients were treated with dasatinib for 2 years. If DMR was maintained for a minimum of 1 year, second TFR (TFR2) was attempted. Ninety-four patients were included in the study. Twelve patients were taken out of the study in the first 24 months (8 patients for AEs, 2 patients due to death unrelated to CML, 1 patient for unknown reasons and 1 patient was lost to follow up). At the time of data extraction (October 2022), 62 patients met the criteria and attempted TFR2. Of those patients, 61%, 56% and 46% maintained TFR2 at 6, 12 and 24 months respectively. In those, who failed, the median time to molecular recurrence was 3.2 months. Ninety-seven percent of patients with molecular recurrence re-achieved MMR or better response after TKI re-treatment (one patient had transcript level at 0.22% and one died from reasons unrelated to CML) (7). These results clearly indicate that even after the first failed TFR attempt (TFR1), patients still have a high chance of achieving stable TFR2 in future after prolonging their TKI treatment and their time in DMR. The final analysis of the study will be heavily expected.

More studies on TFR2 have been performed, most in concordance with results of the DAstop2 trial, with RE-STIM being the first one. The reported probability of stable TFR2 was 66%, 48%, 42% and 35% at 6, 12, 24 and 36 months respectively (8). In NILO post-STIM, another TFR2 study, the probability of TFR at 6 and 12 months was 68% and 60% (9). In the observational A-STIM trial, some patients attempted TFR repeatedly. TFR2 rates were 46.8%, 35.8% and 31.3% at 1, 3 and 5 years respectively (10). In contrast, Canadian TRAD study reported that only 9/35 patients (25.7%) achieved stable TFR2 (Table 1). The authors argued, that the discrepancy might be caused by differences in re-therapy duration, molecular response before discontinuation and the definition of molecular relapse (11).

All TFR2 reports confirm that repeated TFR attempts are safe. The TFR success rates varied based on inclusion criteria, as these are not yet fully agreed upon, nonetheless such reports may present an opportunity for patients and physicians to change their perspective. Until now, failed TFR1 meant a mandatory resumption of life-long therapy without an alternative. With this accumulating evidence, molecular recurrence could be interpreted as the need for longer period of the TKI therapy until another possible TFR attempt.

As shown above, many eligible patients refuse such attempts based on their fear of the outcome. Years ago, when their treatment started, they were promised a life-long therapy that would keep the disease at bay and today they are presented with entirely different approach. Of those who participate in TFR studies and experience molecular recurrence, feelings of anxiety and even despair are often present (5,6). The willingness of those “failed” patients to take part in further discontinuation attempts may be questionable. On the other hand, based on clinical experience, there is a group of patients, which shows considerable motivation to try to successfully stop the TKI treatment for many reasons and even after previous loss of MMR. Chronic adverse effects and economic burden of the therapy or just the thought of being medication-dependent for the rest of their life have negative impact on the quality of life of those patients (12).

For many patients, hopeful or worried about their TFR attempts, a change in terminology may prove helpful. For instance, still often-used term molecular relapse should be replaced with the term “molecular recurrence” (13). In recent commentary, the change of the label “failure” to “caution” was proposed in cases of patients not achieving current milestones recommended by the European LeukemiaNet (ELN) (14). The removal of accelerated phase from World Health Organization (WHO) CML classification is debated, because of its impact on individual treatment strategies, clinical study designs etc. (15,16). A small change of words could relieve the sense of pressure and have positive psychological impact on patients with CML. Maybe after further confirmation of repeated TFR attempts, it could be possible to present TFR not as an attempt to indefinitely stop the TKI, but more as a proposition of another type of “drug holidays” when the patient can safely pause the use of the TKI, similarly to intermittent medication with days on/days off or month on/month off which has been also proposed previously (17,18). In this case, the molecular recurrence would not be perceived as “failure” and the reason to worry, but as a manageable event consisting of resuming the treatment until the targeted molecular response is achieved again. Then, after a set period of time, the possibility of pausing the TKI would be available again. Such change could significantly reduce the number of patients not willing to attempt TFR and relieve negative emotions in case of molecular recurrences, which could have a great impact and possibly even introduce a new paradigm of CML therapy.

Acknowledgments

Funding: This publication was supported by the grant MUNI/A/1558/2023.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-97/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-97/coif). T.H. reports payments for lectures, presentations from Novartis, support for attending medical conferences from Novartis, Angelini Pharma. D.Z. reports consulting fees from Novartis, Angelini Pharma, honoraria from Pfizer, Novartis, Angelini Pharma, support for attending meetings and/or travel from Novartis, Angelini Pharma, Pfizer, Astra Zeneca; and is the advisory committees of Novartis. The authors have no other conflicts of interest to declare.

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