The dramatic success of tyrosine kinase inhibitors (TKIs) has led to the widespread perception that chronic myeloid leukemia (CML) has become another chronic disease, where lifelong commitment to pharmacologic control is the paradigm. Recent trials demonstrate that some CML patients who have achieved stable deep molecular response can safely cease their therapy without relapsing (treatment free remission [TFR]). Furthermore, those who are unsuccessful in their cessation attempt can safely re-establish remission after restarting their TKI therapy. Based on the accumulated data on TFR, we propose that it is now time to change our approach for the many CML patients who have achieved a stable deep molecular response on long-term TKI therapy. Perhaps half of these patients could successfully achieve TFR if offered the opportunity. For many of these patients ongoing therapy is impairing quality of life and imposing a heavy financial burden while arguably achieving nothing. This recommendation is based on the evident safety of cessation attempts and TFR in the clinical trial setting. We acknowledge that there are potential risks associated with cessation attempts in wider clinical practice, but this should not deter us. Instead we need to establish criteria for safe and appropriate TKI cessation. Clinical trials will enable us to define the best strategies to achieve TFR, but clinicians need guidance today about how to approach this issue with their patients. We outline circumstances in which it would be in the patient's best interest to continue TKI, as well as criteria for a safe TFR attempt.

As the era of up-front stem cell transplantation for chronic phase chronic myeloid leukemia (CML) came to an end, it was proposed that lifelong imatinib treatment might offer an “operational cure,” durable freedom from disease progression and disease-related symptoms and signs. A decade later, the field has moved on to the more ambitious goal of operational cure without the need for continuing tyrosine kinase inhibitor (TKI) treatment. In doing so, we must always bear in mind that patients with a good response to TKI treatment should not be exposed to unnecessary risk. Stopping effective treatment has until now been largely confined to the clinical trial setting. In this article, we acknowledge that many patients with a sustained deep molecular response would stop their TKI if they could do so safely, and we discuss patient selection criteria and institutional requirements for the provision of safe monitoring and reinstitution of TKI treatment outside a clinical trial.

The introduction of imatinib, and subsequent TKIs, for the treatment of CML in the early chronic phase has been one of the great success stories of modern medicine. The natural history of CML has been dramatically altered, so that patients who might once have died of progressive disease within 5 to 7 years of diagnosis are now more likely to die of other causes than from CML.1  Results from the United States Surveillance, Epidemiology, and End Results (SEER) database from the period 2000 to 2005 showed that the proportion of deaths in CML patients from cancers other than CML slightly exceeded those attributed to CML (36.1% vs 34.9%, respectively), with a further 29% of deaths from nonmalignant causes.1 

There has been a corresponding increase in the overall survival of CML patients. Chronic phase CML patients treated with TKIs in clinical trials in the MD Anderson Cancer Center since 2000 had a 5-year overall survival estimated at 94.7% relative to the general population of the United States.2  Results from clinical trials in centers of excellence are frequently better than “real world” results, but population-based registries also confirm the improvement in survival since the introduction of TKIs. Based on data primarily from the first half of the decade in which TKIs were introduced, the 5-year relative survival was ∼70%, in comparison with relative survival as low as 10% to 20% a decade earlier when interferon (IFN)-α or allogeneic stem cell transplantation was the standard of care.3  More recent data are likely to be better still: in the same population-based study, the 5-year relative survival for CML patients diagnosed in 2002 was 63% and increased to 80% for patients diagnosed in 2006.

Assuming that the incidence of CML is relatively constant, the prevalence of the disease is dependent on patient survival. In fact, the incidence is likely increasing in most developed countries where the median age of the population is increasing. Considering the near-normal relative survival of CML patients, the number of patients living with CML is rising dramatically. One study projected that the peak prevalence of CML will be reached around the year 2050, with ∼180 000 CML patients living in the United States at that time (an approximate ninefold increase since the year 2000).4  In this context, the provision of lifelong TKI treatment is a substantial and growing financial burden for CML patients and health funding agencies. Generic imatinib is now available in some countries, but TKIs remain unaffordable for many patients, especially those for whom imatinib is not the preferred choice.

The phase 3 International Randomized Study of Interferon and STI571 (IRIS) trial compared imatinib with IFN plus cytarabine and showed a significant improvement in progression-free survival for patients randomized to the TKI, even though the majority of patients in the IFN arm crossed over to imatinib.5  This was accompanied by unprecedented rates of cytogenetic response: a complete cytogenetic response was observed in 8.5% of patients treated with IFN vs 73.8% of patients treated with imatinib. The level of minimal residual disease (MRD) achieved in chronic phase CML patients is so much better with TKI treatment that, in the great majority of patients, cytogenetic analysis is no longer informative after the first 6 months of TKI treatment.6  This therapeutic success ultimately led to the widespread adoption of molecular monitoring by sensitive real-time quantitative reverse transcriptase-polymerase chain reaction for Breakpoint Cluster Region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) transcripts (RQ-PCR). In turn, the goals of treatment are increasingly based on molecular definitions, as outlined in the respective guidelines of the European Leukemia Net7  and the National Comprehensive Cancer Network (available at www.nccn.org).

In the first 2 years of TKI treatment, the achievement of a major molecular response (MMR; BCR-ABL ≤0.1%) is a primary goal of treatment, because it is associated with very high rates of progression-free survival.8  Many patients achieve MMR in the first 6 to 12 months of treatment, but a large fraction of these patients will have a further reduction in the level of MRD with continuing TKI treatment, leading to progressively deeper molecular responses and even undetectable MRD (UMRD).9  The level of MRD that is undetectable is determined by the lower limit of detection of the assay in use. PCR-based methods vary in efficiency from run to run, as can RNA extraction. Sample quality may also vary, especially if there is a delay from collection to RNA stabilization. This inherent variability makes it difficult to standardize UMRD. Consequently, there has been a move away from reporting UMRD to reporting a fixed level of molecular response.10  The lower limit of detection of RQ-PCR currently averages around MR4.5 (BCR-ABL ≤0.0032%), so that UMRD and MR4.5 are approximately equivalent in many laboratories today. MR4.5 includes both patients with detectable BCR-ABL ≤0.0032% and patients with undetectable BCR-ABL in a sample with a calculated detection limit of ≥4.5 logs below standardized baseline.

MR4.5 occurs in ∼20% of imatinib-treated patients in the first 2 to 3 years, but this proportion rises to ∼40% after 5 to 7 years.9  This progressive slow recruitment of patients to MR4.5 raises the possibility that with very prolonged treatment, the level of MRD may continue to fall, as long as effective treatment is continued. Using more potent TKIs, such as nilotinib and dasatinib, the rates of MR4.5 in the first 2 years are higher,11,12  and it is hoped that this will ultimately lead to even higher proportions of patients with MR4.5. In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials newly diagnosed (ENESTnd) study, the rate of MR4.5 by 4 years was 40% with nilotinib 300 mg twice daily vs 23% with imatinib 400 mg daily.11  In the Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients (DASISION) study comparing dasatinib 100 mg with imatinib 400 mg daily, MR4.5 was achieved by 3 years in 22% vs 12% of patients, respectively.12 

A truly successful chemotherapy is one that is given for a finite period of time and is then no longer needed. This is a paradigm that most people are familiar with, following the example of cytotoxic chemotherapy for acute leukemia or Hodgkin lymphoma. For many CML patients, the chronic illness that they are aware of is not CML, but a syndrome of TKI side effects. In our experience, most patients who have achieved a deep molecular response eventually ask whether they can stop their TKI.

A study of patients treated with several TKIs found that approximately one-third of patients experienced moderate to severe TKI-related side effects.13  Importantly, the severity of TKI side effects tended to remain relatively constant over time. A study undertaken in imatinib-treated patients showed impaired physical and mental health status in patients <60 years of age, whereas older CML patients on average had a health status comparable to age-matched controls.14 

In addition to these chronic TKI toxicities, there is growing awareness of other uncommon, but potentially serious, risks of long-term TKI treatment that may emerge after months or years. These risks include pleural effusion and pulmonary hypertension with dasatinib15  and vascular events with nilotinib.16  Imatinib appears to be relatively free of such late toxicities, but an accelerated decline in glomerular filtration rate has been reported.17  None of the TKIs are recommended for patients trying to conceive or during pregnancy or lactation.

More than 20 years ago, it was reported that some CML patients treated with IFN could remain in stable cytogenetic remission after their IFN was stopped, despite having detectable BCR-ABL by reverse transcriptase-PCR.18  In 2002, Mahon and colleagues reported on a small number of patients with UMRD during IFN treatment, who stopped IFN and remained in molecular remission.19  Patients in that study who had achieved MMR, but not UMRD, all showed molecular relapse. The maintenance of UMRD, or MRD detectable at a stable low level, without the need for ongoing treatment is commonly termed a treatment-free remission (TFR). The French CML Intergroup went on to report TFR in the Stop Imatinib (STIM) study in ∼40% of 100 imatinib-treated patients who had maintained UMRD for ≥2 years.20  In this study, half of the patients had received prior therapy with IFN, and the remainder were treated de novo with imatinib. The Australasian Leukaemia & Lymphoma Group Trial of Withdrawing Imatinib in Stable Remission (TWISTER) study reported almost identical results in 40 patients with similar clinical characteristics.21  Both studies reported a higher TFR rate in patients with prior IFN exposure, although this observation is potentially confounded by a selection bias, because high-risk patients may have been unlikely to remain on IFN for long enough to benefit from the switch to imatinib. Both studies reported higher TFR rates in Sokal low-risk patients, although this difference was not statistically significant in the smaller Australian study. Both studies also reported that most patients regained UMRD within 3 to 6 months of restarting imatinib treatment in response to a conservative RQ-PCR–defined trigger. In TWISTER, this trigger was loss of UMRD with any 2 consecutive positive RQ-PCR results. In STIM, the trigger also included a requirement for a significant (10-fold) rise in BCR-ABL between the first and subsequent RQ-PCR measurements.

A follow-up study (A-STIM; According to STIM) from the French group enrolled 80 patients, again with a similar mix of de novo patients and prior IFN treatment.22  A-STIM tested the use of a less stringent definition of molecular relapse as the trigger to restart therapy. Patients who lost UMRD remained under close observation, and imatinib was restarted only at loss of MMR. This enabled the investigators to determine the TFR rate using both the original STIM definition and the newer MMR-based definition. The TFR rate using the STIM definition was close to that of the 2 earlier studies, but a higher proportion of patients (64% at 2 years) maintained MMR without treatment. In contrast to the original STIM study, no effect of Sokal score was seen. Whether this difference is related to the relatively small numbers of high-risk patients or whether the effect of Sokal score differs between “grades” of TFR (UMRD vs MMR) is unclear. Remarkably, some patients in MMR with detectable BCR-ABL mRNA have maintained a stable level of response for periods in excess of 2 years, whereas the doubling time of BCR-ABL without treatment (<14 days) is normally such that cytogenetic or hematologic relapse would have been expected.23  The biology underlying this observation is an area of active study.

The large, multinational European Stop Kinase Inhibitor study (EuroSKI) study is enrolling patients treated with multiple TKIs, and uses both a less stringent entry criterion of MR4.0 for ≥12 months and the less stringent retreatment trigger: loss of MMR. At the time of the latest abstract, ∼480 patients had been enrolled, but outcome data were reported for only the first 100 patients with ≥6 months of follow-up.24  At this early time point, the TFR (MMR) rate was similar to A-STIM, but these results require confirmation with longer follow-up.

Updated results of the Korean Imatinib Discontinuation Study (KIDS) were recently published on a cohort of 82 patients who had received up-front imatinib (and 8 patients with prior IFN).25  Fifty-nine percent of the 90 patients remained in MMR at 2 years. The French group has reported interim results of the STIM2 study in abstract.26  This study is enrolling only patients treated de novo with imatinib. The preliminary analysis showed a TFR (MMR) rate that was similar to KIDS and A-STIM at ∼60%.26  First-line TKI treatment represents the bulk of contemporary patients, and studies in first-line patients will give bring the opportunity to study the effect of Sokal score and imatinib response kinetics without the confounding effects of prior IFN treatment. The key inclusion criteria used in TFR studies to date and the respective triggers for restarting TKI therapy are summarized in Table 1.

Table 1

Summary of key inclusion criteria and TKI retreatment triggers used in clinical trials

StudyTKINumber of patients reportedRequired depth of MRMinimum duration of MR (years)Trigger to resume TKI
STIM20  Imatinib (±prior IFN) 100 UMRD (MR5.0) Loss of UMRD* 
TWISTER21  Imatinib (±prior IFN) 40 UMRD (MR4.5) Loss of UMRD 
A-STIM22  Imatinib (±prior IFN) 80 UMRD Loss of MMR 
EuroSKI24  Imatinib/nilotinib/dasatinib 200 MR4.0 Loss of MMR 
Stop 2GTKI28  Nilotinib/dasatinib first and second line 52 UMRD (MR4.5) Loss of MMR 
KIDS25  Imatinib (±prior IFN) 90 UMRD (MR4.5) Loss of MMR 
HOVON32  Imatinib 18 UMRD (MR4.5) Loss of UMRD 
DADI27  Second-line dasatinib 63 MR4.0 Loss of MR4.0 
STIM226  Imatinib 124 UMRD (MR4.5) Loss of UMRD 
StudyTKINumber of patients reportedRequired depth of MRMinimum duration of MR (years)Trigger to resume TKI
STIM20  Imatinib (±prior IFN) 100 UMRD (MR5.0) Loss of UMRD* 
TWISTER21  Imatinib (±prior IFN) 40 UMRD (MR4.5) Loss of UMRD 
A-STIM22  Imatinib (±prior IFN) 80 UMRD Loss of MMR 
EuroSKI24  Imatinib/nilotinib/dasatinib 200 MR4.0 Loss of MMR 
Stop 2GTKI28  Nilotinib/dasatinib first and second line 52 UMRD (MR4.5) Loss of MMR 
KIDS25  Imatinib (±prior IFN) 90 UMRD (MR4.5) Loss of MMR 
HOVON32  Imatinib 18 UMRD (MR4.5) Loss of UMRD 
DADI27  Second-line dasatinib 63 MR4.0 Loss of MR4.0 
STIM226  Imatinib 124 UMRD (MR4.5) Loss of UMRD 

DADI, Dasatinib Discontinuation study; HOVON, Stichting Hemato-Oncologie voor Volwassenen Nederland.

*

A-STIM allowed occasional low level positive RQ-PCR results during the 2 years of UMRD.

Loss of UMRD in STIM and STIM2 was defined as ≥2 consecutive samples with detectable BCR-ABL and a 1-log increase; in TWISTER and the HOVON study, any 2 consecutive samples at any level were considered loss of UMRD.

Data on TFR after more potent TKIs are currently very limited, but major studies are underway with both nilotinib and dasatinib. The first prospective TFR study with dasatinib was recently reported from Japan. The DADI study enrolled 63 patients treated with dasatinib second line after imatinib.27  Most of the patients switched due to intolerance or “patient preference,” with only 21% having European Leukemia Net suboptimal response to imatinib or treatment failure. Using loss of MR4.0 as the trigger to restart dasatinib, Imagawa and colleagues reported a TFR rate of 58% among those patients switching to dasatinib due to intolerance or patient preference. The TFR rate was only 8% in those with suboptimal response to imatinib. A lower rate of TFR for patients on a second-line TKI after suboptimal imatinib response was also seen in the preliminary results of the Stop 2GTKI study.28  The negative effect of prior suboptimal response was less striking in that study with TFR (MMR) sustained at 12 months in 42% of patients switching for inadequate response vs 67% of the remaining patients.

The minimum duration of TKI therapy required for inclusion in several TFR clinical trials has been as short as 3 years, but it is important to be aware that very few patients have successfully discontinued therapy after such a short time. The median duration of total TKI therapy was typically ∼5 to 8 years in the studies mentioned above. In the large EuroSKI study, only 16% of patients had <5 years of prior TKI treatment.24  A longer duration of TKI treatment has been associated with a higher probability of maintaining TFR: this difference was statistically significant in some studies20,24,29  but not all.27,30  Yet, other studies have shown no effect of total TKI duration.21,22,31,32  These were all retrospective analyses, differing in treatment history or molecular response/relapse definitions and often with relatively small numbers of patients. It is not possible to draw firm conclusions from these data, but there is a suggestion that attempting TFR after a shorter duration of TKI treatment may reduce the likelihood of a successful outcome. This observation leads to several clinically important questions. Is there an optimum duration of TKI treatment prior to attempting TFR, beyond which there is little or no further improvement in the probability of maintaining TFR? If so, it is likely that this duration will vary between patients, and there is a need for clinical or laboratory biomarkers that may improve prediction of TFR. Second, if a patient stops therapy “prematurely” (when he or she might have maintained TFR after several years of additional TKI therapy), has that person’s longer-term chance of TFR been compromised by the initial failed attempt at TFR?

For a patient in deep molecular remission continuing on TKI therapy, the risk of experiencing disease progression and dying from CML is negligible. In this context, any excess risk of CML progression is unacceptable in a patient without significant TKI toxicity. From all of the published reports of TFR to date, involving >1000 patients, we are aware of only 1 such case. This patient was not typical of the contemporary CML population and had started imatinib 10 years after her original diagnosis of CML. She lost MMR after stopping imatinib and was responsive to retreatment, but 8.5 months later developed blast crisis.22 

An imatinib withdrawal syndrome consisting of diffuse myalgia/arthralgia may be encountered. In most cases, this syndrome can be managed with simple analgesia or nonsteroidal anti-inflammatory drugs. It can persist for months but is usually self-limiting.33  Occasional cases are severe enough to warrant prednisolone treatment. There are numerous reports of improvement in inflammatory arthritis during TKI therapy, and we encountered 1 patient in whom a TKI “withdrawal syndrome” turned out to be a flare of undiagnosed rheumatoid arthritis that was presumably masked by TKI treatment. The KIDS investigators reported that patients with an imatinib withdrawal syndrome had a higher probability of maintaining TFR.25 

An issue that has not been formally explored is the psychological impact of being off TKI therapy. Some patients might experience significant anxiety relating to concerns of relapse, and almost 50% of patients in an Italian survey said that they would be afraid of losing their disease response.34  It is also possible that patients who are offered a TFR attempt might misinterpret this as permission to reduce or omit doses.

There are rare CML patients, ∼2% to 3% of all newly diagnosed cases, with atypical BCR-ABL transcripts that cannot be monitored on the BCR-ABL International Scale. For these patients, clinically important RQ-PCR end points, such as MMR or MR4.5, cannot be measured with certainty. Therefore, these patients are not suitable candidates for a TFR attempt. Similarly, there are occasional patients whose original BCR-ABL transcript type at diagnosis is not known (eg, Ph-positive patients who did not have RQ-PCR early in treatment). There is a small risk that such a patient has atypical transcripts, where an apparent low level of MRD will be misleading. These patients may not be suitable to attempt TFR.

In patients with a prior history of TKI resistance, it is clear that the probability of maintaining TFR is lower, and patients should be made aware of this when discussing the option of TFR. A TFR attempt may still be appropriate in such patients if their quality of life is impaired by significant TKI toxicity. Almost all of the statements made about TFR are referring to adult chronic phase CML patients with no prior history of accelerated phase or blast crisis. In patients who have achieved a second chronic phase, we would be very reluctant ever to stop TKI outside of a clinical trial.

Given the rarity of CML in childhood, there are only very limited reports of TFR in children.35,36  The available information is concordant with the adult experience, and we would not preclude children from attempting TFR. However, this would be an area where clinical trials would be especially important and should always be considered the first priority when considering a TKI withdrawal attempt. Children and adolescents face special issues related to growth, self-image, and fertility, and because their lifelong duration of treatment will be so much greater, their potential for TKI toxicity must be greater. Advanced age is not a contraindication to TFR, and age does not appear to be a risk factor for molecular relapse. It is reported that the impairment of quality of life in older patients on TKIs is less than in younger patients,14  and therefore the incentive to attempt TFR may be less in older patients. Conversely, older patients may be at higher risk of specific TKI toxicities, such as pleural effusion and arterial thrombosis, and these risks need to be taken into account. Some of the key factors that determine a patient’s suitability for a TFR attempt are summarized in Figure 1.

Figure 1

Criteria to guide selection of patients suitable for a TFR attempt. KD, kinase domain; AP, accelerated phase; BC, blast crisis.

Figure 1

Criteria to guide selection of patients suitable for a TFR attempt. KD, kinase domain; AP, accelerated phase; BC, blast crisis.

Close modal

The provision of timely RQ-PCR results is crucial to the safety of patients undergoing a TFR attempt. Most patients failing a TFR attempt do so with an exponential increase in BCR-ABL, rising ∼1 log per month. Consequently, there is a need for results to be available rapidly so that they can be acted on. The sensitivity of RQ-PCR testing is also crucial, both for assessing eligibility (confirming deep molecular response) and to detect impending relapse as soon as possible. Because most relapses occur within 6 months of stopping TKI, we would recommend close monitoring during that time. If high-quality RQ-PCR is not available or cannot be provided frequently and promptly, then a TFR attempt cannot be undertaken safely. It is also important that the RQ-PCR assay has been standardized and expressed on the International Scale so that the values of MR4.5 and MMR can be reliably determined.37  Institutional requirements for TFR are summarized in Table 2. Patients who are unwilling or unable to comply with frequent monitoring should not be offered a TFR attempt.

Table 2

Institutional requirements for safe supervision of TFR

1. Availability of high quality internationally standardized, accurate, sensitive RQ-PCR laboratory 
2. Rapid turn-around of RQ-PCR test results, within 4 weeks 
3. Capacity to provide RQ-PCR tests every 4-6 weeks, when required 
4. Structured follow-up established to enable rapid intervention if BCR-ABL is rising 
1. Availability of high quality internationally standardized, accurate, sensitive RQ-PCR laboratory 
2. Rapid turn-around of RQ-PCR test results, within 4 weeks 
3. Capacity to provide RQ-PCR tests every 4-6 weeks, when required 
4. Structured follow-up established to enable rapid intervention if BCR-ABL is rising 

For patients remaining in TFR beyond the first 6 months, the risk of relapse is lower, and less frequent testing, eg, every 2 to 3 months, may be sufficient. The question of how long to continue monitoring is more difficult to answer. The latest reported loss of TFR was at 42 months, so there is clearly a need for monitoring beyond the first few years. In the CML allograft setting late relapses (beyond 5 years) do occur, averaging ∼0.5% to 1% per year.38  At present, the number of TFR patients with reported follow-up in excess of 5 years is so small that we cannot reliably estimate the risk of late relapse. Until such information is available, we would recommend indefinite RQ-PCR monitoring every 3 months.

Where the criteria for a safe TFR attempt are met (see Figure 1), the first step toward TKI withdrawal is a detailed conversation with the patient to ensure that he or she is fully informed of the potential risks and benefits and aware of the need for close follow-up. To minimize unnecessary anxiety, it is important to explain that molecular relapse is completely different from hematologic relapse and that clinically relevant consequences of molecular relapse are rare. Some vignettes to illustrate issues in the decision-making process are presented in Table 3.

Table 3

Informed decision-making for TFR candidates: practical examples

Case summaryRecommendation
Case 1: A 58-year-old woman has been taking imatinib 400 mg daily for 10 years. She has ongoing mild myalgia and arthralgia, but overall she reports that her quality of life is as good as that of many of her friends. She has maintained UMRD for 8 years. In favor of a cessation attempt. Informed that there is a >50% likelihood that TFR could be achieved, but that the risks of stopping need to be weighed carefully against the risks of continuing, which in this case were very low. She decided not to stop TKI at this stage, saying that imatinib had been a normal part of her life for many years. Stopping imatinib would mean having more frequent blood tests, which she saw as an inconvenience with no meaningful gain. She was worried about the hypothetical risk that a period off therapy might lead to a loss of sensitivity to imatinib, arguing that even if this risk is small it is a risk that she need not take. 
Case 2: A 78-year-old man treated with CML on imatinib 400 mg daily for 6 years. He has never achieved UMRD, but has maintained MR4.0 for the last 2 years. He is considering TKI cessation because of side effects (diarrhea and anemia). In favor of a cessation attempt. Chances of TFR may be <50%, because he has received <8 years of TKI therapy and has only achieved MR4.0. However, he has substantial side effects, which in this case would be sufficient justification for a cessation attempt. Counseling here is important so that he understands the high probability that TKI withdrawal will not be successful. 
Case 3: A 31-year-old woman with CML diagnosed 4.5 years ago. She received imatinib 600 mg daily for 2 years and then switched to nilotinib due to failure to achieve MMR. She rapidly achieved MR4.5 on nilotinib, which she has now maintained for 2 years. Against proceeding with a cessation attempt at this stage. Recommended persisting with nilotinib for another 2 years and then consider a cessation attempt. The probability of TFR at this stage given the poor response to imatinib and the relatively short total duration of TKI is likely to be <50%. A premature attempt may significantly delay the time when she can successfully achieve TFR. Recognizing that fertility declines rapidly past the age of 30, there is a significant risk that the patient will go ahead without physician support and adequate monitoring. Some clinicians would stop TKI and use IFN as maintenance therapy in this situation. 
Case summaryRecommendation
Case 1: A 58-year-old woman has been taking imatinib 400 mg daily for 10 years. She has ongoing mild myalgia and arthralgia, but overall she reports that her quality of life is as good as that of many of her friends. She has maintained UMRD for 8 years. In favor of a cessation attempt. Informed that there is a >50% likelihood that TFR could be achieved, but that the risks of stopping need to be weighed carefully against the risks of continuing, which in this case were very low. She decided not to stop TKI at this stage, saying that imatinib had been a normal part of her life for many years. Stopping imatinib would mean having more frequent blood tests, which she saw as an inconvenience with no meaningful gain. She was worried about the hypothetical risk that a period off therapy might lead to a loss of sensitivity to imatinib, arguing that even if this risk is small it is a risk that she need not take. 
Case 2: A 78-year-old man treated with CML on imatinib 400 mg daily for 6 years. He has never achieved UMRD, but has maintained MR4.0 for the last 2 years. He is considering TKI cessation because of side effects (diarrhea and anemia). In favor of a cessation attempt. Chances of TFR may be <50%, because he has received <8 years of TKI therapy and has only achieved MR4.0. However, he has substantial side effects, which in this case would be sufficient justification for a cessation attempt. Counseling here is important so that he understands the high probability that TKI withdrawal will not be successful. 
Case 3: A 31-year-old woman with CML diagnosed 4.5 years ago. She received imatinib 600 mg daily for 2 years and then switched to nilotinib due to failure to achieve MMR. She rapidly achieved MR4.5 on nilotinib, which she has now maintained for 2 years. Against proceeding with a cessation attempt at this stage. Recommended persisting with nilotinib for another 2 years and then consider a cessation attempt. The probability of TFR at this stage given the poor response to imatinib and the relatively short total duration of TKI is likely to be <50%. A premature attempt may significantly delay the time when she can successfully achieve TFR. Recognizing that fertility declines rapidly past the age of 30, there is a significant risk that the patient will go ahead without physician support and adequate monitoring. Some clinicians would stop TKI and use IFN as maintenance therapy in this situation. 

Several studies of IFN in combination with TKI have been completed in recent years or are in progress. Rates of deep molecular response in 2 independent studies in France and Scandinavia were higher in the pegylated IFN-imatinib combination arm than in the standard imatinib arm,39,40  but no such difference was seen in the equivalent arms of the German CML IV study.41  TFR rates for patients achieving deep molecular response with combination therapy have not yet been reported. These data may help to clarify whether a finite period of IFN exposure does have a durable effect on the probability of TFR.

Approximately 40% to 60% of patients with a deep molecular response stopping TKI will require retreatment and regain a deep molecular response. What hope is there for a second attempt at TFR? There is a report on the outcome of a small number of patients from the French TFR studies attempting TFR for a second time.42  The duration of UMRD prior to the second attempt was no longer than the period of UMRD prior to the first attempt, yet ∼20% of these patients remained in TFR at the time of the report. This is another surprising observation: the TKI and the depth of molecular response were unchanged, yet the outcome was different. Enabling patients to have a second attempt at TFR is likely to become an active area of investigation. The rational selection of alternative (or additional) therapies will depend on an improved understanding of the biological factors that determine TFR.

The divergent outcomes of patients in TFR studies with similar levels of minimal residual disease argue that additional biological factors have a major impact on outcome. Some of the most promising research into this question has been in the field of immunology. In several studies, natural killer (NK) cell numbers (or functional subsets of NK cells) have been shown to be higher in patients who sustain TFR than in those who experience molecular response.27,43,44  Immunologic anergy may be a feature of CML, and diverse immunologic effector responses including T-cell cytotoxicity and NK-cell effects may be involved.45,46  Which of these markers of immune function is most relevant is not yet clear, and none of these studies have yet demonstrated that an immunologic end point has positive predictive value for subsequent TFR, independent of clinical parameters. The availability of a biomarker that accurately predicts a very high or very low probability of TFR would be a significant step forward.

Enormous progress has been made in the quantification of BCR-ABL transcripts by RQ-PCR, but the measurement error of any PCR assay is increased by stochastic effects at low levels of the target, and a more sensitive assay could mitigate this effect. In addition, we and others have compared the quantification of BCR-ABL in genomic DNA and RNA in serial samples and have shown that individual patients may have consistently higher or lower expression of BCR-ABL mRNA for a given number of CML cells.47,48  This interindividual difference results in a measurement bias whereby RQ-PCR may underestimate the level of residual disease in some patients. Although genomic Q-PCR for BCR-ABL is not widely available, it is a promising research tool to elucidate the relationship between MRD and TFR outcome.

In our opinion, the safety data from the TFR studies reported to date are sufficiently reassuring that we feel comfortable in offering all eligible patients a supervised test of TKI withdrawal. The optimum eligibility criteria are open to debate, but the available data suggest that patients should have a minimum of 12 months of deep molecular response with MR4.0 or better. A history of prior TKI resistance should be viewed as a relative contraindication to attempting TFR, and such patients should be aware of their higher risk of relapse before making a decision. There is some evidence that a longer duration of treatment/deep molecular response is associated with a higher probability of TFR, but there must be a practical balance between the additional burden of prolonged treatment and the potential to improve the TFR rate. There are still many unanswered questions concerning TFR, so eligible patients should be strongly encouraged to participate in clinical trials where possible. The absence of a suitable trial should not preclude a patient from stopping TKI treatment, but outside the structure of a clinical trial, it would be useful to have consensus recommendations to guide those clinicians for whom TFR represents a new area of practice.

We proposed some criteria for patient selection and some criteria for institutional capability to supervise a TFR attempt, primarily access to timely and accurate standardized RQ-PCR results. If all of these criteria can be met, then we believe that TFR should become a routine part of clinical practice. Unfortunately, in many regions of the world, the availability of quality RQ-PCR is not sufficient, which means that TFR cannot be attempted safely. This poses a dilemma for many clinicians who recognize that some of their patients could otherwise be appropriately offered an attempt at TFR. This represents a new challenge for the global CML community.

Contribution: T.P.H. and D.M.R. wrote the paper.

Conflict-of-interest disclosure: T.P.H. has received research funding and honoraria from Novartis, BMS, and Ariad. D.M.R. has received research funding from Novartis and honoraria from Novartis and BMS.

Correspondence: Timothy Hughes, South Australian Health & Medical Research Institute, PO Box 11060, Adelaide, SA 5001, Australia; e-mail: [email protected].

1
Brunner
 
AM
Campigotto
 
F
Sadrzadeh
 
H
, et al. 
Trends in all-cause mortality among patients with chronic myeloid leukemia: a Surveillance, Epidemiology, and End Results database analysis.
Cancer
2013
, vol. 
119
 
14
(pg. 
2620
-
2629
)
2
Sasaki
 
K
Strom
 
SS
O’Brien
 
S
, et al. 
Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials.
Lancet Haematol
2015
, vol. 
2
 
5
(pg. 
e186
-
e193
)
3
Pulte
 
D
Barnes
 
B
Jansen
 
L
, et al. 
GEKID Cancer Survival Working Group
Population level survival of patients with chronic myelocytic leukemia in Germany compared to the US in the early 21st century.
J Hematol Oncol
2013
, vol. 
6
 
1
pg. 
70
 
4
Huang
 
X
Cortes
 
J
Kantarjian
 
H
Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.
Cancer
2012
, vol. 
118
 
12
(pg. 
3123
-
3127
)
5
O’Brien
 
SG
Guilhot
 
F
Larson
 
RA
, et al. 
IRIS Investigators
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.
N Engl J Med
2003
, vol. 
348
 
11
(pg. 
994
-
1004
)
6
Ross
 
DM
Branford
 
S
Moore
 
S
Hughes
 
TP
Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL.
Leukemia
2006
, vol. 
20
 
4
(pg. 
664
-
670
)
7
Baccarani
 
M
Deininger
 
MW
Rosti
 
G
, et al. 
European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
Blood
2013
, vol. 
122
 
6
(pg. 
872
-
884
)
8
Hughes
 
TP
Kaeda
 
J
Branford
 
S
, et al. 
International Randomised Study of Interferon versus STI571 (IRIS) Study Group
Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia.
N Engl J Med
2003
, vol. 
349
 
15
(pg. 
1423
-
1432
)
9
Branford
 
S
Seymour
 
JF
Grigg
 
A
, et al. 
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
2007
, vol. 
13
 
23
(pg. 
7080
-
7085
)
10
Cross
 
NC
White
 
HE
Colomer
 
D
, et al. 
Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia.
Leukemia
2015
, vol. 
29
 
5
(pg. 
999
-
1003
)
11
Hughes
 
TP
Saglio
 
G
Kantarjian
 
HM
, et al. 
Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib.
Blood
2014
, vol. 
123
 
9
(pg. 
1353
-
1360
)
12
Jabbour
 
E
Kantarjian
 
HM
Saglio
 
G
, et al. 
Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION).
Blood
2014
, vol. 
123
 
4
(pg. 
494
-
500
)
13
Williams
 
LA
Garcia Gonzalez
 
AG
Ault
 
P
, et al. 
Measuring the symptom burden associated with the treatment of chronic myeloid leukemia.
Blood
2013
, vol. 
122
 
5
(pg. 
641
-
647
)
14
Efficace
 
F
Baccarani
 
M
Breccia
 
M
, et al. 
GIMEMA
Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population.
Blood
2011
, vol. 
118
 
17
(pg. 
4554
-
4560
)
15
Kantarjian
 
HM
Shah
 
NP
Cortes
 
JE
, 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
2012
, vol. 
119
 
5
(pg. 
1123
-
1129
)
16
Chai-Adisaksopha
 
C
Lam
 
W
Hillis
 
C
Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis [published online ahead of print October 20, 2015].
Leuk Lymphoma
17
Yilmaz
 
M
Lahoti
 
A
O’Brien
 
S
, et al. 
Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.
Cancer
2015
, vol. 
121
 
21
(pg. 
3894
-
3904
)
18
Lee
 
MS
Kantarjian
 
H
Talpaz
 
M
, et al. 
Detection of minimal residual disease by polymerase chain reaction in Philadelphia chromosome-positive chronic myelogenous leukemia following interferon therapy.
Blood
1992
, vol. 
79
 
8
(pg. 
1920
-
1923
)
19
Mahon
 
FX
Delbrel
 
X
Cony-Makhoul
 
P
, et al. 
Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa.
J Clin Oncol
2002
, vol. 
20
 
1
(pg. 
214
-
220
)
20
Mahon
 
FX
Réa
 
D
Guilhot
 
J
, 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
2010
, vol. 
11
 
11
(pg. 
1029
-
1035
)
21
Ross
 
DM
Branford
 
S
Seymour
 
JF
, et al. 
Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study.
Blood
2013
, vol. 
122
 
4
(pg. 
515
-
522
)
22
Rousselot
 
P
Charbonnier
 
A
Cony-Makhoul
 
P
, et al. 
Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease.
J Clin Oncol
2014
, vol. 
32
 
5
(pg. 
424
-
430
)
23
Branford
 
S
Yeung
 
DT
Prime
 
JA
, et al. 
BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management.
Blood
2012
, vol. 
119
 
18
(pg. 
4264
-
4271
)
24
Mahon
 
FX
Richter
 
J
Guilhot
 
J
, et al. 
 
Interim analysis of a pan European stop tyrosine kinase inhibitor trial in chronic myeloid leukemia: the EURO-SKI study [abstract]. Blood. 2014;124(21). Abstract 151
25
Lee
 
SE
Choi
 
SY
Song
 
HY
, et al. 
 
Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study [published online ahead of print February 17, 2016]. Haematologica. doi:10.3324/haematol.2015.139899
26
Mahon
 
FX
Nicolini
 
FE
Noël
 
MP
, et al. 
Preliminary report of the STIM2 study: a multicenter stop imatinib trial for chronic phase chronic myeloid leukemia de novo patients on imatinib [abstract].
Blood
2013
, vol. 
122
 
21
 
Abstract 654
27
Imagawa
 
J
Tanaka
 
H
Okada
 
M
, et al. 
DADI Trial Group
Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial.
Lancet Haematol
2015
, vol. 
2
 
12
(pg. 
e528
-
e535
)
28
Rea
 
D
Nicolini
 
F
Tulliez
 
M
, et al. 
 
Dasatinib or nilotinib discontinuation in chronic phase (CP)-chronic myeloid leukemia (CML) patients (pts) with durably undetectable BCR-ABL transcripts: interim analysis of the STOP 2G-TKI study with a minimum follow-up of 12 Months: on behalf of the French CML Group Filmc [abstract]. Blood. 2014;124(21). Abstract 811
29
Takahashi
 
N
Kyo
 
T
Maeda
 
Y
, et al. 
Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.
Haematologica
2012
, vol. 
97
 
6
(pg. 
903
-
906
)
30
Benjamini
 
O
Kantarjian
 
H
Rios
 
MB
, et al. 
Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience.
Leuk Lymphoma
2013
, vol. 
55
 (pg. 
2879
-
2886
)
31
Yhim
 
HY
Lee
 
NR
Song
 
EK
, et al. 
Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response.
Leuk Res
2012
, vol. 
36
 
6
(pg. 
689
-
693
)
32
Thielen
 
N
van der Holt
 
B
Cornelissen
 
JJ
, et al. 
Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON).
Eur J Cancer
2013
, vol. 
49
 
15
(pg. 
3242
-
3246
)
33
Richter
 
J
Söderlund
 
S
Lübking
 
A
, et al. 
Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?
J Clin Oncol
2014
, vol. 
32
 
25
(pg. 
2821
-
2823
)
34
Breccia
 
M
Efficace
 
F
Sica
 
S
, et al. 
Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients.
Leuk Res
2015
, vol. 
39
 
10
(pg. 
1055
-
1059
)
35
Giona
 
F
Saglio
 
G
Moleti
 
ML
, et al. 
Treatment-free remission after imatinib discontinuation is possible in paediatric patients with chronic myeloid leukaemia.
Br J Haematol
2015
, vol. 
168
 
2
(pg. 
305
-
308
)
36
Millot
 
F
Claviez
 
A
Leverger
 
G
Corbaciglu
 
S
Groll
 
AH
Suttorp
 
M
Imatinib cessation in children and adolescents with chronic myeloid leukemia in chronic phase.
Pediatr Blood Cancer
2014
, vol. 
61
 
2
(pg. 
355
-
357
)
37
Hughes
 
T
Deininger
 
M
Hochhaus
 
A
, et al. 
Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results.
Blood
2006
, vol. 
108
 
1
(pg. 
28
-
37
)
38
Goldman
 
JM
Majhail
 
NS
Klein
 
JP
, et al. 
Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase.
J Clin Oncol
2010
, vol. 
28
 
11
(pg. 
1888
-
1895
)
39
Simonsson
 
B
Gedde-Dahl
 
T
Markevärn
 
B
, et al. 
Nordic CML Study Group
Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia.
Blood
2011
, vol. 
118
 
12
(pg. 
3228
-
3235
)
40
Preudhomme
 
C
Guilhot
 
J
Nicolini
 
FE
, et al. 
SPIRIT Investigators; France Intergroupe des Leucémies Myéloïdes Chroniques (Fi-LMC)
Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia.
N Engl J Med
2010
, vol. 
363
 
26
(pg. 
2511
-
2521
)
41
Hehlmann
 
R
Müller
 
MC
Lauseker
 
M
, et al. 
Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV.
J Clin Oncol
2014
, vol. 
32
 
5
(pg. 
415
-
423
)
42
Legros
 
L
Rousselot
 
P
Giraudier
 
S
, et al. 
Second attempt to discontinue imatinib in CP-CML patients with a second sustained complete molecular response.
Blood
2012
, vol. 
120
 
9
(pg. 
1959
-
1960
)
43
Ilander
 
MM
Olsson-Strömberg
 
U
Lähteenmäki
 
H
, et al. 
Early disease relapse after tyrosine kinase inhibitor treatment discontinuation in CML is related both to low number and impaired function of NK-cells chronic myeloid leukemia: therapy [abstract].
Blood
2014
, vol. 
124
 
21
 
Abstract 812
44
Rea
 
D
Dulphy
 
N
Henry
 
G
, et al. 
Low natural killer (NK) cell counts and functionality are associated with molecular relapse after imatinib discontinuation in patients (pts) with chronic phase (CP)-chronic myeloid leukemia (CML) with undetectable BCR-ABL transcripts for at least 2 years: preliminary results from Immunostim, on behalf of STIM Investigators [abstract].
Blood
2013
, vol. 
122
 
21
 
Abstract 856
45
Mumprecht
 
S
Schürch
 
C
Schwaller
 
J
Solenthaler
 
M
Ochsenbein
 
AF
Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression.
Blood
2009
, vol. 
114
 
8
(pg. 
1528
-
1536
)
46
Burchert
 
A
Müller
 
MC
Kostrewa
 
P
, et al. 
Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia.
J Clin Oncol
2010
, vol. 
28
 
8
(pg. 
1429
-
1435
)
47
Alikian
 
M
Ellery
 
P
Forbes
 
M
, et al. 
Next-generation sequencing-assisted DNA-based digital PCR for a personalized approach to the detection and quantification of residual disease in chronic myeloid leukemia patients.
J Mol Diagn
2016
, vol. 
18
 
2
(pg. 
176
-
189
)
48
Latham
 
S
Bartley
 
PA
Budgen
 
B
, et al. 
 
BCR-ABL1 expression, RT-qPCR and treatment decisions in chronic myeloid leukaemia [published online ahead of print February 2, 2016]. J Clin Pathol. doi:10.1136/jclinpath-2015-203538
Sign in via your Institution