Frequently Asked Questions
Find answers to some of the most common questions about PCR testing, monitoring, and treatment free remission.
PCR Monitoring
What is PCR?
PCR stands for ‘polymerase chain reaction’. It is a diagnostic and monitoring tool used in CML to measure the response to treatment. It is not only used in CML; PCR is also used in other conditions and is generally one of or the most sensitive ways to “detect” something; for example, BCR-ABL can be detected in a person with CML, anthrax on a mailed letter, or evidence of a specific virus in a person after bone marrow transplant.
Why should I know my PCR level?
Every time the PCR is run the value is important, and conveniently can be compared to prior values. It often is the only test which gives someone an idea about the depth and stability of their response to treatment. A person with CML should always know their PCR level! PCR results should be explained to patients in as much depth as they can understand, so they have a good sense about the response level, how this compares to where they should be, when the next test is due and if any concern or risk has developed. ASK!
What does PCR measure in CML?
CML occurs when a specific change happens between chromosomes 9 and 22; parts of them swap places, creating a protein called BCR-ABL (Philadelphia Chromosome). This BCR-ABL protein is what makes leukemia blood cells different and malignant. In CML, PCR measures the amount of genetic material (called RNA or DNA) or ‘blueprints’ for BCR-ABL present; PCR levels are thus linked to both the amount and activity of leukemia cells remaining in someone with CML. PCR is often said to measure the residual (remaining) disease as it can detect very small levels of BCR-ABL ‘blueprints’.
Is PCR the only test I should have done during my treatment?
PCR is a powerful tool in CML but it is not the only test needed during treatment. A bone marrow test is recommended at diagnosis to look for ‘accelerated’ (more aggressive) features in the marrow. A bone marrow test is also the only way to obtain the ‘karyotype’, where the chromosomes are examined in a number of cells to count the number with the Philadelphia chromosome (the 9:22 swap, which appears as a long chromosome 9 and short chromosome 22) or to see if any other genetic damage is visible.
The karyotype and FISH (fluorescent tagging of cells to count the number with the Philadelphia chromosome) studies are recommended to be repeated until they turn negative (this is called ‘complete cytogenetic remission’ – or CCyR). Once this milestone is passed and confirmed, the PCR test is the only test that will show residual levels of CML and becomes the main way of monitoring.
Why is PCR important in the management of CML treatment?
PCR is a crucial tool in CML for a number of reasons; first, it is ‘patient friendly’, requiring a blood draw only; and second, it is a broad-ranged test, being able to measure untreated (high levels) of BCR-ABL all the way down to the lowest measurable levels.
How often should PCR testing be performed?
Early in treatment other tests (karyotype and FISH) may take priority over PCR; however, since the overwhelming majority of people with CML normalize their chromosome tests (karyotype and FISH) within the first 12-18 months of treatment, the PCR test becomes most important and is recommended every 3 months once further reduction in BCR-ABL levels occurs (this is referred to as moving from cytogenetic response to major molecular response). Once BCR-ABL levels have fallen at or below the major molecular response, it is recommended to keep monitoring them every 3-6 months to ensure stability and/or further reduction.
Should my level always be exactly the same?
No, if your PCR has changed you should not panic; there appears to be an acceptable degree of fluctuation. However, your doctor must look at your results carefully and focus on the trend overtime. In general, for a CML patient in treatment with a TKI, PCR results over time should be going down. At the beginning of treatment we expect that the PCR levels will usually go down significantly over months. Once the remission milestones are reached, the degree of reduction is generally much smaller and stability is often fine, especially when very deep remission is obtained. A rise in PCR needs to be carefully assessed. One important consideration is the point from which the rise in PCR level occurred. For instance, a rise in PCR for a patient who was in deep molecular remission is different from an increase of the level of PCR in a patient who was not in molecular remission. Likewise, the degree of change, minimal or significant, is also an important consideration. Finally, change that leads to a loss of response, such as loss of a major molecular response, needs close assessment and often at this point, other tests should be performed.
What is the ideal PCR level? How long will it take to reach the ideal level of my PCR?
In CML we like to talk about achieving milestones. An important milestone is a complete cytogenetic remission (CCyR) which is very important and very protective. This is generally the equivalent to a 2-log, or 100 fold drop in the leukemia level. Additional protection clearly appears to be gained with further reduction in the PCR level to 3 Logs (1000 fold drop) or greater, referred to as a major molecular response (MMR). The MMR level of response is often referred to as a ‘safe haven’ below which risk of loss of response is the lowest. This being said, the newest TKI therapies increasingly allow patients to achieve deeper responses-4 log and 4.5 log reductions (MR4 and MR4.5). MR4.5 is the level at which measuring the PCR level is difficult in many laboratories, as it no longer detectable or not able to be quantified. This threshold for a period of time was called ‘CMR’ or complete molecular remission but based on the somewhat misleading nature of that name (as it implies complete response, which to many would mean ‘zero’ remaining leukemia) there is movement towards simply using the names that describe the level (MR4, MR4.5).
What can affect my PCR level?
PCR levels generally reflect the ongoing response to treatment; there may be some variability of the shrinking volume of leukemia, and some variability in the test itself. Because it is a very sensitive test, the same patient might get a different result if measured in two different labs. Another big problem is that all labs do not use the same scale to measure and the exact same level of leukemia could result in different test results in two different labs. Great efforts are being taken to standardize PCR results and report all results on a single (International) scale. The first thing to look at, if the PCR result is different from the last one is where the tests were done (same lab, different lab) and is the International scale being used.
Of course, adherence/compliance to therapy (taking medicines for CML) is vital to stable or improving PCR results and one of the first questions physicians and patients need to ask if the PCR level has changed is about therapy -has it been missed or stopped for any reason. Patients who stop taking their treatment daily are more likely to have higher PCR levels and patients who miss even a modest amount of doses early in treatment are less likely to get into deep remission.
My last PCR has gone up; does this mean my treatment is not working?
Not necessarily, but rising PCR needs to be taken seriously. The checklist that needs to be reviewed with any change includes: the range from which the rise has been detected (in cytogenetic remission or not, in molecular remission or not), the degree of change (modest change, change leading to categorical loss of response like for instance, loss of MMR), and the history of the PCR stability to date. Often a rise in PCR prompts a repeat of the PCR at 4-6 weeks to see if the change is sustained and/or confirmed.
Should my PCR always be done in the same lab?
Ideally for now, the answer is yes. Having the PCR done in the same lab will mean reporting on the same scale, making tracking progress easier. Once all labs use the same scale (called the International Scale or IS) having the PCR done in the same lab will likely be less important and reporting will be the same globally. Efforts to have that be the case have been ongoing for many years already and hopefully it will soon be a reality.
What does MMR mean?
MMR is the acronym for major molecular response. MMR means there has been reduction in the PCR level to 3 logs or greater below a standard baseline (1000x reduction). As mentioned above, the combination of achieving the cytogenetic complete remission (CCyR) milestone and the further reduction in PCR levels to MMR levels is often referred to as a ‘safe haven’ below which risk has been maximally optimized. MMR is the last milestone of response for which improvement in outcome has been demonstrated. This improvement in outcome is tied to reduction in risk of any loss of response as well as lowering risk of progression of the disease. At the moment, any benefits of deeper response than MMR (MR4 and MR4.5) have more theoretical benefit (related to the possibility of stopping therapy someday?) than proven benefit, hence the current goal is to get all patients at least into stable MMR.
When should I ask for a second opinion about my CML treatment?
Anytime you want to. If there is a problem on your current treatment (side effects, response not on track, loss of response), if there is uncertainty over which medication to start with or switch to, specific or unusual side effects, etc. these are all good reasons. CML is a disease that requires long term treatment, so you should make sure you choose a doctor that is a “good fit” for you, where you feel you can ask questions, and have an honest and open relationship. There are many CML experts that are truly passionate about working through the details and getting someone back on track, making the right decisions with people about options and explaining things so you can understand and be a part. And they certainly want you to KNOW YOUR PCR!
Treatment Free Remission
1. What is treatment-free remission (TFR)?
TFR is a deliberate, carefully monitored cessation of therapy embarked upon by patients after discussion and agreement with their doctors. When it works, the outcome has been described as a “functional cure”—cure meaning the patient has completed treatment and is in remission; functional because many patients may still have evidence of chronic myeloid leukemia (CML) by a polymerase chain reaction (PCR) test but remain stable and safe off treatment.
Is it different from a drug holiday?
Although patients in TFR do stop taking their CML medication, it is much more than a “drug holiday.” The goal is to achieve continued deep remission without treatment. There are specific requirements to try TFR, the main one being a stable deep molecular response over time. Strict monitoring and prompt action (such as retreatment) in case of relapse are necessary to make it a safe and reasonable pursuit.
2. What are the disease monitoring requirements to try TFR?
What test is required?
The blood test used to monitor levels of BCR-ABL in patients attempting TFR is a quantitative PCR. Test results should be reported on the International Scale (IS) to allow alignment of results between laboratories. PCR can reliably detect deep responses to treatment, down to 0.01% of the BCR-ABL levels found in untreated CML per the IS (known as MR4) or even 0.0032% (known as MR4.5).
How often is testing done?
According to available guidelines, testing needs to be done monthly for the first 6 months of TFR, then every 6 weeks for the next 6 to 18 months. After 2 years, monitoring can continue every 3 months.
Will I need testing for the rest of my life?
It is recommended that patients with successful TFR continue to be monitored indefinitely.
Can I be monitored through standard blood tests?
Standard blood tests are not a good way to monitor TFR because they cannot detect very low BCR-ABL levels. PCR testing, on the other hand, can detect very low BCR-ABL levels such as those in patients with major molecular response (MMR) or deeper molecular responses. When a patient is in TFR, their BCR-ABL levels need to be monitored closely to make sure they do not lose MMR. If they do, they must restart treatment promptly.
3. What if I want to try TFR, but my local laboratory doesn’t have adequate testing methods?
To be monitored correctly for a safe TFR attempt, patients need PCR testing. For PCR testing to be considered adequate, it must be readily available and sensitive enough to detect low level changes; a quick turnaround is also necessary. If your local laboratory does not have these testing options available, PCR kits can be reliably sent to a reference laboratory. If you are interested in this option, you should discuss it with your doctor. Keep in mind that this option can present challenges at different steps, such as having blood drawn into the prepared kits, shipping and handling of the sample, and having results reported, so it is best to try it before stopping medication to ensure that it works smoothly. TFR may be possible even under seemingly challenging circumstances if we plan carefully.
Do I need to be tested at the same lab every time?
It is recommended to have your PCR test at the same laboratory every time if possible because it decreases variability. Even within the same laboratory, tests can have some variation, so adding laboratory-to-laboratory variability can make it harder to interpret any change in your test results. If you cannot use the same laboratory every time, working with a laboratory that uses the International Scale is a critical factor for consistency in your PCR test results. The IS should minimize variability; therefore, using multiple laboratories that report on the IS is reasonable.
4. How long does the process of attempting TFR usually last?
TFR can be broken down into phases or periods of time:
- Before someone can stop their CML medication (TKI), there is generally a required period of time on medication and a minimum period of time in stable and deep molecular remission, meaning either MR4 or MR4.5. This can be called the “monitoring phase”
- During the first 6 months of attempting TFR, patients are monitored monthly. This is the most crucial period because relapse (an increase in BCR-ABL level that results in loss of MMR) is most likely to happen during this time
- If someone has passed the 6-month mark and remains in relatively stable deep molecular response, their chance of relapse decreases dramatically but not entirely. The next 18 months are a period of continued monitoring (every 6 weeks), where “late relapse” is possible, but occurs in a smaller fraction of patients
- The risk of relapse after 2 years in TFR is even smaller but not zero; therefore, monitoring is done every 3 months
How is TFR success measured?
TFR success is measured by a patient feeling well off treatment and reaching key time milestones with a deep molecular response:
Key TFR Milestones
- 6 months off treatment – lower relapse risk
- 2 years off treatment – minimal relapse risk
In clinical trials studying TFR, some patients have been off treatment for more than 10 years. However, currently, most patients in TFR have a shorter duration of TFR.
5. How common is TFR among the CML population?
What are the chances of success with TFR?
After 5 years of treatment with a tyrosine kinase inhibitor (TKI) medication, approximately 30% to 60% of patients with CML (depending on which TKI they receive) achieve the deep molecular responses required to try TFR. This means that not everyone will be able to consider TFR, at least at this time. However, with access to second-generation TKIs (nilotinib, dasatinib, and bosutinib) as first-line treatment and/or maximal use of imatinib, roughly half of CML patients could eventually be eligible for TFR. The success rate of TFR is approximately 50%, so an estimated 20% to 25% of patients with CML can achieve TFR.
The chance of successful TFR is roughly 50%; this has been consistent across clinical trials for more than a decade even though the requirements to try TFR have evolved over the last few years. What is also consistent is that, in most cases, relapse (loss of MMR—which is grounds to restart treatment) occurs within 6 months of stopping treatment. The number of people who lose MMR between 6 and 18 months is much lower.
6. Does TFR mean that CML can be completely cured?
The term that is used for successful TFR in CML is “functional cure.” In most cancer treatments, a cure is defined as the absence of any signs of the disease and being off treatment for enough time that relapse is unlikely to happen. A “functional cure” means not having “active” disease and not needing treatment for the cancer, even if there is some sign of the cancer. This is the case with CML; many patients in successful TFR still show a sign of the disease (trace amounts of BCR-ABL) with standard PCR testing.
How long does it take to achieve a “functional cure”?
In CML, a “functional cure” means that a person has been off treatment without loss of MMR for more than 6 months, when it is more likely they will have a successful TFR. Based on our experience so far, a “functional cure” is more firmly established if the patient has been off treatment for 2 years or more without loss of MMR. Monitoring would still be needed in every case to track ongoing success.
7. What are the risks associated with TFR?
Can I develop TKI resistance?
Resistance has generally not been observed in the setting of TFR. After TFR failure and retreatment, there have been extremely rare cases of CML progression, with the odds appearing to be less than 1 in 1000. Retreatment with the same TKI that was stopped is highly effective, with rapid recovery of MMR, MR4, or MR4.5 in nearly all cases. Longer follow-up of patients for whom TFR was not successful in clinical trials will help confirm that there is no TKI resistance or incomplete recovery of deep remission, but the experience to date is very reassuring.
In case of relapse, would I restart the same medicine or try a new one?
Retreatment with the same TKI that was stopped has been highly effective in clinical studies. Some people may switch to a different TKI if they experienced some intolerance (troubling side effects) with the medicine they stopped. In the future, there will likely be better strategies for determining the best option for retreatment (for example, a different TKI or combinations of medicines) to make a second TFR attempt possible and more successful, but this needs to be studied further.
Should I expect the same symptoms after restarting treatment?
It is reasonable to expect that similar side effects from TKI treatment will return with retreatment. Although many people worry about side effects becoming worse, this is unlikely. In fact, given the fact that people—or their systems—may have grown accustomed to TKI side effects, sometimes side effects do not return as strongly as before.
What are the chances of regaining MMR?
Retreatment has been shown to be highly successful after an unsuccessful TFR attempt, based on studies in which patients had ongoing strict monitoring and retreatment occurred quickly after loss of MMR. Regaining MMR appears universal, and deep remission returns in nearly all patients. In time, the ongoing clinical studies will tell if there is any change in the quality of deep remission after retreatment. It is important not to delay retreatment, not to keep retesting to “see if it will go back down,” and not to miss monitoring visits for fear of MMR loss. Information is power, and loss of MMR is powerful information that needs to be acted on to be safe.
8. How do I know if I’m a candidate to try TFR?
The requirements to be eligible for attempting TFR include:
- Age 18 years or older
- Chronic-phase CML without a history of accelerated- or blast-phase CML
- A non-high Sokal score at diagnosis (EU only; Sokal score is a risk
assessment tool) - TKI treatment (imatinib, dasatinib, nilotinib, bosutinib, or ponatinib)
for at least 3 years (US guidelines) or at least 5 years (EU/ESMO
guidelines) - Prior evidence of measurable BCR-ABL
- Stable molecular response (MR4) for 2 years, documented on at least
4 tests, performed at least 3 months apart (US guidelines); optimal
response to first-line therapy, having reached MR4.5 (EU) - Access to reliable IS PCR testing that can detect at least MR4.5 and
provides results within 2 weeks (US; or 4 weeks in the EU) - Being able to have PCR tests done every 4 to 6 weeks when required
(EU); for most patients, monthly molecular monitoring for 1 year, then
every 6 weeks for the second year, and every 12 weeks thereafter
indefinitely for patients who remain in MMR (US) - Promptly resuming TKI medication within 4 weeks of losing MMR, with
monthly molecular monitoring until MMR is re-established; testing every
12 weeks thereafter is recommended indefinitely for patients who have
reinitiated TKI therapy after losing MMR - Those who do not achieve MMR after 3 months of resuming TKI should be
tested for BCR-ABL mutations and have molecular monitoring monthly for
another 6 months - Consulting with a CML Specialty Center to discuss eligibility to attempt
TFR and the potential risks and benefits of stopping treatment, including
TKI withdrawal syndrome (US) - Reporting of the following to a member of the NCCN CML panel is strongly
encouraged:- Any significant side effect believed to be related to stopping
treatment - Progression to accelerated- or blast-phase CML at any time
- Not regaining MMR after 3 months from treatment reinitiation (US)
- Any significant side effect believed to be related to stopping
Can children be candidates to try TFR?
Research about TFR in children with CML is ongoing, and not as much is known about it as is known about TFR in adults. At this time, this would be considered a research question, but of course a good one to ask, and hopefully a path for children to have successful TFR will be developed. Don’t hesitate to ask!
9. How do my physician and I prepare to try TFR?
Will I go through withdrawal?
Approximately 1 in 4 patients (25%) who stop a TKI will have withdrawal syndrome—physical symptoms that are caused by stopping the medication. This tends to be mild to moderate in intensity, mainly leading to muscle and joint aches and pains, and rarely skin symptoms (hives, hairfollicle rash). Stopping medication may remove effects that the TKI had on unintended targets and trigger an inflammatory response, almost like a brief allergic flare. In some cases, antihistamines may help.
Should I expect psychological/anxiety challenges?
There certainly can be many TFR-related challenges not just for the body but also for the mind. The first challenge is embracing the idea that this is a good plan—many immediately think, “Why on earth?” or “If it’s not broken, don’t fix it.” TFR should always be viewed as an option, not a requirement or “must.” It should be a decision made by the person, with the advice and guidance of their CML doctor and those who care for them (like loved ones). It needs to feel right. Studies have looked at the reasons why some choose TFR and some don’t, the stress and anxiety such an endeavor brings about, and how to manage it. Communication and open dialogue are very important to help you work through the challenges; it’s also important to be careful to not miss monitoring checks and understanding ‘what is your PCR’ is always important!
What does my physician need to know to manage my care in TFR?
Ideally a CML specialist—someone who is very familiar with TFR requirements, the monitoring plan, retreatment strategy, etc—should manage your care if you choose to attempt TFR. However, this may not always be possible. If the CML doctor managing the TFR has access to a CML specialist and they can work together to follow the rules carefully, this can also work well. It is a good idea to see a CML specialist at least once before making the decision to try TFR. The patient needs to be comfortable that their CML doctor can handle this important decision properly and safely. And as mentioned before, open dialogue along with easy access to the doctor’s office and clinic and to the testing required needs to be worked out before attempting TFR.
Where can I find these specialists?
CML specialists are eager to help and can be found through
global organizations like The International CML Foundation, the CML Advocates
Network, and more. Patients and CML doctors should be comfortable asking for help and advice on this very important topic from experts in the field at any time. People interested in TFR and CML doctors can easily find and use guidelines such as those from the National Comprehensive Cancer Network (NCCN) in the United State and the European Society for Medical Oncology (ESMO). The European LeukemiaNet (ELN) is another authority in the field, and their latest update of guidelines for CML should be available soon.