The goal of treatment changes, and there is no limit to pursuing TFR-so that every CML patient has at least one opportunity to pursue TFR

At one time, there was a saying among patients: "It will be incurable for three and a half years", which is about chronic myelogenous leukemia (CML)
.

It can be seen that CML itself is a very lethal hematological malignancy
.

In the era of conventional chemotherapy, the annual mortality rate of CML patients is 15%-20%, and the 10-year survival rate is less than 20% [1-2]
.

With the advent of targeted drug tyrosine kinase inhibitors (TKI), the prognosis of CML patients has been greatly improved.
The life expectancy of those who respond well to TKI treatment is close to normal, and they are the "lucky ones" in tumors [3]! When survival is no longer a problem, the shortcomings of long-term or even life-long TKI treatment have gradually become prominent, including the impaired quality of life caused by expected and unexpected toxicity, heavy economic burden, and impact on fertility [4]
.

Many patients are beginning to pay attention to when the drug can be stopped, and they also start to look forward to living and nurturing lives like normal people
.

(Image source: Photograph.
com) The exploration of the road to change.
CML patients who have obtained stable deep molecular response (DMR) after TKI treatment are likely to maintain this response after stopping TKI treatment, that is, treatment free remission.
, TFR), which triggered researchers to explore TFR [5]
.

Since the pioneer trial STIM1, a number of clinical trials have evaluated the feasibility of stopping TKI treatment (close monitoring) in patients who have been strictly selected and have achieved and maintained DMR for more than 2 years [6]
.

In the STIM1 study, 100 patients had a TFR rate of 43% at 6 months after discontinuation of imatinib, and a TFR rate of 38% at 60 months [7]
.

Other subsequent studies evaluating the discontinuation of imatinib have reported similar results [6]
.

The ENESTFreedom and ENESTop studies that studied the first-line or second-line treatment of the second-generation TKI drug nilotinib showed that the TFR rate at 96 weeks after stopping the drug was 49% and 53% [6]
.

The largest study on TFR to date is the ongoing EURO-SKI trial
.

A total of 758 patients were included in the study, which has been initiated in 68 centers in 11 countries
.

Data with a median follow-up of 27 months showed that the patient’s 24-month TFR rate was 50% [8]
.

Table 1 Summary of long-term follow-up data of TKI discontinuation trials At present, more than 2,000 patients worldwide have successfully discontinued TKI in clinical trials [4]
.

40-60% of patients pursuing TFR successfully achieved TFR[9]
.

It seems to be more and more feasible to achieve TFR, but in clinical practice, many doctors and patients are swinging between stopping and not stopping the drug
.

What is the reason? The swing survey of non-stop medication found that not all patients are willing to stop treatment [10]
.

The main reason for reluctance to try TFR is that they do not understand TFR and related management, and worry about unsuccessful TFR and disease recurrence [10]
.

55% of the interviewees said that even after discussing with their doctors, they were still worried about the unsuccessful TFR and the recurrence of the disease [10]
.

In addition, they are also worried that hospital testing is not standardized, it is not safe to stop treatment, and they are afraid of withdrawal symptoms[10]
.

When the patients were first notified of the disease recurrence, more than half of the respondents felt scared, anxious, disappointed, and depressed [10]
.

It can be seen that patient education is very important in CML management but is often overlooked
.

(Image source: Photograph.
com) Although about 40%-60% of patients relapse within 6 months after stopping treatment, almost all patients who have relapsed have recovered DMR after restarting TKI treatment, that is to say, stopping the drug.
Will not bring greater risks to patients [6]
.

For patients who are worried about the limited conditions and cannot standardize the test, they can go to a more authoritative laboratory to do the threshold test for discontinuation of the drug, and monitor it in the local hospital after the drug is discontinued
.

Some patients may have "TKI withdrawal syndrome" when the drug is stopped, but most people have mild symptoms and will gradually disappear over time
.

Therefore, "TKI withdrawal syndrome" should not become an obstacle to our pursuit of TFR
.

Healthcare personnel should actively understand the motivations and worries of patients, inform them of the benefits and risks of TFR, and pay attention to the mental health of patients when the drug is stopped and when treatment is restarted [10]
.

During the cessation of treatment, monitor and assist in the management of withdrawal symptoms [3]
.

Every patient with chronic particles should pursue a TFR to solve their worries.
In what ways should doctors and patients try to reach TFR? To successfully reach TFR, we must first obtain a sustained and stable DMR
.

Studies have shown that the duration of TKI treatment and the DMR time maintained before discontinuation are related to TFR [6,11]
.

This reminds clinicians and patients: "Before treatment, it is impossible to judge whether the patient can touch TFR.
It should be judged whether there is a chance to achieve TFR according to the patient's response to treatment
.

"So, "every patient has the opportunity to pursue TFR!" How can we reach TFR faster and earlier? Optimize treatment and reach TFR sooner DMR to provide security for the realization of a CML patient, informed and shorter TFR pathway appears increasingly viable [9]
.

data show that the use of the drug generation TKI imatinib patients achieved TFR median of 4.
9 years, while the use of the second generation The median time to reach TFR in nilotinib patients was 3.
6 years[7-8]
.

In the ENESTnd study, the cumulative incidence of MR4.
5 in the nilotinib group at 5 and 10 years was higher than that in the imatinib group.
[6 ]
.

MR4.
5 is an indicator for patients to reach DMR
.

Reaching DMR means that the residual amount of white blood cells in the patient's body has dropped to 0.
0032%, and there is basically no risk of disease progression [12]
.
It
can be seen that with the use of second-generation TKIs, faster and faster Deeper DMR and earlier access to TFR can be achieved [3]
.

CML patients pursuing TFR should strictly evaluate the current first-line treatment strategy [3]
.
If
necessary, optimize the first-line treatment
.

Figure 1 First and second generation TKI drugs reach TFR median time to ensure safety and to prevent disease progression, for the shortest duration of any TKI, DMR should be stable for 2 years [6]
.

after treatment, patients must be monitored monthly by qPCR at least 6 months, 6 months after It should also be monitored regularly [2]
.
It
needs to be emphasized that almost all patients with molecular relapse after stopping the drug can achieve DMR after retreatment, and some of them can try to stop the drug again [9,10]
.

The possibility of reaching TFR again depends on several factors: leukemia or patient characteristics, TKI type, duration of treatment, duration of DMR, etc.
[2]
.

TFR is an important means to avoid long-term adverse effects of treatment, reduce social and family economic burdens, improve patient compliance, and improve patient health and quality of life [10]
.

To achieve TFR, CML patients can realize their desires and expectations for a normal life.
Every CML patient should try to reach TFR
.

Conclusion CML can be called a model and a model of targeted therapy for human malignant tumors
.

TKI drugs have greatly changed the prognosis of CML patients, and the life expectancy of CML patients receiving TKI treatment is close to normal [3]
.

Improving the quality of life of patients and reducing the burden on society have become new goals for the treatment and management of CML patients
.

One of the best ways to address these two points is to consider discontinuing TKI in patients who respond well
.

Many clinical trials have evaluated the possibility of successful withdrawal.
At present, more than 2,000 patients worldwide have successfully stopped TKI in clinical trials, with a successful withdrawal rate of 40%-60%
.

Patients who relapsed after stopping the drug and restarting TKI therapy can restore DMR, and will not bring worse results to the patient
.

In addition, drug withdrawal will have a huge positive impact on CML patients, the healthcare system and the entire society.
Patients will no longer suffer from adverse reactions, the quality of life and happiness index will increase, and the social medical burden will decrease
.

Therefore, doctors and CML patients should have firm confidence in trying TFR, and hope that every patient can achieve TFR and enjoy a healthy and worry-free life! References: [1] Goldman L, Schafer A, Arend W, et al, eds.
Cecil Medicine.
24 ed[M].
Philadelphia, PA: Elsevier Saunders; 2012:1209-1218.
[2] Baccarani M, Abruzzese E , Accurso V, et al.
Managing chronic myeloid leukemia for treatment-free remission: A proposal from the GIMEMA CML WP[J].
Blood Advances, 2019, 3(24):4280-4290.
[3] Leukemia E.
The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts.
2013.
[4] Saußele S, Richter J, Hochhaus A, et al.
The concept of treatment-free remission in chronic myeloid leukemia[J].
Leukemia, 2016,30,1638-1647.
[5] Kaushansky K, Marshall AL, Prchal JT, et al.
Williams Hematology (9th edition)[M ], Translated by Chen Zhu, Chen Saijuan.
Beijing: People's Medical Publishing House, 2018.
[6] NCCN Clinical Practice Guidelines in Oncology: