Treatment-free remission drug for chronic myeloid leukemia

Dongwook Kim, Professor of Hemato-Onocology, Uljeongbu Eulji Medical Center, Eulji University.

Revolutionary improvement made after the introduction of targeted anticancer therapies… raises expectations of achieving TFR that allows disease management without drugs

Potential for TFR depend on early stages of treatment… need to find the optimal drug for each patients

The introduction of the world’s first targeted anticancer drug ‘Gleevec,’ has brought a revolutionary change in the field of chronic myeloid leukemia (CML) treatment.

 

Patients who mostly died if they were unable to receive hematopoietic stem cell transplantation, may now not only survive long-term but can maintain a high quality of life and even discuss the possibility of treatment-free remission (TFR), where a patient can maintain a state of remission in their cancer cells even after discontinuing his/her treatment.

 

Analysis shows that the possibility of TFR is determined by the response to the drug used in the initial stages of treatment.

 

This means that patients with a higher rate of achieving an early molecular response (EMR, BCR-ABL1 (IS) ≤10%) at 3 months of treatment are more likely to be able to discontinue drug treatment in the future.

 

And selecting an appropriate targeted therapy is of utmost importance in achieving such a high response in the early stages of treatment.

 

Patients diagnosed with CML may select one of the 5 first-line treatments: the 1st generation drug ‘Gleevec (imatinib),’ the 2nd generation ‘Sprycel (dasatinib),’ ‘Tasigna (nilotinib),’ ‘Supect (ladotinib),’ ‘Bosulif (bosuinib).’ Each drug has a different method of intake, effect and side effects, and therefore a drug suited for each patient should be selected according to the patient’s characteristics.

 

The Hemato-Oncology Professor Dongwook Kim of the Uljeongbu Eulji Medical Center, who is known as the authority in CML treatment, said, “We need to search for the best drug for each patient should be identified by monitoring the patient’s condition for around a year.” Kim added, “It is the ability of the doctor to tune the regimen while maintaining a treatment response.

 

As compliance is crucial, choosing the right drug that fits each patient’s lifestyle, as well as appropriate medication education, is also very important." Dailypharm met with Professor Kim to hear about how to select the appropriate treatment for TFR in CML.

 

Dongwook Kim, Professor of Hemato-Onocology, Uljeongbu Eulji Medical Center, Eulji University.

-Discussion of treatment-free remission (TFR) has been ongoing in CML during the past few years.

 

I believe patients would be very interested in achieving TFR. =Around half of the 2,200 patients I treat may take the drug discontinuation approach.

 

Around 200 patients (that participated in clinical trials) have discontinued their drugs.

 

The patient who had stayed off the drug the longest has discontinued taking medications for 17 years since 2004.

 

His cancer cell level had risen and fell at a low rate and then turned 0 about three times in the first year, and has had no problem ever since.

 

-If around half of the patients have the possibility of achieving TFR, that is quite much, isn’t it? =It is.

 

And this is now possible due to the improvement of drugs.

 

However, the important consensus on when and how the patients should be treated.

 

has not been reached yet.

 

Until now, patients who received drug treatment for at least 3 years and maintained their condition for at least 2 years, and showed a sustained molecular response (level of 0 in a genetic test) discontinued their drugs.

 

We conducted a study on discontinuing Gleevec with the 2010-2015 patient data provided by the Ministry of Health and Welfare.

 

Data showed that around 50% of the patients who received drug treatment for at least 3 years and showed genetic test results of 0 for at least 2 years relapsed.

 

2 patients have died from disease progression, and one patient is being treated using a different drug.

 

Globally, around 1% of the patients who discontinue treatment may be at risk, and around half experience recurrence.

 

Of course, most of these relapsed patients who receive drug treatment again become better.

 

-Patients who have a white blood cell count of 10% or less at 3 months have the possibility of TFR.

 

What factors contribute to achieving a good response in the early stages of treatment? =Prognosis differs greatly according to the drugs you select, so accurate drug selection is important.

 

And patients experience a lot of side effects in the first 3 months of using anticancer drugs.

 

Therefore, you cannot use the full dose during that period, and many patients discontinue or reduce their dose.

 

The first three months are an important period in which treatment decisions may vary depending on whether patients respond or not respond to treatments as well as compliance.

 

A treatment-naive patient can choose from one of five targeted anticancer therapies.

 

In choosing the one treatment, all features of the patient’s character need to be from age, gender, food preference, to his/her family medical history.

 

The patient may choose their treatment from the scope of the information they know.

 

I will be presenting on ‘How I select targeted anticancer therapies in CML’ at the International Conference on Hematology and Blood Disease in October.

 

-Could you tell us in more detail what needs to be considered in determining what drug is appropriate for which patient? =You could largely consider three things.

 

What underlying disease does the patient have?

 

I check for diabetes, high blood pressure, high cholesterol, etc.

 

to account for the side effects of the targeted anticancer therapies.

 

Each anticancer drug has different side effects, and using a targeted therapy that has the side effect of increasing one’s blood pressure may treat his/her CML, but would require separate treatment for diabetes.

 

Some drugs from blood clots or raise the cholesterol level of a patient as a side effect.

 

Also, age is important.

 

In particular, the prevalence of leukemia increases with age, and patients may develop CML at 70.

 

Cells also age with humans in the aging process, and blood cells die faster with age Therefore, whether to use the 2nd or 3rd generation drugs that have much potent effect over Gleevec becomes the question.

 

For patients in their 70s, prolonging survival to 10 or 15 years with less potent drugs that have fewer long-term side effects may be more important than being fully cured.

 

Genetic mutations are also an important consideration.

 

However, how the mutations affect treatment was not clearly identified, so we use the ELTS score to predict the differences in prognosis, by low-risk, moderate-risk, and high-risk patients.

 

If we can find a gene that can predict the treatment effect using next-generation sequencing, it would become an important biomarker in the treatment of CML.

 

-Does that mean the first-generation treatment is better for the elder patients and second-generation treatment is better for the younger patients?

 

=Yes.

 

Compared to Gleevec, second-generation treatment is approximately 20 times, to even 325 times in the case of Sprycel, with varying side effects.

 

Patients who use Sprycel long term may develop pleural effusion, a condition where water fills up in the lungs.

 

Tasigna can increase the risk of blood clots in the heart and brain by 25% in 10 years, and by 10 times in the same age range.

 

Supect can increase blood glucose levels.

 

Tasigna and Supect have slightly more side effects, increasing glucose levels or cholesterol levels than other drugs.

 

Therefore, older patients that use such drugs may develop arteriosclerosis and significantly increase the probability of developing myocardial infarction, cerebral infarction, or thrombosis.

 

So if a patient has a family history of hypertension or hyperlipidemia, the use of the two drugs I mentioned should be ruled out.

 

This is simply looking at the side effects, and we also need to consider the presence of additional chromosomal abnormalities, additional genetic mutations, and other factors of high-risk groups, to select the drug with the lowest risk of developing side effects for each patient’s underlying condition among the second-generation drugs.

 

Therefore, prescriptions made by each doctor for the same patient may differ by doctor.

 

In particular, hospitals with a low prevalence and incidence rate may tend to prescribe a particular drug.

 

Hospitals like Uljeongbu Eulji Medical Center which has a large CML patient population may be better in the selection of drugs and treatment.

 

For example, some patients of mine came from hospitals that rarely treat CML patients after failing treatment.

 

And I sometimes wonder why they used that drug for the patient.

 

Also, records show many failures to treatment where the appropriate dose was not used, etc.

 

It may also be due to side effects from other drugs that the patients had originally taken.

 

-Also, the doing regiment for each drug is also different.

 

This may also affect the selection of treatment according to each patient’s lifestyle.

 

=That is true.

 

Sprycel is taken once a day, and Tasigna or Supect is taken twice a day.

 

Tasigna or Supect is taken in an empty stomach, so it needs to be taken 1-2 hours before or after meals, but Sprycel does not have such limitations.

 

It has better dosing convenience as it just needs to be taken regularly once a day.

 

In particular, patients who work night shifts or work 3 shifts, like nurses, may have trouble taking a drug twice daily.

 

Therefore, according to each patient’s occupation and lifestyle, one of the two options – of taking drugs once or twice – may be selected.

 

It is already a wide known fact that taking the medicine correctly without skipping is good for treatment.

 

Discontinuing a drug can develop tolerance to the drug, and reduce the treatment effect.

 

This is more important for drugs that are taken daily.

 

Therefore, such a method of administration may be a serious and even critical issue for some occupations.

 

Dosing education has become increasingly important as drug compliance is a very serious issue.

 

A European patient group, CML Advocate, surveyed tens of thousands of patients about drug administration, and only 70% of the patients responded that they took their medication as prescribed for three days in a month.

 

30% did not take the drug properly for over 4 days a month.

 

Surprisingly enough, about 60% of patients have used and survived using Gleevec since its introduction.

 

This is in line with the medication compliance rate.

 

In this sense, compliance to treatment is very important and discussed often.

 

In that sense, dosing compliance of Sprycel, which is taken once a day and can be taken with or without meals, is much higher than other drugs.

 

-In other words, making the effort to find the optimal drug for each patient according to each patient’s underlying condition and lifestyle is the most important process? =That is right.

 

If someone asks when should we search for the right drug, I would say 1 year.

 

I tell my patients that I would be tuning the dose for the patient while monitoring their response and side effects.

 

It is the ability of the doctor to tune the regimen while maintaining a treatment response.

 

And that difference is what makes one doctor more skillful than the other.

 

One of the most frequently asked questions in lectures is what drug I would choose.

 

And I always say, ‘There is no one drug that is best for all patients.’ We need to find the best drug for each patient.