Imatinib in chronic myeloid leukemia: IRIS and ELN 2020

A 52-year-old bank employee has routine tests and discovers 98,000 leukocytes per microliter, with raised basophils and a spleen that extends 4 cm beyond the costal margin. The bone marrow aspirate shows chronic myeloid leukemia (CML) in chronic phase, and PCR confirms BCR::ABL1. She asks two things: whether she will take medication forever and whether the generic imatinib offered by the service is good enough. The scene is fictional and was written for teaching.

This text uses the case as a scenario for clinical reasoning for students and health professionals. The topic is imatinib in chronic phase CML, based on the IRIS study and the 2020 European LeukemiaNet (ELN) recommendations. The question Dr. Alexei proposed for the series is this: how can you tell, month by month, whether the treatment is working? The text does not replace your country's guideline or your service's protocol. If you play the case of the day on NEXO, you know that following how a clue evolves over time is as important as finding it.

Key points

• In IRIS, the estimated 10-year overall survival with imatinib was 83.3 out of 100.
• ELN 2020 considers generic imatinib the initial treatment with the best cost and effectiveness in chronic phase.
• The standard dose of imatinib is 400 mg once a day.
• Response is monitored by quantitative PCR of BCR::ABL1 on the international scale, with targets at 3, 6 and 12 months.
• BCR::ABL1 above 10 out of 100 at 3 months, if confirmed, indicates failure.
• Some patients with a deep and stable molecular response can stop treatment under monitoring.

Why this is a reasoning scenario

CML is a disease in which diagnosis is usually easy and initial treatment is simple: one tablet a day. The difficulty lies in follow-up. ELN 2020 notes that the life expectancy of a patient with chronic phase CML diagnosed today is very close to that of people of the same age in the general population (Hochhaus et al., 2020). This result depends on recognizing early who is not responding.

Branford notes that when IRIS began in 2000, response was measured by blood count and karyotype. Today, response is monitored mainly at the molecular level, by quantitative measurement of BCR::ABL1 transcripts, and the prognostic value of this measurement was first demonstrated in IRIS itself (Branford, 2020). Clinical reasoning in CML is, to a large extent, reading a PCR curve over the months.

The post on how the leukemia team is organized covers the difference between the urgency of acute leukemias and the long follow-up of chronic ones. Here the focus is chronic phase CML.

What makes this error easy to make

Because the patient feels well and the blood count normalizes within a few weeks, it is easy to think the treatment is working and space out the tests. But normalization of the blood count says nothing about molecular response. The error is confusing hematologic remission with disease control, and only noticing the failure when it already appears in the blood count, often along with a resistance mutation.

What IRIS showed

IRIS was an open-label, multicenter, randomized study that compared imatinib with interferon alfa plus cytarabine in patients with newly diagnosed chronic phase CML (Hochhaus et al., 2017). It included 1,106 patients at 177 centers in 16 countries, 553 in each group, between 2000 and 2012.

The first analysis showed that imatinib 400 mg once a day was more active and had fewer adverse effects than interferon. At 18 months, complete cytogenetic response was 76.2 per 100 with imatinib versus 14.5 with interferon and cytarabine, and progression-free survival to accelerated phase or blast crisis was 96.7 versus 91.5 per 100. For this reason, most patients in the interferon arm switched early to imatinib: 65.6 per 100 crossed over, with a median of 0.8 year on initial treatment.

The analysis with a median follow-up of 10.9 years focused on the imatinib group. The main results were these (Hochhaus and colleagues, 2017):

• estimated overall survival at 10 years of 83.3 per 100;
• complete cytogenetic response in 82.8 per 100;
• progression to accelerated phase or blast crisis in 38 of 553 patients, 6.9 per 100, during study treatment;
• 48.3 per 100 completed study treatment with imatinib, and the median duration of use was 8.9 years;
• 15.9 per 100 stopped for unsatisfactory therapeutic effect and 6.9 per 100 for adverse effects.

Serious adverse effects related to imatinib occurred in 51 of 551 patients, 9.3 per 100, and were more frequent in the first year, decreasing over time. The authors concluded that the efficacy of imatinib persisted over time and that prolonged use was not associated with unacceptable cumulative or late toxicity.

Confirmation in the German CML IV study

The CML Study IV randomized 1,551 patients in chronic phase between 2002 and 2012 into 5 arms testing ways to optimize imatinib (Hehlmann and colleagues, 2017). With a median follow-up of 9.5 years, overall survival at 10 years was 82 per 100, progression-free survival 80 per 100, and relative survival, compared with the general population, 92 per 100. Survival did not differ between imatinib 400 mg and the experimental arms.

The multivariate analysis showed that risk group, additional chromosomal abnormalities of major route, comorbidities, smoking and type of center influenced survival, but no form of treatment optimization did. Patients who reached molecular milestones at 3, 6 and 12 months had a survival advantage. The authors concluded that, for those who respond, imatinib 400 mg alone offers a life expectancy close to normal, and that survival depends more on patient and disease factors than on the initial choice of treatment.

Dose and adverse effects

ELN 2020 sets the standard dose of imatinib at 400 mg once a day (Hochhaus and colleagues, 2020). In chronic phase, a lower dose of 300 mg may be used if 400 mg is not tolerated and the response is optimal. In accelerated phase, 400 mg twice a day may be used, but if there is progression to more advanced disease, the recommendation is to switch to a second-generation inhibitor.

The same guideline summarizes what to expect from imatinib:

• early molecular response, with BCR::ABL1 up to 10 per 100 at 3 and 6 months, in 60 to 80 per 100 patients;
• major molecular response in 20 to 59 per 100 at 1 year and in 60 to 80 per 100 at 5 years;
• deep molecular response, MR4 or better, in 35 to 68 per 100 at 5 years;
• switching from imatinib, mainly to another inhibitor, in 26.5 per 100 at 10 years up to 37 to 50 per 100 at 5 years, depending on the study;
• overall survival at 10 years of 82 to 85 per 100, with leukemia-related death in about 6 per 100.

ELN 2020 states that there is no absolute contraindication to imatinib and that no life-threatening complications have emerged, although patients with low ejection fraction or low glomerular filtration should be monitored carefully (Hochhaus and colleagues, 2020). The most frequent causes of poor tolerance are early fluid retention, gastrointestinal symptoms, cramps, joint pain, skin rash and fatigue. Many of these effects improve over time or after a brief pause.

Reducing the dose without losing the response

Copland reviewed dose reduction of tyrosine kinase inhibitors and concluded that, with adequate monitoring, dose optimization is safe, reduces adverse effects and improves quality of life (Copland, 2019). Studies such as DESTINY showed that dose reduction is safe in patients with deep molecular response and may be considered before an attempt to stop treatment.

Risk at diagnosis: Sokal and ELTS

Iezza and colleagues recall that the first prognostic system for CML was the Sokal score, which uses four variables from diagnosis: age, spleen size, platelet count and percentage of blasts in the blood, and separates three risk groups (Iezza and colleagues, 2023). In 2016, the EUTOS long-term survival score (ELTS) was created, designed to predict death from CML. It uses the same four Sokal variables, with different weights and a lower weight for age, and it was the only one that separated three groups with significant differences in disease-specific death.

ELN 2020 recommends assessing risk at diagnosis with the ELTS (Hochhaus and colleagues, 2020). A high-risk ELTS and high-risk additional chromosomal abnormalities appear in the goals table as warning signs already at diagnosis.

The molecular goals of ELN 2020

ELN 2020 uses BCR::ABL1 on the international scale to define whether treatment should continue (optimal response), change (failure) or be reassessed according to the patient's characteristics (warning) (Hochhaus and colleagues, 2020). The table below reproduces the goals, with values converted to the form "in every 100".

Time point	Optimal	Warning	Failure
Diagnosis	not applicable	high-risk additional chromosomal abnormalities or high-risk ELTS	not applicable
3 months	up to 10 in every 100	above 10 in every 100	above 10 in every 100, if confirmed in 1 to 3 months
6 months	up to 1 in every 100	above 1 up to 10 in every 100	above 10 in every 100
12 months	up to 0.1 in every 100	above 0.1 up to 1 in every 100	above 1 in every 100
Any time point	up to 0.1 in every 100	above 0.1 up to 1 in every 100, or loss of major molecular response	above 1 in every 100, resistance mutations or high-risk abnormalities

Table source: ELN 2020, table 4 (PMID 32127639).

The guideline explains that reaching major molecular response, with BCR::ABL1 up to 0.1 in every 100, predicts CML-specific survival close to 100 in every 100, because progression is rare from that level. For those who plan to stop treatment in the future, the optimal response at any time point is BCR::ABL1 up to 0.01 in every 100, MR4. A switch may be considered if major molecular response is not reached between 36 and 48 months. Additional PCR tests may be indicated if the kinetics of the response are not clear or if toxicity forces interruptions and dose reductions.

Mutations and switching inhibitor

When there is failure, testing for mutations in the kinase domain of BCR::ABL1 guides the choice of the next inhibitor. ELN 2020 includes a table with the recommendations (Hochhaus and colleagues, 2020):

• T315I: ponatinib;
• F317L/V/I/C and T315A: nilotinib, bosutinib or ponatinib;
• V299L: nilotinib or ponatinib;
• Y253H, E255V/K and F359V/I/C: dasatinib, bosutinib or ponatinib.

The post about genetics and MRD in acute myeloid leukemia shows how the same logic of measuring residual disease appears in another leukemia.

Imatinib or second-generation inhibitor

ELN 2020 states that generic imatinib is the initial treatment with the best cost-effectiveness in the chronic phase, and that the contraindications and adverse effects of each inhibitor must be considered in the choice (Hochhaus and colleagues, 2020). In DASISION, dasatinib 100 mg once a day produced faster and deeper molecular responses than imatinib, but progression-free and overall survival were similar: 86 versus 85 and 91 versus 95 in every 100. Dasatinib causes recurrent pleural effusion in up to 37 in every 100 patients.

ENESTnd compared nilotinib with imatinib. In the 10-year update, cumulative rates of major molecular response were 77.7 per 100 with nilotinib 300 mg twice daily and 62.5 with imatinib 400 mg once daily; MR4.5 rates were 61.0 versus 39.2 (Kantarjian et al., 2021). Eligibility to stop treatment at 10 years was 48.6 versus 29.7 per 100. Estimated overall survival at 10 years, however, was similar: 87.6 with nilotinib 300 mg and 88.3 with imatinib. Cumulative cardiovascular events at 10 years were more frequent with nilotinib: 16.5 per 100 with 300 mg twice daily versus 3.6 with imatinib, including in patients at low risk by the Framingham score.

The 5-year update of ENESTnd already showed this pattern of more molecular response with nilotinib and more cardiovascular events (Hochhaus et al., 2016). Hehlmann, commenting on ELN 2020, recalls that four inhibitors are approved for first line, imatinib, dasatinib, nilotinib and bosutinib, and that the new goal, after achieving normal survival, is survival with good quality of life and the possibility of stopping treatment (Hehlmann, 2020).

For the patient in the scene, the reasoning is this: survival with imatinib is similar to that with second-generation inhibitors, with more long-term experience and less cardiovascular toxicity than nilotinib. A second-generation inhibitor gains weight if the risk is high or if the goal of stopping treatment is a priority, and the decision should be shared.

Adherence: the factor PCR reveals

One tablet a day, for years, is an adherence challenge. Pandey et al. followed 82 adults with newly diagnosed CML on imatinib in India and found 18 patients without adequate adherence, 22 per 100, defined by a medication possession ratio of up to 85 per 100 over 90 days (Pandey et al., 2025). Cognitive function, the occurrence of adverse reactions and the impact of the disease on daily life and mood were associated with adherence. The authors suggest that identifying these factors early can guide interventions.

In practice, when PCR rises or stops falling, the first question should be about adherence, before testing for mutations. Adverse effects that seem small, such as cramps, nausea and edema, are precisely the ones that lead patients to skip doses without telling the team.

• Ask how and when the tablet is taken, without judgment.
• Ask about cramps, nausea, edema and fatigue, which are often underestimated.
• Review interactions with other medicines in use.
• Agree with the patient on the PCR schedule and explain the meaning of each goal.

Stopping treatment: treatment-free remission

ELN 2020 considers treatment-free remission a new and important goal of CML, and recommends considering it in suitable patients, after careful discussion and shared decision (Hochhaus et al., 2020). The guideline defines requirements at three levels:

• Mandatory: CML in first chronic phase, a motivated patient with structured communication, access to quality quantitative PCR on the international scale with a rapid result, and agreement to more frequent monitoring after stopping, monthly for the first 6 months, every 2 months between 6 and 12 months and every 3 months thereafter.
• Minimum: first line, or second line if the switch was only for intolerance; typical transcripts e13a2 or e14a2; more than 5 years of treatment, or more than 4 years with a second-generation inhibitor; MR4 or better for more than 2 years; no prior failure.
• Optimal: more than 5 years of treatment and deep response for more than 3 years if MR4, or for more than 2 years if MR4.5.

Laneuville recalls that the first study to demonstrate treatment-free remission was STIM1: in patients who maintained undetectable disease for at least 2 years with first-line imatinib, molecular relapse-free survival at 60 months was 36 per 100 (Laneuville, 2018). Total treatment duration is the most consistent predictive factor: in STIM1, remission was 22 versus 50 per 100 below and above 4.5 years of treatment, and in EURO-SKI, 34 versus 57 below and above 5.8 years. Patients with prior advanced disease, additional chromosomal abnormalities, atypical transcripts, resistance, high Sokal or no ability to maintain regular monitoring should, in general, be excluded from the attempt.

Hehlmann cites EURO-SKI, the largest discontinuation study, with 755 patients and a treatment-free remission rate of 49 in 100 at 2 years (Hehlmann, 2020). Branford shows that studies requiring MR4.5 or better to stop had higher remission rates at 24 months than those requiring MR4: 57.2 versus 50.5 in 100 (Branford, 2020).

What happens when the disease comes back

Chen and colleagues bring together the discontinuation studies and show that molecular relapse is usually early and that the response returns when the inhibitor is restarted (Chen and colleagues, 2021). In TWISTER, 15 of 22 relapses happened in the first 6 months, and the 22 patients again had undetectable disease. That is why monthly monitoring in the first six months is mandatory.

Annunziata and colleagues describe that, in a discontinuation study with nilotinib, there was no progression or death from CML, and musculoskeletal pain events decreased from the first to the fourth year after discontinuation (Annunziata and colleagues, 2020). Musculoskeletal pain after stopping the inhibitor is known as withdrawal syndrome, and the team should tell the patient about it.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code. CML is a good exercise because the main clue changes over time: the same test, repeated, tells a story. The post on diagnostic pause shows how to reassess before concluding, and the post on clinical decision-making helps you choose when to repeat a test.

Three exercises with cases

Change the PCR. Say what you would do if BCR::ABL1 at 3 months were 15 in 100.

Change adherence. Say how you would investigate a PCR that rose from 0.05 to 0.8 in 100 over 6 months.

Change the goal. Say whether the patient can stop imatinib after 6 years of treatment and 3 years in MR4.

The post on differential diagnosis helps separate poor adherence from resistance, and the post on diagnostic uncertainty helps in talking about the risk of relapse after discontinuation. The limits on use of the game are described on the NEXO economy page. If you research the teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information under curation and creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

What is the dose of imatinib in the chronic phase?

400 mg once a day; 300 mg is an option if 400 mg is not tolerated and the response is optimal (Hochhaus and colleagues, 2020).

Is generic imatinib suitable?

Yes. ELN 2020 considers it the initial treatment with the best cost and effectiveness in the chronic phase (Hochhaus and colleagues, 2020).

What indicates failure at 3 months?

BCR::ABL1 above 10 in 100 on the international scale, confirmed in 1 to 3 months (Hochhaus and colleagues, 2020).

Do second-generation inhibitors increase survival?

They produce faster and deeper responses, but overall survival at 10 years in ENESTnd was similar to that with imatinib (Kantarjian and colleagues, 2021).

Is it possible to stop treatment?

In selected patients, with a stable deep response and guaranteed monitoring. In EURO-SKI, 49 in 100 were still in remission 2 years after stopping (Hehlmann, 2020).

Can imatinib be used during pregnancy?

ELN 2020 recommends suspending the tyrosine kinase inhibitor during pregnancy (Hochhaus and colleagues, 2020). Planning should be done with the hematology team.

Final checklist

• I confirmed BCR::ABL1 and the transcript type.
• I defined the disease phase and calculated the ELTS.
• I looked for additional chromosomal abnormalities in the karyotype.
• I chose the inhibitor considering comorbidities, risk and the goal of stopping treatment.
• I scheduled quantitative PCR on the international scale at 3, 6 and 12 months.
• I explained the response goals to the patient.
• I asked about adherence and adverse effects at every visit.
• I requested mutation testing in case of failure.
• I assessed the discontinuation criteria when the deep response persisted.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Annunziata M, Bonifacio M, Breccia M, et al. Current Strategies and Future Directions to Achieve Deep Molecular Response and Treatment-Free Remission in Chronic Myeloid Leukemia. Front Oncol. 2020. PMID 32582549.
2. Branford S. Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?. Haematologica. 2020. PMID 33054104.
3. Chen Y, Zou J, Cheng F, et al. Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells. Front Oncol. 2021. PMID 34778088.
4. Copland M. Is There a Role for Dose Modification of TKI Therapy in CML?. Curr Hematol Malig Rep. 2019. PMID 31197525.
5. Hehlmann R, Lauseker M, Saußele S, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017. PMID 28804124.
6. Hehlmann R. The New ELN Recommendations for Treating CML. J Clin Med. 2020. PMID 33207600.
7. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020. PMID 32127639.
8. Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017. PMID 28273028.
9. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016. PMID 26837842.
10. Iezza M, Cortesi S, Ottaviani E, et al. Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights. Cells. 2023. PMID 37443737.
11. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021. PMID 33414482.
12. Laneuville P. When to Stop Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. Curr Treat Options Oncol. 2018. PMID 29520446.
13. Pandey D, Chugh P, Chaudhry S. Identifying Key Factors Influencing Non-adherence to Imatinib Therapy in Patients With Chronic Myeloid Leukemia. Cureus. 2025. PMID 40161156.