Chronic Myeloid Leukemia (CML): historical perspective, pathophysiology, and treatment advances.

Chronic myeloid leukemia (CML) has undergone a significant shift over the past two decades, transitioning from a fatal malignancy to a chronic, highly manageable disease with near-normal life expectancy for most patients. This transformation has been driven by the development of BCR-ABL1-targeted tyrosine kinase inhibitors (TKIs), which have enabled durable disease control and deep molecular responses (DMRs) in the majority of patients with chronic-phase CML. As long-term survival outcomes have plateaued across available agents, contemporary management has shifted beyond disease suppression toward optimizing long-term safety, quality of life, and the achievement of treatment-free remission (TFR). This review summarizes current evidence on molecular monitoring strategies, the comparative efficacy and toxicity profiles of first-, second-, and third-generation TKIs, and emerging advances in response assessment. Patient-centered TKI selection is discussed in the context of cardiovascular risk, comorbidities, treatment tolerability, and survivorship goals, reflecting the growing emphasis on individualized therapy in chronic-phase CML. Molecular monitoring strategies are examined in parallel, highlighting the clinical importance of early and sustained DMRs in guiding therapeutic decisions and TFR eligibility. Although RT-qPCR remains the standard for molecular monitoring, emerging high-sensitivity techniques such as digital droplet PCR and next-generation sequencing provide complementary value by improving the detection of low-level residual disease, refining risk stratification, and enabling earlier identification of resistance. Emerging therapeutic strategies and advances in response assessment further highlight ongoing efforts to enhance the depth and durability of remission while minimizing long-term toxicity. These developments support a more precise, individualized, and outcome-driven approach to modern CML management.

Introduction Chronic myeloid leukemia (CML) management has been revolutionized by tyrosine kinase inhibitors (TKIs), leading to near-normal life expectancy for most patients diagnosed in the chronic phase. The European LeukemiaNet (ELN) recommendations provide the internationally recognized framework for the diagnosis, monitoring, and treatment of CML. Areas covered This review provides a chronological overview of the evolution of ELN recommendations for CML across five updates (2006, 2009, 2013, 2020, and 2025). Relevant literature published up to January 2026 was identified through a search of PubMed/MEDLINE, using keywords including ‘chronic myeloid leukemia,’ ‘CML,’ ‘European LeukemiaNet,’ ‘ELN recommendations,’ ‘tyrosine kinase inhibitors,’ and ‘treatment-free remission.’ Expert opinion Over time, ELN recommendations have shifted from cytogenetic to molecular monitoring, incorporated second-generation TKIs, and introduced treatment-free remission as a major therapeutic goal. The latest framework emphasizes personalized CML management by integrating molecular response with patient-specific factors, reflecting the broader evolution of precision medicine in hematology.

The treatment of chronic myeloid leukemia (CML) was revolutionized with the advent of the first-generation tyrosine kinase inhibitors (TKIs), but drug resistance developed during treatment, leading to the development of the second-generation (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKI. Compared with previous treatment regimens, specific TKI can significantly improve the response rate, overall survival rate and prognosis of CML. Only a few patients with BCR-ABL mutation are insensitive to the second-generation TKIs, so it is suggested to select the second-generation TKIs for patients with specific mutations. For patients with other mutations and without mutations, the second-generation TKI should be selected according to the patient's medical history, while the third-generation TKIs should be selected for mutations that are insensitive to the second-generation TKIs, such as T315I mutation that is sensitive to ponatinib. Due to different BCR-ABL mutations in patients with different sensitivity to the second and third-generation TKIs, this paper will review the latest research progress of the efficacy of the second and third-generation TKIs in CML patients with BCR-ABL mutations.

Identification of Immunological Parameters Related to Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission

Cardiovascular system health becomes important with the extended survival of chronic myeloid leukemia (CML) patients. Cardiotoxicities are related to the second- and third-generation tyrosine kinase inhibitors (TKIs). The most frequent and important cardiovascular events are myocardial infarction, stroke and peripheral arterial disease, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension. The aim of this paper is to review the interactions between administrated TKIs and the cardiovascular system during the clinical course of CML. Elucidation of TKI effects on the cardiovascular system is vital since the current goal of CML therapy is a cure that leads to normal age and gender-similar survival with a normal quality of life. Up to August 2022, literature searches were performed via the internet search engines MEDLINE, EMBASE, GOOGLE SCHOLAR: (i) chronic myeloid leukemia; (ii) tyrosine kinase inhibitor; (iii) cardiovascular system. Only articles in English and research including humans were included in the search. Tailored TKI treatment with individual patient characteristics must account for CML disease risk, patient age, patient comorbidities, patient compliance, TKI drug off-target risk profile, accelerated or blastic phase CML disease, pregnancy and allografting in CML. The treatment-free survival, improving quality of life, limiting adverse events of TKIs, and the optimal dose and administration duration of TKIs are still a matter of controversy. Special attention should be paid to the comorbidities of CML patients and clinical TKI effects on CVS since the aim of CML treatment is a cure that leads to normal age and gender-similar survival with a "normal" quality of life. CVS is an important morbidity and mortality cause for adult patients. The discontinuation of TKI treatment in CML and the treatment-free remission of CML patients are very important in order to reduce the risk for cardiovascular adverse effects of TKIs. The frail CML patients and especially the patients who have cardiac comorbidities, should be carefully evaluated for TKI treatment, and hematopoietic stem cell transplantation (HSCT) should be the last choice in these risky CML patients. The current CML treatment target is a cure that leads to normal age and gender-adjusted survival with a "normal" quality of life. Cardiovascular disorders are one of the major obstacles to reaching this target in CML patients. The treatment choices for CML patients must include a cardiovascular perspective.

Treatment Free Remission (TFR) in Chronic Myeloid Leukaemia (CML): The Tawam Hospital Experience

Assessment of Transitioning from High-Potency to Low-Potency Inhibitors in Chronic Myeloid Leukemia (CML) Patients: The Downgrading-Impact Project, a CML Campus Study

Low-dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous TKIs.

Prospective Monitoring of Peripheral Blood CD26+ Leukemia Stem Cells in Chronic Myeloid Leukemia Patients from Time of TKI Discontinuation

Frontline tyrosine kinase inhibitor selection influences eventual treatment-free remission eligibility and sustained treatment-free remission: A registry analysis of patients treated at CML referral sites in Australia

Background: Treatment free remission (TFR) is currently one of the main goals of CML therapy and data of literature show that 40-60% of patients (pts) that discontinue tyrosine kinase inhibitors (TKI) after a sustained deep molecular response (sDMR) of at least 2 years remain in TFR. Few data are available about second TFR for pts that fail a first TKI discontinuation and another topic not so clear is how many pts with newly diagnosed CML will achieve a successful TFR. Aim: To describe the TFR theme in CML-CP pts followed in our center Methods: We evaluated all consecutive CP-CML pts treated with TKI in our center from 2000 to mid 2024. The main criteria for 1st TKI discontinuation were at least 5 years of TKI therapy and at least 2 years of sDMR. Even for 2nd TKI discontinuation a sDMR of at least 2 years was required. Results: The total number of CP-CML pts referred to our center was 311. From 2000 to the present date, 60 (19%) pts died, 10 of them for CML related cause; 11 pts were lost at follow up and 240 pts are presently in follow up (in TKI treatment or in TFR). Among these 240 pts, 123 were male and 117 were female; the median age at CML diagnosis was 53 (13-86) years (y), median follow up from the beginning of TKI therapy to the last follow up 103 (1-270) months (mo). 1 hundred sixty-three out of 240 pts had TKI treatment of 5 y or more; 115/163 (70%) pts reached a sDMR of at least 2 y, that is the other criteria for TKI discontinuation, and they stopped treatment. Imatinib and 2nd generation TKI (2GTKI) represented 1st line therapy respectively in 73 and 42 of the pts that entered 1st TKI discontinuation attempt, but 19/73 (26%) of pts initially treated with imatinib and 11/42 (26%) of pts initially treated with 2GTKI were on 2nd or 3rd line therapy at the moment of TFR. At the time of 1st TKI discontinuation median age was 63 years (20-85), median time from TKI start 113 months (60-172), median duration of sDMR 60 months (24-153). After a median follow up of 82 mo from 1st TKI discontinuation, 70/115 (61%) pts remain in TFR without treatment, while 45/115 (39%) pts lost major molecular response. The relapsed pts resumed TKI treatment and in 42/45 cases regained DMR: 17 (40%) of these 42 pts, with a median 2nd sDMR of 62 (32-86) mo, entered a 2nd TKI discontinuation. Thirteen out of 17 (76%) pts that attempted a 2nd TKI withdraw, remained in TFR after a median follow up of 14 (2-47) mo from 2nd TKI discontinuation. Overall, among 163 pts with a newly diagnosed CP-CML treated with TKI for at least 5 y, 70 (43%) achieved a successful durable 1st TFR and 13 (8%) were in 2nd TFR. No pts in 1st and 2nd TFR progressed to accelerated/blast phase. Conclusion: Our experience shows that in real-life setting, TFR appears an achievable goal for about half of newly diagnosed CP-CML pts.

Introduction: Tyrosine kinase inhibitors (TKIs) have revolutionized the therapy of chronic myeloid leukemia (CML) in chronic phase, opening up the perspective of a normal life expectancy for most patients and of treatment-free remission for some of them. However, intolerance or resistance may necessitate treatment modifications. Methods: A panel of five Belgian experts reviewed the treatment options in Belgium in 2025 for patients with chronic phase CML with resistance or intolerance to at least two lines of therapy. Discussion: In contrast to the early years of TKI therapy, several options are available as third-line therapy or beyond for CML patients resistant or intolerant to at least two prior TKIs. These include the third generation TKI ponatinib, the allosteric BCR::ABL1 inhibitor asciminib, allogeneic hematopoietic stem cell transplantation, continuation of ongoing second-line TKI therapy with or without dose modification, or switching to alternative second generation TKIs. Careful consideration of the potency and safety profiles of these options, the clinical context, and treatment goal is needed. Ponatinib is currently reimbursed in Belgium for patients with CML showing resistance or intolerance to at least two prior TKIs, or with the BCR::ABL1 T315I mutation, regardless of the number of previous TKIs. Asciminib is currently reimbursed for patients with resistance or intolerance to at least two prior TKIs, excluding those with the BCR::ABL1 T315I mutation. This review provides guidance to weigh available safety and efficacy data in a setting of resistance or intolerance to second-line therapy with the goal of selecting the best available personalized treatment.

Single-Cell Roadmap of Immune Cell Response in Chronic Myeloid Leukemia

7050 Background: Tyrosine kinase inhibitors (TKIs) discontinuation in patients (pts) with CML is increasingly considered. We evaluated the outcome of pts with CML who discontinued TKIs and determined the factors associated with differences in the success rates of TFR. Methods: We reviewed data from 284 pts with CML treated with TKIs at our institution between October 1999 and February 2017 and who subsequently discontinued therapy. Major molecular response (MMR) was defined as a BCR-ABL1/ABL1 transcripts ratio ≤0.1% as determined by real time (RT)-PCR, MR4 as a ratio ≤0.01% IS, and MR4.5 as a ratio ≤0.0032%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response and conducted a multivariate analysis for factors associated with loss of MMR. Results: Median age was 63 years (range, 25-93). 199 pts (70%) had electively discontinued their TKI while 70 pts (24%) stopped therapy because of adverse events. 92 pts (32%) had switched ≥1 TKI prior to discontinuation due to drug intolerance or resistance. The median time from the initiation of frontline TKI to discontinuation was 117 months (range, 16-242). The median duration of MR4 and MR4.5 before TKI discontinuation was 74 months (range, 2-207) and 64 months (range, 0-207), respectively. At a median follow-up of 36 months (95% CI, 32-40) after TKI discontinuation, 53 pts (19%) lost MMR, translating into a 5-year TFR rate of 79%. 50 pts (94%) resumed TKI therapy and, among 47 evaluable pts, all but one pt regained MMR, with 41 pts (88%) achieving MR4.5. The estimated 5-year TFR rates were 91%, 76% and 70% in pts achieving MR4.5 for ≥6 years, between 5 and 6 years, and < 5 years, respectively (P < 0.0001). The estimated 5-year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 < 5 years (87% vs 92% vs 64%; P < 0.0001). Pts who remained on their frontline TKI at the time of discontinuation had a 5-year TFR rate of 82%, compared with 75% and 72% among pts who switched to a second line TKI or beyond because of intolerance or resistance, respectively (P = 0.417). TFR rates did not vary according to the type of frontline TKI used (P = 0.761). By multivariate analysis, only durations in MR4 or MR4.5 ≥5 years before stopping treatment were associated with a lower risk of loss of MMR, with hazard ratios of 0.37 (95% CI, 0.18-0.76; P = 0.007) and 0.20 (95% CI, 0.09-0.45; P < 0.0001), respectively. We evaluated the impact of the frequency of molecular monitoring on the success rate of TFR. The estimated 5-year TFR rate was 79% for pts monitored monthly compared with 85% for pts monitored every 6-8 weeks following discontinuation (P = 0.263). Conclusions: Our findings suggest that achieving MR4 for ≥5 years was associated with a very high probability of maintaining TFR, and that less frequent molecular monitoring could be more cost-effective without any negative impact on outcomes.

Optimum Imatinib Exposure Have Possibility of Leading to Appropriate Immune Response after Imatinib Discontinuation in CML Patients