In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate on dose reduction rather than drug switching to manage toxicities and discuss treatment sequencing. Data have matured for the outcome of treatment discontinuation and for management of parenting for both men and women. We acknowledge that most patients will remain on treatment for many years and emphasize the needs to minimize side effects, manage co-morbidities and optimize quality of life. Recent advances in allogeneic stem cell transplantation have broadened access to alternative donors, and lessened limitations of age and co-morbidities such that transplant remains a valuable option for patients for whom long-term disease control is not achieved through TKI therapy.

• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * therapy   drug therapy   diagnosis   MeSH
• Protein Kinase Inhibitors * therapeutic use   MeSH
• Humans MeSH
• Disease Management MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Practice Guideline MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Protein Kinase Inhibitors * MeSH

BACKGROUND: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib. METHODS: In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily. RESULTS: More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile. CONCLUSIONS: Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice. TRIAL REGISTRATION: NCT03578367.

• Keywords
• ASC4MORE, Add-on, Asciminib, CML, Combination, Deep molecular response, Imatinib, Tyrosine kinase inhibitors,
• MeSH
• Fusion Proteins, bcr-abl antagonists & inhibitors   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   MeSH
• Adult MeSH
• Imatinib Mesylate * therapeutic use   MeSH
• Protein Kinase Inhibitors therapeutic use   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Niacinamide analogs & derivatives   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Pyrazoles MeSH
• Pyrimidines therapeutic use   administration & dosage   MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• asciminib MeSH Browser
• Fusion Proteins, bcr-abl MeSH
• Imatinib Mesylate * MeSH
• Protein Kinase Inhibitors MeSH
• Niacinamide MeSH
• Pyrazoles MeSH
• Pyrimidines MeSH

BACKGROUND: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice. METHODS: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. RESULTS: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). CONCLUSIONS: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.

• Keywords
• chronic myeloid leukemia, first‐line treatment, imatinib, nilotinib,
• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   mortality   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Imatinib Mesylate * therapeutic use   adverse effects   MeSH
• Protein Kinase Inhibitors therapeutic use   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Antineoplastic Agents therapeutic use   adverse effects   MeSH
• Pyrimidines * therapeutic use   adverse effects   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Propensity Score MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Imatinib Mesylate * MeSH
• Protein Kinase Inhibitors MeSH
• nilotinib MeSH Browser
• Antineoplastic Agents MeSH
• Pyrimidines * MeSH

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy   mortality   MeSH
• Adult MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Probability MeSH
• Prognosis MeSH
• Registries MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Protein Kinase Inhibitors MeSH

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

• MeSH
• Survival Analysis MeSH
• Aniline Compounds therapeutic use   MeSH
• Fusion Proteins, bcr-abl antagonists & inhibitors   genetics   metabolism   MeSH
• Quinolines therapeutic use   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis   drug therapy   genetics   mortality   MeSH
• Dasatinib therapeutic use   MeSH
• Gene Expression MeSH
• Imatinib Mesylate therapeutic use   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Clinical Decision-Making MeSH
• Consensus Development Conferences as Topic MeSH
• Quality of Life MeSH
• Humans MeSH
• Disease Management MeSH
• Monitoring, Physiologic MeSH
• Life Expectancy trends   MeSH
• Nitriles therapeutic use   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Pyrimidines therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Aniline Compounds MeSH
• Fusion Proteins, bcr-abl MeSH
• BCR-ABL1 fusion protein, human MeSH Browser
• bosutinib MeSH Browser
• Quinolines MeSH
• Dasatinib MeSH
• Imatinib Mesylate MeSH
• Protein Kinase Inhibitors MeSH
• nilotinib MeSH Browser
• Nitriles MeSH
• Antineoplastic Agents MeSH
• Pyrimidines MeSH

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

• MeSH
• Time Factors MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy   pathology   MeSH
• Imatinib Mesylate therapeutic use   MeSH
• Remission Induction MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   pathology   MeSH
• Survival Rate MeSH
• Follow-Up Studies MeSH
• Withholding Treatment statistics & numerical data   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Imatinib Mesylate MeSH
• Antineoplastic Agents MeSH

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

• MeSH
• Survival Analysis * MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy   therapy   MeSH
• Adult MeSH
• Imatinib Mesylate therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Imatinib Mesylate MeSH
• Antineoplastic Agents MeSH

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%-94%) and the 5-year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94%-99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5-year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%-98%), 88% (95% CI: 76%-95%) and 67% (95% CI: 48%-81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P<0.0001, overall). The EUTOS Long-Term Survival score showed better differentiation of progression-free survival than the Sokal (<45 years), Euro and EUTOS scores in children and adolescents with chronic myeloid leukemia and should be considered in therapeutic algorithms. (Trial registered at: www.clinicaltrials.gov NCT01281735).

• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis   drug therapy   epidemiology   mortality   MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Follow-Up Studies MeSH
• Child, Preschool MeSH
• Disease-Free Survival MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Registries MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

With high survival rates for chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs), emerging consequences, such as arterial ischemic events, require consideration when evaluating treatment options. Cardiovascular ischemic event incidence in clinical trials was evaluated in 2712 dasatinib-treated patients with Philadelphia chromosome-positive (Ph+) leukemias from 11 first- and second-line trials (pooled), newly diagnosed CML patients treated with dasatinib or imatinib (DASISION), and prostate cancer patients treated with dasatinib or placebo plus docetaxel/prednisone (READY). Overall, 2-4% of dasatinib-treated patients had cardiovascular ischemic events. Most dasatinib-treated patients with an event had a history of and/or risk factor for atherosclerosis (pooled 77 with history/risk and event/96 with events; DASISION 8/10; READY 15/18). Most cardiovascular ischemic events occurred within 1 year of initiating dasatinib (pooled 69/96; DASISION 7/10; READY 16/18). Comparison of observed and expected event rates through standardized incidence ratios indicates that dasatinib does not increase risk for cardiovascular ischemic events compared with external reference populations.

• Keywords
• Cardiovascular, Chronic myeloid leukemia, Dasatinib, Ischemic, Tyrosine kinase inhibitors,
• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy   MeSH
• Dasatinib adverse effects   MeSH
• Adult MeSH
• Outcome Assessment, Health Care methods   statistics & numerical data   MeSH
• Incidence MeSH
• Protein Kinase Inhibitors adverse effects   MeSH
• Ischemia chemically induced   epidemiology   MeSH
• Cardiovascular Diseases chemically induced   epidemiology   MeSH
• Clinical Trials as Topic methods   statistics & numerical data   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prostatic Neoplasms drug therapy   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Dasatinib MeSH
• Protein Kinase Inhibitors MeSH