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.

• Publication type
• Journal Article MeSH

Adolescent and young adults (AYAs) with chronic myeloid leukemia in chronic phase (CML-CP) reportedly respond worse to tyrosine kinase inhibitors (TKIs) than adults, potentially due to additional genetic abnormalities, including mutations in cancer-related genes (CRGs). This real-life study compared mutation profiles and their impact on outcomes in 80 AYA, 97 adult, and 16 pediatric CML-CP patients, alongside 81 BCR::ABL1-positive acute lymphoblastic leukemia (Ph+ ALL) patients. CRG mutations were more frequent in AYAs (25.0%) than in adults (19.6%) or children (12.5%). AYAs with Ph+ ALL exhibited higher mutational frequencies (53.3%) compared to children (26.7%) and adults (38.9%). At diagnosis, mutations in ASXL1, DNMT3A, and TET2 dominated in CML-CP and RUNX1, IKZF1, and BCR::ABL1 in Ph+ ALL. ASXL1 mutations correlated with reduced progression-free survival (PFS) in AYAs and adults. Unlike adults, AYAs showed no increase in BCR::ABL1 kinase domain mutations during TKI therapy. Nilotinib improved PFS in AYAs with ASXL1 mutations, highlighting the efficacy of higher-generation TKIs. ASXL1 mutations also impaired erythropoiesis, warranting further validation. Despite a higher mutational burden, AYAs did not exhibit worse prognoses than adults. Lower mutation rates at follow-up suggest potential impact of nilotinib. Mutation profiling and optimized TKI use are crucial to mitigate progression risks in CRG-mutated patients.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   drug therapy   pathology   mortality   MeSH
• Fusion Proteins, bcr-abl * genetics   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * genetics   drug therapy   mortality   pathology   MeSH
• Child MeSH
• Adult MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation * MeSH
• Biomarkers, Tumor * genetics   MeSH
• Follow-Up Studies MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins c-abl MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• ABL1 protein, human MeSH Browser
• Fusion Proteins, bcr-abl * MeSH
• BCR-ABL1 fusion protein, human MeSH Browser
• Protein Kinase Inhibitors MeSH
• Biomarkers, Tumor * MeSH
• Proto-Oncogene Proteins c-abl MeSH

The treatment strategy for children and adolescents with chronic myeloid leukemia in the chronic phase (CML-CP) has evolved from allogeneic hematopoietic stem cell transplantation (HSCT) to tyrosine kinase inhibitors (TKIs). With the advent of next-generation TKIs and new targeted therapies in the CML field, an international pediatric CML expert panel provides recommendations based on the medical literature (including previous pediatric guidelines), national standards, and treatment principles used in adults with CML-CP. Recommendations include diagnosis of the disease and details on managing the initial steps of care of children and adolescents with newly diagnosed CML-CP, including complications such as leukostasis. The treatment recommendations are based on the initiation of therapy with a first- or second-generation TKI according to the allocated European Treatment and Outcome Study (EUTOS) long-term survival score risk group of the patient. The subsequent steps are based on the results of recommended monitoring which can justify a switch to another TKI or a drug in development if there is resistance or toxicity. The panel also provides recommendations regarding the discontinuation criteria for TKIs in children and adolescents in sustained deep molecular response. Allogeneic HSCT is not recommended as the first-line of treatment for children with CML-CP but is to be considered in case of progression to the advanced phase or failure of several lines of treatment. The present treatment and management recommendations are intended to provide advice to clinicians in view of optimizing the care and the outcome of children and adolescents with CML-CP.

• MeSH
• Leukemia, Myeloid, Chronic-Phase * therapy   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * therapy   diagnosis   MeSH
• Child MeSH
• Protein Kinase Inhibitors * therapeutic use   MeSH
• Humans MeSH
• Disease Management MeSH
• Adolescent MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Journal Article MeSH
• Consensus Development Conference MeSH
• Review 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: A lower dosage of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukaemia (CML) has shown efficacy in managing short-term toxicity and maintaining a deep molecular response in patients who fail to achieve treatment-free remission. METHOD: From over 700 patients with CML who were treated at two centres over the last three decades, this retrospective study identified eight patients characterised by long-term treatment failure and simultaneous prolonged significant haematologic toxicity that prevented the use of the standard tyrosine kinase inhibitor dosage. RESULTS: Patients had a high or intermediate ELTS risk score, and most had significant comorbidities. Two patients were treated previously with busulfan, and four were aged over 70, which might explain the reduced pool of normal haematopoietic stem cells. However, concomitant myelodysplastic syndrome or the presence of clonal haematopoiesis of indeterminate potential was not demonstrated. Despite prolonged treatment failure, the survival of these patients (who were ineligible for stem cell transplantation) ranged from 45-396 months. Neither mutations in the ABL kinase domain nor additional cytogenetic abnormalities developed during the treatment of these patients, prompting speculation about the low selective pressure of low-dose tyrosine kinase inhibitors and/or the absence of mutations at diagnosis. CONCLUSION: It is important not to stop treatment with tyrosine kinase inhibitors at a low personalised dosage in CML patients with prolonged significant haematologic toxicity despite long-term treatment failure.

• Keywords
• Chronic myeloid leukaemia, Haematologic toxicity, Intermittent dosage, Kinase domain mutation, Low dosage, Tyrosine kinase inhibitor,
• Publication type
• Journal Article 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

Limited data is available on the health-related quality of life (HRQoL) and symptoms of patients with chronic myeloid leukemia (CML) who are in treatment-free remission (TFR). We herein report HRQoL results from the EURO-SKI trial. Patients who had been on tyrosine kinase inhibitors (TKIs) therapy for at least 3 years and achieved MR4 for at least 1 year were enrolled from 11 European countries, and the EORTC QLQ-C30 and the FACIT-Fatigue questionnaires were used to assess HRQoL and fatigue respectively. Patients were categorized into the following age groups: 18-39, 40-59, 60-69 and ≥70 years. Of 728 patients evaluated at baseline, 686 (94%) completed HRQoL assessments. The median age at TKI discontinuation was 60 years. Our findings indicate that HRQoL and symptom trajectories may vary depending on specific age groups, with younger patients benefiting the most. Improvements in patients aged 60 years or older were marginal across several HRQoL and symptom domains. At the time of considering TKI discontinuation, physicians could inform younger patients that they may expect valuable HRQoL benefits. Considering the marginal improvements observed in patients aged 60 years or above, it may be important to further investigate the value of TFR compared to a lowest effective dose approach in this older group of patients.

• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   MeSH
• Adult MeSH
• Tyrosine Kinase Inhibitors * therapeutic use   MeSH
• Quality of Life * MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Treatment Interruption MeSH
• Surveys and Questionnaires MeSH
• Aged MeSH
• Fatigue chemically induced   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Tyrosine Kinase Inhibitors * MeSH

Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)-based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes, with a limit of detection of 0.2%. Seventy mutations were detected in 57 diagnostic samples (22.4%), whereas 64 mutations were detected in 39 of the follow-up samples (27.9%). Carrying any mutation at initial diagnosis was associated with worse outcomes after TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with imatinib showed higher risks of treatment failure (hazard ratio, 2.53; 95% confidence interval, 1.13-5.66; P = .0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs. The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival, and progression risk. Additionally, there was an observable nonsignificant trend indicating a heightened risk of progression to advanced disease and worse overall survival. In conclusion, mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression and may help upfront TKI selection.

• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * genetics   drug therapy   mortality   diagnosis   MeSH
• Adult MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Mutation * MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Signal Transduction MeSH
• Transcription Factors genetics   MeSH
• Treatment Outcome MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans 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

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

• MeSH
• Blast Crisis * pathology   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   pathology   therapy   mortality   MeSH
• Adult MeSH
• Transplantation, Homologous MeSH
• Tyrosine Kinase Inhibitors * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Disease Management MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Prognosis MeSH
• Registries * MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Hematopoietic Stem Cell Transplantation methods   MeSH
• Treatment Outcome 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
• Geographicals
• Europe MeSH
• Names of Substances
• Tyrosine Kinase Inhibitors * MeSH

• MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   MeSH
• Chronic Disease MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Tyrosine Kinase Inhibitors MeSH
• Humans MeSH
• Leukemia, Myeloid * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• Protein Kinase Inhibitors MeSH
• Tyrosine Kinase Inhibitors MeSH