Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm that accounts for 15 % of adult leukaemias and whose prevalence has been increasing.1 This pathology is defined by the presence of a BCR::ABL1 fusion gene, which encodes a protein with the same name. The expression of this fusion protein leads to the activation of signaling pathways. This activation contributes to increased cell division, reduced apoptosis, and altered adhesion to stromal cells/extracellular matrix, leading to the leukaemic phenotype.2,3

CML is more common in older individuals.1 The natural history of the disease includes three phases: a chronic phase, an accelerated phase, and a blastic phase.4 Until 2000, only 10 % of patients achieved a complete cytogenetic response.5 However, with the study of the disease's pathophysiology and the subsequent development of tyrosine kinase inhibitors (TKIs), the paradigm and course of this disease have changed substantially.6

Currently, CML has become a chronic disease, requiring regular molecular monitoring, adherence to TKI therapy, and proper management of toxicities.7 Patients adequately treated with these agents, who have a good response to TKI, have a survival rate similar to the general population.8–12 Moreover, some patients may discontinue TKI therapy and maintain remission. Since the approval of imatinib in 2001, the therapeutic arsenal for CML has expanded with the introduction of other TKIs such as nilotinib, dasatinib, bosutinib, ponatinib, and asciminib.8–11,13,14 However, clinical trial candidates are not the same as real-world patients, and several authors argue for the need to understand these outcomes.15,16 Although many countries have epidemiological databases and published literature on real-world outcomes for their CML patients,17–21 to our knowledge, there are no published studies on these outcomes in Portugal.

The aim of this article is to describe the population of CML patients treated at Instituto Português de Oncologia do Porto (IPO-Porto), including the characterization of the patients, treatment patterns, therapeutic efficacy, documented adverse effects of TKIs, number of candidates for TKI discontinuation, and whether there was a need to resume TKI therapy.

This retrospective cohort, single-centre study was conducted at the Haematology and Bone Marrow Transplantation Department of IPO-Porto. Patients were selected from the Cancer Registry of the institution. The inclusion criteria were: patients with CML (International Classification of Diseases for Oncology, 3rd Edition, ICD-O-3: 9863/3; 9875/3; 9876/3) treated at IPO-Porto between 1/11/2012 and 31/10/2022 and aged 18 years or older during the study period. Patients whose data were unavailable, incorrect diagnoses, patients admitted solely for hematopoietic progenitor cell transplantation, or those treated in a clinical trial context were excluded. The follow-up of patients continued until death, loss to follow-up, or administrative closure of this project in May 2024.

Patient data were collected through electronic medical records and cancer registry. The extracted variables included:

• 1.

  At the time of diagnosis: gender, age, Charlson comorbidity index,22 clinical presentation (number of leukocytes, percentage of peripheral blasts, splenomegaly, constitutional symptoms, disease phase), presence of additional cytogenetic abnormalities, type and quantity of BCR::ABL1 transcript, and prognostic scores: Sokal Index for CML (SOKAL),23 and EUTOS long-term survival (ELTS) score.24

• 2.

  During treatment: the treatments administered, hematological, cytogenetic, major and deep molecular responses, adverse events, the need for TKI switch and reasons for the switch, progression, death, cause and date of death were collected.

Response evaluation was conducted according to the European Leukaemia Net 2020 recommendations.6 Progression was defined as death from any cause, loss of cytogenetic response, or progression to accelerated or blastic phase.

For event-free survival (EFS), an event was defined as the first occurrence of any of the following: death from any cause during treatment, progression to accelerated-phase CML (characterized by ≥15 % blasts in the blood or bone marrow, ≥30 % blasts plus promyelocytes in the blood or bone marrow, ≥20 % peripheral basophils, or thrombocytopenia <100 × 103/µL unrelated to treatment), or progression to blast-phase CML (defined by ≥30 % blasts in the blood or bone marrow or extramedullary involvement, excluding hepatosplenomegaly). Loss of complete hematologic response (CHR) was defined by the occurrence of any of the following in two blood samples obtained at least one month apart: a white blood cell count >20 × 103/µL, a platelet count ≥600 × 103/µL, the appearance of extramedullary disease, ≥5 % myelocytes and metamyelocytes in the peripheral blood, or the presence of blasts or promyelocytes in the peripheral blood. Loss of major cytogenetic response (MCyR) was defined as an increase in Philadelphia chromosome-positive (pH+) cells in metaphase by at least 30 percentage points on two cytogenetic analyses performed at least one month apart. An increasing white blood cell count was defined as a doubling to >20 × 103/µL measured on two occasions at least one month apart in a patient who had never achieved a strict CHR despite receiving maximally tolerated doses of therapy. Overall survival (OS) was calculated from time to death from any cause. The criteria for discontinuing TKI therapy was based on the 2020 European Leukaemia Net guidelines.6

This study is, to our knowledge, the first to describe patients with CML in Portugal. The patient population exhibited characteristics similar to those seen in clinical trials, with a similar age (52 years), and small proportion of high-risk patients according to the ELTS score.8–11 Imatinib was the main first-line therapy, with good tolerance. A third of patients needed a second line and a fifth successfully discontinued TKI. The rate of Grade 3 and 4 complications was higher in patients with TKI of higher generations. The responses achieved were comparable to expectations, with a complete cytogenetic response of 93 % and major molecular response at 12 months of 49 %, as was the overall survival.

This study reinforces the good outcomes currently achieved in CML. All TKIs are highly effective in newly diagnosed chronic-phase CML, with long-term overall survival rates comparable to age-matched controls.25 This study underlines the results obtained in clinical trials, showing no significant differences in overall survival between patients starting treatment with imatinib versus second-generation TKIs, as described in Table 5.8–11 In this study, the rate of disease progression was low, achieving outcomes as good as those obtained with second-generation TKIs in clinical trials.9–11 However, the study corroborates the faster achievement of molecular responses and deeper responses with second-generation TKIs, which may facilitate TKI discontinuation in selected patients. At 12 months, 49 % achieved major molecular response, while 94 % achieved molecular response. The good tolerability of TKIs was also confirmed. In this sample, as in the DASISION trial, patients treated with imatinib had more myalgias and peripheral oedema, and those treated with dasatinib had more pleural effusion. Although rare, one patient treated with dasatinib developed pulmonary hypertension.9 As demonstrated in the ENESTnd trial, the risk of cardiovascular events was higher in patients treated with nilotinib, even in a small sample (n = 4).11

Several real-world studies have evaluated the efficacy of first-line imatinib treatment in countries such as Italy17 and Spain.18 These studies showed responses comparable to the present study, with major molecular responses at one year of around 50 %. Other studies evaluated not only first-line imatinib but also second-generation TKIs, including countries like Switzerland,19 The Netherlands20 and Italy21 with heterogeneous treatment patterns and response evaluations. Therefore, comparing study results is difficult.

The selection of first-line treatment remains controversial. Several authors advocate starting treatment with a second-generation TKI26; one meta-analysis even recommended the use of second- and third-generation TKIs for younger individuals without comorbidities.27 However, the choice of first-line TKI involves considerations not only of age and comorbidities, but also of treatment intent (survival versus TKI discontinuation), risk scores, costs, and availability.25,28,29

This study shows that first-line imatinib, even for higher-risk and younger patients, continues to be a good option, allowing for excellent responses, good tolerability, and lower financial burden on the National Health Service.

As already mentioned, this study analyses the Portuguese population with CML, including treatment patterns, responses, and adverse effects. Characterizing this population is relevant because it may have different characteristics from other populations and because of the unique organization of the Portuguese healthcare system. The data from this study could potentially inform future therapeutic decisions regarding CML at a national level and improve care for these patients.

This study has limitations, including the small sample size, especially concerning the number of patients treated with second-generation TKIs and inhibitors other than imatinib, which limits the conclusions regarding these drugs. Additionally, due to its retrospective nature, this study is subject to information bias, given that some data were not available.

This is first study to characterize the Portuguese CML patient. The features, responses, survival, and adverse effects of the population are similar to those described in the literature. Furthermore, this study reinforces the good efficacy-tolerability profile of imatinib as a first-line treatment. A more detailed understanding of the population, treatment patterns, and outcomes in Portugal could improve the clinical practice in the country.

This work was supported by a grant from Associação Portuguesa Contra a Leucemia (APCL).