Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights.

The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at "high-risk". Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.

Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24.

BACKGROUND: Health-related quality of life (HRQOL) is a key aspect for chronic myeloid leukemia (CML) patients. The aim of this study was to develop a disease-specific HRQOL questionnaire for patients with CML to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30. PATIENTS AND METHODS: The process followed a predefined and systematic stepwise iterative process as defined by the EORTC guidelines for questionnaire development. The process was divided into 3 phases: (1) generation of relevant HRQOL issues, (2) operationalization of the HRQOL issues into a set of items, and (3) pretesting the questionnaire for relevance and acceptability. Descriptive statistics and psychometric analyses were also performed. RESULTS: Overall, 655 CML patients were enrolled in 10 countries including the USA and countries in Europe and Asia. Interviews with health-care professionals experienced in CML (n = 59) were also conducted. Results from the interviews, clinical experiences, and statistical analyses were used to develop the EORTC QLQ-CML24. The final module consists of 24 items assessing the following aspects: symptom burden, impact on daily life and on worry/mood, body image problems, and satisfaction with care and with social life. Internal consistency, assessed with Cronbach's alpha coefficients, ranged from 0.73 to 0.83 for the proposed scales. CONCLUSION: The EORTC QLQ-CML24 is an internationally developed HRQOL questionnaire for CML patients, and its implementation in clinical research and practice can provide important information to facilitate clinical decision-making.