Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a G0 marker (G0M), we narrow down CML LSCs as G0M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis reveals NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by inhibitors of interleukin-1 receptor-associated kinase 1/4 (IRAK1/4 inhibitors) together with imatinib eliminates mouse and human CML LSCs. Intriguingly, IRAK1/4 inhibitors attenuate PD-L1 expression on CML LSCs, and blocking PD-L1 together with imatinib also effectively eliminates CML LSCs in the presence of T cell immunity. Thus, IRAK1/4 inhibitors can eliminate CML LSCs through inhibiting NF-κB activity and reducing PD-L1 expression. Collectively, the combination of TKIs and IRAK1/4 inhibitors is an attractive strategy to achieve a radical cure of CML.

Introduction Few studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). Materials and methods We retrospectively analysed the clinical features, treatment response, and long-term outcomes of 42 AYA patients, in comparison to older patients. The initial therapies of AYA patients between 2001 and 2016 included imatinib ( n = 24), dasatinib ( n = 13) and nilotinib ( n = 5). Results In AYA patients, the peripheral blood (PB) white blood cell count and percentage of blasts at the diagnosis were significantly higher, haemoglobin levels were lower and the spleen size was larger. The major molecular response (MMR), event-free survival (EFS) and overall survival (OS) rates were comparable. A sub-analysis comparing imatinib to second-generation TKIs as the initial therapy also showed that their prognosis was comparable. Discussion In conclusion, the tumour burden at the diagnosis of CML-CP is higher in AYA patients; however, their prognosis was not worse in comparison to older patients treated with TKIs. KEY MESSAGES Few studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). This study showed the tumour burden at the diagnosis of CML-CP is higher in AYA pa tients; however, their prognosis was not worse in comparison to older patients treated with TKIs. Understanding the biological and non-biological features of AYA patients with CML-CP on TKI therapy is essential for better management and to improve the outcomes.

Background Arterial occlusive events are an emerging problem in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) therapy. Endothelial cell damage is thought to play an important role in the development of vascular events. Measurement of the peripheral vasodilator response by peripheral arterial tonometry (PAT) has reportedly been useful in the non-invasive assessment of endothelial dysfunction. To date, no studies have assessed endothelial function using PAT in patients with CML receiving TKIs. Method We measured the reactive hyperemia index (RHI) using PAT in young patients with CML (men aged ≤ 55 years and women aged ≤ 65 years) receiving TKIs. Results Thirty patients with CML were examined (mean age, 43.5 ± 9.8 years; men, 57%). The median RHI was 1.81. Among these patients, 16.7% and 83.3% were taking imatinib and second- or third-generation TKIs, respectively. There were no differences in the baseline characteristics between the low RHI (< 1.67, n = 10), borderline RHI (≥ 1.67 and < 2.10, n = 14), and normal RHI (≥ 2.10, n = 6) groups. Serum uric acid (UA) levels and the RHI were significantly negatively correlated (r = -0.40, p = 0.029). Conclusion One-third of young patients with CML receiving TKI therapy were classified as having a low RHI. The RHI was negatively correlated with serum UA level. Larger prospective studies are necessary to examine whether the RHI predicts cardiovascular events in such patients.

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