Chronic myeloid leukemia (CML) represents one of the first neoplasms whose molecular pathogenesis was successfully unraveled, with tyrosine kinase inhibitors (TKIs) representing one of the first targeted therapies. TKIs have revolutionized long term outcomes of CML patients and their life expectancy. Nonetheless, a minority of patients will develop TKI resistance due to a complex and multifactorial process that ultimately leads to the emergence of an unresponsive cancer clone. Overcoming TKI resistance is considered one of the major challenges in CML management. In this review, the main findings extrapolated from published research, guidelines, and clinical trials regarding TKI resistance (published before October 2024) are discussed. Data have been obtained through broad research on Medline, Embase, Pubmed, and archives from EHA and ASH congresses. Nowadays, asciminib and ponatinib have expanded the therapeutic arsenal for resistant-CML management and allogenic transplant still represents an important alternative in the context of multiple TKI failures. Off-label use of TKIs combination therapies, although theoretically appealing, lacks robust clinical evidence and regulatory approval. Looking ahead, the introduction of novel technologies such as digital PCR and next generation sequencing (NGS) holds great potential to revolutionize the management of TKI-resistant CML cases.

Chronic myeloid leukemia (CML) prevalence is currently increasing due to the great efficacy of tyrosine kinase inhibitor (TKI) therapy. Discontinuation of treatment in the long-term, owing to avoid off-target side effects or treatment-free remission (TFR), has become an additional treatment goal in CML patients who achieved a deep molecular response (DMR). Second-generation TKIs (2 G-TKIs) have a significantly higher rate of DMR than imatinib. Hence, especially in young patients with a strategy of TFR, 2 G-TKIs are becoming the most frequently used TKIs and may increase TFR attempts in the future. In this review, the main findings extrapolated from clinical trials and real-life evidence regarding 2 G-TKIs discontinuation were discussed, through broad research on Medline, Embase and archives from EHA and ASH congresses. Overall TFR rate after 2 G-TKIs is ranging from 40% to 60% for selected patients with sustained DMR and it can be considered a safe procedure, that have become, nowadays, a daily practice. However, many crucial aspects regarding treatment choices, timings, as well as predictive factors, patient communication and optimal strategies need to be better clarified to improve successful TFR rate.

Internal tandem duplications of FLT3 (FLT3-ITD) in acute myeloid leukemia (AML) are associated with poor outcomes. CD99 is frequently overexpressed in AML and emerged as potential diagnostic marker. Ninety consecutive newly diagnosed AML patients were retrospectively analyzed. Immunophenotypic profiles were correlated with molecular assessment. Patients were categorized into FLT3-ITD^mut (28.9%) and FLT3^wt (71.1%). CD99 was expressed in 100% of FLT3-ITD^mut-AML compared to 48% in FLT3^wt cases. FLT3-ITD^mut-AML exhibited higher CD99 expression percentage. CD34 expression was lower in FLT3-ITD^mut-AML, with a positivity rate of 31% versus 83% in FLT3^wt cases. Multivariate analysis confirmed that CD99 positivity (OR 17.67; p = 0.010) and CD34 negativity (OR 10.00; p = 0.039) were independently associated with FLT3-ITD^mut-AML. CD99 and CD34 displayed NPVs of 100% and 86.9%, respectively, with moderate PPVs (45.6% and 62.1%) for the diagnosis of FLT3-ITD^mut-AML. CD99 is a highly reliable marker in FLT3-ITD^mut-AML and its absence virtually excludes the presence of a FLT3-ITD mutation.