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After nearly 11 years of follow-up, long-term administration of imatinib was shown to be associated with prolonged control of chronic myeloid leukemia and no cumulative or late toxic effects have emerged. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that is characterized by the Philadelphia (Ph) chromosome and driven by its product, the BCR-ABL1 tyrosine kinase. 1 In 2001, imatinib was introduced as a BCR-ABL1 tyrosine kinase inhibitor and was approved for the treatment of CML on the basis of a high level of activity in phase 2 studies. 2 Early results from the phase 3 International Randomized Study of Interferon and STI571 (IRIS) showed that imatinib at a dose of 400 mg once daily was more active and was associated with fewer side effects than interferon alfa plus cytarabine in patients with . . .

With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.

Characterizing the transcriptome of individual cells is fundamental to understanding complex biological systems. We describe a droplet-based system that enables 3′ mRNA counting of tens of thousands of single cells per sample. Cell encapsulation, of up to 8 samples at a time, takes place in ∼6 min, with ∼50% cell capture efficiency. To demonstrate the system’s technical performance, we collected transcriptome data from ∼250k single cells across 29 samples. We validated the sensitivity of the system and its ability to detect rare populations using cell lines and synthetic RNAs. We profiled 68k peripheral blood mononuclear cells to demonstrate the system’s ability to characterize large immune populations. Finally, we used sequence variation in the transcriptome data to determine host and donor chimerism at single-cell resolution from bone marrow mononuclear cells isolated from transplant patients. Single-cell gene expression analysis is challenging. This work describes a new droplet-based single cell RNA-seq platform capable of processing tens of thousands of cells across 8 independent samples in minutes, and demonstrates cellular subtypes and host–donor chimerism in transplant patients.

Key Points FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) involved in the proliferation, differentiation and apoptosis of haematopoietic cells. It is mainly expressed by early myeloid and lymphoid progenitor cells. Many cells of the haematopoietic system produce FLT3 ligand (FLT3L), which promotes dimerization and activation of FLT3. The activated receptor then activates the phosphatidylinositol 3-kinase (PI3K) and RAS signal-transduction cascades. The FLT3 internal tandem duplication (ITD) results from a head-to-tail duplication of 3–400 base pairs in exons 14 or 15, which encode the juxtamembrane domain of FLT3. Point mutations in FLT3 occur in heavily conserved areas of the intracellular tyrosine-kinase domain (TKD), homologous to point mutations that are seen in other RTKs such as KIT and FMS. FLT3 mutations are the most frequent genetic lesion seen in acute myeloid leukaemia (AML). The prevalence of FLT3 ITDs is 15–35%, with an additional 5–10% of patients having FLT3 TKD mutations. Both types of FLT3 mutation cause ligand-independent activation of the receptor and activation of downstream signalling pathways. The presence of a FLT3 ITD is associated with poor clinical outcome in both paediatric and adult patients with AML. Several drugs that target FLT3 are in early clinical trials. Normal haematopoietic cells use complex systems to control proliferation, differentiation and cell death. The control of proliferation is, in part, accomplished through the ligand-induced stimulation of receptor tyrosine kinases, which signal to downstream effectors through the RAS pathway. Recently, mutations in the FMS-like tyrosine kinase 3 ( FLT3 ) gene, which encodes a receptor tyrosine kinase, have been found to be the most common genetic lesion in acute myeloid leukaemia (AML), occurring in ∼25% of cases. Exploring the mechanism by which these FLT3 mutations cause uncontrolled proliferation might lead to a better understanding of how cells become cancerous and provide insights for the development of new drugs.

Purpose ENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 weeks, we here provide an updated 96-week analysis. Methods Attempting TFR required ≥ 3 years of nilotinib, a molecular response of MR 4.5 [ BCR-ABL1  ≤ 0.0032% on the International Scale ( BCR-ABL1 IS )], and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR; BCR-ABL1 IS  ≤ 0.1%). Results Ninety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR 4.5 by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR 4.5 during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR 4.5 during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR 4.5 , MR 4 ( BCR-ABL1 IS  ≤ 0.01%) but not MR 4.5 , and MMR but not MR 4 at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes. Conclusions These results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR.

What can we learn from the study of rare diseases? A lot. Chronic myeloid leukemia (CML) occurs in 3 in 100,000 persons, yet it is perhaps the best example of “bench to bedside” medicine in oncology. The discovery of the signature BCR-ABL translocation found in all CML ushered in an era of molecular diagnostics and targeted therapy with tyrosine kinase inhibitors, with treatment implications beyond this rare disease. 1 Similarly, research on the other rare myeloproliferative neoplasms led to the discovery and potential therapeutic targeting of the JAK2 kinase mutation. 2 In this issue of the Journal, Maxson et al. 3 describe another . . .

The efficient selection and isolation of individual cells of interest from a mixed population is desired in many biomedical and clinical applications. Here we show the concept of using photoswitchable semiconducting polymer dots (Pdots) as an optical ‘painting’ tool, which enables the selection of certain adherent cells based on their fluorescence, and their spatial and morphological features, under a microscope. We first develop a Pdot that can switch between the bright (ON) and dark (OFF) states reversibly with a 150-fold contrast ratio on irradiation with ultraviolet or red light. With a focused 633-nm laser beam that acts as a ‘paintbrush’ and the photoswitchable Pdots as the ‘paint’, we select and ‘paint’ individual Pdot-labelled adherent cells by turning on their fluorescence, then proceed to sort and recover the optically marked cells (with 90% recovery and near 100% purity), followed by genetic analysis. Isolation of individual cells from mixed populations is desirable for many biomedical applications. Here the authors use photoswitchable Pdots to allow 'optical painting', where cells of interest are marked based on their visual characteristics, and can then be isolated by fluorescence activated cell sorting.

The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR 4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR 4.5 . Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR 4.5 . The Kaplan–Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR 4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.

Approximately 1.5 million people worldwide suffer from chronic myeloid leukemia (CML). MicroRNAs (miRs) are important regulators of gene expression and offer an attractive option as biomarkers for cancer detection, diagnosis, and prognosis assessment in solid and liquid tumors. To assess miRs as prognostic and predictive biomarkers among CML patients at the Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia from April 2021 to May 2023. Blood samples were collected from newly diagnosed CML patients before initiation of tyrosine kinase inhibitor (TKI), imatinib treatment, and while on therapy. The expression level of miRs were determined using the NanoString platform. LIMMA analysis was used to identify differentially expressed miR between TKI response groups and disease phases. Fifty-two study participants were enrolled in the study. From each sample, 798 hsa-miRs included on the Nanostring assay were measured. Comparing TKI naive new CML patients (n = 14) with those progressed or had blast crisis (BC) on TKI therapy (n = 12), 97 miRs were differentially expressed (|log2FC|, FDR, and P-value at > 1, < 0.001, and < 0.0001, respectively). Most miRs showed upregulation in BC CML patients compared to new CML cases except miR-223-3p, miR-4454, miR-7975, and miR-630 which were downregulated in patients with BC. In addition, eight miRs were differentially expressed comparing poor molecular responder (n = 12) with good molecular responder (n = 28) patients (P < 0.05). MiR-223-3p, miR-4454, miR-7975, and miR-630 were commonly deregulated in BC and poor molecular response groups. MiRs have significant potential as prognostic and predictive biomarkers for CML patients. MiR-223-3p, miR-4454, miR-7975 and miR-630 could be considered as prognostic and predictive biomarkers for disease progression and treatment response if validated by other large studies.