Imatinib has revolutionized the management of chronic-phase chronic myeloid leukaemia (CP-CML). This study aimed to evaluate the long-term efficacy, safety and prognostic determinants of imatinib in a large cohort of CP-CML patients in real-life clinical practice. We conducted a retrospective, monocentric observational study including all adult patients with CP-CML treated with imatinib between 2000 and 2025. Overall survival (OS), event-free survival (EFS) and progression-free survival (PFS) were estimated using Kaplan-Meier analysis. A total of 210 patients were included, of whom 81% received imatinib as first-line therapy. The median follow-up was 12.4 years. At 25 years, OS and PFS were 71% and 88% respectively. The EUTOS long-term survival (ELTS) score independently predicted OS, EFS and PFS (p < 0.001), while lower risk categories were associated with a faster achievement of major molecular response (MMR) and a higher probability of deep molecular response (DMR). Dose reductions were applied in 26.2% of patients, mainly older individuals with higher Charlson comorbidity index (CCI), without affecting molecular or survival outcomes. Higher CCI values correlated with inferior OS. The ELTS score remains a powerful prognostic tool for long-term outcomes. No unexpected safety concerns were observed in the long term. Over 25 years of real-world experience, imatinib has demonstrated sustained efficacy, safety and tolerability in CP-CML.

Real-world data on the use of asciminib in chronic-phase chronic myeloid leukemia after two or more prior tyrosine kinase inhibitors: Results of the Turkish managed access program along with a literature review.

The ASC4OPT non-comparative phase 3b study (NCT04948333) evaluates asciminib once daily (QD) or twice daily (BID) in chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 tyrosine kinase inhibitors (TKIs). This study enrolled 169 patients not in major molecular response (MMR), with unsatisfactory response (intolerant, warning or failure) as defined by European LeukemiaNet (ELN) 2020 criteria. Patients intolerant to their most recent TKI and in MMR at baseline (n = 30) were also enrolled. The primary endpoint was the MMR rate at Week 48 for patients not in MMR at baseline. Results showed an overall MMR rate of 39.4% at Week 48 (40 mg BID, 43.4%; 80 mg QD, 35.4%) and 43.6% at Week 96 (40 mg BID, 45.8%; 80 mg QD, 41.5%) in patients not in MMR at baseline. Among 40 patients who had their asciminib dose escalated to 200 mg QD, 17.5% were in MMR at Week 96. Most patients in MMR at baseline remained in MMR at 48 and 96 weeks (93.3% and 86.7%, respectively). Safety for both dosing regimens was consistent with that of previous studies. Findings support asciminib as a potential standard of care for patients with CML-CP who have not responded optimally to prior TKI therapy.

Following asciminib's initial approval in Japan for chronic myeloid leukemia (CML) resistant or intolerant to previous therapy, this all-patient, postmarketing surveillance study was initiated. Predefined safety specifications, overall safety, and effectiveness were assessed for 48weeks from asciminib initiation (safety analysis set, n = 523). The approved daily dose of asciminib (80mg [40mg twice daily]) was most frequently used (63.9%) and not exceeded. Discontinuations (28.5%) were primarily due to adverse events (18.2%), including disease progression. Incidences of the safety specifications myelosuppression, pancreatitis, QT interval prolongation, infections, vascular occlusive events, and photosensitivity were 8.6%, 4.4%, 2.5%, 1.3%, 0.2%, and 0%, respectively, with low rates of treatment discontinuation for these events. There were no notable trends in the rates or types of adverse drug reactions in patients aged ≥ 65years or with concurrent renal impairment, hepatic impairment, or cardiac dysfunction. The cumulative major molecular response rate was 61.2% by week 48 and was not affected by age (≥ 65years) or comorbidities. Cumulative MR4.0 and MR4.5 rates by week 48 were 42.3% and 26.5%, respectively, with some patients harboring baseline BCR::ABL1 mutations showing these responses. These real-world outcomes support the safety and effectiveness of asciminib for patients with resistant/intolerant CML.

Canada’s Drug Agency (CDA-AMC) recommends that Scemblix should not be reimbursed by public drug plans for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase previously treated with 1 tyrosine kinase inhibitor (TKI). Evidence from a clinical trial (ASC2ESCALATE) of 101 patients who could not tolerate or did not respond to their first-line TKIs suggested that Scemblix was associated with a clinically meaningful proportion of patients achieving major molecular response (MMR) at 9 months. However, these results were highly uncertain because of the lack of a control group that did not compare Scemblix to other treatments and the short and incomplete study duration that relied on early data that had not reached the primary end point. Additionally, there was no indirect comparison with other available drugs, so it was not possible to determine the benefit or risks of Scemblix compared to other treatments. Patients and clinicians identified the need for additional effective treatments that improve symptom control, reduce side effects, and enhance quality of life. Patients also want multiple treatment options as resistance or intolerance to other TKIs are common. However, the committee was unable to conclude that Scemblix would meet the clinical needs of patients and provide an effective treatment with improved symptom control and quality of life, or superiority in efficacy relative to other treatments in Ph+ CML in second line.

SummaryThe modern management of chronic myeloid leukaemia (CML) identifies a new therapeutic goal of treatment‐free remission (TFR). Half of CML patients in durable deep molecular response (DMR) (MR4 or better) can remain off tyrosine kinase inhibitors (TKIs) without experiencing loss of major molecular response. Despite a large number of TFR studies to date, there are no consistent predictors of successful TFR. We conducted a single‐centre cohort study on 197 patients discontinuing TKIs in DMR ≥1 year and TKI therapy ≥3 years. After TKI discontinuation, 98 patients (49.7%) lost MR4; of these, 90 (91.8%; and 45.7% of the whole cohort) lost major molecular response (MMR or MR3) after a median of 3.8 months (1–93.3). The 2‐year probability of TFR (pTFR) was 57.7%. In multivariable analysis, male sex, age at diagnosis >40 years, faster achievement of MR4 and longer duration of DMR were the only variables significantly associated with higher pTFR. Based on the multivariable analysis results, we built a TFR prognostic score (TPS) able to distinguish three groups with different 2‐year pTFR: good (89.9%), intermediate (61.2%) and poor (18.4%) TFR probability (p < 0.0001). We validated the TPS on an independent cohort of 91 patients. We propose that the TPS could become a useful guide for CML clinicians.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder driven by the BCR::ABL1 fusion gene. Although tyrosine kinase inhibitors (TKI) have revolutionized disease management, leukemic stem cells (LSCs) persist, sustaining minimal residual disease and relapse. A subset expressing the CD26 membrane marker represents a population of proliferating LSCs detectable in bone marrow and peripheral blood. Parallelly, extracellular vesicles (EV) have emerged as promising circulating biomarkers, as they carry BCR::ABL1 transcripts protected within their lipidic membrane. However, the relationship between residual CD26+ LSCs and EV-associated BCR::ABL1 remains unclear. This study aimed to explore the correlation between circulating CD26+ LSCs and vesicular BCR::ABL1 transcripts as complementary indicators of residual disease activity in CML.Peripheral blood (PB) from 44 adult CML patients in at least major molecular response under TKI therapy was analyzed. Circulating CD26+ LSCs were quantified by multiparametric flow cytometry on the CD45+/CD34+/CD38- population using four-color staining. The extracellular vesicle-enriched secretome (EVES) was isolated from plasma and characterized by Western blot, colloidal nanoplasmonic assay, and atomic force microscopy. Vesicular BCR::ABL1 transcripts were quantified by digital PCR (dPCR) and compared with BCR::ABL1 levels in PB cells.EVES characterization confirmed vesicular particles expressing CD63 and FLOT-1 (Figure 1A), with minimal soluble protein contamination (Figure 1B) and typical spherical morphology (Figure 1C). The median number of circulating CD26+ LSCs was 0.00625 cells/μL (range 0-0.1565), with 32% of patients showing undetectable levels. Median EVES BCR::ABL1 was 0.230 copies/μL (range 0-0.790), with 14% undetectable (Figure 1D). No correlation was found between CD26⁺ cells or EVES BCR::ABL1 and molecular response, BCR::ABL1 IS%, or dPCR values in PB cells, nor with age or therapy duration (Figure 1E). A significant inverse correlation was observed between CD26+ LSC counts and vesicular BCR::ABL1 transcripts (r = –0.39, p = 0.0085), even stronger in deep molecular responders (r = –0.45, p = 0.0079) (Figure 1F). Patients in treatment-free remission showed higher CD26+ LSC counts, whereas EVES BCR::ABL1 tended to be higher in those under TKI treatment (Figure 1G).Circulating CD26+ LSCs and vesicle-associated BCR::ABL1 transcripts show an inverse relationship, reflecting complementary aspects of residual leukemic activity in CML. As CD26+ LSCs decline, vesicular BCR::ABL1 may increase, possibly indicating activation of alternative leukemic compartments or enhanced vesicular secretion. Combined monitoring of these cellular and vesicular biomarkers may improve detection of residual disease and provide new insights into CML biology. Larger studies are needed to validate these findings and define the biological and prognostic significance of BCR::ABL1-loaded vesicles.

Although chemotherapy-free regimens have improved initial remission rates in patients with newly diagnosed Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph + B-ALL), outcomes for relapsed or refractory (R/R) Ph + B-ALL remain poor. This study reports the efficacy and safety of CD19 chimeric antigen receptor (CAR) T-cell therapy in R/R Ph + B-ALL. This study retrospectively analyzed 93 patients with R/R Ph + B-ALL who received CD19 CAR T-cell therapy across China between August 2015 and March 2024. We evaluated the overall response rates, long-term efficacy, safety, and prognostic factors associated with CD19 CAR T-cell therapy. Complete remission (CR) or CR with incomplete hematologic recovery rate was 87.1% (81/93), with 96.3% (78/81) of responders achieving minimal residual disease negativity by flow cytometry. Molecular response rate was 78.5% (73/93), including 63.4% achieving complete molecular remission and 15.1% major molecular remission. Twenty patients underwent consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). After a median follow-up of 25.4months (range, 0.1-68.5), the median overall survival (OS) was 20.8months, and the median leukemia-free survival (LFS) was 8.1months. Better Eastern Cooperative Oncology Group performance status and absence of adverse genetic features were associated with improved OS and LFS. In contrast, consolidative allo-HSCT following CAR T-cell therapy was not independently associated with improved OS or LFS. Grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 14.0% and 2.2% of patients, respectively. The most common and predictable adverse events were hematologic, primarily cytopenias, which were manageable with supportive care. CD19 CAR T-cell therapy can achieve high response rates and long-term clinical benefits for patients with R/R Ph + B-ALL, with a manageable safety profile. The preliminary study was presented as a poster presentation (Publication Number: 4201) at the 66th American Society of Hematology Annual Meeting, San Diego, CA, on December 7-10, 2024.

Introduction. Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for approximately 25% of ALL cases in adults. It typically presents with an aggressive clinical course, but the integration of tyrosine kinase inhibitors (TKIs) into chemotherapy regimens has allowed a notable increase in remissions. Despite the significant progress, some patients relapse in the central nervous system (CNS) after treatment, due to the low blood–brain barrier permeability of TKIs. Currently, CNS relapse monitoring is performed by conventional imaging techniques and cytology analysis of the cerebrospinal fluid (CSF). However, these techniques have limited sensitivity. We describe the usefulness, in terms of non-invasiveness and sensitivity, of cell-free tumor DNA testing (Liquid Biopsy, LB) on CSF in a patient with Ph-positive ALL (M-BCR: BCR-ABL p210 b3a2 transcript) who developed a meningeal recurrence after imatinib-based treatment.Methods. The patient was a 75 year old man with a story of Ph+ LLA, with Complete Hematologic Remission for &gt;5 years. After the development of headache, brain MRI, lumbar puncture and minimal residual disease (MRD) testing on peripheral blood were requested for suspected CNS relapse.Follow-up of (MRD) on peripheral blood was carried out with one-step Real-Time PCR monitoring of the BCR-ABL p210 b3a2 transcript on RNA extracted from buffy coat and with Philadelphia chromosome FISH.Free circulating DNA and RNA were extracted from a sample of CSF to investigate the presence of relapses in the central nervous system and to characterize it from a molecular point of view. The molecular research was conducted through the Next-Generation Sequencing (NGS) analysis, with Ion Torrent technology, of a myeloid panel which simultaneously interrogates 45 DNA target genes and 35 fusion driver genes (RNA). Results. Brain MRI revealed enhancement areas in the subarachnoid space. Lumbar puncture showed high opening pressure an increased cell count, with 468 cells / μL with 51% blasts.FISH and Real-Time PCR on peripheral blood had low positivity (ratio BCR/ABL x 100 (IS) = 0.013%), consistent with complete hematological response. Conversely, Real-Time PCR on CSF was positive, with an imbalance score of 0.0002% for the BCR::ABL1B13A transcript, consistent with brain relapse. Real-Time PCR quantitative monitoring of MRD show in peripheral blood a major molecular response (MMR) constant in time. Meningeal relapse was confirmed in CSF by the presence of the BCR::ABL1B13A transcript with an imbalance score of 0.0002%. Conclusions. Liquid biopsy (LB) of the cerebrospinal fluid has proven to be a very sensitive technique that allows the identification of molecular relapse on of free cell-free tumor DNA (ctDNA) in a less invasive way. The results of the molecular evaluation of the response to therapy by NGS study allowed the therapeutical switch to second generation TKIs Dasatinib.

Outcomes of Patients Treated With Dasatinib 50 mg/d: A Pooled Analysis.

Treatment-free remission (TFR) is an emerging goal for patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKI). However, long-term TFR durability in real-world settings remains understudied. The J-SKI study, a large observational study, was conducted to evaluate long-term TFR outcomes in Japanese patients with CML. This interim analysis included 795 eligible patients from the prospective (n = 283) and retrospective (n = 512) cohorts. With a median follow-up of 32months (range 0.8-168) after TKI discontinuation, the 5-year TFR rate was 65.2% (95% confidence interval [CI]: 59.6-70.6%). Among patients who experienced molecular relapse, 99% (95% CI: 97-100%) regained a major molecular response after resuming TKI therapy, with no observed disease progression. Multivariate analysis identified the duration of deep molecular response (DMR) as the sole independent predictor of successful TFR, with each additional year of DMR reducing the relapse risk by 12.5% (HR: 0.875, p < 0.0001). A second TFR attempt was successful in 41% (95% CI: 22-59%) of the 32 patients. This study demonstrated that TKI discontinuation is a safe and feasible strategy in a real-world clinical setting. A sustained DMR is critical for TFR success, supporting its importance as a key therapeutic objective.

The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with at least two prior tyrosine kinase inhibitors (third-line, 3L+). Given that no randomized controlled trial has been conducted for second-line (2L) patients with CML, this analysis aims to infer the efficacy of asciminib in the 2L setting using the 80 mg once-daily dosing regimen and to support the use of asciminib in patients with CML-CP irrespective of line of therapy. Data (n = 430) were used from three studies, including first-in-human and ASCEMBL in 3L+ and ASC4FIRST in 1L trials, to evaluate the effect of line of therapy on efficacy on the basis of the time-course of BCR::ABL1 mRNA transcripts. Previously adapted to characterize the effect of nilotinib as a 1L and 2L therapy on a CML surrogate marker, the model has three compartments representing quiescent leukemic stem cells and proliferating drug-susceptible and resistant bone marrow cells, wherein the effect of asciminib was modeled as an enhancement of the elimination of susceptible cells. Asciminib efficacy in 2L was inferred from 1L by borrowing information from nilotinib data. A credibility assessment showed robust prediction accuracy and precision of the model with external 2L data from the ASC2ESCALATE study (n = 36). Major molecular response (MMR) rates in 2L were predicted to be 61-67% at week 48 and 70-76% at week 96, with the 80 mg total daily dose. A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.

The cellular composition of the chronic myeloid leukemia (CML) bone marrow (BM) beyond granulocyte enrichment remains poorly understood. We analyzed 1548 routinely stained BM aspirate slides from 598 patients across seven sites using deep learning‐based image analysis to identify cytomorphological markers predictive of major molecular response. Erythroid precursor enrichment, monocyte nuclear lobulation, and low peripheral leukocyte count were associated with improved tyrosine kinase inhibitor (TKI) response. These features were validated both visually and computationally in two independent cohorts. We developed a Morphoclinical model integrating these image‐derived and clinical variables, outperforming (area under the receiver‐operating curve [AUROC] 0.76) the clinically used EUTOS long‐term survival score (AUROC 0.53) and BCR::ABL1 halving time (AUROC 0.61). Notably, poor‐risk patients treated with second‐generation TKIs achieved outcomes similar to favorable‐risk patients on imatinib. These results underline the overlooked prognostic value of BM cytomorphology to refine risk stratification and support more personalized frontline therapy in CML.

Abstract This study compared the efficacy and safety of dasatinib 70 mg/day versus the standard 100 mg/day dose in newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) patients from Hubei Province, China. In this prospective, randomized, multicenter trial, 91 patients were assigned to receive dasatinib 70 mg/day ( n = 47) or 100 mg/day ( n = 44). The primary objective was to compare the rates of optimal response, complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4.0(MR4.0) at 3, 6, and 12 months. Safety was assessed via adverse event (AE) monitoring. No significant differences were observed in optimal response, CCyR,, MMR or MR4.0 rates between the two groups at any time point (all P &gt; 0.05). By 12 months, CCyR rates were 100% in both groups. The overall incidence of AEs was similar, except for elevated lactate dehydrogenase ( P &lt; 0.05). However, the proportion of patients requiring treatment interruption or dose reduction due to AEs was significantly lower in the 70 mg/day group (4.1% vs. 14.7%, P &lt; 0.05). Dasatinib 70 mg/day demonstrated comparable efficacy to the 100 mg/day dose over 12 months, with a potential trend towards better tolerability, suggesting it is a viable first-line treatment option for CP-CML patients.

Background: Macrocytosis commonly develops during imatinib therapy, but its relationship with cytogenetic and molecular outcomes in chronic myeloid leukemia (CML) remains unclear. We investigated whether increases in mean corpuscular volume (MCV) during imatinib treatment are associated with response depth and treatment persistence. Methods: In this retrospective study, we analyzed 101 adults with chronic-phase CML treated with a stable imatinib dose of 400 mg/day for at least 12 months. Patients with conditions that could confound MCV (hydroxyurea exposure, megaloblastic anemia, hypothyroidism, chronic liver disease, alcoholism) were excluded. Complete cytogenetic response (CCyR) and major molecular response (MMR) were assessed by conventional karyotyping and the BCR-ABL1 International Scale, respectively. Increased MCV was defined as MCV > 100 fL after six months of therapy, persisting thereafter. Associations between MCV dynamics, response, and switching to second-generation tyrosine kinase inhibitors were evaluated. Results: Twenty patients (20%) developed increased MCV. Overall, 86 patients (85%) achieved CCyR and 70 (69%) achieved MMR. All patients with increased MCV attained CCyR, compared with 66 of 81 (81%) without MCV elevation (p = 0.037), while MMR rates were 90% versus 64% (p = 0.030). During a median follow-up of 69 months, treatment modification was required in 1 of 20 (5%) patients with increased MCV versus 25 of 81 (31%) in the non-increased group (p = 0.018). Conclusions: MCV elevation during imatinib therapy is associated with deeper molecular response and reduced need for treatment modification. MCV dynamics may serve as an inexpensive pharmacodynamic marker to support risk assessment and guide monitoring in chronic-phase CML.

BackgroundThis study aims to comprehensively evaluate the safety and effectiveness of flumatinib in both first-line and subsequent-line therapies in 244 chronic-phase chronic myeloid leukemia (CML-CP) patients.MethodsResponse criteria were applied according to the European LeukemiaNet. Adverse events (AEs) occurring after flumatinib treatment were documented and graded for severity.ResultsThe study encompassed 244 patients with CML-CP, stratified by treatment lines: first-line (1L, N=138), second-line (2L, N=63), and third-line or above (≥3L, N=43). First-line flumatinib therapy resulted in a major molecular response achieved by 50.7% at 6 months and 66.7% at 12 months, with a deep molecular response (DMR) achieved by 20.3% at 6 months and 35.5% at 12 months. In subsequent treatment lines, those with baseline MR2 had a DMR rate of 42.9%, compared to 23.3% for those without it. Significant differences in molecular response rates were observed based on treatment line and prior tyrosine kinase inhibitors (TKI) resistance (p<0.05). However, subgroup analyses showed no significant differences in treatment responses between the warning and resistance groups after flumatinib therapy. Dose reduction strategies, implemented in 19.3% of patients, have proven feasible without compromising efficacy. Eight patients subsequently attempted treatment cessation, with five maintaining treatment-free remission. AEs were predominantly grade 1–2, with diarrhea (27.0%), fatigue (12.3%), and thrombocytopenia (11.5%) being the most frequent. Grade 3/4 AEs were infrequent, highlighting flumatinib’s manageable safety profile.ConclusionFlumatinib displays significant clinical efficacy and a superior safety profile compared to other second-generation TKI, whether administered in first-line or subsequent treatment settings.

Approximately half of patients with chronic myeloid leukemia (CML) who attempted tyrosine kinase inhibitor (TKI) discontinuation for the first time experienced molecular relapse and restarted TKIs. Although several studies have already investigated first treatment-free remission (TFR) attempts (TFR1), few previously published articles have focused on the plausibility and predictors of second TFR (TFR2). To evaluate the feasibility and likelihood of TFR2 success in real-life, 90 patients with CML regularly followed in 23 Italian hematological centers were analyzed; these patients reattempted TKI discontinuation after a first failed attempt. Forty-five (50.0%) patients lost major molecular response after a median of 4.0 months off therapy, whereas 45 (50.0%) remained treatment-free for a median of 18.8 months. In univariate analysis, there was no association between TFR2 and the following variables: age, gender, Sokal risk score, BCR::ABL1 transcript type, prior interferon exposure, type and number of previous TKIs, resistance to any prior TKIs, and TKI switching after TFR1. In contrast, factors identified as associated with TFR2 success included a lower ELTS risk score, a longer time from TFR1 to molecular relapse (≥3 months), as well as a longer TKI treatment and deep molecular response (DMR) duration (≥4 years) before TFR2. While confirming the critical prognostic role of ELTS risk and TKI treatment and DMR duration even before TFR2, this real-life study provides further information to support the safety of a second effort to discontinue TKIs in patients with CML, as a failed first attempt does not appear to preclude a second successful one.

Data and guidelines for a second attempt at treatment-free remission (TFR) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) are limited. We retrospectively analyzed the clinical data of six patients with CML-CP who attempted a second discontinuation of tyrosine kinase inhibitors (TKIs) for TFR at Peking University People's Hospital from October 2006 to October 2024. Before the first TKI discontinuation, all six patients had received imatinib treatment for a median of 82.5 months (range, 40-87 months) and maintained a sustained deep molecular response, specifically MR(4.5), for a median of 34.5 months (range, 24-62 months). They lost major molecular response (MMR) at a median of 3 months (range, 2-4 months) after discontinuing imatinib treatment. All six patients resumed TKI treatment within 4 weeks following failure of the first TFR (TFR1). After a median of 4.5 months (range, 3-7 months) on TKI, they achieved MR(4.5) again and voluntarily attempted a second TKI discontinuation at 93, 84, 76, 76, 33, and 44 months, respectively, after resuming therapy. Four out of six patients maintained TFR, with sustained TFR durations of 42, 23, 21, and 58 months, respectively. All four patients who had resumed TKI treatment for >6 years and maintained MR(4.5) for >5 years achieved a sustained second TFR of ≥21 months; among these, three had received second-generation TKI for >1 year during the resumption of TKI treatment. The other two patients lost MMR at 4 and 3 months, respectively, after the second TKI discontinuation but regained MR(4.5) at 2 and 3 months, respectively, after resuming TKI treatment again.

Treatment-free remission (TFR) after discontinuation of ABL tyrosine kinase inhibitors (TKIs) is an important therapeutic goal in chronic myeloid leukemia (CML). Interferon-α (IFN) has been suggested to promote durable TFR. The phase 3 ENDURE trial (NCT03117816; EUDRA-CT 2016-001030-94) prospectively tested this hypothesis in patients with stable deep molecular remission after TKI therapy. A total of 203 patients were randomised 1:1 to receive ropeginterferon alfa-2b (ropeg-IFN; 100 µg subcutaneously every two weeks for 15 months, n = 95) or observation alone (n = 108) after TKI discontinuation. The primary endpoint was molecular relapse-free survival (MRFS), defined as time to loss of major molecular response (MMR) or death. At a median follow-up of 36 months, 25-month MRFS was 56% (95% confidence interval (CI), 45-66) with ropeg-IFN and 59% (95% CI, 49-68) with observation (hazard ratio (HR), 1.02; 95% CI, 0.68-1.55; P = 0.91). Among 83 patients with molecular data after TKI restart, 79 (95%) regained at least MMR, 78 within 12 months (median 3 months, interquartile range: 2-4 months). Ropeg-IFN was well tolerated (median administered dose of 92 µg, range 3-104), and no new safety signals were observed. Ropeg-IFN maintenance did not improve the probability of sustained TFR after TKI discontinuation.

ABSTRACTBackgroundDasatinib, a potent second‐generation tyrosine kinase inhibitor (TKI), is highly effective in chronic myeloid leukemia in chronic phase (CML‐CP) resistant to imatinib at standard dosing (100 mg daily), but is often limited by adverse events. Emerging evidence suggests low‐dose dasatinib (50 mg daily) may maintain efficacy with improved safety, but data in imatinib‐resistant CML‐CP remain limited.AimsTo evaluate the efficacy and safety of low‐dose dasatinib (50 mg daily) in patients with imatinib‐resistant CML‐CP and to identify predictors of treatment response and disease progression.Methods and ResultsThis retrospective cohort study included 53 adults with imatinib‐resistant CML‐CP treated with low‐dose dasatinib at a tertiary center in Northern India (2002–2025). Early molecular response (EMR), major molecular response (MMR), deep molecular response (DMR), progression‐free survival (PFS), overall survival (OS), and adverse events were assessed. Multivariate Cox regression identified predictors of poor response and disease progression. Among 53 patients (median age 50 years), 41.5% achieved MR4.5, 20.8% MR4.0, and 15.1% MMR without DMR. Prior loss of MMR on imatinib significantly correlated with a superior response to dasatinib (p = 0.002). TKD mutations were present in 32.1%; the T315I mutation, high ELTS risk, and baseline BCR‐ABL1 ⟩ 100% independently predicted poor response. Clinically significant adverse events occurred in 49.1%, primarily cytopenias and pleural effusion. Among our cohort, 22.6% required a TKI switch due to inadequate response and 7.5% due to intolerance.ConclusionLow‐dose dasatinib is effective and tolerable in imatinib‐resistant CML‐CP, with nearly two‐thirds achieving DMRs. Predictive biomarkers (T315I mutation, high ELTS risk, high baseline BCR‐ABL1) can guide dose optimization.