Ponatinib, a third-generation tyrosine kinase inhibitor, is effective in patients with chronic myeloid leukemia (CML), particularly in cases of resistance or BCR::ABL1 T315I mutation. However, arterial occlusive events (AOEs) remain an important safety concern. The PONDEROSA registry evaluated ponatinib use under routine clinical conditions in Germany and the Czech Republic. This observational cohort study included 99 adult CML patients treated with ponatinib; patient recruitment took place between 2015 and 2022 at 31 centers. The median follow-up was 22 months (range: 1–83). Among the 99 patients (median age 54 years at CML diagnosis), 91.9

Currently there is no established prognostic scoring system for patients with chronic myeloid leukemia (CML) in blast phase (BP). This study aimed to identify prognostic factors of CML-BP in a large cohort of prospectively and retrospectively collected patients and to develop a readily available prognostic scoring system at the onset of BP to enable future comparison between different trials and series. The analyses were based on 275 patients from thirteen countries, collected within the European LeukemiaNet Blast Phase Registry with a median observation time of 45 months and a median OS of 18.9 months. A Cox proportional hazards model for overall survival (OS) was employed, missing values were imputed. The study identified six independent prognostic factors: blast percentage, platelet count, age (all at onset of CML-BP), immunophenotype of BP, extramedullary disease, and previous history of CML. The low-risk group, encompassing 14% of patients, had a median OS of 97 months, the intermediate-risk group (59% of patients) of 22 months, and the high-risk group (27% of patients) of 9 months. Cross-validation demonstrated a good performance of the score, although external validation is strongly recommended. Despite the inherent limitations of registry data, the findings offer robust insights into prognostic factors for CML-BP.

BACKGROUND:Terminally ill patients often have difficulty taking medications. Suitable, minimally invasive, fast-acting administration routes are particularly important. Trials on alternative drug administration routes in palliative care are essential to base therapy decisions on evidence rather than experience. AIM:To evaluate the effectiveness of intranasal compared with subcutaneous midazolam for the initial management of terminal agitation in palliative care patients. DESIGN:Randomized, investigator-initiated open-label phase-II trial, August 2022-July 2024. SETTING/PARTICIPANTS:Monocentric trial at the palliative care ward of a German University Hospital. 180 patients were assessed for suitability, 60 patients (median age, 68 years (SD 12.3), 26 female) were randomized 1:1 and analyzed. Patients with terminal agitation fulfilling all eligibility criteria were randomized to midazolam 5 mg administered either intranasal (n = 30) or subcutaneous (n = 30). PRIMARY OUTCOME:Improvement of terminal agitation by midazolam administration assessed by RASS-PAL-score. SECONDARY OUTCOME:Midazolam plasma concentrations after administration. RESULTS:Median RASS-PAL-scores decreased significantly in both groups. Intranasal group: 2 at baseline, to -1 at 5 min and -2 at 20 min. Subcutaneous group: 1,-0 and -1. Within-group reductions exceeded the clinically relevant threshold of ⩾ 1 point at 5 and 20 min (all p < 0.0001). Median midazolam plasma concentrations were significantly higher intranasal (5 min: 90 ng/ml, 20 min: 83 ng/ml) than subcutaneous (5 min: 15 ng/ml, 20 min: 24 ng/ml). No patients withdrawn due to adverse effects. CONCLUSION:Midazolam intranasal administration was effective in reducing terminal agitation and achieves higher plasma concentrations compared to subcutaneous administration. It is an alternative route of application to improve end-of-life care for terminally ill patients. TRIAL REGISTRATION:MinTU Study 173-01, Eudra CT No.: 2021-004789-36, DRKS ID: 00026775 (07.07.2022, https://drks.de/search/de/trial/DRKS00026775).

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.

Introduction: “The Frontline asciminib in combination” - FASCINATION study (NCT03906292) is a multicenter, prospective, open-label, interventional phase II trial to evaluate efficacy and tolerability of asciminib as first-line treatment in combination with conventional ATP-competing BCR::ABL1 inhibitors for patients (pts) with chronic myeloid leukemia (CML) in chronic phase. The aim of the study is to improve the rate of deep molecular response and thereby increase the proportion of patients in treatment-free remission (TFR) over time. Here, we report the 3-year follow-up of the trial. Methods: Adult pts with newly diagnosed BCR::ABL1-positive CML were allocated to one of four combination cohorts: nilotinib 300 mg BID plus asciminib 20 mg BID (cohort 1) or asciminib 40 mg QD (cohort 2), dasatinib 100 mg QD plus asciminib 80 mg QD (cohort 3), or imatinib 400 mg QD plus asciminib 60 mg QD (cohort 4). The primary endpoint was the rate of MR4 (BCR::ABL1 transcripts ≤0.01% on the International Scale, IS) at month 12. Patients who did not achieve MR4 at month 24 stopped asciminib combination and were treated with an ATP competing TKI monotherapy at the discretion of the investigator. Subjects with MR4 continued the previous asciminib combination treatment for one year. Patients with MR4.5 were de-escalated to asciminib monotherapy 80 mg QD for one year. At month 36, asciminib treatment was stopped for all pts. Pts with MR4 or better for at least one year entered a TFR phase. Results: Between September 2019 and January 2022, 144 pts were recruited from 21 sites in Germany. Combination therapy was commenced in 125 pts (67% male). Median age at diagnosis was 46 years (range, 19-89). 57.6, 30.3, and 12.1% were low, intermediate, and high risk according to the ELTS score, respectively. BCR::ABL1 independent mutations were identified in 22 pts (18%), most commonly ASXL1 mutations (8 pts, 7%). A total of 114 pts were eligible for evaluation of molecular response at month 12. According to the intention to treat, rate of MR4at month 12 (primary endpoint) was 37.7%. At month 24, a total of 92 pts (73.6%) were allocated to further treatment arms based on their molecular response: 45 pts did not achieve MR4 at month 24 and continued with an ATP competing TKI monotherapy, 17 pts achieved MR4 and continued the previous combination treatment, 30 pts achieved MR4.5and were de-escalated to asciminib monotherapy. A total of 101 pts were eligible for evaluation of molecular response at month 36 (secondary endpoint). Rate of MMR, MR4, MR4.5, MR5 and MR5.5was 91%, 65%, 45%, 27% and 20%, respectively. Six of 8 pts with ASXL1 mutations achieved MR4 at month 12 and 7 pts at month 36, respectively. Within the 3-year follow-up, loss of MMR was observed in 5 pts with a BCR::ABL1-E275G mutation detected in one patient. Two pts progressed to blast phase and received allogeneic stem cell transplantations (month 7 and 13, respectively). Adverse events (AEs) grade 3-4 decreased from 37.6% of pts within the first year to 24.0% and 9.6% within the second and third year, respectively. Most commonly observed AEs were lipase increase (10 pts) and hypophosphataemia (6 pts). One patient died due to a myocardial infarction (month 24). A total of 37 pts (29.6%) entered the TFR phase at month 36. Conclusions: The combination of asciminib as frontline therapy with ATP competing BCR::ABL1 inhibitors was associated with a high rate of deep molecular response but moderate tolerability in the first year. The 3-year follow-up of the FASCINATION trial shows high efficacy (even in pts with ASXL1 mutations), no evidence for development of clinically relevant BCR::ABL1 mutations and improved tolerability without any unsuspected AEs. Further follow-up is needed to investigate TFR.

INTRODUCTION:In chronic myeloid leukemia patients, second-line treatment requires careful consideration of response and tolerability. As most patients need a more efficient tyrosine kinase inhibitor, ponatinib at a lowered dose should be evaluated in this setting. METHODS:We studied a lowered dose of 30 mg ponatinib in second line in patients selected toward a low cardiovascular risk. In 22 screened patients, ponatinib was started in 18 patients previously treated with imatinib (n = 3), dasatinib (n = 9), or nilotinib (n = 6). Patients were frequently monitored for cardiovascular toxicities by testing of blood pressure, vital signs, ankle brachial index or duplex, oral glucose tolerance test, echocardiography, ECG, and fundoscopy. The study protocol allowed dose reductions in patients achieving MMR. Both previously resistant or intolerant patients were recruited. RESULTS:No serious cardiovascular events were observed, and low-grade cardiovascular toxicity was negligible. By 12 months, 13 patients (92.9%) were in complete hematologic remission, 10 patients (55.6%) were in MMR, and 5 patients (27.8%) were in MR4. Most importantly, we demonstrated that thorough monitoring of cardiovascular risk is feasible. CONCLUSIONS:We demonstrated that a lowered dose of 30 mg ponatinib in selected patients can be maintained without serious cardiovascular complications, provided cardiovascular risk monitoring is performed. In our patient cohort, this approach resulted in favorable response rates.

There are two major isoforms of BCR::ABL1, the Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) specific p185BCR::ABL1, and the p210BCR::ABL1, which defines 95% of chronic myeloid leukemia (CML). These two isoforms differ in the presence of the oncogenic pleckstrin- and DBL-homology domains (DH and PH) in p210BCR::ABL1. The p210BCR::ABL1 induces genomic instability (GI) by double-strand breaks (DSB). The DNA damage and repair response (DDR) repairs DSBs. BCR::ABL1 compromises the fidelity of DDR by promoting the repair of DSB through single-strand annealing (SSA), a mutagenic pathway, and through non-homologous end joining (NHEJ). Both DDR mechanisms may not be sufficiently suppressed by tyrosine kinase inhibitors (TKI), resulting in imprecise repair and mutations. As a model, we used early passages of thirteen long-term cultures derived from patients (PD-LTCs) with acute lymphoblastic leukemia (ALL). Five PD-LTCs were from Ph+ ALLs with the associated p185BCR::ABL1, one of them with the T315I mutation. The two PD-LTCs from lymphoblastic CML blast crisis (CML l-BC) had the p210BCR::ABL1 fusion protein. The Ph-like PD-LTC exhibited an ETV6::ABL1 fusion protein. Two PD-LTCs harbored the t(1;19), which encoded the E2A::PBX1 fusion protein. The t(11;19) translocation encoding MLL::MLLT1 characterized one PD-LTC. We used the two PD-LTCs with no translocation and a complex karyotype as a reference. These cells represent the closest model to primary ALL cells as they are genomically and immunologically stable and did not undergo the classical crisis of a transformed cell line. They also enabled the determination of a relationship between GI and the response to TKI therapy in Ph+ ALL, as each of the Ph+ and Ph-like PD-LTCs has a different response to TKI. For the genome-wide measurement of the DSBs, we focused on INDUCE-seq, a technique we have recently developed. It allows for defining every single DSB at a molecular level, followed by bioinformatic analysis of DSBs. In this way, it is possible to define the absolute number of DSBs, their recurrency, and the number of DSBs per chromosome and their role in response to therapy and leukemogenesis. We aimed to determine the role of GI induced by rearranged ABL1 in the pathogenesis of Ph+ and Ph-like lymphoblastic leukemia and the response to TKI. We also wanted to compare the two major BCR::ABL1 isoforms, p185BCR::ABL1 and p210BCR::ABL1, regarding the induction of GI. We found that PD-LTCs from Ph+ ALL with their p185BCR::ABL1 induced a higher rate of GI by DSB than those from CML l-BC with their p210BCR::ABL1. We observed a higher absolute number of DSBs normalized to the amount of DNA extracted in p185BCR::ABL1-positive PD-LTCs (mean of ~89K) than in p210BCR::ABL1-positive PD-LTCs (mean of ~47K) and every other PD-LTC (mean of ~42K). ETV6::ABL1 induced a total number of DSB close to p185BCR::ABL1 (mean of ~ 75K) in the Ph-like PD-LTC. For both BCR::ABL1 isoforms and the Ph-like PD-LTC, the recurrency (the rate of DSBs in single genes) was higher than in other PD-LTCs, with a higher rate in p185BCR::ABL1-positive PD-LTCs than in those harboring p210BCR::ABL1. There was a relationship between sensitivity to TKI and the recurrency of DSB in the TKI-sensitive PD-LTCs. The lower the recurrency, the higher the sensitivity to TKI. The p185BCR::ABL1 fusion strongly induced DSBs in chromosomes 5 and 8. As no the induction of DSBs in chromosomes 5 and 8 was more likely related to the leukemogenesis of Ph+ ALL. Our still preliminary data demonstrate the significance of GI for the leukemogenesis and the response to TKI of lymphoblastic leukemia with the rearrangement of ABL1. It is not yet clear whether GI may be independent of ABL1 kinase activity, a target of TKI. It has to be confirmed by clinical studies.

Introduction Maintaining good quality of life (QOL) is a key consideration for pts with CML, yet there remains a lack of clarity and dialog around its impact on daily functioning. These issues are often underreported in clinical settings, contributing to a communication gap between pts and healthcare providers (HCPs). This gap highlights the need for tools that help pts routinely assess and share QOL concerns. To address this unmet need, we developed a digital CML Quality of Life Tracker that guides patients through up to 3 steps (rating the impacts on daily life, identifying symptom-affected areas, and selecting relevant symptoms from a list) culminating in a summary report to support conversations around QOL challenges, as previously described by Žáčková, et al. Here we report initial insights from prototype testing with pt advocates, HCPs, and consultants involved in the tool's development. Methods The CML Quality of Life Tracker was developed with input from HCPs and pts across multiple countries to ensure relevance and usability. Prototype testing was conducted with 3 distinct groups: pt advocates (n=7), HCPs (n=9), and a group of consultants (n=7) composed of 4 HCPs and 3 pt advocates. Each group reviewed the tool and participated in dedicated feedback sessions in which they completed surveys tailored to their respective roles as pts or HCPs, shared impressions, identified strengths and limitations, and provided recommendations. Quantitative input was collected via surveys from pt advocates (n=5), HCPs (n=5), and consultants (n=5); additional qualitative insights came from participants who did not complete the full survey (pt advocates, n=2; HCPs, n=4; HCP consultants, n=2). Insights from these sessions were collected and synthesized to inform future updates to the tool. Results Pt advocates and pt advocate consultants rated step 1 (impact on daily life) as easy (4/8 [50%]) or very easy (4/8 [50%]), step 2 (impact on body) as neither easy nor difficult (1/8 [12.5%]), easy (5/8 [62.5%]), or very easy (2/8 [25%]), and step 3 (associated symptoms) as easy (3/8 [37.5%]) or very easy (5/8 [62.5%]). They agreed on the high relevance of these 3 core steps and rated their likelihood of recommending the tracker as high or very high (7/8 [87.5%]), with only 1 respondent (12.5%) selecting a neutral score. Of HCPs, 100% agreed that the tracker is useful and pt-centric, and all indicated plans to use it regularly. Pt advocates outside of the consulting group found the tracker's 2 summary reports somewhat challenging to understand, rating the results of the questionnaire as difficult or neutral (2/5 [40%]), and the consolidated view of patient data over time as difficult or neutral (3/5 [60%]). In contrast, nearly all HCPs and consultants found them easy or very easy to read and understand. Recommendations shared across groups included prioritizing symptoms, saving progress, customizing reporting pathways, and generating summaries tailored for care teams. Improving navigation and visual design was a consistent theme among pt advocates and consultants, while both HCPs and consultants emphasized the need to track multiple symptoms simultaneously. Of pt advocates in the consultant group, 100% said it would be useful to see comparative data points on users that experience the same symptoms as them. While HCPs emphasized integration into clinical workflows and cross-device accessibility, pt advocates prioritized education materials and self-evaluation tools, and consultants stressed inclusivity features such as multilingual support and audio options. Conclusions Prototype testing of the digital CML Quality of Life Tracker revealed pt advocates' optimism about its relevance and utility, and HCPs' interest in its potential for clinical implementation. While viewed as a valuable tool for facilitating communication around QOL, feedback highlighted key areas for enhancement, including simplifying navigation, expanding symptom tracking, integrating comparative/historical data, and improving report customization. Group-specific insights emphasized inclusivity, educational resources, and technical refinements. These findings will guide further development to better support discussions about QOL. The tracker is expected to launch globally in September 2025, following final alignment with the consulting group. Future updates will incorporate real-world usage data and user feedback to enhance the tool over time.

ABSTRACT:The efficacy of and disease control afforded by tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia in chronic phase (CML-CP) have led to increased longevity and thus the continued pursuit of alternative therapies that are efficacious and maximize tolerability. The 24- and 96-week analyses from ASCEMBL demonstrated superior efficacy, safety, and tolerability of asciminib when compared with bosutinib in later-line therapy, thereby meeting the primary and key secondary objectives. With nearly 4 years of follow-up, data from ASCEMBL continued to demonstrate the superior efficacy, safety, and tolerability of asciminib over bosutinib. At week 156, the major molecular response (MMR) rates remained higher with asciminib (33.8%) than with bosutinib (10.5%); the difference in MMR rates between arms, after adjusting for baseline major cytogenetic response, was 23.2% (95% confidence interval, 13.14-33.18; 2-sided P < .001). Asciminib continued to cause fewer grade ≥3 adverse events (AEs; 59.6% vs 68.4%) and fewer AEs that led to treatment discontinuation (8.3% vs 27.6%) than bosutinib. This updated analysis also includes patients who switched to asciminib because of a lack of efficacy with bosutinib. Two of the 25 patients who switched achieved MMR by the end of study, suggesting that earlier incorporation of asciminib, before other TKIs, may improve responses, albeit modestly. These long-term results further solidify asciminib as the therapy of choice for patients with CML-CP who were previously treated with ≥2 previous TKIs. This trial was registered at clinicaltrials.gov as #NCT03106779.

In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate on dose reduction rather than drug switching to manage toxicities and discuss treatment sequencing. Data have matured for the outcome of treatment discontinuation and for management of parenting for both men and women. We acknowledge that most patients will remain on treatment for many years and emphasize the needs to minimize side effects, manage co-morbidities and optimize quality of life. Recent advances in allogeneic stem cell transplantation have broadened access to alternative donors, and lessened limitations of age and co-morbidities such that transplant remains a valuable option for patients for whom long-term disease control is not achieved through TKI therapy.

CML is characterized by a reciprocal translocation of t(9;22)(q34;q11), leading to the BCR::ABL1 fusion gene. Most patients have a typical fusion transcript: e13a2 (b2a2) and/or e14a2 (b3a2). However, approximately 2% have an atypical fusion transcript (Cross, 2023) for which there is limited data available about prognosis and response to tyrosine kinase inhibitors (TKIs). Moreover, emerging data show that e13a3(b2a3) and e14a3(b3a3) atypical BCR::ABL1 translocations cannot be inhibited by allosteric TKIs targeting the myristoyl pocket (e.g. asciminib; Leske, 2024; Leyte-Vidal, 2024). In contrast, these translocations should be sensitive to active site TKIs. ELVN-001 is a highly selective active site TKI of BCR::ABL1 with broad pre-clinical activity against native and mutant BCR::ABL1. In patients with typical transcripts, ELVN-001 demonstrated favorable safety and tolerability across a wide range of doses, and encouraging preliminary efficacy was observed. Here, we first report tolerability and anti-CML activity of ELVN-001 in patients with atypical transcripts enrolled in ENABLE (NCT05304377), a phase 1 study of ELVN-001 in patients with previously treated CML. Updated data will be presented at the meeting. Patients with previously treated chronic phase CML who had an atypical transcript received ELVN-001 orally at doses from 20 mg to 160 mg daily in the dose escalation phase of the ENABLE study. Testing for molecular response is non-standardized for atypical transcripts and was therefore assessed locally by individual molecular response (Schäfer, 2021). As of 28 April 2025, 6 patients were enrolled with atypical transcripts. Four patients had a baseline transcript available and thus could be assessed for efficacy. One patient with e13a3 was enrolled. The patient discontinued prior imatinib and nilotinib due to lack of efficacy, had a concurrent diagnosis of MDS (treated with dasatinib plus azacitidine), a prior allogeneic myeloablative stem cell transplant, and was last treated with asciminib (discontinued due to lack of efficacy). The patient received ELVN-001 at 80 mg QD (224 days on study), achieved a > 1 log decrease in transcript and has not experienced any TEAEs. One patient with e13a3 transcript and T315I/S348L mutations was enrolled. The patient discontinued prior nilotinib and ponatinib due to lack of efficacy, had an allogeneic myeloablative stem cell transplant and was subsequently treated with ponatinib and asciminib (alternating; discontinued due to intolerance and/or lack of efficacy). The patient received ELVN-001 at 120 mg QD (449 days on study), had a decrease in transcript from 0.95% to 0.15% and has not experienced any TEAE >G2. One patient with e19a2 transcript and a T315I mutation was enrolled. The patient discontinued prior nilotinib, dasatinib, ponatinib, asciminib and a combination of asciminib and ponatinib due to lack of efficacy. The patient received ELVN-001 at 80 mg QD with dose escalation to 120 mg QD (505 days on study), achieved a >1 log decrease in transcript and has not experienced any TEAE >G2. One patient with e1a3 transcript was enrolled. The patient discontinued prior bosutinib due to intolerance (transcript remained >10%) and prior dasatinib, ponatinib and asciminib due to lack of efficacy. The last therapy prior to ELVN-001 was allogeneic stem cell transplantation followed by 2 donor lymphocyte infusions. The patient received ELVN-001 at 80 mg BID (80 days on study), had a decrease in transcript from 43% to 18% and has not experienced any TEAE >G2. Two patients with e1a2 transcript were enrolled. Both patients had no baseline transcript available and are therefore not efficacy evaluable. However, on study, transcripts remained stable. One patient discontinued prior bosutinib and dasatinib due to lack of efficacy, received ELVN-001 at 120 mg QD (176 days on study) and has not experienced any TEAE >G2. Another patient discontinued prior imatinib, radotinib and dasatinib due to lack of efficacy, received ELVN-001 at 20 mg QD with dose escalation up to 120 mg QD (537 days on study) and has not experienced any TEAE >G2. ELVN-001 demonstrated encouraging anti-CML activity in patients with atypical transcripts, including in patients with the e13a3 transcript, which is resistant to TKIs targeting the myristoyl pocket.

Chronic myeloid leukemia (CML) is a chronic condition with excellent long-term survival under tyrosine kinase inhibitor (TKI) therapy. However, patient priorities regarding treatment goals and quality of life remain insufficiently understood. We conducted a nationwide online survey among German CML patients in collaboration with the German CML Alliance and patient organizations to assess treatment goals at diagnosis, during therapy, and in the treatment-free remission phase. The questionnaire included validated measures of treatment satisfaction, fear of progression, and quality-of-life priorities, supplemented by newly developed items. Between November 2024 and February 2025, 582 patients (median age 56 years, 48.8% female) completed the survey. Overall TKI tolerability was rated positively (median 4/5), particularly in first-line therapy and among patients with shorter disease duration, whereas long-term survivors reported more daily-life limitations. Younger patients ( < 45 years) emphasized fertility, sexuality, and work-related concerns, while older patients prioritized tolerability, independence, and mental health. Treatment history shaped expectations: those with discontinuation experience were more willing to accept adverse effects for the prospect of remission. Overall, patient priorities diverged between achieving deep molecular response and maintaining optimal tolerability. Integrating patient-reported preferences into shared decision-making may enhance satisfaction, adherence, and long-term outcomes of patients with CML.

Background: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib. Methods: In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily. Results: More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile. Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice.

The ability of women of child-bearing age to have successful pregnancies despite their diagnosis of chronic myeloid leukaemia (CML) is now well-documented. All are advised to discontinue their tyrosine kinase inhibitor (TKI) before, or immediately on discovery of, conception. What is less well-known is their risk of losing their pre-existing disease responses during their pregnancy, which in turn limits our ability to advise best practice. We collected the disease responses before, during and after pregnancy from women with established CML, to better understand the kinetics of their disease whilst off TKI, and after re-starting treatment. Our study was restricted to pregnancies resulting in live births. 152 pregnancies were observed in 107 women (median age 33 yrs, range 18-43), after a median treatment duration of 6 yrs (0.3-19.4). 28 infants were premature (<37 wks gestation) and fetal abnormalities including 5 cardiac, were seen in 10 (6.4%). 2 patients with poorly controlled disease and poor compliance prior to unplanned conceptions progressed to blast phase: both are alive after allografting. We initially focussed on 107 first pregnancies to observe disease responses unaffected by previous periods of treatment discontinuation. The median duration of TKI therapy was 4.7 yrs (0.3-15), 67 (63%) of pregnancies were planned and 57 women (53%) were on 1st line therapy at, or prior to, conception. Molecular responses at time of stopping TKI were molecularly undetectable disease, MR4.5, MR4, MMR, CCyR or less than CCyR in 13%, 22%, 18%, 31%, 9% and 7% respectively (84% in at least MMR). Of 38 women in at least MR4.5 at stopping, 19 (50%) lost MMR with 13 losing CCyR. Of 57 women in at least MR4 at stopping, 32 (56%) lost MMR with 23/32 also losing CCyR. Duration of TKI therapy impacted the risk of losing MMR but only after 3 years duration of at least MR4: 73% of women in MR4 for <3 yrs lost MMR compared to 40% in MR4 for >3 yrs. Achievement of MMR only prior to conception did not protect against loss of MMR whilst off TKI: 26 of 33 women (78%) whose best response was MMR, lost MMR with 18 losing CCyR and 2 losing CHR. There was no clear impact of duration of MMR on the risk of loss of MMR with 24% and 13% of women treated for more or less than 2 years retaining MMR. 32 women received interferon during their pregnancy of whom 30 were In at least CCyR at the time of stopping TKI: 24, 3 and 3 lost CCyR, MMR or MR4 off TKI: 4 of the 24 regained CCyR after starting interferon. 2 patients remained in at least MMR on interferon and stayed on interferon after delivery without re-starting TKI. 3 women received TKI after the first trimester for loss of prior responses. The median duration off TKI for all 152 pregnancies was 10.2 mths (2.3-72.4). 25 women remained in at least MMR and did not re-start a TKI, 2 remained on interferon only, 2 are yet to re-start and 1 was treated for disease progression, Of 120 women who have been re-treated with a TKI for at least 6 months, 97%, 94% and 68% achieved or remained in CCyR, MMR and MR4 respectively. The median times to CCyR, MMR or MR4 were 3.1, 3.9 and 6 mths respectively.In conclusion patients in at least MR4 behave as candidates for TKI discontinuation with 44% remaining in at least MMR at the time of delivery. The high number of these patients who also lost CCyR is most likely attributable to the inability to re-start TKI at the time of MMR loss. In contrast stopping TKI for pregnancy when in MMR only is associated with a high risk of loss of MMR with no obvious protection for longer durations of response. Despite this the incidence of disease progression was <2% and probably explicable by unplanned pregnancies in poorly controlled disease. The role of interferon in maintaining or deepening prior responses remains unclear. We cannot exclude the possibility that the occurrence of congenital abnormalities at higher than background levels (3%) may be attributable in some to delay in discontinuing TKI. The vast majority of women have regained or improved on prior responses on re-starting TKI. We demonstrate the feasibility of managing pregnancy in CML, highlighting the importance of individualised planning and vigilant monitoring to balance disease control and pregnancy outcomes.

6501 Background: ASC, the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket, recently received FDA Accelerated Approval for newly diagnosed CML-CP based on major molecular response (MMR) rates in the ASC4FIRST trial (NCT04971226). We present results from ASC4START (NCT05456191), with the primary objective of assessing the tolerability of ASC vs second-generation tyrosine kinase inhibitor NIL in patients (pts) with newly diagnosed CML-CP. Methods: Adults were randomized 1:1 to receive ASC 80 mg once daily or NIL 300 mg twice daily, stratified by ELTS risk category. The primary endpoint is TTDAE. Events included AEs leading to treatment (tx) discontinuation and deaths due to AEs. Secondary endpoints include molecular response and safety. Results: Pts were recruited by 120 participating sites across 24 countries and randomized to ASC (n=284) or NIL (n=284). Two pts who did not receive NIL were excluded from safety analyses. Median follow-up was 9.7 mo. At cutoff (Sep 3, 2024), 10.9% and 17.3% of pts discontinued ASC and NIL, respectively, most commonly due AEs (4.9% vs 11.6%) and unsatisfactory therapeutic effect (2.5% vs 2.8%). The study met its primary endpoint, showing statistically significant difference in TTDAE in favor of ASC with a cause-specific hazard ratio of 0.45 (95% CI, 0.25-0.81; P =.004). Fewer pts discontinued due to AEs with ASC (16/284 [5.6%]) vs NIL (34/282 [12.1%]). There were 3 deaths on study due to AEs (ASC: cardiac arrest and suicide, n=1 each; NIL: cardiac arrest, n=1). Median duration of exposure was 39.1 wk with ASC vs 38.0 wk with NIL. Mean relative dose intensity was 94.8% vs 92.6%, respectively. Any-grade AEs occurred in 80.3% of pts with ASC vs 86.5% with NIL. Grade ≥3 AEs occurred in 25.0% and 31.9% of pts, respectively. AEs leading to dose adjustment/interruption occurred in 24.3% of pts with ASC vs 30.1% with NIL. Most frequent any-grade AEs (≥10%) with ASC vs NIL were thrombocytopenia (15.1% vs 13.8%), headache (10.2% vs 13.1%), myalgia (10.2% vs 8.2%), rash (8.5% vs 16.3%) and increased alanine aminotransferase (3.2% vs 12.4%). AEs of special interest included arterial occlusive events (0.7% vs 2.1%), acute pancreatitis (clinical events; 0.4% vs 2.5%), and hepatotoxicity (including laboratory terms; 8.1% vs 24.8%). BCR::ABL1 IS ≤10% (89.8% vs 82.0%), BCR::ABL1 IS ≤1% (69.0% vs 52.5%), MMR (22.9% vs 10.2%), MR 4 (4.6% vs 1.1%), and MR 4.5 (2.5% vs 0.4%) rates by wk 12 were higher with ASC vs NIL. Conclusions: The study met the primary endpoint with ASC showing significantly superior tolerability vs NIL based on TTDAE. The study is ongoing with additional analyses planned for tolerability and efficacy. The findings further support the potential for ASC to be a preferred therapy for newly diagnosed CML-CP, allowing more pts to meet tx goals without requiring tx switch. Clinical trial information: NCT05456191 .

Diagnosis and treatment of chronic myeloid neoplasms with two concurrently present driver mutations is challenging. We report on 10 JAK2 V617Fpos/BCR::ABL1pos patients in whom both mutations were identified simultaneously in 5/10 (50%) patients or in whom BCR::ABL1 appeared a median of 14 years after the primary diagnosis of JAK2 V617Fpos myeloproliferative neoplasia (MPN) in the remaining 5 patients. Granulocyte-macrophage colony-forming unit (CFU-GM) analysis demonstrated subsequent acquisition of BCR::ABL1 in a pre-existing JAK2 V617Fpos clone in 8/9 (89%) of evaluable patients. Despite the presence of JAK2 V617F in all patients, atypical BCR::ABL1 transcripts (e1a2/e19a2) in 3/9 (33%) patients and additional somatic mutations in 5/9 (56%) patients, molecular remission of BCR::ABL1 was achieved with different ABL1 TKIs (imatinib, n = 2, dasatinib, n = 2, nilotinib, n = 3) in 7/9 (78%) patients. During a total of 217 months of treatment, concomitant treatment with ABL1 TKIs and ruxolitinib did not affect dosing, efficacy or side effects. We conclude that (i) a second driver mutation might occur in chronic phase MPNs, (ii) clonality analyses largely support a common disease origin, and (iii) the dose, efficacy and safety of ABL1 inhibitors and ruxolitinib are not mutually affected by concurrent treatment.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The European Stop Kinase Inhibitors (EURO-SKI) study is the largest clinical trial for investigating the cessation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in stable deep molecular remission (DMR). Among 728 patients, 434 patients (61%; 95% CI, 57 to 64) remained in major molecular response (MMR) at 6 months and 309 patients of 678 (46%; 95% CI, 42 to 49) at 36 months. Duration of TKI treatment and DMR before TKI stop were confirmed as significant factors for the prediction of MMR loss at 6 months. In addition, the type of BCR::ABL1 transcript was identified as a prognostic factor. For late MMR losses after 6 months, TKI treatment duration, percentage of blasts in peripheral blood, and platelet count at diagnosis were significant factors in multivariate analysis. For the entire study period of 36 months, multiple logistic regression models confirmed duration of treatment, blasts, and transcript type as independent factors for MMR maintenance. In addition to the duration of treatment, transcript type as well as blasts in peripheral blood at diagnosis should be considered as important factors to predict treatment-free remission.

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.