The landscape of Allogeneic Haematopoietic Cell Transplantation (allo-HCT) for Chronic Myeloid Leukaemia (CML) remains dynamic with the advent of tyrosine kinase inhibitors (TKIs). There remains an absence of widely agreed evidence-based guidelines for post-transplant monitoring and relapse management. To evaluate current real-world practices for ‘high risk’ CML, the CML subcommittee of the Chronic Malignancies Working Party (CMWP) of the European Blood and Marrow Transplantation (EBMT) society developed an electronic survey, which was distributed to 39 EBMT-registered transplant centres in April 2024. Centres were chosen based on CML allo-HCT activity. Twenty-three centres (59%) responded, providing clinical perspectives into pre-transplant chemotherapy regimens, TKI use, ABL1 kinase domain mutation analysis, post-transplant monitoring, and their practice regarding sequencing/ integration of TKIs with donor lymphocyte infusions (DLI). Most centres conduct monthly BCR::ABL1 transcript monitoring during the first three months post-transplant, transitioning to quarterly assessments upon achieving a deep molecular response. TKI maintenance is widely adopted across centres, with treatment duration guided by molecular response, and TKIs are generally preferred over DLI for managing molecular relapse. However, DLI remains a valid option for TKI-refractory chronic-phase (CP)-CML relapse. Survey findings illustrate significant heterogeneity in practice, offering insights to inform research aimed at improving allo-HCT outcomes in CML.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22. This alteration gives rise to the BCR::ABL1 fusion oncogene, whose constitutive tyrosine kinase activity promotes uncontrolled proliferation and survival of leukemic cells. The discovery of this molecular driver laid the foundation for the development of tyrosine kinase inhibitors (TKIs), which transformed CML management from treatment with non-specific modalities to establishing a new paradigm for precision oncology with targeted therapies. Imatinib, the first TKI, demonstrated unprecedented hematologic, cytogenetic, and molecular responses, rapidly becoming the standard of care in CML. Subsequent generations of TKIs were developed to overcome resistance and intolerance to imatinib. These advances improved survival in CML, bringing life expectancy close to that of the general population for the patients who respond to treatment, and shifting treatment goals towards quality of life and the possibility of treatment-free remission (TFR). Landmark discontinuation studies showed that approximately half of eligible patients can maintain TFR. Despite these achievements, important challenges remain, including TKI resistance, safety considerations, and the relatively low proportion of patients who achieve and maintain TFR. Newer-generation TKIs, combination strategies, immunomodulatory approaches, and emerging treatment modalities such as degraders offer promising avenues to further improve outcomes, expand TFR eligibility, ensure optimal quality of life, address resistance mechanisms, and render therapy available and affordable to all patients with CML worldwide.

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.

Introduction: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) that potently inhibits native and mutant forms of BCR::ABL1, including T315I. The phase 2 OPTIC (NCT02467270) study evaluated a response-based ponatinib dosing strategy to optimize efficacy and improve safety of ponatinib in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) whose disease was resistant to ≥2 TKIs or who had the T315I mutation. The 45-mg once-daily (QD) starting dose with dose reduction to 15 mg QD upon achievement of BCR::ABL1IS ≤1% (MR2) was associated with optimal benefit:risk outcomes, resulting in FDA approval of this response-based dosing strategy for the treatment of pts with CP-CML with disease resistant to ≥2 TKIs or with T315I. We present results from the 5-year update of efficacy and safety outcomes from OPTIC. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg QD. Upon achievement of ≤1% BCR::ABL1IS, doses were reduced to 15 mg in the 45-mg and 30-mg cohorts. The primary endpoint was ≤1% BCR::ABL1IS at 12 months; secondary endpoints included molecular response rates and safety outcomes, including arterial occlusive events (AOEs) adjudicated prospectively by an independent review committee. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methods. Exploratory mutational analyses were conducted with baseline and end-of-treatment (EOT) blood samples. Results: A total of 283 pts were randomized (45 mg/30 mg/15 mg: n=94/95/94; median age, 48 years [range: 18‒81 years]; male, 50%; race: White 79%, Asian 15%, Black 2%; ethnicity: 74% not Hispanic or Latino; T315I mutation, 24%). Median dose intensity was 27.7, 23.5, and 14.7 mg/day in the 45-mg, 30-mg, and 15-mg cohorts, respectively. As of the data cutoff (May 2, 2024), when the last pt still on study reached at least 5 years of treatment, 73 pts (26%) remained on ponatinib treatment; the most common reasons for treatment discontinuation were adverse event (45 mg/30 mg/15 mg: n=20/19/17), lack of efficacy (n=16/22/28), and progressive disease (n=8/10/7). By 60 months, 60% (56/93), 41% (38/93), and 40% (36/91) of pts in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1IS. Pts with a T315I mutation at baseline also had a higher MR2 rate by 60 months at the 45-mg starting dose (64%; n=25), which was comparable to those with no mutations at baseline (60%; n=50). Median duration of ≤1% BCR::ABL1IS was not reached in any cohort. By 60 months, the rates of ≤0.01% BCR::ABL1IS were 24% (22/93), 18% (17/93), and 19% (17/91) in the 45-mg, 30-mg, and 15-mg starting dose cohorts, respectively, and rates of ≤0.0032% BCR::ABLIS were 13% (12/93), 14% (13/93), and 15% (14/91), respectively. The estimated PFS rates at 60 months were 63%, 57%, and 60% in the 45-mg, 30-mg, and 15-mg cohorts. Estimated OS rates at 60 months were similar across starting dosing cohorts. Among pts who had dose reduction to 15 mg after achieving ≤1% BCR::ABL1IS, 29% (13/45) in the 45-mg cohort and 23% (6/26) in the 30-mg cohort lost the response after dose reduction. Of the pts in the 45-mg and 30-mg cohorts who had dose re-escalation after loss of ≤1% BCR::ABL1IS response, 69% (9/13) and 80% (4/5), respectively, regained a ≤1% BCR::ABL1IS response. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), and hypertension (10%). Exposure-adjusted AOE rates per 100 pt-years (95% confidence interval) were similar across the 3 cohorts: 45 mg, 4.1 (1.8-6.4); 30 mg, 3.4 (1.0-5.8); 15 mg, 1.2 (0.0-2.5). For the first time, EOT mutation analyses will be shared. Among 74 pts with no baseline mutation and available EOT data, only 6 had BCR::ABL1 mutations detected; 5 received the 15-mg starting dose and 1 had the 45-mg starting dose (E255K). Conclusion: Long-term results from OPTIC highlight the clinical benefits of ponatinib in patients with CP-CML resistant to ≥2 TKIs or harboring a T315I mutation. These results are consistent with previous OPTIC analyses and demonstrate that the approved ponatinib starting dose of 45 mg QD with reduction to 15 mg QD upon attainment of ≤1% BCR::ABL1IS provides the optimal benefit:risk ratio. Mutation data from EOT samples support ponatinib suppression of emerging mutations at the approved 45-mg starting dose.

Rationale: Imatinib, 400 mg daily, reduces pulmonary vascular resistance and improves exercise capacity in patients with pulmonary arterial hypertension. Concerns about safety and tolerability limit its use. Objectives: We sought to identify a safe and tolerated dose of oral imatinib between 100 mg and 400 mg daily and evaluate its efficacy. Methods: Oral imatinib was added to the background therapy of 17 patients with pulmonary arterial hypertension, including 13 who were implanted with devices that provide daily measurements of cardiopulmonary hemodynamics and physical activity. The first patient was started on 100 mg daily. The next 12 patients, recruited serially, were started on 200 mg, 300 mg, or 400 mg daily, following a continuous reassessment dose-finding model. An extension cohort (Patients 14-17) received 100 mg or 200 mg daily. Measurements and Main Results: The continuous reassessment model recommended starting dose was 200 mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (-6.5 mm Hg; 95% confidence interval [CI] = -2.4 to -10.6; P < 0.01) and total pulmonary resistance (-2.8 Wood units; 95% CI = -1.5 to -4.2; P < 0.001), with no significant change in cardiac output. The reduction in total pulmonary resistance was dose and exposure dependent; the reduction from baseline with imatinib, at 200 mg daily, was -20.3% (95% CI = -14.3 to -26.3%). Total pulmonary resistance and night heart rate declined steadily over the first 28 days of treatment and remained below baseline up to 40 days after imatinib withdrawal. Conclusions: Oral imatinib, 200 mg daily, is well tolerated as an add-on treatment for pulmonary arterial hypertension. A delay in the return of cardiopulmonary hemodynamics to baseline was observed after imatinib was stopped.

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.

Background: Despite the excellent survival for chronic myeloid leukaemia (CML) patients treated with tyrosine kinase inhibitors (TKI), most CML patients report poorer quality of life due to TKI side-effects. In the DESTINY trial ([NCT01804985][1]), CML patients halved their TKI dose for 12 months prior to TKI cessation, with 24 months of follow-up off therapy. Enrolled patients (n=174) were in stable deep molecular remission (DMR; BCR::ABL1[IS] <0.01%) or major molecular response (MMR; BCR::ABL1[IS] <0.1%), assessed in peripheral blood (PB) following more than 3 years of TKI treatment. Molecular recurrence-free survival (MRFS) at 3-years was 72% (DMR) and 36% (MMR), indicating PB BCR::ABL1[IS] burden at TKI de-escalation/cessation is predictive for recurrence. As shown previously, BCR::ABL1 kinetics during dose de-escalation are predictive for molecular recurrence after TKI stop. However, it has not been determined if BCR::ABL1 RT-qPCR in bone marrow (BM) improves risk prediction compared to PB. Objectives: We compared the predictive value of BCR::ABL1[IS] measurements at the time of dose de-escalation between PB and BM with respect to molecular recurrence, including assessing if the inclusion of a BM measurement at time of dose de-escalation improved the predictive power of BCR::ABL1 kinetics during de-escalation. Methods: With written informed consent, PB and BM samples were collected and BCR::ABL1[IS] was measured using RT-qPCR. Of 107 patients evaluated, 42 had molecular recurrence and 65 maintained TFR. To describe BCR::ABL1 kinetics during dose de-escalation, we applied linear regression. Estimated individual intercept and slope parameters were used within a logistic regression model to check for their predictive value for molecular recurrence. Results: The median log10[BCR::ABL1[IS]] at the time of dose de-escalation was higher in patients who experienced recurrence in both BM and PB (BM: -2.69 for recurrence vs. -4 for TFR; PB: -2.78 for recurrence vs. -2.98 for TFR). Based on samples with detectable log10[BCR::ABL1[IS]], transcript levels were moderately correlated between PB and BM (Spearman r=0.6). Using logistic regression, log10[BCR::ABL1[IS]] values from either BM or PB taken at time of de-escalation were similarly predictive of TFR success at 36 months post de-escalation (BM: OR=1.8; PB: OR=2.6). Moreover, using intercept and slope as characteristics of the treatment kinetics during dose de-escalation jointly as independent, PB-based predictors (OR[intercept]=13.8, OR[slope]=1.5) led to a similar conclusion and allowed for classification of patients into three risk groups: low, high, unclear. We identified 54 patients (50%) with low risk, 20 patients (19%) with high risk, and 33 patients (31%) with unclear risk. Considering TFR success, patients in the low-risk group show 87% MRFS 24 months after TKI stop, whereas all high-risk patients had molecular recurrence within 16 months of trial entry. Conclusion: No difference in the predictive power of a single measurement taken prior to dose de-escalation using either PB or BM samples could be shown. However, predictive power was enhanced by determination of slope and intercept of sequential PB BCR::ABL1 samples obtained during TKI de-escalation. Overall, BM evaluation prior to treatment cessation was not more predictive than PB of TFR success, however using BCR::ABL1 kinetics in PB during TKI de-escalation enabled classification of patients for risk of molecular recurrence. ### Competing Interest Statement Competing Interests Statement M.C. has received research funding from Cyclacel and Incyte, is/has been an advisory board member for Novartis, Incyte, Ascentage, Jazz Pharmaceuticals, Pfizer and Servier, and has received honoraria from Astellas, Novartis, Incyte, Pfizer, Janssen and Jazz Pharmaceuticals. J.F.A has received research funding from Incyte and Pfizer, is/has been an advisory board member for Ascentage, Incyte, Novartis and Terns, and has received honoraria from Incyte and Novartis. The remaining authors have no disclosures. ### Clinical Trial NCT01804985 ### Funding Statement This study was funded by a Cancer Research UK Biomarker Award (CRCPJT/100006) and Blood Cancer UK Award (formerly Bloodwise; 11017). The DESTINY clinical trial was funded by Blood Cancer UK (13020). The study was supported by the Glasgow Adult Experimental Cancer Medicine Centre funded by Cancer Research UK. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted under the DESTINY clinical trial ethics approval from the NRES Committee North West and Liverpool East (13/NW/0265) and the Haematological Cell Research Bank Research (Tissue Bank Approval) from the West of Scotland REC 4 (20/WS/0066). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data generated or analysed using PB-derived samples during this study are available as published in [9]. Researchers wishing access to the BM qRT-PCR data should contact the corresponding author. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01804985&atom=%2Fmedrxiv%2Fearly%2F2025%2F09%2F03%2F2025.09.01.25334821.atom

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.

Asciminib (ASC) is a first-in-class allosteric BCR::ABL1 tyrosine kinase inhibitor (TKI), specifically targeting the myristoyl pocket. It has shown promising efficacy and a favorable safety profile in patients with chronic phase (CP) chronic myeloid leukemia (CML). As ASC use expands, including frontline therapy, clinicians will face complex questions about pregnancy planning and treatment. Preclinical studies revealed no adverse effects on male or female fertility at exposures equivalent to human dosing, and no increased risk of embryo-fetal harm from paternal exposure. In female rats and rabbits, a low incidence of embryotoxic and teratogenic effects (e.g., cardiac malformations, anasarca) occurred only at high doses, above therapeutic levels. Given the limited human data on pregnancy during ASC treatment, we aimed to provide an overview of pregnancy outcomes in CML patients with confirmed paternal or maternal ASC exposure. This analysis includes cases collected from two sources: data provided by the manufacturer upon our request (from clinical trials and post-marketing) and physician reports, encompassing both retrospective and prospective data. A total of 47 pregnancies were identified: 13 with paternal exposure and 34 with maternal exposure, in 32 women (1 with 2 pregnancies, 1 with twins). In the paternal exposure group, 8 men were receiving ASC as monotherapy at the time of conception, while 5 were treated with ASC in combination with nilotinib or imatinib. Among the 11 cases with known outcomes, 8 resulted in live births (including one twin pregnancy), while 2 ended in miscarriage and 1 in an ectopic pregnancy. The ASC dose in mg was reported in 6 cases: 40 QD (ectopic pregnancy), 40 BID (miscarriage); 80 QD in 3 (childbirth, one medically assisted with egg donor), ASC 40 QD+imatinib 400 mg in one (childbirth). All newborns were reported as healthy, with no congenital anomalies. The maternal exposure group included 33 cases treated with ASC monotherapy and one case of combination with imatinib. In one instance, the patient transitioned to interferon after discontinuing ASC at 6 weeks (W) of gestation. Among the 23 pregnancies with known outcomes, 10 ended in elective abortion, mostly due to the patient's preference to continue therapy or uncertainty about fetal safety, 3 resulted in miscarriage, and 11 in 12 live births (one twin pregnancy). Few embryo-fetal data were available. In one elective termination at 14–15W with ASC stopped at 4W, the fetus exhibited anasarca and monosomy 45, considered unrelated to ASC. Another case of miscarriage at 9W involved a non-developing gestational sac, with no direct association to the treatment. In 6 cases, the pregnancy outcome was unknown due to loss to follow-up or missing consent, while 4 pregnancies were still ongoing at the time of reporting. Among the ongoing cases, three women had discontinued ASC early in pregnancy while exposed to 40 to 80 QD. In total, 10/12 normal newborns were reported following maternal exposure. In most cases, ASC had been discontinued during the first trimester, often between 4 and 9W, with daily doses ranging from 20 to 120 mg, and one ASC 40 QD+imatinib 400 mg. One woman used ASC 200 QD until the third month of pregnancy without reported complications. Another case involved continued ASC use into the 2nd and 3rd trimesters; the child was born healthy (transient aspiration pneumonia resolved fully). Two cases of congenital anomalies were documented, one with ventricular septal defect, coarctation of the aorta, fetal growth restriction (40 BID discontinued at 5W) and another with a non-specified major anomaly (80 QD discontinued at 6W) both considered unrelated to ASC and possibly linked to other factors, including concurrent medications. This series represents the largest collection of pregnancy outcomes related to ASC to date. Despite limited data, these findings suggest that paternal ASC exposure appears uneventful, and early treatment discontinuation during pregnancy in women is feasible. Notably, one case of 2nd and 3rd trimester exposure was recorded. However, contraception is advised for women on ASC, especially if previously failing other treatments; no contraception is needed for men. The presentation will provide updated clinical details, including CML management during gestation and reproductive outcomes, offering insights to improve patient counseling, support informed reproductive choices, and guide personalized treatment.

Background Resistance or intolerance to the available tyrosine kinase inhibitors (TKIs) remains a treatment challenge for patients with chronic myeloid leukaemia. We aimed to report the safety, antileukaemic activity, and pharmacokinetics of oral vodobatinib, a novel selective BCR::ABL1 TKI, in patients with Philadelphia chromosome- positive (Ph-positive) chronic myeloid leukaemia who previously received at least three TKIs, including ponatinib and asciminib. Methods This open-label, multicentre, phase 1/2 trial was conducted at 28 clinical sites across ten countries (Belgium, France, Hungary, India, Italy, Romania, South Korea, Spain, UK, and the USA). Patients aged 18 years or older with Ph-positive chronic myeloid leukaemia or acute lymphoblastic leukaemia (eligible only for the phase 1 study), and an Eastern Cooperative Oncology Group performance status of 2 or lower were eligible. Phase 1 included patients who previously received at least three TKIs or had no other available treatment options. Phase 2 required patients to have treatment resistance or intolerance (or both) with loss of response to at least three TKIs and previous ponatinib use. A key exclusion criterion for both phases was presence of the Thr315Ile mutation. Patients self-administered oral vodobatinib (12-240 mg) once per day for each 28-day treatment cycle and for up to 60 months (ie, 65 cycles) unless patient discontinuation due to adverse events, progressive disease, lost to follow-up, or death. The primary endpoints were to determine the maximum tolerated dose (based on dose-limiting toxicities in phase 1) and antileukaemic activity of vodobatinib (ie, major cytogenetic response for chronic-phase and major haematological response for accelerated-phase or blast-phase in phase 2). Assessment of vodobatinib safety, activity, and pharmacokinetics were determined based on the pooled analysis of data from the phase 1 and 2 studies. This trial is registered with ClinicalTrials.gov, NCT02629692 (active). At data cutoff (July 15, 2023), phase 2 enrolment was closed early on June 22, 2023, due to recruitment-related challenges. Findings 78 patients were enrolled and received at least one vodobatinib dose (safety and efficacy analysis set). Between April 6, 2017, and June 20, 2023, phase 1 enrolled 58 patients and phase 2 enrolled 20 patients between March 3, 2020, and March 29, 2023. We included 66 (85%) patients with chronic-phase, eight (10%) with accelerated-phase, and four (5%) with blast-phase chronic myeloid leukaemia. 43 (55%) of 78 patients were male and 35 (45%) were female. The median age was 590 years (IQR 470-660). The median follow-up was 223 months (IQR 111-439). Two patients receiving vodobatinib 240 mg had dose-limiting toxicities (one had grade 3 dyspnoea and the other had grade 2 fluid overload), thus the 204 mg dose was considered to be the maximum tolerated dose. 73 (94%) patients had one or more treatment-emergent adverse events, with most events being haematological or gastrointestinal that were grade 2 or lower in severity. Grade 3 or higher treatment-emergent adverse events occurred in 47 (60%) patients and included thrombocytopenia (14 [18%]), neutropenia (10 [13%]), anaemia (nine [12%]), and increased lipase (eight [10%]). Seven (9%) patients died during the study; one death was considered related to treatment by the clinical investigator. At data cutoff, major cytogenetic response was observed in 44 (70%) of 63 patients with chronic-phase chronic myeloid leukaemia, of which 12 (75%) of 16 patients in the phase 2 study had major cytogenetic response. For patients with accelerated-phase chronic myeloid leukaemia, six (86%) of seven patients had a major haematological response (median duration 178 [IQR 102-243]) at data cutoff; major haematological response was observed in three (100%) evaluable patients in the phase 2 study. Major haematological response was reached by two (50%) of four patients with blast-phase chronic myeloid leukaemia and the median duration of response was 62 months (IQR 32-93); no blast-phase patients were enrolled in the phase 2 study. Interpretation Pooled analysis of the phase 1 and 2 studies showed clinically meaningful antileukaemic activity of vodobatinib and a tolerable safety profile in patients with advanced chronic myeloid leukaemia who previously received multiple TKIs, including ponatinib and asciminib, addressing an otherwise unmet clinical need. The phase 2 study was statistically underpowered and warrants further investigation in a phase 3, randomised controlled trial and in an earlier treatment setting of the disease. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Probability of treatment-free remission (TFR) in CML patients with additional chromosomal abnormalities (ACA) in the Philadelphia-positive clone or variant Philadelphia translocations (ACA/Var-Ph group, blue panel), in those with no cytogenetic abnormality other than the classical Philadelphia translocation (c-Ph group, green panel) and in the subgroups of CML patients with high-risk ACA (HR-ACA, yellow panel) and Var-Ph (red panel).

The administration of certain cancer therapies can be associated with the development of cardiovascular toxicity or complications. This spectrum of toxicities is broad and requires nuanced approaches for prevention, identification, and management. This expert panel summarizes the consensus of opinions of diverse health care professionals in several key areas: 1) cardioprotection involves strategies aimed at the primary prevention of cancer therapy-related cardiovascular toxicity; 2) surveillance entails monitoring for cancer therapy-related cardiovascular toxicity during cancer therapy; 3) permissive cardiotoxicity is the informed continuation of cancer therapy in the presence of cardiovascular toxicity, along with the implementation of mitigating cardiovascular treatments; and 4) special considerations include the invasive management of severe cardiovascular disease in patients receiving treatments for advanced cancer and the exploration of drug-drug interactions in cardio-oncology. In this expert panel, we also highlight gaps in evidence in an effort to continue to advance science in the cardiovascular care of our patients undergoing cancer therapy. (JACC CardioOncol. 2024;6:815-834) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.

Outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) for chronic myeloid leukemia (CML) with post-transplantation cyclophosphamide (PTCy) using an unrelated donor (UD) or a mismatched related donor (MMRD) remain unknown. We report a retrospective comparison of PTCy-based allo-HCT from a UD, non-PTCy allo-HCT from a UD, and PTCy allo-HCT from an MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 and 2019 from a UD with either PTCy or non-PTCy graft-versus-host disease (GVHD) prophylaxis or from an MMRD using PTCy. The primary endpoint was GVHD-free/relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43% in the non-PTCy cohort, 37% in the PTCy-UD cohort, and 39% PTCy-MMRD cohort (P = .15). Multivariable analyses revealed no significant differences among the 3 cohorts in terms of overall survival (OS), progression-free survival, RI, and nonrelapse mortality. Factors independently associated with worse OS in the overall cohort were Karnofsky Performance Status <90 (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.41 to 2.45; P < .001), older age (HR, 1.24, 95% CI, 1.11 to 1.38; P < .001), and disease stage (compared to chronic phase [CP] 1): blast phase (HR, 2.25; 95% CI, 1.60 to 3.16; P < .001), accelerated phase (HR, 1.63; 95% CI, 1.05 to 2.54; P = .03), and CP >2 (HR, 1.58; 95% CI, 1.15 to 2.17; P = .005). These results suggest that allo-HCT in patients with CML using either a UD or an MMRD with PTCy-based GVHD prophylaxis are feasible transplantation, platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance of closely monitoring CML patients and proposing transplantation when indicated when still in CP1.

Autologous hematopoietic cell transplants (auto-HCTs) remain the standard of care for transplant-eligible MM patients. The general practice has been to undergo upfront apheresis following induction to collect sufficient number of CD34+ cells to facilitate two auto-HCTs. However, 5-30% of MM patients do not initially mobilise a sufficient number of hematopoietic stem cells and are classified as poor mobilizers (PM). We compared the baseline characteristics and outcomes of 61 PMs and 816 non-PM patients who underwent a second auto-HCT and who were enrolled in the non-interventional CALM study (NCT01362972). Only patients who collected CD34+ prior to auto-HCT1 were included. Auto-HCT2 comprised both tandem and salvage transplants. PMs were re-mobilized with plerixafor (n = 24, 39.3%) or non-plerixafor-based regimens (n = 37, 60.7%). There were no significant differences in engraftment, progression-free survival (PFS) or overall survival (OS) after the second auto-HCT between PM and non-PM patients. There was a trend to shorter PFS in PM patients undergoing salvage auto-HCT (median 9.6 vs. 12.9 months; p = 0.08) but no significant difference in OS. The median OS was 41.1 months for PM and 41.2 months for non-PM patients (p = 0.86). These data suggest that salvage mobilization is effective and does not affect overall outcomes after a second auto-HCT.