This papers studies centralizers of an element, a, in the nucleus of a non-associative algebra with a special type of valuation. We prove that the centralizer of a is a free module of finite rank over the algebra generated by a.

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.

Prior studies combining pegylated interferon-α to Imatinib and Nilotinib in newly diagnosed CML patients have indicated an additive effect with faster and deeper molecular responses (SPIRIT, TIGER, NordCML002, NiloPEG). In this trial we used a bosutinib (BOS) backbone combined with low-dose ropeginterferon alfa-2b (BESREMi, AOP Health), which in contrast to previously tested interferons has a longer half-life and a more favorable tolerability profile. The aim was to investigate efficacy and tolerability of the combination, with the goal of deepening molecular response to eventually allow a higher proportion of patients to achieve treatment free remission. Patients were in 1st chronic phase and TKI-naïve. Inclusion criteria were standard including good organ function without history of liver, autoimmune or psychiatric disease. Based on clinical experience to improve tolerability, BOS was introduced at 200 mg OD and the dose titrated to 400 mg OD if tolerated. At month 3 (M3), patients who tolerated ≥300 mg OD and had transaminase levels grade ≤1 were randomized 1:1 for addition of ropeginterferon 50 μg every second week or not. The primary endpoint was MR4 at M12 in the intention-to-treat (IIT) population (all randomized patients). Other endpoints were safety and other response levels (e.g. MR4.5). Data up to M12 are presented. We also examined the response and tolerability of BOS up to M3 as the ramp-up dosing is not standard although frequently used in the clinic. 163 patients were included from 2019 to 2023 in 18 hospitals in Denmark (6), Finland (1), Norway (4) and Sweden (7). Despite gradual up-titration of BOS, many patients experienced toxicity as described in the BOS prescribing information, including grade 2, 3 and 4 transaminase elevations (11%; 16%; 3%). Dose reduction or interruption were insufficient to manage transaminase elevations, which frequently recurred upon BOS re-exposure. Compared with data from the BOS registration study (BFORE), GI AEs were less frequent with our present schedule. Twenty-seven % of patients could not be randomized: 15% for transaminitis, 4% for GI AEs and 8% for other reasons including inability to tolerate BOS 300mg OD. Non-randomized patients had M3 responses on par with randomized patients, indicating no harm of the dosing strategy despite the lower or intermittent BOS dose. Their responses at M6, M9 and M12 were similar to the standard arm. At M3, 118 patients were randomized, 58 to BOS and 60 to the combination. AEs were distributed evenly between study arms, but hematological toxicity (grades 3-4, 6.7% vs 0%), neuropsychiatric disorders (grade 2, 13% vs 4%) and infections grade 3-4 (13% vs 0%) were more frequent in the combination arm. Of note, transaminase elevations were similarly distributed, but analysis of attributability to the study drugs is ongoing and will be updated Overall, efficacy in the present study compared favorably with previous experience with BOS. The combination arm demonstrated a clear trend for faster and deeper response at all time points: The combination arm compared with the standard arm showed MR4 or better in 22.0% vs 13.8% at M6, 32.8% vs 17.2% at M9, and 38.3% vs 31.0% at M12. Attainment of MR4.5 or better was at M6, M9 and M12, 11% vs 5,2%, 22,4% vs 6,9% and 31,7% vs 20,7%, respectively. Discontinuation of treatment occurred in 22% of patients in the combination arm and 8,3% in the standard arm, of whom 11,5% and 5% for treatment resistance. The primary endpoint in the IIT dataset was not statistically significantly different between treatment arms; note that all patients were included in the ITT analysis even if no interferon was administered or the TKI was switched. Most switched patients received 1st and 2nd generation TKIs, but some were transplanted or received ponatinib. A per protocol analysis and data on drug exposure will be presented at the meeting. The step-up dosing strategy for BOS reduced GI toxicity, but not transaminitis. Efficacy was excellent in comparison with the registration study (BFORE). The combination of ropeginterferon and BOS was safe and efficacious. Responses occurred earlier and were deeper with the combination.

Chronic myeloid leukemia (CML) is effectively treated with small molecule BCR::ABL1 tyrosine kinase inhibitors (TKIs) but like in all cancers, early identification of suboptimal- and non-responders is a challenge. Through mass cytometry analysis of peripheral blood leukocytes, we collected high-dimensional data from de novo chronic phase CML patients enrolled in two multicenter clinical trials ([clinicaltrials.gov][1] [NCT01725204][2] and [NCT01061177][3]). In leukocytes, dasatinib and nilotinib inhibited intracellular signaling within one or three hours after first per oral dose, and each TKI had a unique signaling signature reflecting its kinase specificity profile beyond BCR::ABL1. An immune and signaling profile was constructed for each patient, predicting the treatment response (BCR::ABL1IS, %) the first 12 months of treatment. These results show that single cell immune and signaling profiles within hours of first dose can predict 12 months treatment response, anticipating future optimalization of kinase inhibitor treatment within days rather than months. ### Competing Interest Statement S.E.G.: Research collaboration with Novartis, H.H.H.: Chairman Nordic CML study group. Study group or institutional support from Bristol-Myers Squibb and Merck (NordCML007); Bristol Myers Squibb (DAStop 2 study), Austrian Orphan health and Pfizer (BosuPeg study); Speakers fees: Incyte and Novartis. B.T.G.: ENEST1st research collaboration with Novartis, collection and shipment of samples; Alden Cancer Therapy AS: Current equity holder in private company; AOP Orphan Pharmaceuticals GmbH: Consultancy; Astellas Pharma: Consultancy; AstraZeneca: Consultancy; Bjorgvin Therapeutic Group AS: Current equity holder in private company; Delbert Pharma: Consultancy; Ha Biotech AS: Current equity holder in private company; Incyte: Consultancy; JAZZ Pharmaceuticals: Consultancy; Kinn Therapeutics AS: Current equity holder in private company; MSD: Consultancy; Novartis: Consultancy; Otsuka Pharma: Consultancy; Sanofi: Consultancy. [1]: https://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01725204&atom=%2Fbiorxiv%2Fearly%2F2025%2F11%2F11%2F2025.11.10.687542.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061177&atom=%2Fbiorxiv%2Fearly%2F2025%2F11%2F11%2F2025.11.10.687542.atom

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.

The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1 IS (%) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis. The patients with treatment failure after 12 months of therapy had a markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multiomic feature landscape enabled visualization of the primitive fraction as a mixture of molecularly distinct BCR::ABL1 + LSCs and BCR::ABL1 - hematopoietic stem cells (HSCs) in variable ratio across patients, and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers. We for the first time show that BCR::ABL1 + LSCs and BCR::ABL1 - HSCs can be distinctly separated as CD26 + CD35 - and CD26 - CD35 + , respectively. In addition, we found the ratio of LSC/HSC to be higher in patients with prospective treatment failure compared to optimal responders, at diagnosis as well as following 3 months of TKI therapy. Collectively, this data builds a framework for understanding therapy response and adapting treatment by devising strategies to extinguish or suppress TKI-insensitive LSCs.

We introduce non-associative skew Laurent polynomial rings and characterize when they are simple. Thereby, we generalize results by Jordan, Voskoglou, and Nystedt and Oinert.

We prove several new versions of Hilbert's basis theorem for non-associpower series rings, and non-associative skew Laurent series rings. For non-associative skew Laurent polynomial rings, we show that both a left and a right version of Hilbert's basis theorem hold. For non-associative Ore extensions, we show that a right version holds, but give a counterexample to a left version; a difference that does not appear in the associative setting.

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61%, 56% and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.

Limited data is available on the health-related quality of life (HRQoL) and symptoms of patients with chronic myeloid leukemia (CML) who are in treatment-free remission (TFR). We herein report HRQoL results from the EURO-SKI trial. Patients who had been on tyrosine kinase inhibitors (TKIs) therapy for at least 3 years and achieved MR4 for at least 1 year were enrolled from 11 European countries, and the EORTC QLQ-C30 and the FACIT-Fatigue questionnaires were used to assess HRQoL and fatigue respectively. Patients were categorized into the following age groups: 18-39, 40-59, 60-69 and ≥70 years. Of 728 patients evaluated at baseline, 686 (94%) completed HRQoL assessments. The median age at TKI discontinuation was 60 years. Our findings indicate that HRQoL and symptom trajectories may vary depending on specific age groups, with younger patients benefiting the most. Improvements in patients aged 60 years or older were marginal across several HRQoL and symptom domains. At the time of considering TKI discontinuation, physicians could inform younger patients that they may expect valuable HRQoL benefits. Considering the marginal improvements observed in patients aged 60 years or above, it may be important to further investigate the value of TFR compared to a lowest effective dose approach in this older group of patients.

In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1IS (MR4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR4.0 at month 12 (a BCR-ABL1IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553.

LSC analysis at 3 months time point by FISH

Topic: 8. Chronic myeloid leukemia - Clinical Background: The European stop kinase inhibitors (EURO-SKI) trial was set up to deepen the knowledge on successful cessation of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukaemia (CML) patients with stable deep molecular response (DMR: BCR::ABL1 transcripts ≤0.01% on the International Scale, IS). The trial targeted on adult chronic-phase patients on TKI treatment in confirmed DMR for at least one year and under TKI treatment for at least 3 years. One goal of the trial was the investigation of prognostic factors affecting major molecular response (MMR: BCR::ABL1 ≤0.1% IS) maintenance after stop of TKI treatment. Aims: Prognostic factors associated with MMR maintenance 3 years after imatinib stop should be identified and validation be attempted. Methods: The analysis of prognostic factors focussed on patients with first-line imatinib treatment and without interferon-alpha pre-treatment. Candidate prognostic factors were age at diagnosis and at TKI discontinuation, duration of TKI treatment and of DMR before TKI discontinuation, time to DMR while receiving TKI, sex, and, despite reduced number of cases due to missing values, transcript type, spleen size below costal margin, platelet count, and percentage of blasts in peripheral blood at diagnosis. Logistic regression analysis was used to identify the variables with significant (p < 0.05) influence on MMR maintenance at 3 years. Validation of results was attempted in data of the STIM2 trial. Results: Of 868 patients pre-registered for the EURO-SKI trial, 140 patients failed eligibility criteria and were excluded. Of the remaining 728 patients, 52 patients had no data on molecular response at both times, at 6 and 36 months. Further 45 patients did not have imatinib as first-line TKI and another 121 patients were pre-treated with IFN. After removal of these 218 patients, 510 were left for prognostic analysis. At 36 months, 41% of 510 (95% CI: 37-46%) were still in MMR. In univariate regression, longer duration of TKI treatment (p=0.0014), longer duration of DMR while receiving TKI (p=0.0110), and fewer blasts (p=0.0137) were significantly associated with MMR maintenance at 36 months, see table. With transcript type, e14a2 (+e13a2) was more favourable than e13a2 alone (p=0.0051). Three alternative multiple logistic regression models were identified: a) Duration of TKI treatment (p=0.0043) plus blasts (p=0.0116), b) duration of TKI treatment (p=0.0163) plus transcript type (p=0.0047), and c) duration of DMR while receiving TKI (p=0.0149) plus time to DMR while receiving TKI (p=0.0261) plus blasts (p=0.0112). Due to correlations and different sample sizes, the 3 models were not statistically comparable. Data on MMR status at 36 months was available in 184 of 199 patients in the STIM2 trial. MMR was maintained in 45% (95% CI: 38-52%). Univariate significance was confirmed in all factors: Duration of TKI treatment (p=0.0087), duration of DMR while receiving TKI (p=0.0134), blasts (p=0.0291), and transcript type (p=0.0211), see table. Multiple models a) (p=0.0057 and 0.0447) and b) (p=0.0019 and p=0.0053) were confirmed but not model c). Summary/Conclusion: Four prognostic factors and 2 prognostic models for MMR maintenance at 36 months after TKI discontinuation were identified in the EURO-SKI trial and validated in the STIM2 trial, despite much smaller sample size in the latter. It is remarkable that blasts at diagnosis still played a role in good molecular responders, just as in survival of all patients in chronic phase. Next, differences in early and late loss of MMR and the suggestion of a prognostic score will be explored.Keywords: Prognosis, Chronic myeloid leukemia, Tyrosine kinase inhibitor, treatment-free remission

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60–82%) compared to patients with GG (51%, 95% CI: 41–61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.

In this article, we study Ore extensions of non-unital associative rings. We provide a characterization of simple non-unital differential polynomial rings $R[x;\delta]$, under the hypothesis that $R$ is $s$-unital and $\ker(\delta)$ contains a nonzero idempotent. This result generalizes a result by \"Oinert, Richter and Silvestrov from the unital setting. We also present a family of examples of simple non-unital differential polynomial rings.

Background: Stopping long-term therapy with tyrosine kinase inhibitors (TKIs) is now an option for an increasing number of patients with chronic phase chronic myeloid leukemia (CP-CML). However, there is paucity of evidence-based data on health-related quality of life (HRQoL) and symptom profile of these patients, once stopping therapy. Aims: We herein report HRQoL results of the EURO-SKI international study (Saussele S, et al. Lancet Oncol. 19:747-757, 2018) by examining HRQoL trajectories over time by age groups. Methods: The EURO-SKI was a prospective, open label, non-randomized trial enrolling adult patients with CP-CML across 11 countries in Europe. Patients had to be in treatment with any TKI for at least 3 years, and had to be in MR4 (BCR::ABL1 < 0.01% IS) for at least 1 year. HRQoL was a prespecified secondary endpoint of the study and was assessed with the EORTC QLQ-C30. A disease specific validated fatigue measure was also included: the FACIT-F. Evaluations were performed at baseline (at the time of treatment stop) and at month 1, 3, 6 and 12. As we hypothesized that benefits of TKI discontinuation would vary by age, the following four age group categories were considered: 18-39 (n=62 pts), 40-59 (n=272 pts), 60-69 (n=209 pts) and ≥70 (n=143 pts) years. A linear mixed effects model and growth curve analysis was used to analyze EORTC QLQ-C30 scores at baseline, month 1, month 3, month 6 and month 12 after TKI discontinuation. The longitudinal analysis for each age group modeled the different scores using fixed effects for the following variables: sex, Sokal-risk categories, MR4 duration in years, relapse, and times of visit. A random error was considered in the models to account for the within subjects’ design variability. We also analyzed the proportion of patients experiencing improvement, stability or deterioration at 6 and 12 months by using previously established scale specific criteria for the EORTC QLQ-C30. Results: Of the 728 evaluable patients at baseline, 686 (94%) had a HRQoL assessment completed. Median age at the time of stopping TKIs was 60 (range 18-89) years and these patients had a median duration of therapy of 7.6 years. Investigation of the mixed model adjusted HRQoL trajectories over time, revealed a different pattern of changes within each age group category. Younger patients (ie., aged between 18-39 years and 40-59 years) typically reported the greatest benefits across several functional and symptom outcomes. For example, there was a statistically significant decrease of burden of fatigue (FACIT-F) over time in patients aged between 18-39 years (p=.016) and in those aged between 40-59 years (p=.002). No statistically significant improvements were observed in the other two older age groups. This finding was corroborated by results of the fatigue scale of the EORTC QLQ-C30 (Figure 1). Inspection of the proportion of patients with clinically relevant changes (deteriorated, improved, or stable) from baseline to 6 and 12 months, also indicated differences by age groups. For example, in the group of patients with no relapse, the percentage of patients who reported deterioration in physical functioning between baseline and 6 months was: 16%, 44%, 47% and 65%, in the groups aged 18-39, 40-59, 60-69 and ≥70 years, respectively. Summary/Conclusion: This large international study, suggests that HRQoL advantages of stopping long-term TKI therapy vary across different age groups, with younger patients benefiting the most. This information complements current knowledge in this area, and will help patients and physicians to make more informed decisions.Keywords: Chronic myeloid leukemia, Quality of life, Patient reported outcomes

The supplementary Figures 1 to 3 demonstrate the gating procedure post flow cytomety analysis.

Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival is still subnormal and the treatment is associated with adverse events. In a large cohort‐study, we assessed the morbidity in 1328 Swedish CML chronic phase patients diagnosed 2002–2017 and treated with TKIs, as compared to that in carefully matched control individuals. Several Swedish patient registers with near‐complete nationwide coverage were utilized for data acquisition. Median follow‐up was 6 (IQR, 3–10) years with a total follow‐up of 8510 person‐years for the full cohort. Among 670 analyzed disease categories, the patient cohort showed a significantly increased risk in 142 while, strikingly, no category was more common in controls. Increased incidence rate ratios/IRR (95% CI) for more severe events among patients included acute myocardial infarction (AMI) 2.0 (1.5–2.6), heart failure 2.6 (2.2–3.2), pneumonia 2.8 (2.3–3.5), and unspecified sepsis 3.5 (2.6–4.7). When comparing patients on 2nd generation TKIs vs. imatinib in a within‐cohort analysis, nilotinib generated elevated IRRs for AMI (2.9; 1.5–5.6) and chronic ischemic heart disease (2.2; 1.2–3.9), dasatinib for pleural effusion (11.6; 7.6–17.7) and infectious complications, for example, acute upper respiratory infections (3.0; 1.4–6.0). Our extensive real‐world data reveal significant risk increases of severe morbidity in TKI‐treated CML patients, as compared to matched controls, particularly for 2nd generation TKIs. Whether this increased morbidity may also translate into increased mortality, thus preventing CML patients to achieve a normalized overall survival, needs to be further explored.