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.

OBJECTIVE:Oral administration of an antigen can induce immunological tolerance. Insulin is an autoantigen in childhood type 1 diabetes (T1D). We tested the effect of treatment with high-dose oral insulin on disease progression and immune response to insulin in children with stage 1 T1D. RESEARCH DESIGN AND METHODS:We conducted a phase 2 randomized placebo-controlled double-blind trial in children with stage 1 T1D who received daily oral insulin (7.5 mg/day for 3 months and 67.5 mg/day for 9 months; n = 110) or placebo (n = 110) for 12 months. The coprimary outcomes were 1) time from baseline to dysglycemia or clinical diabetes and 2) increased immune response to insulin within 12 months of treatment (assessed in the first 90 participants). RESULTS:Of 220 participants (112 girls; median age 4.8 years; interquartile range 3.6, 6.2), 179 completed the trial. Dysglycemia or diabetes developed in 87 participants (46 receiving oral insulin and 41 receiving placebo; hazard ratio 1.07; 95% CI 0.66-1.73; P = 0.74). The 5-year progression rate was 40% (95% CI 30-51%) in each group. A modest treatment interaction was found with the INS rs689 genotype (P = 0.03). Increased immune response to insulin was observed in 11 (25%) of 44 participants in the oral insulin group and 13 (31%) of 42 in the placebo group (P = 0.63). Oral insulin was well tolerated. No significant study-related adverse events occurred. CONCLUSIONS:In children with stage 1 T1D, 1 year of high-dose oral insulin did not alter progression to dysglycemia or diabetes or immune response to insulin.

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.

Background Evidence has accumulated that somatic mutations in myeloid genes other than BCR::ABL1 at CML diagnosis are associated with treatment failure. Genomic profiling in chronic phase diagnosis samples of unselected cohorts revealed mutations in 17-24% of patients. At diagnosis, ASXL1 is the most frequently mutated gene at 7.3-9%. Genomic profiling using next-generation sequencing is now standard practice for many hematologic cancers where pathogenic variants define molecular classes that stratify risk and assign therapy. However, the genomic profile at diagnosis is not integrated into risk stratification for CML and data is lacking to guide management decisions. Combining many datasets derived from different centers through the iCMLf Genomics Alliance and the HARMONY Alliance Foundation Platform could facilitate the incorporation of genomics-based algorithms into the clinical management of CML based on strong clinical evidence. Objective To pool global genomic data to assess the clinical relevance of pathogenic variants at diagnosis of chronic phase CML. Methods The HARMONY Platform is a central repository of anonymous data from multiple contributors. CML patient whole exome or targeted gene panel sequencing data was submitted to the HARMONY Platform from 12 centers: Europe 6; Middle East 2; Australia 1; Taiwan 1; Singapore 1; and Canada 1. This first analysis was performed for the largest cohort on the platform of 468 frontline imatinib-treated patients at chronic phase diagnosis. The data comprised a mix of consecutively-treated patients at diagnosis or patients retrospectively selected for sequencing based on treatment failure. Kaplan–Meier survival curves were generated to estimate time-to-event outcomes, and the log-rank test was used to assess differences in survival distributions between groups. Five-year survival probabilities are reported to provide time-specific context. Progression was defined as blast phase, accelerated phase or death. Failure was defined as per the ELN 2020 criteria. Survival outcomes were considered from the start date of imatinib to the date of the first event under investigation or death, whichever came first. Probabilities of acquiring BCR::ABL1 kinase domain mutations were calculated using Gray's test with death as the competing risk. Level of significance was 0.05. Results At diagnosis, somatic variants in myeloid genes that met strict criteria for pathogenicity were detected in 96/468 imatinib-treated patients, 20.5%. ASXL1 was the most frequently mutated gene: 53/468 patients, 11.3%. Of 20 mutated genes, only 3 others were mutated at a frequency of >1.5%: TET2, DNMT3A and RUNX1, 2.6%, 2.4% and 1.7%, respectively. The median follow-up time was 4.2 years, range 0.04-20.8. Comparing outcomes for patients with and without pathogenic variants at diagnosis, there was no difference in overall survival. Five-year progression-free survival (PFS) for patients with pathogenic variants at diagnosis compared to patients with no pathogenic variants was 76.3% vs 83.1% (overall PFS comparison P=0.041). Five-year failure-free survival (FFS) for patients with pathogenic variants compared to patients with no pathogenic variants was 43.8% vs 65.2% (overall comparison P <0.0001). BCR::ABL1 kinase domain mutation analysis was performed after diagnosis for 432/468 patients. The 5-year probability of acquiring BCR::ABL1 mutations for patients with pathogenic variants at diagnosis compared to patients with no pathogenic variants was 20.0% vs 11.4% (overall comparison P=0.067, Gray test). Since the frequency of mutated ASXL1 at diagnosis was higher than other genes, the association with outcome was assessed. There was no difference in overall survival or PFS. Patients with mutated ASXL1 had the lowest 5-year FFS compared to patients with other pathogenic variants and those with no variants: 41.0% vs 49.3% vs 65.2% (overall comparison P value=0.0005). The overall FFS comparison P values for mutated ASXL1 vs no variants was 0.0012 and other pathogenic variants vs no variants 0.007. Conclusion This is the largest genomic analysis of frontline imatinib-treated patients that has been undertaken. Pathogenic variants at diagnosis were associated with lower PFS and FFS. This first report from the global alliance awaits validation but provides evidence-based insights that could enhance patient management by refining risk stratification through the integration of large-scale clinical and genomic data.

Viral infections in the first year of life are associated with islet autoimmunity and type 1 diabetes risk. The Anti-Viral Action against Type 1 Diabetes Autoimmunity (AVAnT1A)- study is a clinical phase IV investigator initiated, randomised, controlled, multicentre, primary prevention trial conducted to determine whether vaccination against COVID-19 from 6 months of age reduces the cumulative incidence of islet autoantibodies or type 1 diabetes in children with elevated genetic risk. Additionally, it investigates the role of viral infections in the etiology of islet autoimmunity by intense surveillance within the first two years of life. Infants aged 3.00-4.00 months from Germany, Belgium, UK and Sweden are eligible if they have a >10 % expected risk to develop islet autoantibodies by age 6 years as determined by HLA DR/DQ genotype, polygenic risk score and family history of type 1 diabetes. A total of 2252 eligible children are randomized 1:1 to COVID-19 vaccine (Comirnaty (R) 3 mu g Omicron XBB.1.5 or future new variants) or placebo (0.9% Sodium Chloride) administered three times. Children are followed until the minimum age of 2.5 years and maximum age of 6 years. The intervention is accompanied by analyses of immune and metabolic parameters to determine changes induced by viral infections and to investigate mechanisms by which viral infection may lead to islet autoimmunity. The Sponsor is the Klinikum rechts der Isar, Technical University Munich. The study was approved by Clinical Trials Information System (CTIS, EU Trial number: 2023-507348-35-00) and by Integrated Research Application System (IRAS, IRAS-ID: 1009668).

BACKGROUND:Type 1 diabetes begins with autoimmunity against pancreatic islet antigens, including insulin. The aim of the Primary Oral Insulin Trial (POInT) was to evaluate the efficacy and safety of daily high-dose oral insulin to prevent the development of islet autoantibodies and diabetes. METHODS:In this randomised, controlled, primary prevention trial, genetic screening in seven obstetric and paediatric clinics in Germany, Poland, Sweden, Belgium, and the UK identified newborns with a greater than 10% risk of developing islet autoimmunity. Eligible infants aged 4-7 months were randomly assigned in a 1:1 ratio to receive insulin manufactured from human zinc-insulin crystals administered orally at a once-daily dose of 7·5 mg for 2 months, increasing to 22·5 mg for 2 months and 67·5 mg until age 3 years, or placebo. Participants were randomly assigned via a web-based application and were stratified by site. The primary outcome was the development of two or more islet autoantibodies or diabetes assessed throughout follow-up until a maximum age of 6·5 years. A secondary outcome was the development of dysglycaemia or diabetes. Islet autoantibodies were measured in samples collected at baseline and during study visits conducted at outpatient clinics at 2, 4, and 8 months after randomisation, at age 18 months, and every 6 months thereafter. All participants and their family members, investigators of the study, and laboratory personnel remained masked to treatment allocation during the whole study. All randomly assigned participants who correctly fulfilled eligibility criteria and had not reached the primary outcome at the baseline visit (modified intention-to-treat) were included in the primary analysis. All participants who received at least one dose of study drug were included in the safety analysis. POInT is registered with ClinicalTrials.gov (NCT03364868) and is complete. FINDINGS:Of 241 977 screened newborns, 2750 (1·14%) had an elevated genetic risk of developing islet autoimmunity and 1050 (38·2%) of the eligible infants (531 males [51%], 519 females [49%]), were assigned to oral insulin or placebo between Feb 7, 2018, and March 24, 2021. Two participants in the oral insulin group and none in the placebo group were excluded from the modified intention-to-treat analysis. The primary outcome developed in 52 (10%) participants in the insulin group and 46 (9%) in the placebo group (hazard ratio 1·12 [95% CI 0·76-1·67], p=0·57). An interaction between treatment and the INS rs1004446 genotype was observed, with an increase in the primary outcome in participants in the insulin group carrying non-susceptible INS genotypes compared with the placebo group (2·10 [1·08-4·09]) and protection against diabetes or dysglycaemia in participants in the insulin group carrying susceptible INS genotypes compared with the placebo group (0·38 [0·17-0·86]). Blood glucose values less than 50 mg/dL were observed in two (0·03%) of 7210 measurements in the insulin group and six (0·08%) of 7070 measurements in the placebo group. Of 10 252 reported adverse events, 5076 (49·5%) occurred in 507 (96·0%) of 528 participants in the oral insulin group and 5176 (50·5%) occurred in 500 (95·8%) of 522 participants in the placebo group. One death occurred in the oral insulin group and was unrelated to the study drug following independent review. INTERPRETATION:There was no evidence that high-dose, daily oral insulin prevents the development of islet autoantibodies. Further studies are needed to assess the benefit of primary oral insulin therapy for preventing diabetes in INS genotype-selected infants. FUNDING:Leona M and Harry B Helmsley Charitable Trust.

Prognostic scores are an important tool in medical statistics. In chronic myeloid leukaemia (CML), prognostic models have existed for many years, enabling the classification of patients into groups that can be clearly differentiated in terms of their prognosis. However, over time, the focus of these models has shifted from solely survival outcomes to a broader range of diverse endpoints. This review explores the development and applications of these scores, offering recommendations for their use, and looks ahead to potential future advancements in the field. As the landscape of CML treatment evolves with newer therapeutic options, it is crucial to adapt prognostic models to reflect not only survival rates but also other important clinical milestones such as molecular remission, progression-free survival, and CML-related survival. The continued refinement of these tools, alongside international validation efforts, will be essential in providing clinicians with more accurate and individualized patient prognostication, ultimately improving therapeutic decision-making and patient outcomes.

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.

Introduction: Currently, six tyrosine kinase inhibitors (TKIs) are approved for chronic phase chronic myeloid leukemia (CML). Unfortunately, treatment sequence has never been tested prospectively, and, therefore, it remains unclear which TKI should be chosen, especially after first-line treatment with more potent second generation (2G)-TKIs. The original goal of the “Bosutinib Dose Optimization Study” (BODO) study was to evaluate whether a bosutinib step-in dosing regimen decreases gastrointestinal (GI) toxicity while maintaining optimal efficacy in patients (pts) with CML after failure or intolerance to 2G-TKIs. Despite its premature study end, it thereby contains one of the largest cohorts of 2nd generation TKI treatment after failure/intolerance of a 2G-TKI in first line. Methods: This is a sub-analysis of the BODO trial (NCT03205267), a multicenter, open-label single arm phase II study testing tolerability and efficacy of 2nd and 3rd line bosutinib step-in dosing in chronic phase CML pts intolerant and/or refractory to previous imatinib and/or nilotinib, and/or dasatinib therapy. Bosutinib was commenced with 300 mg QD and was (in the absence of > grade 1 toxicities) dose-increased by increments of 100 mg daily dosing every 14 days up to a maximum dose of 500 mg QD. 127 pts were planned to be recruited. However, due to slow recruitment, the trial had to be stopped prematurely after inclusion of 57 pts. For this analysis, we focused on the 45 patients treated with either nilotinib (n=23) or dasatinib (n=22) as first-line therapy. Cumulative incidence curves of response to bosutinib were calculated and compared using Gray's test. Results: 45 pts (n=28 males; median age 51 years, range: 19 - 77) were included in the analysis. The ECOG status was 0 (n=36, 80%) or 1 (n=9, 20%). Prior to study inclusion, a median daily dose of 600 mg nilotinib (range: 300 - 800) and 100 mg of dasatinib (range: 57 - 200) had been administered. The median duration of previous nilotinib and dasatinib therapy was 20.0 months (range: 23 days - 8.0 years) and 16.6 months (range: 3.7 - 34.3 months, p = 0.184), respectively. 18 (40%) pts were intolerant, 17 resistant (38%), and 10 (22%) both intolerant and resistant to previous TKI treatment. 17 (38%) pts entered the study in molecular response (at least major molecular remission (MMR) at screening). The odds of being in MMR at screening were higher in patients with longer pretreatment duration (OR = 1.9; CI: 1.1, 3.7; p = 0.038 per additional year of pretreatment). The corresponding probabilities of MMR were 40% (CI: 26, 54%), 58% (CI: 42, 71%), 68% (CI: 51, 80%) at 3, 6, and 12 months, and 79% (CI: 62, 89%) at 18 and 24 months, respectively. Median time to MMR was 4.9 months. MMR probabilities by pretreatment did not differ between nilotinib and dasatinib (p=0.788). 3 out of 4 intolerant pts without MMR at baseline reached MMR or a better molecular response level with bosutinib. 24 pts refractory to previous therapy (16 resistant; 8 both resistant and intolerant) were lacking baseline MMR, of which 16 pts achieved MMR or better (1 pt with MR4.5, 2 with MR4 and 13 with MMR). In the 24 refractory pts without MMR at baseline, the cumulative MMR and MR4 rates by 1 year were 48% (CI: 26, 68%) and 10% (CI: 2, 27%), respectively. One patient reached MR4.5 after 15.2 months of bosutinib therapy. Response to bosutinib was not significantly different in patients pretreated with either dasatinib or nilotinib. 33 pts received bosutinib for at least 6 months and also had a 6-months molecular response evaluation. At 6 months, median dose levels of bosutinib were not significantly different between responders and non-responders. No disease progressions were reported during the study and follow up. All pts had ≥1 any grade treatment emergent adverse event (TEAE), occuring a median of 15 days after starting bosutinib (range: 1 - 225 days). Cumulative probability of grade 3/4 TEAEs, and serious adverse events by 1 year was 69% (53, 81%) and 26% (CI: 13, 40%), respectively. The most common TEAE was diarrhea with a cumulative probability of 63% (CI: 47, 76%) by 1 month. Conclusion: Despite of the limitations of a single-arm study with incomplete recruitment, bosutinib was able to induce optimal responses in two thirds of pts previously resistant to 2G-TKIs while GI toxicity rarely led to treatment discontinuation. We conclude that bosutinib is a safe option after intolerance/failure of a 2G-TKI in first-line.

Clones characterized by gene mutations independent of BCR::ABL1 have been identified in approximately 20-30% of newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase with mutations in epigenetic modifier genes (e.g., ASXL1, TET2, DNMT3A) being the most common. We previously reported an inferior molecular response rate to nilotinib therapy in CML patients harboring ASXL1 mutations at diagnosis (TIGER study, NCT01657604, Schönfeld et al. Leukemia 2022;36:2242-9). Here, we sought to evaluate the clinical impact of these mutations in newly diagnosed CML patients treated with asciminib in combination with ATP competing tyrosine kinase inhibitors. The “Frontline asciminib in combination study” (FASCINATION, NCT03906292) is an ongoing multicenter, prospective, open-label, interventional phase II trial to evaluate efficacy and tolerability of asciminib in combination with conventional ATP-competing BCR::ABL1 inhibitors (imatinib, nilotinib, dasatinib). The primary endpoint was the rate of MR4 (BCR::ABL1 transcripts ≤0.01% on the International Scale, IS) at month 12. Between 2019 and 2022, 144 patients were recruited from 21 sites in Germany and 125 patients started the combination therapy with asciminib. Median age at diagnosis was 45.5 years (range, 19.0-89.0) and 66% were male. A total of 119 CML patients were investigated by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. Mutation status was correlated with the primary endpoint of the study. At diagnosis, 24/119 CML patients (20%) carried mutations in addition to BCR::ABL1 affecting the genes ASXL1, ATRX, BCOR, BCORL1, CBLB, CEBPA, CUX1, DNMT3A, ETV6, IKZF1, KDM6A, RAD21, STAG2, TET2, and ZRSR2. Five patients showed mutations in more than one gene. ASXL1 mutations were observed in 9 patients (8%, median age 45 years, range 32-65 years; ELTS low risk, n=5; intermediate risk, n=2; high risk, n=2). At month 12, 8/9 (89%) and 7/9 (78%) patients harboring ASXL1 mutations at diagnosis showed MMR and MR4, respectively. In comparison, patients with other mutations or no mutation had MR4 rates of 33% and 34%, respectively. In conclusion, mutations in addition to BCR::ABL1 are common at diagnosis of CML. The combination of asciminib with ATP competing drugs might be able to overcome the negative impact of ASXL1 mutations with regard to molecular response. However, the optimal therapy for CML patients with ASXL1 mutations needs to be defined within future studies.

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.

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

Background: The TIGER-trial (NCT01657604) is a multicenter, randomized phase III study to evaluate efficacy and tolerability of nilotinib (NIL) vs NIL+pegylated interferon alpha2b (IFN) combination therapy with IFN maintenance as first-line treatment for patients (pts) with chronic myeloid leukemia (CML) in chronic phase. Methods: A total of 717 pts were recruited from 110 sites in Germany, Switzerland, and the Czech Republic. A pilot phase (n=25) validated the feasibility of the combination of NIL 300 mg BID and IFN (30-50µg/week according to tolerability and commenced after ≥6 weeks NIL monotherapy). In the main phase, 692 pts were randomly assigned to NIL (n=353) and NIL/IFN (n=339). Achievement of major molecular remission (MMR, BCR::ABL1 ≤0.1% on the International Scale, IS) after >24 months (mo) of therapy was the trigger to start the maintenance phase; treatment-free remission (TFR) started in pts with ≥12 mo persistence of MR 4 ( BCR::ABL1 ≤0.01% IS) after >36 mo total therapy. Quality of life (QoL) was evaluated using EORTC QLQ-C30 and CML24 questionnaires. Results: From 692 randomized pts, 411 were male (59%), median age was 51 years (range, 18-85). In the monotherapy arm, median treatment duration with NIL was 3.1 years (0.02-8.9), median daily dose 600 mg (183-764). In the combination arm, median treatment duration with NIL was 2.3 years (0.02-9.1), median daily dose 600 mg (106-792). Median duration of IFN therapy was 2.4 years (0-9.0). A median of 77 (0-485) IFN injections were administered, the median dose of IFN per injection was 30µg (0-50). Probabilities of MMR and MR 4.5 ( BCR::ABL1 ≤0.0032% IS, Fig 1) by 24 mo were 89% (95% CI: 85-92%) and 49% (44-55%) vs 93% (89-95%) and 64% (59-69%) with NIL vs NIL/IFN, respectively. In 356 pts (53%) qualifying for the discontinuation phase (NIL, n=197; NIL/IFN, n=159), probabilities of maintained MMR by 24 mo were 53% (45-60%) and 62% (54-70%) after NIL and NIL/IFN, respectively, in an intention-to-treat-analysis (p=0.13). 273 (40%) eligible pts actually discontinued therapy (per-protocol-analysis, NIL, n=163; NIL/IFN, n=110). Probabilities of TFR by 24 mo were 53% (45-61%) vs 59% (49-68%) for NIL and NIL/IFN, respectively (Fig 2). Fifteen pts (2.2%) with atypical BCR::ABL1 transcripts (e1a2, n=7; e19a2, n=4; e8a2, n=2; e13a3 and e14a3, n=1 each) were randomized to receive NIL (n=7) or NIL/IFN (n=8). After a median treatment period of 37 mo (36-39) 9 pts achieved and maintained a BCR::ABL1 reduction of at least 4 orders of magnitude and were eligible for TFR. 6 pts failed to achieve an individual transcript decline by at least 3 logs. TFR was commenced in 7 and maintained in 6 pts after 32 (range, 20-84) mo. Adverse events of special interest grades 3-5 were arterio-vascular disorders in 9 vs 8%, fatigue in 2 vs 4%, thrombocytopenia in 8 vs 8%, and alanine aminotransferase elevation in 4 vs 9% of pts in the NIL vs NIL/IFN arms, respectively. QoL analyses revealed the perception of a decreased cognitive function and higher rates of fatigue in pts in the NIL/IFN arm, particularly in pts older than 40 years. In total, 24 pts (NIL, n=13; NIL/IFN, n=11) progressed to advanced disease. By 8 years, progression-free survival was 94% (95% CI: 90-96%) and 92% (88-95%), overall survival 95% (92-97%) and 94% (91-97%) in the NIL and NIL/IFN arms, respectively. 28 pts (3.9%) received an allogeneic stem cell transplantation, 14 after disease progression. 35 pts died (NIL, n=18; NIL/IFN, n=17), 9 related to CML. Conclusions: Survival of CML pts has reached probabilities close to normal. The combination of NIL with IFN is associated with a higher rate of molecular responses but also impaired tolerability. IFN maintenance is feasible, and resulted in a trend towards higher rates of long-term TFR. The study was conducted on behalf of the German CML Study Group in cooperation with the East German Study Group on Hematology and Oncology (OSHO) and the Swiss Group for Clinical Cancer Research (SAKK).

Background: “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 – a first-in-class BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket (STAMP) - as first-line treatment in combination with conventional ATP-competing BCR::ABL1 inhibitors (nilotinib, dasatinib, or imatinib) for patients (pts) with chronic myeloid leukemia (CML) in chronic phase. Aims: The aim of the study was to pilot asciminib in combination with ATP competing tyrosine kinase inhibitors (TKI) as first-line therapies in CML pts to improve the rate of deep molecular response (MR4) after 1 year of therapy. A higher rate of patients in deep molecular response compared to standard therapies could increase the proportion of patients in treatment-free remission (TFR) over time. Here, we report results of the pre-planned interim analysis of the primary endpoint according to the protocol. Methods: Adult pts with newly diagnosed BCR::ABL1-positive CML were included in the study until 3 months after diagnosis. A <4 week pretreatment with hydroxyurea was permitted. Pts treated for <6 weeks with nilotinib 300 mg BID, dasatinib 100 mg QD, or imatinib 400 mg QD were eligible for recruitment and allocated to one of four respective cohorts (Table). Cohorts were filled consecutively and were designed to allow assessment of QD and BID asciminib-based combinations to optimize quality of life (QoL) and compliance. Asciminib therapy was commenced 12 weeks after start of nilotinib, dasatinib, or imatinib, and after complete recovery of normal hematopoiesis. Dose of asciminib was based on pharmacokinetic data (area under the curve) of the combination cohorts within the phase I trial (NCT02081378). Nilotinib 300 mg BID was combined with asciminib 20 mg BID (cohort 1), or asciminib 40 mg QD (cohort 2), dasatinib 100 mg QD was combined with asciminib 80 mg QD (cohort 3), and imatinib 400 mg QD was combined with 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. Results: Between 2019 and 2022, 144 pts were recruited from 21 sites in Germany. Two pts were screening failures and 17 pts did not tolerate the initial TKI and were excluded from the study before start of asciminib. Combination therapy was commenced in 125 pts (66% male). Median age at diagnosis was 45.5 years (range, 19.0-89.0), 57.3, 28.1, and 14.6% were low, intermediate, and high risk according to the ELTS score, respectively. Adverse events grade 3-4 were observed in 37.6% of the pts. A total of 21 pts (17%) discontinued the combination therapy within the first 12 months due to dermal toxicity (n=4), gastroenterological toxicity (n=4), treatment failure/progression (n=3), cytopenia (n=2), papillitis/ocular papilla edema (n=1), polyneuropathy (n=1), pain (n=1), incompliance (n=1), and withdrawal of consent (n=4). One patient who progressed to blast phase received an allogeneic stem cell transplantation. A total of 114 pts were eligible for evaluation of molecular response at month 12. According to intention to treat, rate of MR4 at month 12 was 37.7% (95%-CI: 30.1-45.8%). Summary/Conclusion: The combination of asciminib as frontline therapy with ATP competing BCR::ABL1 inhibitors is associated with a high rate of deep molecular response but also impaired tolerability. Longer follow up is planned to investigate asciminib maintenance treatment after deep molecular response and TFR.Keywords: Chronic myeloid leukemia, Tyrosine kinase inhibitor, Clinical trial, BCR::ABL

The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bosutinib Dose Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2(nd) or 3(rd) line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II-IV, primary study endpoint) to < 40% (overall rate of 60%; 95% CI: 45-74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926.

Dysregulated hyperinflammatory response is key in the pathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2–31). On day 7, median CIS declined to 6 (range, 1–13); 71% of patients (CI 64–77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3–5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.