The rarer p190 (e1a2) transcript in chronic myeloid leukemia (CML) is associated with atypical presentations; yet, its biological basis remains poorly understood. Using a cohort of 60 patients including 42 chronic phase patients age-matched 1:1 with 42 e13a2/e14a2 patients in the chronic phase, we investigated the clinical, genomic, and clonal features of e1a2 BCR::ABL1 CML. We identified 60 e1a2 BCR::ABL1 CML patients showing distinctive hematologic features including lower leukocyte and platelet counts and higher monocytosis (12.3% vs. 2.0%, P < 0.001). Additional somatic mutations were detected in 37/42 (88%) e1a2 BCR::ABL1 cases compared with 7/42 (17%) e13a2/e14a2 BCR::ABL1 cases. The mutational spectrum was dominated by ASXL1 and TET2, and closely resembled CMML-like profiles. Genomic breakpoint sequences of 34 e1a2 BCR::ABL1 cases showed that BCR and ABL1 coordinates were similar to those observed in 394 B-ALL. Longitudinal mutational tracking revealed two distinct clonal architectures. In 71% of patients, mutations disappeared with molecular response, consistent with BCR::ABL1 as the founding event. In contrast, 29% of patients had mutations with stable VAFs, while BCR::ABL1 transcript levels decreased after treatment, indicating that the fusion had been acquired within a pre-existing mutated clone. Single-cell genotyping experiments confirmed these clonal architectures. These patients frequently developed cytopenias under tyrosine kinase inhibitor therapy and half required red blood cell transfusions, reflecting persistence of the ancestral clone rather than BCR::ABL1-driven disease. These findings show that e1a2 BCR::ABL1 CML frequently arises within complex, premutated clonal backgrounds, providing a biological basis for its atypical presentation and heterogeneous treatment response.

Background :ABL1 kinase domain (KD) mutations are a well-established mechanism of resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukaemia (CML). Early detection of emerging clinically relevant mutations is crucial for timely treatment modification, yet there are currently no standardized recommendations on screening frequency. Traditional Sanger sequencing lacks the sensitivity to detect low-level mutations, potentially delaying clinical intervention. In contrast, next-generation sequencing (NGS) offers superior sensitivity (≥3% variant allele frequency, VAF), enabling earlier detection of resistance-associated mutations that may impact clinical outcomes and guide treatment optimization. Aims To assess the utility of sensitive NGS-based BCR::ABL1 KD mutation screening in a large, prospective cohort of CML patients receiving TKI therapy, and to characterize the mutational landscape, temporal evolution, and clinical impact of NGS-based KD mutations screening results across centres in the UK, Ireland, and France (CALLS trial, NCT03647215). Methods In this prospective, multicentre, non-interventional study, CML patients receiving first-line or subsequent TKI therapy were screened for BCR::ABL1 KD mutations using NGS and results were communicated to the treating hematologist. Patients were enrolled based on European LeukemiaNet (ELN) criteria, and sequential NGS was performed to monitor mutation evolution over time. Mutational burden, frequency, clinical relevance, and treatment outcomes were analysed descriptively. Results Of 415 patients consented, 402 were enrolled and 381 (94.8%) had confirmed chronic phase CML (CP CML) and are the subject of this analysis. At the time of trial enrollement, 160 (42%) patients were treated with imatinib, 101 (26.5%) with dasatinib, 62 (16.3%) with nilotinib, 33 (8.7%) with bosutiinib, 24 (6.3%) with ponatinib and one with asciminib. BCR::ABL1 KD mutations were detected in 37 patients in CP CML (9.7% of enrolled cohort). Among mutation-positive patients, 89.2% (33/37) harboured a single mutation, 5.4% (2/37) had two mutations, and 5.4% (2/37) had three or more mutations. Themost frequently identified mutation was T315I, detected in 12 of 37 patients while other recurrent mutations included F317L, E279K, Y253H, G250E, E255K, and H396R. Several mutations were identified at low VAFs otherwise undetectable by conventional Sanger sequencing, demonstrating the enhanced sensitivity of NGS. Sequential NGS data revealed new KD mutations in 11 patients despite a first negative screening by NGS on the first sample taken as part of the study. The median time between the negative and the first sample tested positive by NGS was 7 months (range: 5-31 months) with 90% acquiring mutations conferring resistance to their current TKI. Of 27 patients with detected mutations in sequential analysis, 12 (44%) ultimately switched TKIs due to lack of response (67%) and intolerance (25%). Among patients with sequential NGS, 70% demonstrated increased VAF over time, suggesting clonal evolution under therapeutic pressure. Notably, 36% of patients who switched TKI achieved improved clinical responses, validating the clinical relevance of mutation-guided therapy. Conclusion NGS-based screening detects clinically relevant BCR::ABL1 KD mutations at low VAFs, enabling earlier intervention than conventional methods. The high prevalence of T315I and frequent detection of resistance-conferring mutations support the routine use of NGS, in line with the 2025 ELN guidelines. Sequential monitoring using NGS allowed detection of KD mutations in patients previously tested negative. Given the absence of evidence-based guidelines on screening frequency in this group, these findings may support the integration of sensitive, routine NGS monitoring at regular interval to optimize clinical management and enable proactive treatment adjustments in order to reduce the risk of delayed intervention in CML patients treated with TKIs.

Accelerated-phase (AP) or blast-phase (BP) myeloproliferative neoplasms (MPNs) are associated with dismal prognosis, with non-curative therapies such as hypomethylating agents (HMAs) considered in patients not eligible for intensive therapy, while some studies advocate for combination therapy with either ruxolitinib (RUXO) or venetoclax (VEN). To assess the relationship between treatment modalities and outcome, herein, we report a multicentric cohort of 149 patients (median age, 75 years) with AP/BP MPN not eligible for intensive therapy and/or allogeneic hematopoietic cell transplantation who received azacitidine (AZA) alone (n = 60) or in combination (n = 89; VEN [n = 51], RUXO [n = 27], or both [n = 9], isocitrate dehydrogenase inhibitors [n = 2]) between January 2019 and October 2023. With a median follow-up of 15 months, the median overall survival of the full cohort was 8.04 months, with a 3-year overall survival (OS) of 13%. Among disease characteristics, OS was lower in patients with BP (6.24 vs. 18.00 months in patients with AP disease, P = 0.03), complex karyotype (6.00 vs. 13.08 months, P = 0.005), and TP53 mutations (8.04 vs. 11.04 months, P = 0.009). OS was nonsignificantly higher in patients receiving AZA combinations (10.08 vs. 6.96 months in patients receiving AZA monotherapy, P = 0.12). When analyzing AZA combinations separately, patients who were treated with AZA-RUXO had higher OS (18.00 vs. 9.00 vs. 10.08 months in patients receiving AZA-VEN and AZA-VEN-RUXO, P = 0.015). The improved survival with AZA-RUXO in the absence of complex karyotype and/or TP53 mutations warrants further prospective validation. New therapeutic options are urgently needed, especially in patients with complex karyotype and/or TP53 mutations.

Introduction Treatment-free remission (TFR) is currently the ultimate goal for patients with chronic myeloid leukemia (CML). However, nearly 50% of patients relapse after treatment cessation. While some clinical and biological factors have been shown to be associated with TFR, there is currently no validated score to predict TFR in the clinical setting, and the factors underlying molecular relapse are still poorly understood. The main objective of this study was to use transcriptomic data to predict TFR before imatinib (IMA) cessation in patients with CML. Methods Patients enrolled in the STIM2 multicenter trial (ClinicalTrials.gov, NCT01343173) and with available frozen peripheral blood cells (PBC) sample before IMA cessation were included in the main cohort (n=96 patients). In the STIM2 trial, IMA first-line cessation was proposed in CML patients with a sustained deep molecular response (defined as remission lasting more than 2 consecutive years and confirmed on five datapoints of BCR::ABL1 analyses by quantitative RT-PCR during these 2 years). Molecular relapse after TKI cessation was defined as loss of MMR at 1 point. Additional patients with available frozen PBC just before IMA or nilotinib (NIL) cessation from three French academic centers (Centre Hospitalier Lyon Sud, Centre Leon Bérard, Institut Bergonié) were included in the independent validation cohort (n=72 patients, including n=37 IMA and n=35 NIL first-line). High-throughput RNA sequencing was conducted on an Illumina® NovaSeq6000™ platform after polyA selection generating paired-end reads of 2x100bp per sample. The primary outcome was TFR success at 2 years as a binary endpoint. The main cohort was randomly split into a training (n=73) and a testing (n=23) set, with a stratification on TFR at 2 years. Differential gene expression analysis was performed using DESEQ2 on n=500 bootstrap samples with replacement of the training set. A transcriptomic signature was built upon genes showing a stable differential expression (i.e. with an FDR < 0.1 in at least half of the models). Results Ninety-six patients were included in the main cohort from the STIM2 multicenter trial. Median age was 55 [IQR: 45-65] years, with n=56 (58,3%) females. Fifty-two (54,2%) patients presented an e14a2 transcript, n=34 (35.4%) an e13a2 transcript (missing value for n=10). ELTS scores were low in 69 (71.9%), intermediate in 11 (11.5%), high in 8 (8,3%) and missing in 8 (8,3%) patients. The median duration of IMA was 77.3 [IQR: 53.9-107] months, and median MR4 duration was 39.5 [27.4-56.7] months before TKI cessation. Differential gene expression analysis using a custom machine learning approach identified 48 genes with a stable and significant differential expression across bootstrap samples of the training set. A gene expression signature based on these 48 genes demonstrated a good discrimination of TFR at 2 years, with AUROC [95%CI] of 0.84 [0.74-0.94] and 0.73 [0.60-0.97] in the training and testing sets, respectively. Evaluation on the external validation cohort confirmed the signature's discriminative power, with an AUROC of 0.71 [0.58-0.83] in the overall validation cohort, 0.77 [0.61-0.92] among IMA-treated patients and 0.68 [0.48-0.87] among NIL-treated patients. Considering TFR as a time-dependent variable, multivariate cox analysis confirmed a significantly higher probability of TFR associated with the signature, with an adjusted hazard ratio (aHR) of 0.32 [95%CI 0.14-0.74] for the high-median versus low-median expression group, independent of MR4 and TKI duration (p=0.008). Gene-set enrichment analysis of hallmark pathways revealed an enrichment of glycolysis, angiogenesis and TNF-a signaling via NFK-b in the high-median group (associated with TFR) and an enrichment in interferon-a, interferon-g, IL2/STAT5 and inflammatory response pathways in the low-median group (associated with molecular relapse). Summary/Conclusion These data provide evidence that TFR can be predicted in patients with CML in the chronic phase attempting TFR, at TKI cessation, using a transcriptomic approach. A prospective trial is currently ongoing to further validate the signature and establish cutoff that can be used at the individual level.

BACKGROUND:The FIP1L1-PDFGRA (F/P)-associated hypereosinophilic syndrome (HES) is a rare condition. The F/P fusion gene testing is one of the first-line investigations in patients with unexplained eosinophilia and yields poor diagnostic performance. OBJECTIVE:To build and validate the factor interacting with PAPOLA and CPSF1 (FIP) score: a set of weighted criteria warranting testing for the F/P fusion gene. METHODS:We merged data from 151 patients with F/P-associated HES and 320 patients with either F/P-negative HES (n = 279) or hypereosinophilia of undetermined significance (n = 41). Training and validation cohorts (comprising, respectively, 90% and 10% of all patients) were randomly dichotomized. Variables with a P value less than .20 in univariate analysis were included in the multivariable forward-backward logistic regression model to assess their independent contribution to testing positive for the F/P fusion gene. Beta coefficients from multivariable logistic regression were used to assign points for the construction of the score. RESULTS:Age younger than 66 years, male sex, splenomegaly, lymphomatoid papulosis, absence of gastrointestinal involvement, high serum vitamin B12, high serum tryptase, and normal serum immunoglobulin E levels were the 8 variables retained in the model. The best cutoff value was greater than 48. The model yielded a sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve, respectively, of 88.3%, 93.7%, 87.1%, 94.4%, and 0.962 in the training dataset and of 85.7%, 97.0%, 85.7%, and 97.0%, 0.986 in the validation dataset. CONCLUSIONS:The FIP score highlights the need for closely selecting patients with hypereosinophilia for whom F/P fusion gene testing should be performed, resulting in medical time reduction and substantial cost-savings.

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.

Introduction The permanent discontinuation of treatments with tyrosine kinase inhibitors (TKIs) (treatment-free remission, TFR) has become a major goal in chronic myeloid leukemia (CML) to prevent the occurrence of adverse events, improve quality of life, and reduce treatment costs. Various strategies are being evaluated to improve the TFR rate, including the use of second-generation TKIs (2G-TKIs) and the addition of interferon alpha. Interestingly, greater success has been observed by introducing a dose reduction phase (half-dose) prior to TKI cessation (UK DESTINY trial). Here, we present a comparative, phase III, prospective clinical trial designed to demonstrate that a dose de-escalation strategy prior to treatment discontinuation optimizes TFR rates. Beyond the expected benefits of dose de-escalation, we aim to study the recovery of anti-leukemic immune effectors before and after the de-escalation phase. Methods We are conducting a prospective, randomized, open-label, multicenter, French clinical trial in CML (NCT05753384) to compare TFR outcomes at 24 months (primary endpoint) between a group with sudden treatment discontinuation after a 12-month maintenance phase and a group undergoing a 12-month dose de-escalation phase (dosage reduced by 50%) prior to cessation. After these 12 months of therapy, patients in both arms are eligible in the two arms for treatment discontinuation upon confirmation of sustained deep molecular response (DMR). Inclusion criteria include CML patients in chronic phase (CML-CP), aged ≥ 18 years, with a typical BCR::ABL1 transcript, a molecular response ≥ 4 log (MR4) lasting ≥ 1 year, and treatment duration ≥4 years for imatinib, ≥3 years for 2G-TKIs, or ≥4 years for both, with no treatment changes in the 6 months prior to inclusion. Minimum TKI doses required for eligibility are: imatinib (≥ 300 mg/day), dasatinib (≥ 50 mg/day), nilotinib (≥ 300 mg/day), and bosutinib (≥ 200 mg/day). Main exclusion criteria include uncontrolled chronic disease, ECOG performance status ≥ 3, prior TKI resistance, previous TKI discontinuation attempts, and prior allogenic stem cell transplantation. A dynamic randomization process (minimization) is used to allocate patients while balancing known prognostic factors for TFR (treatment duration, DMR duration, type of TKI: imatinib versus 2G-TKIs) between the two groups. To detect a 25% difference between arms, with a two-sided alpha of 5% and a statistical power of 80%, 60 patients per arm achieving TKI cessation are required. Accounting for possible DMR loss during the treatment, 170 patients must be enrolled. Secondary endpoints include the proportion of patients maintaining DMR and major molecular response (MMR) during treatment, the impact of reduced plasma TKI levels on innate lymphocyte reactivity, and their predictive value for successful discontinuation. Longitudinal immunomonitoring is being conducted at treatment initiation, end of the TKI phase and throughout discontinuation, along with assessment of residual plasma TKI concentrations. Results As of August 5, 2025, a total of 163 patients had been enrolled (95.8% to completion of recruitment). If our hypothesis about the superiority of the de-escalation strategy over sudden discontinuation is confirmed, our findings may inform future recommendations. Our study will provide critical data on dose de-escalation strategy (optimal treatment and DMR durations) as well as early treatment discontinuation: 4 years or 3 years of standard-dose treatment required for imatinib and 2G-TKIs, respectively. We also aim to demonstrate that immunologic surveillance of residual leukemic cells is a critical factor predicting successful TFR. A key objective of the planned immunomonitoring is to identify an innate T cell-based immunological signature predictive of successful treatment discontinuation, which may guide personalized management and inform future immunotherapeutic strategies. Finally, this trial offers a unique opportunity to explore the hypothesis of an inverse correlation between the number and function of anti-leukemic effector cells and the plasma TKI levels. Conclusions We aim to demonstrate that de-escalation of TKI therapy improves the proportion of patients who can successfully discontinue treatment, thus maintaining a stable MR4 and achieving prolonged TFR. We also seek to provide evidence that this benefit is supported by the immune system effectors, particularly by innate T cells.

Introduction: The primary results of the ASC4OPT study (NCT04948333), assessing asciminib 40 mg twice daily (BID) and 80 mg once daily (QD) in pretreated patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), showed high efficacy and a favorable safety profile for both dosing regimens. Here we present longer-term results from ASC4OPT. Methods: This Phase 3b, international, non-comparative study in adults with CML-CP without the T315I mutation and previously treated with ≥2 tyrosine kinase inhibitors (TKIs) enrolled two different cohorts. The main cohort included pts not in major molecular response (MMR; treatment failure/warning categories as per European LeukemiaNet [ELN] 2020 or intolerant to their most recent TKI). Dose escalation to 200 mg QD was permitted for pts who did not achieve MMR at Week 48 or lost response between Weeks 48‒108. An exploratory cohort of pts intolerant to their most recent TKI and in MMR at baseline was also enrolled and analyzed separately. All pts were randomized 1:1 to each dosing regimen. The primary endpoint was MMR rate at Week 48 for pts in the main cohort; response rates were assessed separately for the exploratory cohort. Pt-reported outcomes were assessed with the MD Anderson Symptom Inventory (MDASI)-CML questionnaire. Results: 169 pts were recruited to the main cohort. At data cutoff (11 February 2025, after the last pt completed their Week 96 visit), treatment was ongoing for 55.0% of pts, 18.3% had reached the end of the study at Week 144 and 26.0% had discontinued treatment; reasons for discontinuation included adverse events (AEs, 7.7%) and unsatisfactory therapeutic effect (5.3%). Four pts in the main cohort had a T315I mutation at baseline, which was detected after treatment start; these pts were excluded from efficacy analyses. MMR rates increased at Week 96 vs Week 48 (43.6% vs 39.4% overall; 45.8% vs 43.4% on 40 mg BID and 41.5% vs 35.4% on 80 mg QD, respectively). Deep molecular response (DMR) rates were maintained at Week 96 vs Week 48 (overall, MR4: 17.0% vs 17.0%; MR4.5: 10.9% vs 10.3%, respectively). Overall, 94.0% and 37.5% of pts in the main cohort experienced any-grade and Grade ≥3 AEs, respectively (94.0% and 32.1% on 40 mg BID, and 94.0% and 42.9% on 80 mg QD, respectively). The most frequent AEs included thrombocytopenia (16.7%), arthralgias (16.1%), COVID-19 and fatigue (13.1% each). AEs leading to discontinuation were reported in 7.1% of pts (40 mg BID, 8.3%; 80 mg QD, 6.0%). Forty pts (23.7%) in the main cohort had their asciminib dose escalated to 200 mg QD (40 mg BID, n=16; 80 mg QD, n=24); at data cutoff, 60.0% remained on treatment and 27.5% had reached the end of the study at Week 144. Among the 5 pts who discontinued treatment, the most common reason for discontinuation was disease progression/loss of response (n=2). At Week 96, 17.5% of these pts were in MMR. Among pts in the exploratory cohort (n=30), treatment was ongoing for 53.3%, 33.3% had reached the end of the study at Week 144 and 13.3% had discontinued treatment by data cutoff. Reasons for treatment discontinuation included AEs (n=2), physician decision and pt decision (n=1 each). At Week 96, 86.7% of pts maintained MMR (vs 93.3% at Week 48); 2 pts had discontinued treatment due to AEs (both on 80 mg QD) before Week 24 and were counted as non-responders. One more pt achieved MR4 in Week 96 vs Week 48 (7/14 at both timepoints on 40 mg BID; 9/16 vs 8/16 on 80 mg QD, respectively). MDASI-CML Symptom and Interference Total scores decreased slightly and quickly at Weeks 4‒12, denoting some improvement in main cohort pts' symptoms and reduced interference with their daily life activities; scores then stabilized. Similar results were observed for pts in the exploratory cohort, although with slightly larger reductions in scores. Two deaths were reported overall, assessed as not treatment related: one on treatment (in the 80 mg QD arm, main cohort, due to stroke) and one that occurred >30 days after the last treatment (in the 40 mg BID arm, exploratory cohort, due to hypoxemic respiratory failure). Conclusions: The 96-week results from the ASC4OPT study further strengthen asciminib as a standard of care for pretreated pts with CML-CP, regardless of dosing regimen, including those who are intolerant to previous TKIs: a considerable proportion of these pts maintained or deepened their response regardless of asciminib regimen.

Recently, the presence of a variety of AGA to the BCR-ABL1 oncogene in CP-CML has been described to impair the prognosis of this disease and response to TKIs. We have taken the opportunity of the Trial of Imatinib After Ponatinib Induction (TIPI) to explore such consequences by NGS targeting the most frequently mutated lympho-myeloid genes in AL, in newly diagnosed CP-CML patients (pts) undergoing this sequential therapy. . TIPI is an open-label phase II national academic trial (Clinical Trial: NCT04070443) for newly diagnosed adult CP-CML pts ≤65 years, harbouring major BCR::ABL1 transcripts. The primary endpoint is the rate of pts reaching TFR criteria at M36. Pts were treated with ponatinib 30 mg QD for 6 months, followed by a de-escalation with imatinib 400 mg QD until TFR criteria (MR4.5 ≥2 years) are reached, before M60. Molecular assessments were centralised and BCR::ABL1/ABL1 transcripts expressed in % on the international scale. BCR::ABL1 TKD mutations were screened by NGS. AGA were assessed by NGS (30-genes panel). Only VAF>5% were retained as pathological. The MMEJ signature was inferred from the BCR::ABL1 breakpoint sequences determined by an asymmetric capture sequencing strategy, as described by H. Guerineau et al (AJH 2025; 100: 507–510). One hundred and sixty nine pts were enrolled between November 2019 and October 2022, median age was 48 (18-65) years, 113 pts were males (67%) and 15 (9%) pts harboured additional chromosomal abnormalities (ACA). Eighty-four (51.5%) pts had b2a2 and 99 (61%) b3a2 transcripts and could eventually harbour both. ELTS were low for 67 (40%), intermediate for 73 (44%) and high for 27 (16%) pts, data unavailable for 2. The median follow-up was 18 (2.8-46.1) months. The CI of MR4 and MR4.5 were respectively 33 (26-40)% and 10 (5-14)% at M12; 40 (33-48)% and 13 (8-18)% at M18. One possible toxic death and 2 progressions (1 MBC, 1 LBC) occurred, resulting into death after allo-SCT. Only 3ABL1 mutations (2%) were observed, [1 on ponatinib, E255K at M6 (MBC pt), and 2 M244V on imatinib]. Full clinical results have already been presented (Nicolini FE et al. ASH 2024). At the time of writing, 148 patients were sequenced on diagnosis samples and mutated clones are followed-up and presented, on ponatinib and further on imatinib. We compared pts with AGA (n=30, 20%) with pts with no AGA (n=118). Thirty patients (20%) were harbouring AGA consisting in ASXL1 (n=18, 60%), KDM6A (n=3, 10%), DNMT3A (n=2, 7%) IKZF1, RUNX1, SETD1B, BCORL1, BCOR, TET2 and WT1 (n=1 each, 3.3%) and 24/133 (18%, 15 MD) patients showed a MMEJ signature. There was no difference between the 2 groups in age and sex. ACA were present in 4/30 patients with AGA (13%) and in 5/117 (1 MD, 4%) patients without AGA. Sokal score was low in 45%, intermediate in 36% and high in 19% of pts with AGA versus low in 17%, intermediate in 33% and high in 50% of pts without AGA (p<0.001). ELTS score was low in 40.5%, intermediate in 47.5% and high in 12.5% of patients with AGA versus low in 30%, intermediate in 37% and high in 33% of pts without AGA (p=0.02). While the 18-month cumulative incidence (CI) of MMR and MR4 were not different between the 2 groups, the CI of MR4.5 was significantly higher in the AGA group 24% (8.2-40.2) vs without AGA 10.25% (4.73-15.78) with HR=2.62 (95% CI: 1.03-6.64), p=0.043 in univariate analysis. Moreover, the presence of MMEJ had a strong negative impact on the 18-month CI of MR4.5: 0% with MMEJ vs 16.5% (9.5-23.5) without MMEJ p<0.001. The MMEJ+ versus MMEJ- groups show no difference except the ELTS intermediate + high scores were higher in the MMEJ+ group (p=0.016). Neither the presence of AGA nor the presence of MMEJ had an impact on 18-month EFS (p=0.38 and p=0.166 respectively). Interestingly, one of the 2 BC that occurred harboured AGA at diagnosis (WT1, VAF=6%) but no MMEJ signature. Multivariate analysis adjusted on MR4.5 at M18 identified the presence of AGA as beneficial [HR=3.46 (1.29-9.26), p=0.014].The kinetics of AGA on sequential treatment by ponatinib followed by imatinib will be presented. Twenty percent of newly diagnosed CP-CML harbour AGA at diagnosis that significantly impact on molecular response at 18 months on sequential therapy by ponatinib followed by imatinib. Additionally, the role of MMEJ seems to have a strong negative impact on obtaining deep molecular response.

Introduction Treatment-free remission (TFR) has become a new and important goal of therapy for patients (pts) with chronic myeloid leukemia (CML). We aim in this analysis to evaluate predictive factors for successful TFR. Methods We retrospectively reviewed pts with CML in chronic phase (CP) or accelerated phase (AP, defined by clonal evolution only) who discontinued tyrosine kinase inhibitor (TKI) therapy at MD Anderson Cancer Center, Texas, USA (n=226) and Léon Berard Center, Lyon, France (n=183). We analyzed the duration of therapy and sustained (≥12 months) deep molecular remission (DMR; BCR::ABL1 transcripts ≤0.01% on the International Scale [IS]) before TKI discontinuation (DC) and their association with molecular relapse-free survival (MRFS). Molecular relapse was defined as the loss of major molecular response (MMR; BCR::ABL1 transcripts >0.1% [IS]) at any time following DC. MRFS was defined as the duration between DC and molecular relapse, death, or last follow-up. Univariate and multivariate analyses were performed to analyze factors associated with MRFS. Results A total of 409 pts were included, 399 in CP (98%); 222 were males (54%). Sokal score was low in 203 pts (50%), intermediate in 150 (37%), and high in 47 (11%); it was not available for 9 pts (2%). The median age was 51 years (range, 15-80) at diagnosis and 61 years (range, 25-92) at DC. First-line TKI was imatinib in 196 pts (48%), nilotinib in 100 (24%), dasatinib in 93 (23%), ponatinib in 16 (4%), and bosutinib in 4 (1%). 309 pts electively discontinued TKI (76%), 72 (18%) discontinued therapy due to adverse events, 7 (2%) for pregnancy, 7 (2%) for financial reasons, 6 (1%) due to the diagnosis of another malignancy, and 6 (1%) for other reasons. The median number of prior therapies received prior to DC was 1 (range, 1-5). Imatinib was the last TKI used at the time of DC in 142 pts (35%), followed by dasatinib in 132 (32%), nilotinib in 121 (30%), bosutinib in 11 (2%), and ponatinib in 3 (1%). At the time of DC, 305 pts (75%) were on the same type of TKI used as first-line therapy. The median duration of therapy before DC was 97 months (range, 27-261). The median duration of sustained MR4 before DC was 60.4 months (range, 12.2-239): <2 years in 22 pts (5%), 2-5 years in 179 (44%), and >5 years in 208 (51%). The median duration of sustained MR4.5 before DC was 43.8 months (range, 12.03-239). Among 359 pts who achieved MR4.5 before DC, 77 (21%) had MR4.5 duration <2 years, 153 (43%) between 2-5 years, and 129 (36%) >5 years. After a median follow-up of 63 months after DC, 147 pts (36%) lost MMR, 94 (64%) within 6 months, 31 (21%) between 6-12 months, and 22 (15%) after 12 months. This translated into a 5-year MRFS rate of 63% overall. All pts achieved sustained MR4 or deeper before DC; their 5-year MRFS rates were 37%, 55%, and 73% for MR4 duration of <2 years, 2-5 years, and >5 years, respectively (p<0.001). 359 of 409 pts achieved sustained MR4.5 before DC; their 5-year MRFS rates were 53%, 54%, and 84% for MR4.5 duration of <2 years, 2-5 years, and >5 years, respectively (p<0.001). We then compared the outcome of pts who received imatinib (n=110), dasatinib (n=83), or nilotinib (n=72), as the only TKI before DC. The 5-year MRFS rates were 65%, 58%, and 77%, respectively (p=0.086 overall and p=0.031 after excluding imatinib). The 5-year MRFS was similar with imatinib (65%) compared to second-generation TKIs, 65% and 67%, respectively (p=0.84). By multivariate analysis, a longer duration of TKI therapy before DC (HR, 0.99; p=0.031) and a duration of sustained MR4 or deeper of >5 years (HR, 0.41; p=0.007) were independently associated with TFR. The type of TKI therapy was not associated with TFR by univariate analysis. Out of the 147 pts who lost MMR, 142 resumed TKI therapy; of them, 138 (97%) regained MMR or deeper response after a median of 2.9 months (range, 0.4-123). Three pts did not regain MMR, and one was lost to follow-up. After a median follow-up of 15 years from the time of diagnosis, the 15-year OS rate was 92% with no deaths attributed to CML. Conclusion Treatment DC is a safe approach in pts with CML who achieve a prolonged DMR, with no increase in the risk of disease progression or CML-related deaths. A sustained duration of DMR of more than 5 years was associated with the highest rates of MRFS and TFR.

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 treatment of chronic myeloid leukemia relies on orally available tyrosine kinase inhibitors targeting the BCR::ABL1 oncoprotein. Bosutinib is a second generation adenosine triphosphate-competitive inhibitor approved for use in frontline adult chronic phase-chronic myeloid leukemia and all phases-chronic myeloid leukemia in the second line setting or beyond. Its efficacy was demonstrated in several pivotal clinical trials at 400mg once daily in the first line context and at 500mg once daily beyond first line. Bosutinib-related adverse events frequently occur early after treatment initiation and include gastro-intestinal symptoms and cytolytic hepatitis. These drug-related adverse events must be properly managed in order to preserve safety, efficacy and treatment acceptability. The French chronic myeloid leukemia study group gathered a panel of experts in hematology, pharmacology and hepatology in order to elaborate practical recommendations on the management of bosutinib treatment. These recommendations aim at optimizing the short and long-term tolerance and benefit/risk balance of bosutinib, mainly focusing at gastro-intestinal and liver toxicities.

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.

The management of chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare and challenging situation. We report the treatment and outcome of 87 cases diagnosed in chronic phase from 2001–2022 derived from the largest international observational registry, supported by the European LeukemiaNet (ELN), of 400 pregnancies in 299 CML women. Normal childbirth occurred in 76% without an increased rate of birth abnormalities or life-threatening events, including in patients untreated or treated with interferon-α and/or imatinib in 2nd–3rd trimester. The low birth weight rate of 12% was comparable to that seen in the normal population. Elective and spontaneous abortions occurred in 21% and 3%, respectively. The complete hematologic response rate before labor was 95% with imatinib and 47% with interferon only. No disease progression during pregnancy was observed, 28% of the patients switched their therapy at varying times after delivery. Treatment options balance the efficacy and safety for mother and infant: interferon-α can commence in the 1st trimester and continued throughout in cases of good disease control and tolerability. Because of limited placental crossing, selected tyrosine kinase inhibitors (imatinib and nilotinib) seem to be safe and effective options in 2nd and 3rd trimester while hydroxycarbamide offers few benefits.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Background & Objectives The primary objective of this observational study was to perform an exhaustive description concerning patients receiving extracorporeal photopheresis (ECP) as second line treatment after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes. Study design A total of 106 patients were included, 65 (61%) males and 41 (39%) females with a median age at transplantation of 52 years (range: 20-67). ECP was initiated after transplantation either for acute GVHD [N=25 (24%), 12 grade III and 13 grade IV] affecting skin alone (N=5), gut alone (N=12), gut and liver (N=8), or chronic GVHD [N=81 (76%), 15 (14%) limited and 66 (62%) extensive]. Results Among the 25 patients treated for acute GHVD, 67% were responders and among the 81 patients with chronic GVHD, 78% were responders. Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 35% [95%CI: 14-56]. Patients with chronic GVHD had a median OS of 72 months with a survival probability at 2 years of 68% [95%CI: 56-78]. There was a significant difference in terms of survival for patients responding to ECP compared to non-responders in both acute and chronic GVHD forms. Acute GVHD grade III-IV, negatively impacted on OS (HR=7.77, 95%CI: 1.7-34), p=0.007 and on disease relapse HR=5.88, 95%CI: 1.7-20, p=0.005. Conclusion We demonstrated that ECP is an effective treatment for GVHD in a good proportion of patients with high overall response rate.

ABSTRACT Background Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome–positive leukemias. Herein, we report the long‐term follow‐up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Methods Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6‐month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Results Fifty‐one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21–75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2–25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second‐line TKI ( n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6‐month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24‐month event‐free survival rate was 97%. After a median follow‐up of 128 months, the 10‐year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Conclusion Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio‐/vaso‐occlusive and other severe toxicities.