RARA overexpression defines a molecularly distinct subset of acute myeloid leukemia (AML). Tamibarotene, an oral selective RARα agonist, synergize with azacitidine (AZA) but its addition to Venetoclax (VEN) with AZA has not been assessed. SY-1425-202 was a multicenter, open-label, randomized study evaluating tamibarotene combined to VEN/AZA (TAMI/VEN/AZA) versus VEN/AZA (VEN/AZA) alone in newly diagnosed RARA-positive, unfit AML. Part 1 assessed safety of TAMI/VEN/AZA, Part 2 randomized participants to TAMI/VEN/AZA vs VEN/AZA, and Part 3 explored salvage therapy with TAMI/VEN/AZA after VEN/AZA failure in Part 2. Tamibarotene 6 mg twice daily was administered. Randomization occurred after confirmation of RARA positivity by Cycle1 Day8. The primary endpoint was complete remission (CR) + CR with incomplete hematologic recovery (CRi) in Part 2 and Part 3, and safety in Part 1. In Part 1 (n=10), overall response rate (ORR) was 77.8% (5 CR, 2 CRi). In Part 2 (n=51), CR/CRi was 60.0% for TAMI/VEN/AZA and 69.2% for VEN/AZA. Median CR/CRi duration was 293 vs 253 days. ORR was 80.0% vs 73.1%, respectively. In Part 3, 2/5 patients responded (CR, MLFS). Grade ≥3 treatment-emergent adverse event occurred in 76% of patients. Deaths were attributed mainly to disease progression or known complications of therapy; none were attributed to TAMI. The study met pre-specified futility criteria and was discontinued early. The addition of TAMI to VEN/AZA was tolerable but did not improve efficacy over VEN/AZA. These results did not demonstrate clinical benefit of TAMI in the frontline unfit RARA-positive AML setting receiving VEN/AZA. (NCT04905407)

Objective: To describe the evolution of the nutritional status of patients hospitalized for CAR-T cell therapy and to identify the main risk factors for malnutrition. Materials and methods: This was a retrospective single-center study including 100 adult patients hospitalized at Bordeaux University Hospital between 2023 and 2024 for CAR-T cell therapy. Nutritional status was assessed at admission and at discharge according to the French HAS diagnostic criteria. Daily oral caloric intake was recorded from day-5 to day +20, and body weight changes were monitored up to six months after reinfusion. Results: The prevalence of malnutrition increased from 34% at admission to 70% at discharge. The mean weight loss during hospitalization was 3.9 +/- 4.1%, with an average caloric intake covering 65 +/- 20.9% of estimated needs. Patients who developed cytokine release syndrome (CRS) covered 60.9 +/- 18.5% of their needs, compared with 88.3 +/- 19.7% in those without CRS. Combined CRS and ICANS were associated with malnutrition in 89.3% of patients at discharge. Conclusion: Immunological toxicity-particularly CRS and ICANS-appears to be the main determinant of malnutrition in patients treated with CAR-T cells. These findings support the need for an early, proactive, and protocolized nutritional management approach.

Abstract FLT3 internal tandem duplications (FLT3-ITD) are major genetic events in acute myeloid leukemia (AML). Although the clinical impact of FLT3-ITD “macroclones” (allelic ratio [AR] ≥0.05) is well established, the significance of low-level FLT3-ITD subclones (“microclones”) remains uncertain. We conducted a post hoc analysis of 1733 patients with newly diagnosed AML enrolled in the Backbone Intergroup 1 trial (ClinicalTrials.gov identifier: NCT02416388). Using next-generation sequencing (NGS), we detected FLT3-ITD microclones (AR between 0.0004 and 0.05) in 17.4% of patients without FLT3-ITD macroclones. Microclones and macroclones (low and high AR) were independently associated with increased relapse risk (cause-specific hazard ratio, 1.50 [95% confidence interval (CI), 1.18-1.91]; 1.98 [1.50-2.62]; and 2.33 [1.69-3.22], respectively) after adjustment for age, white blood cell count, other gene mutations, midostaurin treatment, and allogeneic hematopoietic stem cell transplantation. At 2 years, the cumulative incidence of relapse reached 42.5% (95% CI, 37.0-47.9) in patients with macroclones, 45.1% (38.3-51.6) in patients with microclones, and 29.4% (26.6-32.3) in patients without FLT3-ITD. In NPM1-mutated AML, both microclones and macroclones were associated with higher levels of measurable residual disease (MRD) and increased relapse risk, without independent impact on overall survival after adjustment for MRD. An analysis of paired samples further revealed that 41.8% of relapses in patients with FLT3-ITD microclones at diagnosis were associated with a macroclone at relapse. These findings challenge current risk stratification models and support the integration of NGS-based FLT3-ITD detection into the diagnostic and prognostic workflow for AML. Prospective trials addressing the management of patients with FLT3-ITD microclones are warranted, as is their consideration in future European LeukemiaNet guidelines.

The addition of midostaurin (MIDO) to intensive chemotherapy (IC) improves survival in younger adults with FLT3-mutated acute myeloid leukemia (AML); however, real-world data in elderly patients (≥ 60 years) are limited. This large, retrospective, multicenter study from three European registries (PETHEMA, FILO, DATAML) evaluated MIDO+IC (n = 194) versus IC alone (n = 371) in 565 patients with FLT3-mutated AML aged ≥ 60 years (median age 67.5 years; 35.6% ≥ 70 years). MIDO+IC was associated with lower day-60 early death (8.2% vs. 21.4%, p < 0.0001) and higher composite complete remission (CRc) rates (78.9% vs. 63.1%, p < 0.0001). After a median follow-up of 46.0 months, median overall survival (OS) was 24.2 months for MIDO+IC versus 8.7 months for IC (p < 0.0001), with 5-year OS rates of 40.6% vs. 12.9%, respectively. Event-free survival (EFS; median 13.5 vs. 4.6 months; 5-year EFS: 36.0% vs. 10.1%) and relapse-free survival (RFS; median 20.2 vs. 8.0 months; 5-year RFS: 45.4% vs. 15.7%) were also significantly improved (both p < 0.0001). The 5-year cumulative incidence of relapse was lower with MIDO+IC (47.8% vs. 67.1%, p < 0.001). In multivariate analyses, midostaurin was an independent favorable prognostic factor for CRc (aOR 1.97 [95% CI: 1.29-2.98]), OS (aHR 0.46 [95% CI: 0.36-0.58]), EFS (aHR 0.49 [95% CI: 0.39-0.60]), and RFS (aHR 0.47 [CI: 0.36-0.62]) (all p ≤ 0.002). These benefits were confirmed by propensity score matching. This large real-world study demonstrates that combining midostaurin with IC significantly improves remission rates and survival outcomes in elderly patients with FLT3-mutated AML, supporting its consideration in this population.

But/objectif Décrire l’évolution du statut nutritionnel des patients hospitalisés pour une thérapie par cellules CAR-T et identifier les principaux facteurs de risque de dénutrition. Matériels et méthodes Étude rétrospective monocentrique incluant 100 adultes hospitalisés au CHU de Bordeaux entre 2023 et 2024 pour un traitement par CAR-T cells. Le statut nutritionnel a été évalué à l’admission et à la sortie selon les critères diagnostiques de la HAS. Les apports caloriques oraux ont été relevés quotidiennement de J−5 à J+20, et l’évolution pondérale a été suivie jusqu’à six mois après la réinjection. Résultats La prévalence de la dénutrition est passée de 34 % à l’admission à 70 % à la sortie. La perte de poids moyenne pendant l’hospitalisation était de 3,9±4,1 %, avec une couverture calorique moyenne de 65±20,9 % des besoins estimés. Les patients avec CRS couvraient 60,9±18,5 % de leurs besoins, contre 88,3±19,7 % en l’absence de CRS. La combinaison CRS+ICANS était associée à une dénutrition chez 89,3 % des patients à la sortie. Conclusion La toxicité immunologique, en particulier le CRS et l’ICANS, apparaît comme le principal déterminant de la dénutrition chez les patients traités par CAR-T cells. Ces résultats soutiennent la nécessité d’une prise en charge nutritionnelle proactive et protocolisée.

6523 Background: Mutations in isocitrate dehydrogenase 1 (m IDH1 ) occur in 7%-14% of patients with AML. Olutasidenib is a potent, oral small-molecule mIDH1 inhibitor that selectively inhibits IDH1 variants but preserves wild-type IDH1 function. The registrational phase 2 trial (NCT02719574) of olutasidenib in patients with relapsed/refractory (R/R) m IDH1 AML reported a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 35% and a median CR/CRh duration of 25.3 mo. This analysis examines patient, disease, and molecular characteristics of patients with a LT CR/CRh response to olutasidenib without transplant. Methods: Adults with R/R m IDH1 AML treated with olutasidenib 150 mg twice daily who had a CR/CRh and a duration of response (DOR) >12 mo were included. Overall survival (OS), DOR, event-free survival (EFS), and adverse events (AEs) were assessed. Univariate and multivariate logistic regression analyses were used to examine baseline factors that predicted DOR >12 vs ≤12 mo. Results: Of 147 evaluable patients, 51 (35%) achieved a CR/CRh; of these, 32 (63%) maintained a CR/CRh >12 mo. Excluding 6 patients who proceeded to transplant, 26 (51%) had a DOR >12 mo (Table). Among these patients at baseline, median age was 72 y; 69% were female; 73% had an R132C mutation; 12% had prior venetoclax; 88% were platelet transfusion independent (TI); 73% were red blood cell (RBC) TI. Patients had a median (range) of 2 (0, 5) comutations, most commonly DNMT3A (n=6) or NPM1 (n=5); 2 patients with NPM1 also had FLT3 mutations. Median (95% CI) time to response was 1.9 (1.0, 1.9) mo. Median OS and EFS were not reached. Estimated 48-mo OS was 74% (95% CI: 51%, 88%). Estimated 48-mo EFS was 69% (95% CI: 47%, 83%). 5 (19%) patients relapsed (including 1 after 24 mo); 10 (38%) patients were on treatment at data lock. Significant predictors of response >12 vs ≤12 mo by multivariate analysis were relapsed AML vs refractory AML (odds ratio [OR]: 0.19) and female sex (OR: 0.21). Age, number of comutations, m IDH1 variant, RTK pathway mutations, number of prior therapies, and baseline TI were not significant predictors. Common AEs were nausea (35%), increased ALT, asthenia, constipation, and cough (31% each). Common grade ≥3 AEs were increased ALT, gamma glutamyltransferase increased (19% each), and RBC count decreased (15%). 9 (35%) patients experienced grade ≥3 all-cause AEs after 12 mo (only 1 AE in >1 patient [Coronavirus infection]). Conclusions: Olutasidenib enabled LT CR/CRh in half of R/R m IDH1 AML patients with CR/CRh without transplant (longest response >54 mo). Multivariate analysis identified relapsed (vs refractory) AML and female sex but not baseline TI or molecular factors as a significant predictor of LT response with olutasidenib. Clinical trial information: NCT02719574 . Patients with LT response. DOR Group Patients, n (%) >12 mo 26 (100) >24 mo 19 (73) >36 mo 15 (58) >48 mo 5 (19)

Complete remission (CR) rates for patients with acute myeloid leukaemia (AML) treated with intensive chemotherapy (IC) have increasingly improved. Yet, relapse remains a concern with a dismal prognosis. In this report, results are presented of a retrospective analysis comparing salvage therapy based on intermediate (I) or high (H)-dose cytarabine (DAC) (n = 203) and venetoclax-azacitidine (VEN-AZA) (n = 114) for patients with AML in first relapse. Patients (median age 60 years, interquartile range [IQR] 48-67) had reached CR1 after a standard 7 + 3 (n = 305) or CPX351 schedule (n = 12). I/HDAC-based and VEN-AZA salvage, respectively, resulted in CR2 in 66.0% and 66.7% of the patients (p = 0.96). Allogeneic haematopoietic stem cell transplantation (allo-HSCT) was performed for 115 patients in CR2 and 18 in failure. Relapse-free survival was 13.2 (IQR 7.0-not reached [NR]) and 13.7 (IQR 7.8-NR) months while overall survival (OS) was 14.5 (IQR 6.2-NR) and 12.3 months (IQR 4.8-NR; p = 0.41) for patients who received I/HDAC-based salvage and VEN-AZA respectively. In multivariable analysis, relapsing patients ≥60 years with low/intermediate-risk cytogenetics and VEN-AZA had a better OS (p = 0.002), while I/HDAC was more efficient for those with poor risk cytogenetics and < 60-year-old (p = 0.002). VEN-AZA salvage therapy thus appears promising compared with conventional I/HDAC-based IC; this question warrants evaluation in randomized studies.

We report a large cohort of 95 adult patients with acute myeloid leukemia (AML) harboring NUP98 rearrangements (NUP98r). Patient characteristics included a young age (median 50 years [IQR 38-64]), 20% of therapy-related AML, a high WBC count (median 52×109/L), normal karyotype in 32%, FLT3-ITD in 48% and WT1 mutations in 34%. NUP98::NSD1 fusion was the most common (54%), and these patients were significantly younger (41 y vs. 61 y), had more de novo AML (94% vs. 64%), higher rates of normal karyotypes (56% vs. 4.5%), FLT3-ITD (76% vs. 18%) and WT1 mutations (50% vs. 16%) than other NUP98r AML. The median overall survival (OS) for the entire cohort was 15.2 months (95% CI, 11.9-20.8) and event-free survival was 5.8 months (2-7.5). Among patients treated intensively (n = 73), age (HR = 2.7), FLT3 inhibitor therapy (HR = 0.45) and hematopoietic stem cell transplant (HR = 0.5) influenced OS in univariate analysis. Compared with NUP98 wild-type (WT) AML, NUP98r patients had a prognosis more similar to that of NUP98 WT ELN adverse patients whether initially classified as intermediate (20.3 months [11.7-30.2]) or adverse (15.7 months [13.5-42.9]). However, treatment with FLT3 inhibitors improved prognosis, with median OS not reached and 5-year OS of 53.3%, approaching that of intermediate-risk patients.

Given the uncertainty regarding the optimal management of molecular relapse in patients with CBF or NPM1-mutated AML, we retrospectively analyzed the outcome of 121 adults from 12 centers with CBF (n=28) or NPM1-mutated (n=93) AML and first molecular relapse according to the salvage strategy used (upfront allogeneic HCT [n=19], intensive chemotherapy [IC; n=21], venetoclax and azacitidine [VEN-AZA]; n=70), and other strategies (n=11; including AZA, gemtuzumab ozogamicin, selective inhibitors). At three years, OS was not statistically different between the four groups (84% for upfront allo vs. 81% for IC vs. 79% for VEN-AZA vs. 64% for other, P=0.31). Allogeneic HCT was received by 98 patients (81%) with a cumulative incidence of allogeneic HCT at 12 weeks of 100% for upfront allo, 71% for IC, 73% for VEN-AZA, and 82% for other (P<0.001) with better outcomes in transplanted patients. In patients who received allogeneic HCT, type of salvage therapy was not statistically associated with post-HCT relapse, relapse-free survival, or OS. Our data suggests that upfront allogeneic is a valuable option, if feasible, while other salvage strategies are associated with favorable outcomes and relatively low non-relapse mortality after allogeneic HCT.

Measurable residual disease (MRD) is a major prognostic factor in Core Binding Factor (CBF) AML. KIT or FLT3 mutations also have prognostic relevance, but little is known about their prognostic value when accounting for MRD. We analyzed the prognostic value of genetic alterations adjusting for early MRD response in adult CBF-AML patients. We grouped data from the retrospective multicenter study RetroCBF (NCT05070208, training set) and the prospective CBF-2006 trial (NCT00428558, validation set). Centralized high-throughput sequencing was performed with 36 genes. 656 CBF-AML patients in first CR were included between 2007 and 2020 (RetroCBF n = 461; CBF-2006 n = 195). In a LASSO-penalized model including MRD and genetic alterations performed in the RetroCBF training cohort, KIT-TKD in RUNX1::RUNX1T1 and FLT3-ITD in CBFB::MYH11 were associated with a higher risk of relapse. Including these genetic alterations with MRD in the training cohort, 3-year cumulative incidence of relapse was 22% (95%CI:13-33%) in low-risk patients (MRD low AND no KIT-TKD [RUNX1::RUNX1T1] or FLT3-ITD [CBFB::MYH11]) versus 53% (95%CI 46%-60%) in high-risk patients (csHR=3.21 [95%CI:1.83-5.62], p < 0.0001). These results were confirmed in the CBF-2006 validation cohort. KIT-TKD mutations in RUNX1::RUNX1T1 and FLT3-ITD in CBFB::MYH11 worsen prognosis independently of MRD and must be included in risk stratification of CBF AMLs.

Background and objectives Intensive therapy with autologous hematopoietic stem cell transplantation (HSCT) for lymphomas and myelomas significantly increases the risk of malnutrition. Artificial nutrition is crucial to meet nutritional needs. Although learned societies recommend enteral nutrition (EN) via nasogastric tube when the digestive tract is functional, it often fails, requiring parenteral nutrition (PN) in these patients with deep aplasia. This prospective cohort study evaluated the role of prophylactic EN in meeting the needs of 200 patients receiving autologous HSCT, according to BEAM and Melphalan conditioning regimens. Material & Methods Our study is a prospective cohort study. EN was considered sufficient when, associated with food intake, it covered at least 70% of nutritional needs without requiring to PN. In case of EN failure, a primary failure was defined when EN was not started whereas a secondary failure was defined when EN was started but discontinued. Statistical analyses used descriptive statistics, chi-square tests, and Mann-Whitney U tests. Results Overall, 200 patients were included: 120 were treated with Melphalan for myeloma and 80 with BEAM for lymphoma. EN was sufficient without requiring PN in 25.89% of patients (95% CI: 19.92; 32.59), higher in Melphalan-conditioned patients: 32.20% (95% CI: 23.90; 41.43), compared to BEAM-conditioned patients 16.45% (95% CI: 9.06; 26.49).Primary failures accounted for 21.5% of cases, mainly due to difficulties in inserting the nasogastric tube (13%), vomiting of the tube (3%), or patient requests for removal (4.5%). Secondary failures accounted for 38% of cases, primarily due to patient requests for removal (15.5%), vomiting of the tube without reinsertion (12.5%), and upper digestive intolerance (4%).The median percentage of weight loss was 3.8% (IQR: 1.6- 6.3%) , with a significant higher loss in the BEAM group (5.2%, IQR: 2.0–7.0%) compared to the Melphalan group (3.3%, IQR: 1.5–5.1%). The prevalence of malnutrition increased from 20% at admission to 48% at discharge, with severe malnutrition rising from 5.1% to 30%.This study highlights the limits of prophylactic EN in autologous HSCT, particularly in BEAM-conditioned patients. Combined strategies (EN + PN) should be considered to optimize nutritional support in this high-risk population.

Literature shows heterogeneous impact of recommendations to deal with sars-cov-2 infection on AML management during the 2020 Covid-19 pandemic. Available French data only rely on monocentric observations or simulations. From the DATAML cohort, including all AML patients cared for in the centers of South-West France, we compared the characteristics of patients diagnosed in two periods: 2020 and 2015–2019. We use time series approach to describe the monthly proportion of patients with extreme values on hemoglobin, white blood cells, platelets, and blasts counts, as well as early deaths. We found a slight impact of the first lockdown on hemoglobin and platelets, with statistical significance reached only for platelets distribution gap between the two periods. Similar but less marked patterns were found for WBC and blood blasts. These did not translate in terms of early deaths, which was considered to be likely due to a favorable local conjuncture associating a moderate incidence of sars-cov-2 and the absence of bed closing in oncohematology or ICU dedicated to hematology in any centers providing intensive care for AML patients. Yet, our results might still be seen as an insight of what would have happened in less favorable contexts.

IntroductionMRD assessment in AML provides a quantitative approach to define a deeper remission status and refine the risk assessment of postremission relapse. Currently, the two most extensively validated methodologies are multiparameter flow cytometry-based MRD (MFC-MRD) and molecular MRD (Mol-MRD) assessed by quantitative PCR (qPCR). The latest update of the ELN recommendations on MRD includes new technical guidance for standardized MFC-MRD and Mol-MRD analyses, MRD thresholds, definitions of MRD response, and recommendations for clinical application. In this context, we evaluate the clinical utility of MRD assessment using MFC and qPCR in patients with NPM1-mutated AML.MethodsBetween January 1, 2015, and September 30, 2024, 506 adult patients (≥18 years) with NPM1-mutated AML were included in the DATAML registry. Immunophenotyping at diagnosis was available for 383 patients from Toulouse University Hospital and 123 patients from Bordeaux University Hospital. Among them, 306 patients received a standard intensive chemotherapy regimen. 270 patients achieved complete remission (CR/CRi), and 194 of these were monitored for post-induction bone marrow minimal residual disease (MRD1) using both MFC-MRD and qPCR techniques.MFC analysis of leukemic cells was performed on fresh bone marrow samples. For leukemic bulk analysis, the antibody panel included CD34, CD13, CD38, CD7, CD33, CD56, CD117, HLA-DR, and CD45, as recommended by ELN. MFC-MRD data were analyzed using the FlowSOM algorithm (Vial et al., Cancers, 2021). The threshold for MRD1 positivity was defined as ≥0.1% for MFC-MRD and ≥2% for low-level (LL) Mol-MRD.Results194 NPM1-mutated AML patients in first CR/CRi after induction chemotherapy were included. Main co-mutations were: DNMT3A (38%), FLT3-ITD (34%) IDH1 (18%), IDH2 (14%) and FLT3-TKD (14%). 31 patiens (16%) had NPM1/DNMT3A/FLT3-ITD mutations.The median follow-up (FU) was 40 months. In patients with positive MFC-MRD, 1-y and 3-y OS was 83% and 67%, vs 93% and 82% in patients with negative MFC-MRD (Hazard Ratio [HR]: 2.39, p=0.0056). The 3-y cumulative incidence of relapse estimation (CIR) was 55% for MFC-MRD positive patients vs 30% for MFC-MRD negative patients (HR: 3.17, p<0.0001).In patients with LL Mol-MRD, 1-y and 3-y OS rates were 83% and 59% vs 93% and 85% in patients with negative Mol-MRD (HR: 3.52, p=0.0001). The 3-y CIR estimation was 58% in LL Mol-MRD positive patients vs 30% in Mol-MRD negative patients (HR: 3.01, p<0.0001).The combination of Mol-MRD and MFC-MRD identified four distinct patient groups: double negative (-/-; n=74, 38%), MFC-MRD positive only (-/+; n=49, 25%), Mol-MRD positive only (+/-; n=41, 21%), and double positive (+/+; n=30, 15%). At 3 years, OS estimates were 90%, 77%, 72% and 48% respectively in these 4 subgroups (p<0.0001). CIR estimates were 18%, 45%, 49% and 71% respectively (p<0.0001). In multivariate analysis, both LL Mol-MRD positivity and MFC-MRD positivity were independently and significantly associated with inferior OS (HR: 3.59, p<0.001; HR: 2.16, p=0.014, respectively) and increased CIR (HR: 2.82, p<0.001; HR: 2.30, p=0.001, respectively) whereas DNMT3Am, FLT3-ITD or allo-HSCT did not retain statistical significance.ConclusionIn NPM1 mutated AML, where transcript levels typically decline rapidly after induction, FlowSOM assisted MFC-MRD yields prognostic information that is complementary to qPCR. Combining both assays at post-induction (MRD1) delineates four clinically distinct groups, ranging from a double-negative cohort with excellent outcomes (3-year OS=90%, CIR 18%) to a double-positive cohort at very high risk (3-year OS=48%, CIR 71%). MFC-MRD positivity at MRD1 remained independently associated with inferior OS and higher relapse, even after adjusting for molecular MRD. Although larger prospective studies are needed, these findings strongly suggest that MFC-MRD may not be redundant in NPM1-mutated AML. Notably, when integrated with qPCR, it could improve the accuracy of predicting early relapse. These results support the incorporation of dual-modality MRD monitoring into prospective testing.

Introduction Therapy-related CBF-AMLs represent approximately 10% of all CBF-AMLs and are associated with poorer outcomes, partly due to the associated solid tumor. Existing studies are small, and more data—especially NGS and cytogenetics—are needed to better define their characteristics and prognosis. Methods We analyzed data from a retrospective multicenter study (NCT05070208) and the prospective CBF-2006 trial (NCT00428558, Jourdan et al. 2014) from the French AML intergroup, including CBF-AML patients diagnosed between 2007–2020. Cases with prior chemo- or radiotherapy were classified as therapy-related (t-AML). Baseline characteristics were compared in the overall cohort. Outcomes were assessed in a sub-population of fit patients (≤80 years, cancer in remission, intensive chemotherapy). Centralized NGS was performed using 40- and 68-gene panels (36 genes in common), and MRD was assessed by RT-qPCR for RUNX1::RUNX1T1 and CBFB::MYH11. Results Among 749 CBF-AML patients included between 2007 and 2021, 78 had t-AML. t-AML patients were older (median age: 59 vs. 45 years, p<0.001), more likely to be female (68% vs. 44%, p<0.001), and had lower white blood cell counts (WBC) at diagnosis (median: 6 vs. 15 G/L, p<0.001). was the most common prior neoplasm (42%). Median interval from chemo/radiotherapy to t-AML onset was 38 months (IQR [interquartile range]: 25–69). Neoplasms were in complete remission after chemotherapy (74%) and/or radiotherapy (49%) at CBF-AML diagnosis in 83% pts and remained in sustained remission in 78% after a median follow up of 1.8 years. The distribution of RUNX1::RUNX1T1 and CBFB::MYH11 subtypes was similar between therapy-related and de novo cases (44% and 43% for RUNX1::RUNX1T1, p>0.9). Cytogenetically, X chromosome deletions were more frequent in t-AML (16% vs. 8%, p=0.016). t-AMLs showed fewer on NGS (63% vs. 75%, p = 0.019), and fewer FLT3 mutations (10% vs. 24%, p = 0.03). No other difference was observed in the mutational landscape of t-AML, including KIT and TP53 alterations. In the selected population of patients without active cancer at AML diagnosis and treated with intensive chemotherapy (n=693, including 57 t-AML), induction regimens were mainly based on 7+3 ( in t-AML vs 72% in non-t-AML, p=0.07) and consolidation courses on intermediate/high dose cytarabine courses (93% in t-AML vs 90% in non-t-AML, p=0.64). Gemtuzumab-ozogamycin was added to Cx in 9% of t-AML (vs. 10% of non-t-AML, p=1.0). Allogeneic transplant in first complete remission was performed in 9% of t-AML and 5% of non-t-AML (p=0.21). Therapy-related AML patients had a CR/CRp rate of 95%, not different from de novo patients (95%, p=0.74). MRD after one cycle of induction was not different in t-AML in bone marrow (median: 0.20% [IQR: 0.04-0.82%] vs. 0.17% [IQR: 0.03-0.49%], p=0.50) nor in peripheral blood (median: 0.02% [IQR: 0.002-0.14%] vs. 0.03% [IQR: 0.001-0.19%], p=0.85). With a median follow-up of 5.3 years (IQR :3.9-6.8), the 3-year cumulative incidence (CI) of relapse was 41% (95%CI [confidence interval]:27%-54%) in t-AML patients and 38% (95%CI:34%-42%) in non-t-AML patients (csHR=1.07 [95%CI:0.69-1.68], p=0.76). No difference was also observed for non-relapse mortality (NRM) (3-year CI-NRM: 2% [95%CI:0%-9%] for t-AML vs. 3% [95%CI:2%-5%] for non-t-AML, csHR=0.87 [95%CI:0.21-3.66], p=0.85). Overall survival (OS) was lower in t-AML in univariable analysis (3-year OS: 62% [95%CI:50%-77%] in t-AML vs 79% [95%CI:75%-82%] in non-t-AML, p=0.03). Nevertheless, this was not confirmed in multivariable analysis (HR=1.36, 95%CI:0.84-2.18, p=0.21 for t-AML) when accounting for age (per 10 years of age HR=1.27, 95%CI:1.14-1.42, p<0.001), WBC count (log10 scale HR=1.25, 95%CI:0.94-1.65, p=0.12), and CBF subtype (HR=1.19, 95%CI:0.87-1.62, p=0.29 for RUNX1::RUNX1T1). In patients who experienced relapse (n=249 including 21 t-AML), OS after relapse was dismal in t-AML (16% [95%CI:6%-45%] vs 56% [95%CI:50%-64%], p<0.0001). Conclusion This study shows that therapy-related CBF-AML patients are older, have lower WBC at diagnosis, and present with similar molecular profiles compared to de novo cases. Among a homogenous cohort of patients without active cancer and treated with intensive chemotherapy, there were no differences in CR/CRp rates, relapse incidence, or non-relapse mortality. Unlike previous studies, overall survival was not significantly different after multivariable adjustment for age, WBC count, and CBF subtype.

IDH1 R132 mutations are found in about 5-10% of AML at diagnosis. Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of the mIDH1 enzyme, approved for IDH1mut newly diagnosed AML aged ≥75 years or who are ineligible for intensive induction chemotherapy. In relapse/refractory settings (R/R), IVO monotherapy yielded promising complete remission or complete remission with partial hematologic recovery (CR/CRi) rate of 30.4% associated with a median overall survival (OS) of 8.8 months (Di Nardo, NEJM, 2018). However, there are very few data regarding IVO use outside clinical trials. In this study, we aimed to evaluate the efficacy and safety of IVO in R/R AML patients in real life settings. Method IVOOBS (NCT06377579) is a retrospective, non-interventional, multicentric study including patients from 32 French centers with newly diagnosed or R/R IDH1mut AML treated with IVO through a compassionate use program. Here, we focused on R/R patients treated with IVO, either as monotherapy or in combination with other therapies between January 2017 and February 2024. The primary objective was OS. Secondary objectives were response rate (ELN2022 criteria), and toxicity. Overall response (ORR) was defined as patients reaching CR, CRi, or CRh at any time. Results Overall, 127 patients were included. Secondary AML were observed in 15.8% (post-MDS/MPN=16, t-AML=4). Median number of previous lines prior IVO onset were 1 [IQR:1-3]; 82 patients (67%) received intensive chemotherapy as first line,36 (29% ) were pre-exposed to VEN prior IVO initiation, while 20 (15.8%) patients received IVO as post hematopoietic stem cell transplantation (HSCT) salvage treatment. 93 patients received IVO monotherapy, 26 in combination with azacitidine (AZA) and 8 with venetoclax (VEN) +/- AZA (defined as AZA/IVO (+/-VEN) group) Most frequent co-mutations were NPM1 (32%), RUNX1 (23%), ASXL1 (21%) and BCOR (18%). Clinicians reported differentiation syndrome (DS) of any grade in of 12 patients (9.5%) (8 with IVO and 4 with IVO+AZA (+/-VEN)). QTc prolongation and febrile neutropenia was observed in 8 (7%) and 15 (12%) patients respectively. Regarding grade 3-4 hematological adverse events (AE), neutropenia, thrombocytopenia and anemia occurred in 4%, 14% and 18% respectively. There were 2 grade 5 AE related to IVO (1 pneumocystis carinii pneumonia and 1 DS) both in IVO monotherapy treated patients. ORR (CR/CRi/CRh) rates was 45.9% (35.8%/9.2%/0.9%), with 46.6% showing no response and 4.6% MLFS (6 patients died prior evaluation). Median time to best response was 2.8 months. Median time on IVO treatment was 6.2 months. ORRs were 39%, 48.6% (p=0.55) with a median time to achieve ORR of 3 months, and 2.8 months in IVO and IVO/AZA (+/-VEN) treated patients, respectively. 65% (68/102) and 75% (55/73) of patients were transfusion independent at 3 and 6 months after IVO initiation, respectively. Prior VEN exposition did not significantly influence ORR probability: (36.1% (13/36) in VEN pre-exposed vs 44.4% (40/90) in VEN naïve (p=0.39). Co-mutations at AML diagnosis did not influence ORR probability including MAPK/RTK mutations. In multivariate analysis for ORR, only higher platelets at IVO onset (HR=1.05, p=0.01) and HU use (HR=0.13, p=.002) were independently associated with ORR. In the 22 patients who received HU to manage initial leukocytosis, ORR rate was 13.6% compared to 53.5% for those without HU requirement (p<0.001). In responding patients, 22.8% (13/57) were bridged to HSCT after a median time of 4.2 months. Only 2 patients relapsed post-transplant. After a median follow-up of 13.9 months, median OS (mOS) of the entire cohort was 14 months. mOS with IVO monotherapy and AZA/IVO (+/-VEN) was 13.2 and 20.2 months, respectively (p=0.16). VEN exposure pre-IVO did not significantly influence OS compared to VEN-naïve patients (HR=0.90, p=0.69). In multivariate analysis, only higher platelets (HR=0.96, p=0.015) and HU use (HR=2.95, p<.001) were independently associated with OS. Conclusion In this real-life study, IVO compares favourably with previously reported prospective studies in R/R settings, with a manageable safety profile. HU use for proliferative disease at IVO onset is associated with a lower response rate and inferior outcome.

Introduction:Adults with relapsed or refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia (R/R Ph+ BCP-ALL) have a dismal outcome. Blinatumomab as a single agent has shown activity in R/R Ph- BCP-ALL, and second or third-generation tyrosine kinase inhibitors (TKIs) can produce high remission rates in Ph+ leukaemias. We aimed to assess the activity of blinatumomab and TKI in combination with intensive chemotherapy in the relapsed or refractory setting. Methods:Ten patients with R/R Ph+ BCP-ALL were treated with the combination of a modified hyper-CVAD (mHCVAD) regimen (cyclophosphamide, vincristine, adriamycin, dexamethasone), blinatumomab and TKI (mainly ponatinib). Results:Complete remission (CR) was achieved in 10/10 patients, with deep molecular responses, and 6/10 were alive in remission after a median follow-up of 19.4 months. Three major cardiovascular events were noted. Conclusion:These preliminary data, suggest that the mHCVAD-blinatumomab-TKI (mainly ponatinib) regimen may achieve a high rate of CR with undetectable measurable residual disease in adults with R/R Ph+ BCP-ALL and could be proposed to such patients, but cardiovascular or infectious complications should be warning, especially in older or frail patients.

Introduction: Prognosis in relapsed acute myeloid leukemia (AML) patients (pts) is dismal, with no standard chemotherapy. Intermediate (I) or high (H)-dose cytarabine (DAC)-based regimens are common salvage treatments (Döhner, Blood 2022) leading to around 50% CR/CRi (Megías-Vericat, AJH 2018). Venetoclax (VEN)-azacitidine (AZA) is a front-line standard of care for unfit pts but is also widely used in pts with molecular relapse, primary induction failure (PIF) or morphologic relapse (Rel). In this study, we report the largest cohort of pts with AML treated with VEN-AZA compared to salvage I/HDAC-based intensive chemotherapy (IC) in first Rel. Methods: Inclusion criteria were 18-75y old AML pts, first Rel after front line IC, treated by I/HDAC-based IC or VEN-AZA between January 2015 and September 2023. Exclusion criteria were 3rd drug added to VEN-AZA, molecular Rel, CR1/CRi1 after 2 induction courses. Results: 347 pts from 9 centers treated with VEN/AZA (n=125, 36%) or I/HDAC (n=222, 64%) were included. 191 (55%) were male, median age was 63y (IQR 54.4-70; range 20-75) and 57y (IQR 45-63; range 19-73) in VEN-AZA and I/HDAC groups (p<0.0001), respectively; 29 (23.4%) and 15 (6.8%) pts had secondary AML, cytogenetic risk was intermediate in 83 (68%) and 172 (77.5%) (p=0.03); 17 (14.3%) and 82 (41%) pts had a NPM1 mutation (p<0.0001), in VEN-AZA and I/HDAC groups, respectively. Induction chemotherapy was 3+7 including 15 (4.3%) CPX-351. All pts were in CR1/CRi1 and post remission strategy was I/HDAC-based for 245 (74.7%) pts whereas other pts received non-IC. Finally, 49 (39.2%) and 39 (17.5%) pts underwent an allogeneic stem cell transplantation (HSCT) in CR1/CRi1 (p<0.0001), in VEN-AZA and I/HDAC groups, respectively. All pts relapsed after a median delay of 12 months (IQR 7-22; range 1-226), 73 (21%) pts ≤6 months and 274 (79.0%) pts >6 months. Performans status (PS) at relapse was 0-1 in 247 (86.7%) pts and ≥2 in 38 (13.3%) pts. Median WBC at relapse were 3x109/l (IQR 1.9-7.1; range 0.3-265.7). There was no significant difference between the 2 groups for these characteristics. Finally, at relapse, 76 (60.8%) and 147 (66.2%) pts obtained a CR2/CRi2 in VEN-AZA and I/HDAC-based salvage groups, respectively (p=0.35). Pts received a median of 2 cycles of VEN-AZA (IQR 2-5; range 1-21), best response has been considered whatever the time. Early death during first month occurred in 18 (14.4%) and 20 (9.0%) pts in VEN-AZA and I/HDAC groups, respectively (p=0.15). Bridge to transplant has been obtain for 31 (24.8%) and 120 (54.1%) pts in VEN-AZA and I/HDAC group, respectively (p<0.0001). Multivariate logistic regression for factors associated with CR2/CRi2 included gender, sAML, cytogenetic, FLT3-ITD and NPM1, consolidation in CR1/CRi1, previous HSCT, age at Rel, VEN-AZA or I/HDAC, PS at relapse. Independent factors associated with CR2/CRi2 were female (OR 0.55, CI95% 0.32-0.94, p=0.03) and PS 0-1 at Rel (OR 0.35, CI95% 0.17-0.76, p=0.008). After a median FU for alive pts from Rel of 21 months, median OS was 15 and 16 months; 1y-OS was at 51.7% and 55.3%, in VEN-AZA and I/HDAC groups (p=0.19), respectively. Cox model for factors associated with OS included also time to relapse and HSCT in CR2/CRi2 and found secondary AML (aHR 1.73, CI95% 1.18-2.56, p=0.006), adverse cytogenetic risk (aHR 1.52, CI95% 1.07-2.16, p=0.02), time to relapse >6 months (aHR 0.38, CI95% 0.28-0.52, p<0.0001) and HSCT in CR2/CRi2 (aHR 0.28, CI95% 0.21-0.39, p<0.0001). Median LFS was 14 months in both groups; 1y-LFS was at 55.5% and 52.9%, in VEN-AZA and I/HDAC groups (p=0.95), respectively. Cox model for factors associated with LFS were time to relapse >6 months (aHR 0.37, CI95% 0.23-0.59, p<0.0001) and HSCT in CR2/CRi2 (aHR 0.39, CI95% 0.27-0.57, p<0.0001). Conclusion: This cohort is characterized by first relapse including three quarters of relapse > 6 months, no PIF, no previous exposure to HMA for AML and mostly intermediate risk cytogenetics. Salvage treatment allowed high CR2/CRi2 rates, close to those observed in front-line for VEN-AZA and at the upper limit for salvage treatment based on I/HDAC. These high response led to interesting bridge to transplant rates in both groups and long LFS and OS. These results raise the question of prospective evaluation of non-intensive chemotherapy in first relapse for AML patients.

ABSTRACT:The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here, we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary end points were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR + CRh), safety, and tolerability. Secondary end points included overall response rate (ORR) and duration of response. As of 18 September 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined, efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 previous lines of therapy, 35.9%; previous venetoclax, 75.0%). The CR + CRh rate was 23.4% (1-sided P = .0014); the ORR was 46.9%. Median duration of CR + CRh was 4.7 months. Of 30 responders, 5 (16.7%) proceeded to hematopoietic stem cell transplant (HSCT) and 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as #NCT04065399.

MP0533 is a tetra-specific CD3-engaging DARPin designed for avidity-driven T cell-mediated killing of acute myeloid leukemia (AML) cells expressing ≥2 of the 3 leukemia-associated antigens CD33, CD123, and CD70, while sparing healthy cells. MP0533 is evaluated for the treatment of adults with AML or myelodysplastic syndrome (MDS)/AML. The results of the Phase 1/2a dose-escalating dosing regimens (DR) 1–7 showed an acceptable safety profile with evidence of target engagement, T cell activation, and preliminary antitumor activity. However, serum pharmacokinetics (PK) suggested that MP0533 exposure is impacted by target-mediated drug disposition and anti-drug antibodies (ADA) (Jongen-Lavrencic et al. ASH 2024). To mitigate these effects and optimize exposure to treatment, initial MP0533 dose-densification in cycle 1 was introduced in DR 8. Encouraging preliminary antitumor activity was observed (Bories et al. EHA 2025). DR 9 comprises further dose-densification plus anti-CD20 pretreatment. We report the latest results of this first-in-human, multicenter, open-label, Phase 1/2a study of MP0533 (NCT05673057) with focus on the outcomes of DR 8 and 9. Safety, PK, pharmacodynamics (PD), ADA, and antileukemic activity of MP0533 are assessed. Whilst DR 1–7 utilized MP0533 step-up dosing (SUD) on day 1, 5, 8, followed by target dose (TD) on day 15, DR 8 implemented a higher starting dose and earlier TD administration on day 12. Across DR 1–8, TD on day 15 was followed by weekly dosing (28-day cycles). For DR 9, MP0533 is administered with higher frequency vs DR 8 in cycle 1 and beyond, reaching the TD on day 3, and obinutuzumab is given >3 days prior to the first MP0533 dose. Treatment-emergent adverse events (TEAEs) are assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Response is evaluated at weeks 4, 8, and 12 using 2022 European Leukemia Net (ELN) criteria, with additional bone marrow assessment (BMA) on day 14 in DR 9. Centralized molecular measurable residual disease (MRD) is conducted using next-generation sequencing and polymerase chain reaction. As of 21 Jul 2025, 52 patients with relapsed/refractory disease were treated (DR 1=1, DR 2=1; DR 3=3; DR 4=6, DR 5=8, DR 6=9, DR 7=9, DR 8=10, DR 9=5). Median baseline age was 73 years (range 22–82). ELN genetic risk was adverse in 35 patients (67%) and intermediate in 14 (27%). Thirty-one patients (60%) received ≥2 prior treatment lines. Patients received a median of 6 TDs (range 1–21) in DR 1–7 (complete) and 6 TDs (range 1–40) in DR 8 (1 patient still on treatment). DR 9 is ongoing, with a median of 13 TDs (range 8–21) administered; 2 patients completed the 28-day dose-limiting toxicity (DLT) period to date. In addition to the 3 DLTs reported previously (DR7: proctitis, muscular weakness; DR 8: fatal pulmonary hemorrhage in context of disseminated intravascular coagulation, resulting in TD decrease for subsequent patients), 1 DLT of grade 4 liver enzyme elevation was observed in DR 9. The most frequent MP0533-related TEAEs across DR 1–9 were cytokine release syndrome (CRS, 35 patients [67%]) and infusion-related reactions (IRRs, 25 patients [48%]). Three CRS and 6 IRRs transiently reached grade 3 (DR 5–8); all others, including those reported in DR 9, remained of grade ≤2. In DR 8, 3 of 8 evaluable patients achieved a response (1 complete remission [CR]; 2 CR with partial hematologic recovery) vs 4 of 33 in DR 1–7 (1 CR, 3 morphologic leukemia-free state). Two patients in DR 8 maintained response for ≥12 weeks, including 1 in ongoing CR for >9 months. One of the 3 responders in DR 8 showed transient MRD negativity and the 2 others a decrease of variant allele frequency from baseline mutations. In DR 9 to date, 1 of 4 patients with available BMA up to day 14 responded (1 CR) and 2 further showed initial signs of blast count reduction. Serum PK data from DR 8 showed higher drug exposure in cycle 1 vs previous DRs; PK and ADA assessments of DR 9 to confirm expected levels of MP0533 exposure with densified treatment regimen and anti-CD20 pre-treatment is ongoing. MP0533 shows an acceptable safety profile across DR 1–9. Based on initial data, densified MP0533 dosing and anti-CD20 pre-treatment appear tolerable. Preliminary antitumor activity signs with the densified treatment regimens are encouraging. Further efficacy and PK/PD data for DR 9 are currently being collected.