OBJECTIVES:This study aims to evaluate the safety, biological activity, and exploratory clinical effects of CD19-directed T-cell engagement with blinatumomab in patients with severe, treatment-refractory antitopoisomerase I-positive systemic sclerosis (SSc). METHODS:We conducted an exploratory case series of 5 patients with refractory SSc who received a 14-day continuous intravenous infusion of blinatumomab (9 µg/d for 7 days, escalated to 28 µg/d for 7 days) in 2 tertiary hospitals. Safety assessments included cytokine release syndrome (CRS), neurotoxicity, infections, and serum immunoglobulin levels. Exploratory efficacy outcomes comprised modified Rodnan skin score (mRSS), pulmonary function tests, and patient-reported outcomes. Immunologic endpoints included serial peripheral CD19⁺ B-cell counts, B-cell subset phenotyping, and a 6-gene type I interferon signature. Patients' follow-up was a median of 8 months (range: 6-12). RESULTS:Blinatumomab administration was generally well tolerated. Three patients experienced low-grade CRS (grade 1, n = 2; grade 2, n = 1), managed conservatively; no neurotoxicity or severe infections occurred. Rapid peripheral CD19⁺ B-cell depletion was achieved in all patients. B-cell repopulation occurred by 1 month in all but 1 patient and was dominated by naïve and transitional subsets. At 3 months, modest clinical improvements were observed, including a median mRSS change of -4 points (range: +1 to -8) from a baseline of 16 (range: 0-25) and a transient improvement in lung function and patient-reported outcomes. However, all patients experienced clinical relapse between months 3 and 6, leading to resumption of immunosuppressive therapy in most cases. CONCLUSIONS:CD19-directed T-cell engagement with blinatumomab induces rapid B-cell depletion and short-term clinical improvement in refractory SSc but lacks durability after a single treatment cycle.

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.

Patient characteristics of the national cohort according to the type of PARPi received (olaparib vs. other PARP inhibitors).

Univariate analysis for overall survival from t-MN diagnosis of patients diagnosed with t-MN after OC according to PARPi exposure.

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.

Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.

Introduction Despite the increasing number of therapeutic options for immune thrombocytopenia (ITP), refractory disease remains an unmet need in clinical practice. Anti-CD38 monoclonal antibodies such as daratumumab have recently been shown to be a promising treatment in ITP. The aim of this study was to assess safety and efficacy of daratumumab given for refractory ITP. Patients and methods We conducted an observational, retrospective, multicenter study throughout the network of the French reference center for adult' immune cytopenias including patients receiving compassionate off-label treatment by daratumumab for ITP (either primary or secondary) between 01/01/2020 and 01/06/2025. ITP was diagnosed according to international guidelines. Patients were excluded if daratumumab was given to treat plasma cell malignancy. Complete response (CR) was defined by platelet count >100x109/L and response (R) by platelet count 30 to 100x109/L with at least a 2-fold increase from baseline. Patients who required any other treatment including rescue therapy more than six weeks after first daratumumab infusion were considered non-responders regardless of platelet counts. All patients were informed and gave consent to ‘off-label’ use of daratumumab. The study received institutional review board approval (00011558, UPEC University, AP-HP). Results Twenty-one patients (43% females) with a median age at first daratumumab infusion of 67 years [range 21-88] were included in the study. Eight had secondary ITP (38%; Evans syndrome, n=6, and/or antiphospholipid syndrome (APLS), n=2, or rheumatoid arthritis, n=1). In addition, 2 patients had antibodies against GPIIb-IIIa (acquired Glanzmann syndrome, n=1) and GPVI (n=1) responsible for chronic bleeding symptoms. Median ITP duration was 78 months [range 4-594], and patients had previously received a median number of 8 [range, 3-12] treatment lines for ITP, including corticosteroids (100%), rituximab (100%), intravenous immunoglobulin (95%), thrombopoietin receptor agonists (95%; including eltrombopag [90%] and romiplostim [86%]), mycophenolate mofetil (81%), splenectomy (71%), fostamatinib (48%), and one or more other immunosuppressive drug (43%). Fifteen patients (71%) had bleeding symptoms despite treatment in the previous month. Patients received a median number of 6 [range 3-20] infusions of daratumumab either at 16mg/kg of body weight intravenously (n=10) or at a fixed dose of 1800 mg subcutaneously (n=11) with dexamethasone premedication. Daratumumab was given with other ITP treatments in 15 patients (71%). Median follow up after daratumumab was 16 months [range 1-60]. Ten (48%) patients had adverse events imputable to daratumumab, including 5 patients (24%) with infectious events requiring hospitalization (sepsis, n=2, bacterial pneumonia, n=2, acute tonsillitis, n=1), 2 patients with transient neutropenia (but without infection), and 3 patients with immediate reaction after infusion. During follow-up, 4 patients (19%) died (1 splenectomized patient had campylobacter sepsis 1 month after daratumumab initiation, 1 patient with stroke and APLS had sepsis 23 months after daratumumab, 1 patient died from refractory ITP, and 1 patient with metastatic cancer died from cardiac failure). In the 6 months following daratumumab, among the 10 patients with available gammaglobulin assessment without intravenous immunoglobulin administration, 8 (80%) had concentrations below 6g/L. Overall response (CR+PR) was achieved in 11 patients (52%), including 9 CR (43%), and 2 PR (10%), with a median time to response of 35 days [range 7-84]. Relapses occurred in 3/7 (43%) of responders that had a follow-up >6 months after daratumumab. Four patients had long-lasting CR without any other ITP treatment, with relapses in 2 (50%) after 10 and 32 months, respectively. Two patients with initial CR and experiencing a relapse had a second course of daratumumab, resulting in 2 new initial CR but eventually with relapses in both patients. Discussion Overall, these results suggest that daratumumab has the potential to induce durable remissions even in multirefractory ITP patients, although response appears transient in most responders. However, this came at the cost of a high rate of severe infections in this particular group of heavily treated, frequently splenectomized, immunocompromised and fragile patients. Careful assessment of benefit/risk balance is therefore warranted before daratumumab administration.

Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.

ABSTRACT:Higher-risk myelodysplastic syndrome (HR-MDS) with RARA gene overexpression is a subset of patients (pts) with an actionable target for tamibarotene, an oral and a selective retinoic acid receptor-α (RAR-α) agonist. Tamibarotene with azacitidine (AZA) showed complete remission (CR) rates in myeloid leukemia. SELECT-MDS-1 was a phase 3 study comparing the activity of tamibarotene + AZA to placebo + AZA in these pts with newly diagnosed HR-MDS with RARA overexpression. Eligible pts had confirmed RARA overexpression, untreated MDS with higher-risk features by revised International Prognostic Scoring System (IPSS-R), and marrow blast count >5%. Pts were randomized 2:1 to receive tamibarotene + AZA or placebo + AZA, respectively. A total of 246 participants were randomized with 164 and 82 in the tamibarotene + AZA and placebo + AZA groups, respectively. Baseline characteristics included: 69.9% male; median age 75 years (range, 38-93); primary MDS, 89.8%; MDS-excess blasts-1, 48% and MDS-excess blasts-2, 52%; and IPSS-R risk category intermediate (25.5%), high (35.7%), and very high (38.9%). The study did not meet the primary end point of CR, with a P value of .2084 for the treatment effect in the tamibarotene + AZA group. The CR rates were 23.81% and 18.75% in the tamibarotene + AZA and placebo + AZA groups, respectively. The use of tamibarotene-based therapy to target RAR-α as a novel approach in pts with HR-MDS with RARA gene overexpression is not a paradigm, which can augment response rates beyond AZA monotherapy. Further explorations of alternative approaches, including those with a biomarker, to alter the natural history of this disease are warranted. This trial was registered at www.clinicaltrials.gov as #NCT04797780.

Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.

Introduction: FLT3 internal tandem duplications (ITD) are found in approximately 25% AML and defined by an allelic ratio (AR)≥0.05, hereinafter referred to as macroclones (Mclones). We previously described the prevalence of FLT3-ITD microclones (µclones), defined by an AR<0.05, in a cohort of patients with FLT3-ITD Mclones (Joudinaud, Blood Adv 2025). Here we aimed at assessing the prevalence and prognostic value of FLT3-ITD µclones in the French multicenter BIG-1 trial. Methods: The BIG-1 trial (NCT02416388) included patients (pts) aged 18-60 years with newly diagnosed AML treated by intensive chemotherapy (CBF-AML and APL excluded). This post-hoc analysis required DNA fragment analysis (FA) to detect FLT3-ITD Mclones (AR≥0.05). Samples with negative or AR<0.05 FA were used for NGS on a NovaSeq 6000. Regions of interest were sequenced with an average depth of 3000x then analyzed with FiLT3r algorithm for quantification of FLT3-ITD (Boudry, BMC Bioinformatics 2022) allowing an AR threshold detection at 4x10e-4. Patients with an AR 0.0004-0.05 were referred to µclones, other patients were considered without FLT3-ITD. Midostaurin (MIDO) has been introduced in 07/2018 according to its label. Results: 1,733 pts with available DNA were included in this analysis from 01/2015 to 02/2022, 353 (20.4%) had FLT3-ITD Mclones (±µclones, MACRO group) including 175 (49.6%) pts with high AR (≥0.5), 240 (13.8%) had FLT3-ITD µclones only (MICRO group) and 1,140 (65.8%) were FLT3-ITD negative. Overall, median age was 50y and 848 pts were female without differences between the three groups. As expected, according to ELN-2022, risk groups were favorable for 0.6%/40.9%/35.2%, intermediate for 82.4%/28.3%/15.8% and adverse for 17.0%/30.8%/49.0% of pts in MACRO, MICRO and negative groups, respectively. Among the 668 pts with NPM1 mutation, 237 (35.5%), 130 (19.4%) and 301 (45.1%) pts were in MACRO, MICRO and negative groups, respectively, with significant differences for each pairwise comparison. MIDO was administered to 134 patients (38%) in the MACRO group, 18 (7.5%) in the MICRO group, and 18 (1.6%) in the negative group, the latter two based on FLT3-TKD mutations. In multivariate analyses, compared to absence of FLT3-ITD, µclones were significantly and independently associated with an increased risk of relapse (sHR 1.46 [1.15-1.85]; P=0.002), as well as presence of FLT3-ITD Mclones (sHR 2.09 [1.65-2.66]; P<0.001), as a whole, or divided in two groups with low AR<0.5 (sHR 1.93 [1.46-2.56]; P<0.001) and high AR≥0.5 (sHR 2.36 [1.73-3.22]; P<0.001), adjusted for confounding factors including allo-SCT in CR1 as time-dependent variable. The other independent predictive factors in multivariate analyses for CIR were: age, cytogenetic risk, NPM1, CEBPA bZIP and TP53 mutations, MIDO and allo-SCT. 5y-CIR estimations were 47.5%, 47.9% and 37.5%, 2y-CIR estimations were 42.5%, 45.1% and 29.4% in MACRO, MICRO and negative groups, respectively. Presence of FLT3-ITD µclones was also significantly and independently associated with an increased risk of death or relapse (aHR: 1.39 [1.13-1.71]; P=0.002), as were Mclones with low and high AR. 5y-RFS were 41.9%, 40.6% and 47.7% in MACRO, MICRO or negative groups, respectively. Given the impact of FLT3-ITD mutations in the ELN 2022 risk definition of patients with NPM1 gene mutation, we conducted an analysis in this subgroup. In multivariate analyses, FLT3-ITD µclones were significantly and independently associated with increased CIR (sHR 1.66 [1.24-2.24]; P=0.001), shorter RFS (aHR 1.71 [1.29-2.27]; P<0.001) and shorter OS (aHR 1.48 [1.02-2.14]; P=0.04) compared to negative group. After two courses of chemotherapy, NPM1 BM MRD was ≥1% in 24.1%, 15.7%, 16.3% and 6.7% of pts in MACRO group with high and low AR, MICRO group and negative group respectively. Conclusion: In younger AML pts, FLT3-ITD microclones increase the risk of relapse and shorten RFS. In the NPM1 mutated subgroup, such FLT3-ITD microclones also shorten OS. Our results advocate for a change of practice from fragment analysis to high-sensitivity molecular techniques for FLT3-ITD detection, consider the mutation in the ELN classification regardless of the diagnostic threshold of 0.05 and investigate FLT3 inhibitors in this population.

Introduction: Midostaurin (MIDO) was approved by the FDA in 04/2017 for the treatment of FLT3 mutated AML patients in combination with intensive chemotherapy (ICT) with daunorubicin (DAUNO) administered at 60 mg/m² for 3 days based on the findings of the RATIFY trial (Stone, NEJM 2017). Moreover, the UK NCRI AML17 trial (Burnett, Blood 2016) demonstrated that higher DAUNO exposure at 90 mg/m² (without MIDO) provided a particular benefit for patients with FLT3 mutated AML. The aim of this post-hoc study was to assess the impact of MIDO in combination with higher-dose anthracyclines (DAUNO or idarubicin) in the BIG-1 trial (Hunault, NEJM Ev 2025). Methods: Between 01/2015 and 07/2021, the BIG-1 trial (NCT02416388) included patients (pts) aged 18-60 years with newly diagnosed AML treated with ICT (CBF-AML and APL excluded). DNA fragment analysis (FA) detected FLT3-ITD (AR≥0.05 for positivity) and FLT3-TKD mutations were detected depending on each center's usual procedures. The protocol planned single and first induction cycle containing anthracycline. Pts may receive either DAUNO (90 mg/m², d1-3) or idarubicin (9 mg/m², d1-5), combined with cytarabine 200 mg/m² (d1-7). After its approval, MIDO has been introduced in 07/2018 during the course of the trial and provided by Novartis. This offered the opportunity to assess the role of MIDO in this context using an internal control group. Of note, MIDO was omitted during the post-induction cycles in the few pts who entered nested randomized studies evaluating dexamethasone (N=46) or vosaroxin (N=13) in combination with HDAC or IDAC, respectively. Results: Overall, 382 (84.7%) pts had FLT3-ITD, 83 (18.4%) had a TKD mutation and 14 had both, leading to the inclusion of 451 pts in this analysis. 282 (62.5%) pts received ICT without MIDO (ICT group: internal control) and 169 (37.4%) received ICT with MIDO (ICT+MIDO group). Median age was 50.1y and 263 pts were female. ELN-2022 genetic risk was favorable, intermediate and adverse in 49 (10.9%), 319 (70.7%) and 77 (17.1%) pts. 302 (67%) pts carried also a NPM1 mutation without significant differences between the two groups. Following induction, the rate of CR/CRi was 77.3% vs 88.7% in ICT vs ICT+MIDO groups (p=0.002), respectively. Early death rate at d30 was 4.3% vs 1.2% (p=0.006). After adjustment on confounding factors including allo-HSCT in CR1 as a time-dependent variable in multivariate analysis, MIDO was significantly and independently associated with a decreased risk of relapse (sHR 0.63 [0.46-0.85]; P=0.003). At 2 and 5 years, cumulative incidence of relapse (CIR) was 43.6% vs 35% and 48.1% vs 40.9%, in the ICT and ICT+MIDO group respectively. The two other independent predictive factors for relapse were ELN-2022 genetic risk and allo-SCT in CR1 as protective factor. Anthracycline, gender, age and WBC did not significantly influence CIR. MIDO was also significantly and independently associated with a decreased risk of death or relapse (aHR 0.74 [0.55-0.98]; P=0.036), as well as ELN-2022 genetic risk and allo-SCT in CR1. At 2 and 5 years, RFS was 49.7% vs 55.4% and 42.5% vs 46.4%, in the ICT and ICT+MIDO group respectively. Again, anthracycline, gender, age and WBC did not significantly influence RFS. MIDO was significantly and independently associated with a decreased risk of death, relapse or failure (aHR: 0.65 [0.50-0.84]; P=0.001), as well as WBC, ELN-2022 genetic risk and allo-SCT in CR1. At 2 and 5 years, EFS was 43.3% vs 54.2% and 37.6% vs 44%, in ICT and ICT+MIDO groups respectively. Anthracycline, gender and age did not significantly influence EFS. Finally, MIDO was significantly and independently associated with a decreased risk of death (aHR: 0.70 [0.50-0.96]; P=0.02), as well as WBC, age and ELN-2022 genetic risk but neither allo-HSCT in CR1, nor sex, nor the type of anthracycline was associated with OS. At 2 and 5 years, OS was 62.8% vs 73.2% and 52.8% vs 62%, in ICT and ICT+MIDO group respectively. Conclusion: Subject to the limitations of this non-randomized study, adding MIDO to high-dose anthracycline-based chemotherapy improves CIR, RFS, EFS and OS independently of other factors, resulting in notable 5-year cure rates.

Flow chart of the study displaying the three cohorts.

Introduction The BIG-1 multicenter study was a prospective trial for younger AML patients with multiple randomizations at each stage of treatment, including induction, post-induction and allo-HSCT (Hunault M, NEJM Evid 2025). BIG-1 was designed to allow sequential evaluation of several agents in consolidation through nested randomized phase 2-3 trials over the trial period. Studies of adding either venetoclax or vosaroxin to IDAC vs IDAC alone have been completed (Vey N, ASH 2020; Gastaud L, ASH 2023). Based on recent preclinical data showing that cytarabine resistance acquisition is associated with increased glucocorticoid sensitivity, as well as the clinical impact of dexamethasone (DEX) in hyperleukocytic AML, we aimed to establish whether adding DEX to HDAC could reduce the relapse risk in patients who had achieved first remission (Récher C, Front Oncol 2021). Methods Patients (pts) aged 18-60y with newly diagnosed AML, post-MDS AML, or t-AML were eligible if they were included in BIG-1, in first CR/CRi after 1 or 2 chemotherapy courses, classified in the favorable or intermediate risk group according to the protocol classification, randomized in the HDAC post-induction arm, ECOG PS ≤ 2, without active infection or organ dysfunction. APL, Ph+ AML, CBF AML, or post-MPN AML pts were not eligible. Pts were randomly assigned to receive either HDAC alone (3g/m²/12h, d1-3-5) or HDAC combined with dexamethasone (10 mg/12h, d1-3-5, i.v). The protocol planned for 2 cycles in pts with allo-HSCT indication or 3 cycles in favorable-risk pts or for those without the possibility of allo-HSCT. Minimization factors for randomization were CR after 1 vs 2 cycles, WBC (< 30 vs ≥ 30 G/L) and NPM1 gene mutation. The primary endpoint was relapse-free survival (RFS). Evaluations of treatment effects were adjusted on ELN-2022 risk groups, anthracycline used in induction (daunorubicin vs idarubicin), and time-dependent HSCT in first CR. According to French's regulation, no racial or ethnic data were collected. Results 220 eligible pts were included from 01/2018 to 04/2021, 111 in the HDAC arm and 109 in the HDAC-DEX arm. Pts characteristics were well balanced between the two arms. Median age was 50y and 112 pts (51%) were female. According to ELN-2022, 101 (53%), 67 (26%) and 35 (16%) were favorable, intermediate or adverse risk; 11 pts (5%) were non-classified. Median CRP was 4 mg/L. Because dexamethasone was recommended in pts with high WBC at diagnosis, 50 pts were pre-exposed to dexamethasone during induction, 27 in the HDAC arm and 23 in the HDAC-DEX arm. There were no difference regarding antimicrobial prophylaxis or G-CSF use between the two arms. Allo-HSCT in first CR was performed in 29 and 48 pts in the HDAC and HDAC-DEX arm, respectively. With a median follow-up of 49.3 months, estimated 5y-RFS was 46% (95% CI, 36-56) in the HDAC arm vs 39% (95% CI, 29-49) in the HDAC-DEX arm (adjusted HR, 0.94 [95% CI, 0.62-1.43], p=0.77). When evaluated in patient subgroups including ELN-2022 risk group, anthracycline used in induction, WBC or allo-HSCT in first remission, no significant interactions with the HDAC-DEX vs HDAC treatment effect were observed for RFS. 5y-OS was 62% (95% CI, 51-71) in the HDAC arm vs 63% (95% CI, 51-72) in the HDAC-DEX arm (adjusted HR, 0.93 [95% CI, 0.54-1.62], p=0.81). 5y-CIR was 43% (95% CI, 34-52) in the HDAC arm vs 42% (95%CI, 31-52) in the HDAC-DEX arm (adjusted HR, 0.77 [95% CI, 0.46-1.29], p=0.32). The severity of HDAC-induced myelosuppression was lower in the HDAC-DEX arm. During the whole HDAC consolidation cycle period, the mean number of days with neutrophils <0.5 G/L was 20.7 (+/-13.2) with HDAC vs 15.4 (+/-11.4) with HDAC-DEX (p=0.002). The mean number of days with platelets < 20 G/L was 18.6 (+/-18.9) with HDAC vs 13.9 (+/-13.0) with HDAC-DEX (p=0.033). There were also lower needs for RBC and platelets transfusions with HDAC-DEX. The rate of fungal infections was lower in the HDAC-DEX arm (2.9%) vs HDAC arm (12.7%) (p=0.008). The rate of vomiting was also significantly reduced by DEX. Of note, post-hoc analysis showed that the 77 pts with CRP ≥ 5mg/L before consolidation had worse CIR, RFS and OS compared to pts with CRP < 5mg/L. Conclusions With the dosing schedule used in this trial, DEX did not improve RFS but did markedly improve tolerability of HDAC. Further studies are needed to investigate the prognostic role of inflammatory markers in AML.

BACKGROUND:We conducted a randomized controlled trial to compare intermediate doses (IDAC) with high doses of cytarabine (HDAC) as postinduction therapy in patients 18 to 60 years of age with newly diagnosed acute myeloid leukemia (AML). The main objectives were to evaluate noninferiority in overall survival (OS) after IDAC and safety. METHODS:Patients 18 to 60 years of age with newly diagnosed AML, except those with core-binding factor, acute promyelocytic, Philadelphia chromosome-positive, or post-myeloproliferative neoplasm AML, were eligible. After the induction course, we randomly assigned patients to either IDAC (1500 mg/m2/12 hours) or HDAC (3000 mg/m2/12 hours). Patients with intermediate- and adverse-risk AML were eligible for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. The primary end point was OS in a predefined per-protocol analysis population. The primary analyses were performed in 1132 randomly assigned patients, with a noninferiority outcome adjusted on the European Leukemia Net (ELN) 2022 risk group, the use of induction anthracycline, the response to induction, and HSCT as a function of time following treatment. RESULTS:At 5 years, OS was estimated at 59.3% (95% confidence interval [CI], 55.0 to 63.3) in the IDAC group versus 57.5% (95% CI, 53.3 to 61.5) in the HDAC group (adjusted hazard ratio, 0.96; 95% CI, 0.80 to 1.15; noninferiority test, P=0.0042). A preplanned analysis was unable to detect any interaction between IDAC or HDAC treatment effect and patient subgroups, including those defined by the ELN 2022 risk group or response to induction prior to random assignment. In addition, the severity of chemotherapy-induced myelosuppression and the incidence of related adverse events were lower after IDAC. CONCLUSIONS:Our trial shows noninferior outcomes in patients 18 to 60 years of age with newly diagnosed AML treated with low- versus high-dose cytarabine; this occurred with similar or lower toxicities. (Funded by the Regional Clinical Research Office, Angers and others; EudraCT number, 2014-000699-24; ClinicalTrials.gov number, NCT02416388.).

TP53 mutations characteristics among t-MN PARPi national cohort.