BACKGROUND:Diagnosing acute respiratory failure (ARF) in patients with hematologic malignancies is complex and prognostically critical. We hypothesized that immune dysfunction driven by disease and treatments determines ARF etiologies and outcomes. METHODS:This post-hoc analysis of a prospective multicenter cohort included patients with hematological malignancies admitted to ICU with hypoxemic ARF. Immune dysfunctions were classified as phagocytic, humoral, or cellular. Associations between malignancies, immune profiles, treatments, and ARF causes were assessed by multivariate logistic regression. Unsupervised hierarchical clustering identified immune-phenotypic subgroups. RESULTS:Among 708 patients, the most frequent malignancies were acute myeloid leukemia (AML, 29.5%), non-Hodgkin lymphoma (25.6%), and myeloma (21.3%). Immune dysfunctions were frequent: humoral (71.5%), cellular (57.9%), and phagocytic (55.5%). Main ARF etiologies were bacterial pneumonia (40.4%), viral infections (18.8%), and invasive fungal infections (16.8%), while 12.7% remained undiagnosed. Phagocytic dysfunction was associated with bacterial (OR 1.60, p = 0.026) and infiltrative causes (OR 2.17, p = 0.007). Humoral dysfunction was linked to viral infections (OR 1.83, p = 0.014), and cellular dysfunction to viral infections (OR 1.70, p = 0.01) and Pneumocystis jirovecii pneumonia (PJP) (OR 2.33, p = 0.03). AML was associated with infiltrative ARF (OR 2.63, p = 0.009) but negatively with influenza (OR 0.34, p = 0.002) and PJP (OR 0.15, p = 0.009). Lymphomas were linked to pleural effusion (OR 4.31, p < 0.001), airway obstruction (OR 4.30, p = 0.009), and aspiration pneumonia (OR 2.58, p = 0.042). Corticosteroids correlated with undiagnosed ARF (OR 2.07, p = 0.03), and neutropenia with Gram-negative (OR 2.42, p < 0.001) and fungal infections (OR 1.73, p = 0.050). Cluster 1 (myeloid infiltration/uncertainty) had 53% mortality, Cluster 2 (mixed immunosuppression) 49%, and Cluster 3 (chronic lymphoid diseases) 39%. CONCLUSION:Immune dysfunction strongly influences ARF patterns and prognosis. Immune-guided diagnostic strategies could improve early etiological identification and outcomes in high-risk patients with hematological malignancies.

Abstract Background Venetoclax (VEN) has transformed the management of patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. When combined with azacitidine (AZA), approximately 2/3 of pts achieve complete remission (CR) and median overall survival (OS) is 14 months. Although the benefit of early intensive care unit (ICU) admission has been shown in young AML pts, there is limited data on non-intensively treated pts admitted to the ICU. However, this issue is becoming increasingly important in routine practice, as some pts can now expect prolonged long-term survival. Methods In this multicenter retrospective study, we collected data on adult pts treated with VEN-AZA for newly diagnosed AML, admitted to the ICU between Jan 2018 and Feb 2025, in 14 French centers from the FILO group. We describe the outcome of pts admitted to the ICU before VEN-AZA initiation (“diagnosis” group) or after starting VEN-AZA for a complication (“post VEN-AZA” group). Post ICU OS was calculated from the date of ICU admission to death or last FU. Results We included 183 pts treated upfront with VEN-AZA (n=151, 82.5%) or VEN-AZA in alternance with cladribine/low dose ARAC (n=11, 6%) or triplets including targeted therapies or immunotherapies (n=21, 11.5%). Median age was 73 years (range, 19-85) and 123 pts were male (67.2%), 45 (24.6%) had a prior cancer, 43 (23.5%) a prior MPN and 24 (13%) a prior MDS including 8 (4.4%) previously treated with AZA. ELN 2024 risk was favorable (fav.) in 70 (38.3%), intermediate (int.) in 36 (19.7%), poor in 39 (21.3%) and missing for 38 (20.8%) pts. Seventy-four (40.4%) were admitted to the ICU in the “diagnosis” group, and 109 (59.6%) in the “post VEN-AZA” group, including 69 (37.7%) during cycle 1, 19 (19.4%) during cycle 2 and the 21 remaining pts (11.5%) after cycle 2. Among the 142 pts evaluable for response, best response was CR/CRi in 66 pts (46.5%). Main reasons for ICU admission were acute respiratory failure (37.7%), shock (20%), hyperleukocytosis and/or tumor lysis syndrome prophylaxis (TLS, 15.8%), sepsis (12%), acute kidney injury (7.7%) and other causes (6%). Median Sequential Organ Failure Assessment (SOFA) at admission was 6 (range, 1-18). During ICU stay, 141 pts (77%) needed respiratory assistance, including 40 (21.9%) requiring mechanical ventilation and 49 (26.8%) non-invasive ventilation and/or high flow oxygen. Seventy-four (40.4%) required vasopressors and 23 (12.6%) renal replacement therapy. Median duration of ICU stay was 5 days (range, 0-33). Sixty-four pts (34.9%) died within 30 days after ICU admission. Median post ICU OS was 3.4 months (1.7-5.1) and 12-month post ICU OS was 28.5%. In multivariate analyses for post ICU OS, taking into consideration gender, age, ELN 2024 risk, disease response and SOFA score, the factors that remained significant were the absence of response (HR=5.28, IC95%, 1.54-18.1, p=0.008) and a high SOFA score (HR=1.23, IC95%, 1.05-1.44, p=0.011). We compared “diagnosis” vs “post VEN-AZA” subgroups. Pts of the “diagnosis” group were less often male (52.7% vs 77.1%). ELN 2024 classification was fav., int. and poor in 48.3%, 36.2% and 15.5% of patients vs 48.3%, 17.2% and 34.5% of pts, respectively. SOFA score was 6 (range, 1-13) vs 6.5 (range, 1-18) in the two groups. In the “diagnosis” group, more pts were admitted to the ICU because of hyperleukocytosis/TLS (=37.8% vs 1%), or shock (29.4% vs 8.1%) compared to the “post VEN-AZA” group. Organ replacement was different as 59.3% vs 9.5% needed amines in and 31.2% vs 8.1% had mechanical ventilation in the diagnosis and the post VEN-AZA group, respectively. In the post VEN-AZA group, 37/65 (56.9%) evaluable pts were in response at time of ICU admission. ”Diagnosis” pts had a Day-30 post ICU OS of 89% (vs 48%). Median post ICU OS was 7.3 months (IC95%, 2.2-12.7) in the “diag” group, and 42% and 22% of pts were still alive at 1-y and 2-y, respectively. By contrast, pts from the “post VEN-AZA” group had a median post ICU OS of 0.8 month (IQR 0-2.4), and only 19% were alive at 1-y and 0% at 2-y. Conclusion Early ICU management, prior to initiating VEN-AZA, is associated with prolonged OS. By contrast, older AML pts admitted to the ICU after the beginning of VEN-AZA have a dramatically poor outcome (<1 month). This may help ICU admission discussion conducted between intensivists, hematologists and palliative care practionners, which also takes pts and families choices in consideration.

Abstract Background: CD71/TfR1 (transferrin receptor 1) is highly expressed in proliferative malignancies, including acute leukemias, and is associated with poor prognosis. INA03 is a first-in-class antibody-drug conjugate (ADC), transferrin competitive, targeting CD71, designed to exploit the iron dependency and high metabolic demands of leukemic blasts. INA03 selectively delivers MMAE, a cytotoxic payload to malignant cells while sparing normal tissues with low CD71 expression. Here we report the final results of the first in human (FIH) trial of INA03 in patients with relapsed or refractory (R/R) acute leukemia. Methods: This is an open-label, multicenter Phase I study (NCT03957915) evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of escalating doses of INA03 administered as a single agent IV infusion every 2 weeks in adult patients with R/R acute leukemia. Eligible patients must have exhausted standard treatment options. The study was conducted in 2 parts. In Part 1, 14 patients were treated across dose levels ranging from 0.02 to 1.5 mg/kg on Day 1, combined with either 0.02 or 0.10 mg/kg on Day 15 of each 28-day cycle. In Part 2, 20 patients received higher doses ranging from 1.5 to 3.0 mg/kg on Day 1 and 0.5 to 2.0 mg/kg on Day 15. The dose escalation design used a Bayesian Approach, with dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) as the primary endpoints. Secondary endpoints include PK parameters, pharmacodynamic (PD) biomarkers, and clinical response as defined by European LeukemiaNet (ELN) 2017 recommendations. Results: A total of 34 patients have been treated across 12 different dose sequences of INA03 administered intravenously on Day 1 and Day 14 of a 28-day cycle. Diagnoses included acute myeloid leukemia (AML); n=33, and mixed-phenotype acute leukemia (MPAL); n=1. Median age was 75 [39-83] years (74% male). According to ELN 2017 classification (available for 33 patients), 51.5% were classified as adverse risk, 45.5% as intermediate, and 3% as favorable. No DLTs were observed in Part 1 of the study. 4 DLTs occurred at the highest dose levels tested (2 out of 6 patients at 2.5/1.5 mg/kg and 2 out of 2 patients at 3.0/2.0 mg/kg). Adverse events were reported in all patients. A total of 11 patients (79%) in Part 1 and 19 patients (95%) in Part 2 experienced Grade 3–4 AEs. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 35.9% of patients; most common were gastro-intestinal (GI, 14.7% including stomatitis [8.8%], colitis [5.9%], large intestine perforation [2.9%] and ileus [2.9%]), and infusion related reaction (14.7%). No Grade 5 TRAEs were reported. Treatment discontinuation due to adverse events occurred in 26.4% of patients. The most frequent TRAEs of any grade were infusion related reaction (38.2%), gastro-intestinal disorders (35.3%) and rash (17.6%). PK analysis of MMAE confirmed dose-proportional exposure, with a terminal half-life of approximately 56 hours. Early signs of clinical activity were observed starting at 1 mg/kg. An exploratory efficacy cohort included 20 patients treated at dose levels ≥1 mg/kg. In this cohort, at time of analysis, 9 patients (45%) experienced a blast reduction >50%, 4 patients (20%) achieved an objective response per ELN2017: 2 complete responses (CR/CRi) and 2 partial responses (PR).Conclusions: INA03, first in class CD71/TfR1-targeted ADC, demonstrated a manageable safety profile and favorable pharmacokinetics in patients with relapsed or refractory acute leukemia. The MTD was defined at 2 mg/kg. Early signs of biological and clinical activity above benchmark of this novel targeted asset support continued investigation in Phase II studies and rational combination strategies.

Acute myeloid leukemias (AMLs) are the hematological malignancies with the highest need for intensive care unit (ICU) admission due to their association with various life-threatening situations. Limited data exist regarding the outcomes of elderly individuals with AML admitted to the ICU. However, current therapeutic protocols offer the potential for extended survival in this population. This retrospective, monocentric study focused on the outcomes of individuals aged ≥ 60 years admitted to the ICU for newly diagnosed AML. It included 139 patients admitted to the ICU at the Paoli-Calmettes Institute between April 2010 and October 2020, during the initial phase of AML management. Patients were categorized into three groups based on the presence of biological criteria indicating "high risk" for complications (thrombocytopenia < 50 000/mm3 and leukocytosis > 50 000/mm3) and organ failure. Multiple logistic regression models were employed to identify predictive factors for in-hospital and day 90 mortality, while Cox regression was used for 1-year mortality. The rates of in-hospital, day 90, and 1-year mortality were 37%, 42%, and 60%, respectively. Variables associated with in-hospital mortality included the Charlson Comorbidity Index, the need for invasive mechanical ventilation (MV), and multi-organ failure. ELN17 risk was significantly associated with 1-year mortality rates. This study demonstrates the benefits of ICU management for individuals aged ≥ 60 years during the initial phase of AML. It illustrates the effects of age, comorbidities, and the severity of organ failures on short-term mortality and highlights the impact of classical prognostic markers on long-term mortality.

PURPOSE:Prophylactic platelet transfusions (PT) aim to reduce bleeding. We assessed whether restrictive PT compared to prophylactic strategy could apply in ICU. MATERIAL AND METHODS:We conducted a retrospective monocentric study including patients >18 yo with haematological malignancy admitted to the ICU with thrombocytopenia <20 G/L between 2018 and 2021. Patients were classified in 2 groups according transfusion strategy applied during the first 3 days: prophylactic or restrictive transfusion. RESULTS:180 patients were included, 87 and 93 in the restrictive and prophylactic groups respectively. After propensity-score analysis, 2 groups of 54 matched patients were analyzed. Restrictive strategy led to a significant reduction in PT with incidence rate for 100-ICU-patients-days of 34.9 and 49.9, incidence rate ratio = 0.699 [0.5-0.9], p = 0.006, representing a 31% decrease. Decreased PT persisted until day 28 with platelet concentrates transfusions-free days at day 28 of 21 [13-25] and 16.5 [10.2-21] in the 2 groups (p = 0.04). Restrictive strategy did not result in higher grade ≥ 2 bleeding. Transfusion efficiency was low with similar number of days with platelet <10 or < 20 G/L regardless of strategy. Platelet transfusion strategy was not associated with 28-day mortality. Platelet nadir <5G/L was associated with day-28 mortality with HR = 1.882 [1.011-3.055], p = 0.046. CONCLUSION:A restrictive PT strategy appears feasible in the ICU.

IntroductionElderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients.Materials and MethodsWe included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019.ResultsTwenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06).ConclusionVEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.

OBJECTIVES:To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML).METHODS:We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021.RESULTS:Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates.CONCLUSION:VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.

Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.

OBJECTIVES:Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with intensive chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pretransplant treatment results in a general deterioration of the patient's health and quality of life. Furthermore, allo-HSCT can be responsible for significant toxicity with risks of graft-versus-host disease (GvHD). Developing strategies to prevent physical deconditioning, undernutrition and psychological distress could help maintain a satisfactory general state of health before transplantation and thus limit these deleterious effects. This protocol evaluates the feasibility and adherence to a personalised prehabilitation programme, which can be modulated and assisted by connected objects, provided from the diagnosis to the allo-HSCT.METHODS AND ANALYSIS:This multicentre interventional study will include 50 patients treated for AML or high-risk MDS with intensive chemotherapy and eligible for allo-HSCT. The intervention consists of a coached, supervised or self-directed physical activity programme, organised during the hospitalisation phases and periods at home. At the same time, patients will receive a weekly dietary follow-up. The whole intervention is controlled and modulated through the use of a dedicated application and connected objects allowing adaptation and individualisation. The rate of participation in the prescribed physical activity sessions will assess the feasibility of this study. In addition, the evolution of physical capacities (Short Physical Performance Battery, grip and quadriceps strengths), psychosocial parameters (Functional Assessment of Cancer Therapy - Leukaemia, Functional Assessment of Cancer Therapy - Fatigue, subjective well-being, Hospital Anxiety and Depression Scale, self-efficacy, Coach-Athlete Relationship Questionnaire, interviews) and clinical status (weight, lean body mass, survival rate, number of infections, days of hospitalisation, GvHD) will be evaluated.ETHICS AND DISSEMINATION:The study procedures have been approved by the National Ethics Committee (21.00223.000003). Consent is given in person by each participant. The information collected on the participants contains only a non-identifiable study identifier. The results of this protocol will be published in a scientific paper and communicated to the medical staff of the medical centre.TRIAL REGISTRATION NUMBER:NCT03595787.

Abstract A 66-year-old man presented with fatigue and fever. He was in excellent health status, with no comorbidity, working as a gamekeeper. Blood count revealed 80 G/L leukocytes, 84% blasts, hemoglobin 10.5 g/dL and platelets 27 G/L. He was hospitalized in intensive care unit (ICU) because of oxygen requirement and acute renal failure due to tumor lysis syndrome. Acute myeloid leukemia (AML-5b) with complexe karyotype was diagnosed on bone marrow examination. After initial cytoreduction with Hydroxyurea and Dexamethasone, intensive chemotherapy (Idarubicine and Cytarabine) was initiated in the ICU under close monitoring. Extra-renal epuration was required for tumor lysis syndrome.

Background: Relapsed or refractory (R/R) acute leukemias (AL) represent major therapeutic challenges. Several reports have highlighted the deregulation of iron metabolism in various proliferative tumor models (and notably AL) which includes the over-expression of the transferrin receptor (TfR1/CD71). Our strategy is thus to harness CD71 overexpression to specifically target cytotoxic agents to leukemic cells. INA03 is an antibody drug conjugate (ADC) constituted of a humanized monoclonal IgG 4 against CD71 and MMAE. We herein report the preliminary safety and efficacy data of a phase 1 trial INA03 (NCT03957915) evaluating INA03 in R/R AL. Methods: INA03 is given as 30 minutes IV infusion on days 1 (Loading dose,LD) followed by maintenance injections on D15 for cycle 1 and on D1 and D15 of cycle 2 and beyond. Eligibility criteria are age >18y, ECOG<2, R/R AL after at least one line of treatment with high dose chemotherapy and/or Vidaza and Venetoclax (VEN), LVEF>50%, Creatinine Clearance >30ml/min, normal liver function. The study design is based on a continuous reassessment method and includes 2 parts: a Loading Dose (LD) Titration study (Part 1, completed), followed by a Dose Escalation Part 2. During Part 1, sequential cohorts of 2 pts were included to receive ascending LD of INA03 followed by repeated fixed doses of INA03 to deal with a potential sink effect related to the high expression of CD71 in normal erythroblasts. During Part 2, sequential cohorts of 3 pts received escalating doses of INA03 Q2 weeks in 28-day cycles. The objectives were to establish the maximal tolerated dose (MTD) for subsequent administration and both safety/tolerability and anti-leukemic activity. Results: With a cutoff date of July 05, 2023, 27 patients (pts) across 10 cohorts were included in the study. The median age was 73 (range: 39 - 83), 25 (93%) pts had AML and two (7%) had ALL. Four (14.8%) pts had a prior allogeneic stem cell transplantation and 18 (66.6%) had prior VEN exposure. Pts received escalating doses of INA03 of 0.02 mg/kg to 3 mg/kg. Two patients in the 3 mg/kg loading dose cohort presented a dose limiting toxicity (DLT), one with grade 3 toxic erythema, grade 3 hepatitis and grade 3 mucositis and one with grade 4 colonic perforation. Up to the 2.5 mg/kg dose, no grade 2-4 treatment emerging adverse events (TEAE) were observed among the 19 evaluable pts and only one related grade 1 TEAE (hyperkalemia/phosphatemia) was reported. Transient decrease of reticulocyte count and erythroblasts percentage were observed at 0.5 mg/kg and above. Blasts reductions were seen in 6/20 (30%) evaluable pts at dose > 1 mg/kg including two partial responses according to ELN 2022 classification. MMAE pharmacokinetics (PK) appears dose-proportional with a small accumulation after repeated IV, while INA03 PK exhibits target-mediated drug disposition without accumulation. Conclusions: The preliminary results of this phase 1 study indicate that INA03 is well tolerated for doses up to 2.5 mg/kg. Induction of transient erythroblastopenia indicates effective targeting of CD71 in vivo and early signs of antileukemic efficacy have been observed in patients with refractory AL. Inclusion in the trial are continuing and additional data will be presented.

Background: With the advances in allogenic stem cell transplant (Allo-SCT), disease relapse has replaced transplant-related mortality (TRM) as main cause of treatment failure in acute myeloid leukemia (AML). Relapse risk after allo-SCT is about 30%, but is extremely variable depending on clinical and genomic features. The prognostic is very poor, with a 2-year survival rate reported to be less than 20%.There is no standard of care in this situation given the variability in patient’s and disease’s characteristics. In patients with good performance status, intensive chemotherapy can be considered, with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or 2nd allo-SCT. For unfit patients, the main goal is to provide acceptable quality of life. Aims: Our aim is to evaluate the outcome of AML post-transplant relapse. Methods: We presented here a single-institution series of 118 AML patients who relapsed after allo-SCT between January 2009 and December 2019. Results: Median age was 53 (20 – 69) years. 22% of the patients had FLT3 mutation and 53% had adverse genetic risk according to ELN. 79% have been transplanted in CR and 21 % with active disease. Conditioning regimen were myeloablative (MAC) in 39% and reduced intensity (RIC) in 61%. 45% of patients received an allograft from a matched related donor (MRD), 22% from an unrelated donor (MUD), 18% from a haplomismatch related donor, 10% from cord blood cells and 5% from a mismatched unrelated donor (MMURD). 18 patients received prophylactic DLI. 22 developed grade >1 aGVHD, and 23 cGVHD (all grades included). Median time from allo-SCT to relapse was 4.7 months (0.43-88.6). Intensive salvage therapy was used for 28% of the cohort, with a CR rate of 54% and an early mortality of 18%. 64% of patients received non intensive salvage therapy (i.e. demethylating agents, targeted therapies, DLIs…) with a CR rate of 18%. Four of these patients are still alive in CR, all after an association of Azacytidine plus Sorafenib with or without DLI. 8% received supportive care only. Seventeen patients of the cohort underwent a 2nd allo-SCT, 14 in CR (13 after intensive salvage, 1 after non intensive salvage) and 6 with active disease. Conditioning regimen were MAC in 35% and RIC in 65% and 90% of patients had a different donor. Donor was haplomismatch related (60%), MRD (20%), MUD (10%), MMUD (10%). The aGVHD (grade≥1)) and cGVHD (all grades included) rates were respectively 25% and 15%. Early TRM after 2nd allo-SCT was 25%. Four patients (25%) are alive in CR, after intensive salvage treatment and a 2nd allo-SCT in CR. In the whole study group, 1year OS from relapse was 25%, and median OS 5.1months. Factors influencing OS in univariate analyses were Sorror comorbidity score ≥3 at 1st Allo-SCT (1 year OS 17% vs 32%, p=0.036), time to relapse after Allo-SCT < 6months (1 year OS 16% vs 35%, p=0.020), and intensive salvage treatment (1 year OS 33% vs 24%, p=0.019). By multivariate analysis, only PS at relapse (2-3 vs 0.1, HR 1.96, p=0.01) independently influenced OS. Median follow-up (patients alive) was 70.2 (46.3-83.5) months. Summary/Conclusion: Our data are in line with published studies, and confirm the poor outcome of post-transplant relapse. Intensive salvage therapy shows reasonable response rate, but subsequent cellular therapy seems necessary to provide long term disease-free survival. Azacytidine in association with targeted therapy and/or DLI could be an alternative option to achieve remission.

Topic: 4. Acute myeloid leukemia - Clinical Background: AML and high-risk MDS are aggressive diseases with poor response to standard therapies. Access to innovative therapies through the inclusions in early-phase clinical trials (EPCT) is possible in Comprehensive Cancer Centers. Retrospective data regarding AML/MDS patients included in EPCT is scarce. Aims: We performed a retrospective analyze of patients with AML/MDS included in a EPCT at the Institut Paoli-Calmettes (IPC) with a CLIP2 label from the French National Cancer Institute. Methods: This monocentric study included all the AML/MDS patients referred for a potential inclusion in an EPCT at IPC. Data were collected from patient electronic medical records. Results: Between Oct 2020 and Dec 2022, 114 AML/MDS patients were referred to the EPCT unit for a potential inclusion. One-hundred and two patients were screened, 65 (63.7%) were included and 37 (36.3%) were screen-failed. Reasons for non-inclusion were poor-general status in 8 patients (25.8%), biological abnormalities in 8 patients (25.8%), infection in 7 patients (22.6%), patient opposition in 5 patients (13.5%), progression in 2 patients (6.5%) and other reasons in 7 patients (18.9%). Thirteen patients (20%) were referred from other centers and 52 (80%) were treated at IPC prior to inclusion. Eleven patients (16.9%) were included in a front-line setting and 64 patients (83.1%) had relapsed/refractory (R/R) diseases. Forty-three (66%), 13 (20%) and 9 (14%) patients were included in a phase 1, 1/2 and 2 EPCT, respectively. Median age was 72 yo (22-85), PS score at inclusion was 1 (0-1). Nine patients (13.8%) had MDS and 56 patients (86.2%) had AML, including de novo, “Myelodysplasia related”, and “therapy related” AML in 36 (64.2%), 17 (30.4%) and 3 patients (5.4%), respectively. ELN 2022 prognostic risk was favorable, intermediate, and adverse for 8%, 29% and 63% of patients respectively. Median number of prior lines of therapy (LOT) was 2 (0-7). Thirty-one patients (47.7%) had been previously exposed to Azacitidine/Venetoclax and 16 (24.6%) patients had undergone prior allogeneic hematopoietic stem cell transplantation (allo-SCT). Investigational drugs were immunotherapy, small molecules, and new cytotoxic agents in 39 (60%), 18 (27.7%) cases and 8 (12.3%), respectively. Treatment related grade 3-4 adverse events was 27,7%. Twelve patients (18.5%), including 7 patients in the R/R group and 5 patients in the 1st line group achieved a complete response (CR) or a CR with incomplete hematological recovery (CRi). Composite complete remission (CRc) rate (including CR, PR and MLFS) was 27.7% (18 patients), including 10 patients (18.4%) in the R/R AML/MDS group, respectively. Median duration of treatment in the study was 49 days (ranges, 6-598). Reasons for study discontinuation were progression, unacceptable toxicity, allo-SCT, or patient decision in 35 (60.3%), 7 (12.1%), 4 (6.9%) and 1 (1.7%) case, respectively. Eleven patients died during the study (all the deaths were judged non-related to the investigational drugs by investigators). Overall Survival (OS) measured from the date of inclusion was 10 months (95%CI, 3.7-16.2) in the whole cohort and 5 months (95%CI, 0-10.9) in the R/R group of patients (Figure). R/R status at inclusion and number of prior LOT (≤ 2 vs > 2) were associated with lower CRc rate (p=0.004 and p=0.006 respectively). R/R status was predictive of worse survival in multivariate analysis (p=0.025, HR 4.98 [95% CI: 1.23-20.19]). Summary/Conclusion: AML/MDS patients enrolled in an EPCT program reached significant CRc response rate (27.7%) and median OS (10 months). Main determinants of efficacy were number of prior LOT and R/R status at inclusion.Keywords: MDS/AML, Acute myeloid leukemia, MDS, Phase I/II

Introduction The last European LeukamiaNet (ELN) recommendations (Döhner H. et al. Blood. 2022) and the International Consensus Classification (ICC, Hasserjian R.P. et al. Virchows Arch. 2023) described a new entity, called myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) with TP53 mutation ( TP53mut), comprising high-risk MDS with an excess of bone marrow blasts cells (more than 10%) and a TP53 mutation (variant allele frequency VAF ≥ 10%). They suggested that MDS and AML represent a biologic continuum rather than two distinct diseases separated by a blast cutoff. Among teams who worked on that topic, T. Grob et al. ( Blood. 2022) studied the molecular characterization of high-risk AML and MDS with TP53mut and suggested that these two types of pathologies should be considered as a single entity, with no difference in molecular characteristics or survival. In this study, we describe the clinical, cytogenetic, and molecular characteristics of a cohort of 96 MDS and AMLs with TP53mut. Patients and methods We included all the patients with AML, MDS/AML, MDS with increased blasts (MDS-IB1) and MDS-low blast (MDS-LB) with at least one TP53mut (VAF ≥ 1%) received between Aug. 2020 and Dec. 2022 at the Institut Paoli-Calmettes (IPC, Marseille, France). Clinical and biological data were extracted retrospectively from the AML IPC database. Morphologic and cytogenetic data were analyzed by standard techniques. NGS was performed using a custom targeted panel of 60 genes (Custom Myeloid Lymphoid Solution, SOPHIA GENETICS). Results We registered 96 patients with a TP53 mutation (VAF ≥ 1%), divided into AML (n=60), MDS/AML (n=14), MDS-IB1 (n=12) and MDS-LB (n=10). Median age was 71 (range, 28-88). Thirty-eight patients had been treated for a prior solid malignancy and 26 patients had a history of myeloid malignancy. TP53mut was detected at diagnosis for 85 patients and at relapse or during follow-up for 12 patients (no NGS data available at diagnosis). We detected 142 mutations in the TP53 gene, mostly missense (73%) between exon 4 and exon 11 with a median VAF of 39% (Figure 1). We found 3 hotspots mutations in positions 273, 248 and 220 with respectively 9, 9 and 8 mutations. Biallelic status (presence of ≥ 2 mutations or a mutation + a deletion) was found in 66 patients (69%). Karyotypes were available for 95 patients. The karyotype was abnormal in 88% of cases, complex in 71% and unfavorable in 80% of cases according to ELN classification or Revised International Prognostic Scoring System (R-IPSS). Complete NGS analysis revealed at least one mutation in 59 of the other genes of the panel in 67 patients (70%), the most frequent being DNMT3A (22%), TET2 (17%), ASXL1 (13%) and PPM1D (11%) (Figure 2). In our cohort of TP53mut LB-MDS (n=10), we found that 9/10 patients had co-mutations in DNMT3A (n=4) , TET2 (n=6) and PPM1D (n=2) genes, 7/10 with biallelic status and 3/10 with complex karyotype. AML and MDS/AML patients with TP53mut detected at diagnosis (n=65) were treated with intensive chemotherapy (n=13), VEN-AZA (n=26), non-intensive therapy (n=14) or best supportive care (BSC, n=12). Seventeen patients were treated with allogeneic stem-cell transplantation (ASCT). With a median follow-up (FU) of 13 months, median overall survival (OS) of the whole cohort was 7 months (ranges, 1-41). Median OS in the AML and MDS/AML group was 6 months (ranges, 1-41). Patients treated with non-intensive approach had the longest median OS (15 months) compared to patients treated with intensive chemotherapy and VEN-based approaches (8 and 6 months, respectively) and patients treated with BSC (1 month, p=0.02). Patients with MDS-IB1 and MDS-LB had 11-months median OS (ranges, 1-28). The four patients treated with upfront ASCT were still alive at the last FU date and have an estimated median OS of 18.5 months (ranges, 6-26). Conclusion Our data confirm that MDS and AML with TP53 mutation are frequently associated with complex karyotypes and have a poor prognosis. nterestingly we identified mutations in PPM1D gene, involved in TP53 pathway, in 11% of cases. Patients with AML or MDS/AML treated with non-intensive approach seem to have the longest OS (15 months). Patients with MDS-IB1 or MDS-LB treated with upfront ASCT seem to have a prolonged OS (18.5 months). Clinical, functional and mechanistic studies are required to complete these findings.

Introduction Spliceosomes are complexes composed of small nuclear RNA that remove introns in protein-encoding genes. Spliceosome mutations ( SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary AML cases. Splicing mutations (splice-mut), in particular SRSF2, correlate with inferior outcomes to standard induction therapy. A recent report in a cohort of 119 patients, of whom 33 had splice mutations and 24 were SRSF2 mutated, reported the lack of impact of splice-mut on prognosis of AML patients treated upfront with Hypomethylating agents (HMA) + VEN in clinical trials (Lachowiez, C. A. et al Blood Adv. 2021). Aims We aimed to assess the impact of splice-mut in a population of patients with newly diagnosed acute myeloid leukemia (ND-AML), treated with VEN-AZA. Methods We performed a retrospective multicentric study including patients treated in three French centers in Marseille (Institut Paoli-Calmettes, CHU La Conception) and Nice (Hôpital L'Archet). Inclusion criterias were ND AML adult patients treated with VEN (7 to 28 days per cycle) and AZA at conventional doses. Next Generation Sequencing (NGS) was performed at diagnosis and was available for all patients. Data were collected from patients' electronic medical records. Statistical analyses were performed using GraphPad Prism v9.5.1 Results We included 117 ND-AML patients (median age = 75 yo; range, 32-89) treated with VEN-AZA between October 2019 and March 2023. The five most frequently mutated genes in the whole cohort were TET2, ASXL1, TP53 and RUNX1in thirty-seven (32%), 36 (31%), 32 (27%) and 31 (26%) patients, respectively. Thirty-four patients (29%) had a mutation in at least one of the spliceosome genes (=Splice-mut), including 20 (17%), 11 (9%), 4 (3%) and 1 (1%) mutations in SRSF2, U2AF1, SF3B1 and ZRSR2, respectively (Fig.1). Median variant allele frequency (VAF) was 42%, 43% and 26% for SRFS2, U2AF1 and SF3B1 respectively. Secondary AML was found in 18 (53%) of the splice-mut AML and 21 (25.3%) of the splice-wt AML groups of patients. Prior HMA was given in seven (20.6%) patients in the splice-mut versus 6 (7.2%) in the splice-wt cohort. Complex cytogenetics was identified in 7 (20.6%) patients in the splice-mut cohort and 28 (33.7%) in the splice-wt cohort. We found a TP53 mutation in 17.6% and 31.3% of splice-mut and wt cohorts, respectively. Best overall response rate (= CR, CRi and MLFS) was 72.6%; with CR, CRi and MLFS observed in 63 (54%), 16 (14%) and 6 (5%) patients, respectively. We did not find any difference in response rate between the splice-mut (=73.5%) and splice-wt (72.3%) AML. Prior treatment with hypomethylating agents and TET2 mutation were the only factors significantly associated with lower response rates (42% vs 82%, p=0.004, and 64% vs 85%, p=0.025, respectively), while IDH2 mutation was predictive of a better response (100%vs 75%, p=0.037, OR: 9.9 [CI 95% 0.57-173]). Median overall survival (OS) and leukemia-free survival (LFS) for the whole cohort was 10.8 and 7.1 months, respectively. In multivariate analysis taking into account TP53 and/or del17p, NRASmut and/or FLT3-ITD, IDH2mut, complex karyotype, and SRSF2, the only factors predicting OS and LFS were mutations in TP53 and SRSF2 genes. Patients mutated for SRSF2 had a 4.8 months OS and a 5 months LFS compared to 11.3 and 8 months, respectively (p=0.034 and p=0.037), comparable with TP53mut AML patients ( Fig.2). Conclusions SRSF2mut seems to be predictive of a worse survival in ND AML treated with VEN-AZA. This finding warrants further exploration in larger cohorts.

Background Acute respiratory failure (ARF) is the leading cause of intensive care unit (ICU) admission in patients with Acute Myeloid Leukemia (AML) and data on prognostic factors affecting short-term outcome are needed. Methods This is a post-hoc analysis of a multicenter, international prospective cohort study on immunocompromised patients with ARF admitted to ICU. We evaluated hospital mortality and associated risk factors in patients with AML and ARF; secondly, we aimed to define specific subgroups within our study population through a cluster analysis. Results Overall, 201 of 1611 immunocompromised patients with ARF had AML and were included in the analysis. Hospital mortality was 46.8%. Variables independently associated with mortality were ECOG performance status ≥ 2 (OR = 2.79, p = 0.04), cough (OR = 2.94, p = 0.034), use of vasopressors (OR = 2.79, p = 0.044), leukemia-specific pulmonary involvement [namely leukostasis, pulmonary infiltration by blasts or acute lysis pneumopathy (OR = 4.76, p = 0.011)] and liver SOFA score (OR = 1.85, p = 0.014). Focal alveolar chest X-ray pattern was associated with survival (OR = 0.13, p = 0.001). We identified 3 clusters, that we named on the basis of the most frequently clinical, biological and radiological features found in each cluster: a “leukemic cluster”, with high-risk AML patients with isolated, milder ARF; a “pulmonary cluster”, consisting of symptomatic, highly oxygen-requiring, severe ARF with diffuse radiological findings in heavily immunocompromised patients; a clinical “inflammatory cluster”, including patients with multi-organ failures in addition to ARF. When included in the multivariate analysis, cluster 2 and 3 were independently associated with hospital mortality. Conclusions Among AML patients with ARF, factors associated with a worse outcome are related to patient’s background (performance status, leukemic pulmonary involvement), symptoms, radiological findings, the need for vasopressors and the liver SOFA score. We identified three specific ARF syndromes in AML patients, which showed a prognostic significance and could guide clinicians to optimize management strategies.

Background: While many older patients with acute myeloid leukemia (AML) reach complete remission (CR) with intensive chemotherapy (IC), ~80% will ultimately relapse. Treatment options in relapse settings are limited and outcome is usually poor. The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial evaluated oral azacitidine (Oral-AZA; formerly CC-486), a hypomethylating agent, in patients with AML in first remission (CR1) after IC, who were not eligible for hematopoietic stem cell transplantation (HSCT). Unprecedentedly in AML, maintenance treatment with Oral-AZA was associated with significantly longer overall survival and relapse-free survival compared with placebo. Therefore, Oral-AZA received a marketing authorization in the EU as maintenance therapy in adult patients with AML who achieved CR or CR with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, HSCT. Also, French health Authority enabled an early access to Oral-AZA in this indication via a Temporary Authorization for Use (ATU) that started in June 2021. Aims: The aim of the study was to describe the characteristics of patients with newly diagnosed AML who received Oral-AZA for maintenance of CR/CRi after IC and consolidation treatment, who were not eligible for HSCT and were enrolled into ATU in France. Methods: ATU is a French early access allowing administration of the drug under a Therapeutic Use Protocol approved by health authorities. Data presented in this abstract were collected on a declaratory basis and were not monitored. A total of 52 patients were included in 32 centers across France and treated with Oral-AZA during the period from 09-Jun-2021 to 14-Sep-2021. Oral-AZA monotherapy was administered at 300mg once daily for 14 days per 28-days cycle. Results: Overall, 52 treated patients were included with a median age of 67.5 years [range: 35-85]. Regarding Performance Status, 22/52 (42.3%) had an ECOG 0, 25/52 (48.1%) 1 and 5/52 (9.6%) ≥2. The majority (43/52 [82.7%]) had a diagnosis of de novo AML, and the genetic risk (according to ELN2017 criteria) was favorable for 13/52 (25.0%), intermediate for 22/52 (42.3%) and adverse for 17/52 (32.7%) of the patients. Most of the patients had received 1 cycle of IC induction (45/52 [86.5%]). The induction regimen was 3 + 7 for 42/52 (80.8%) patients, among those, 3 (5.8%) received midostaurin along with the 3 + 7. Also 7/52 (13.5%) received CPX-351 as induction regimen. The median number of consolidation cycles was 2 [range: 0-6]; 8/52 (15.4%) patients did not receive any consolidation and 6/52 (11.5%) had >3 cycles of consolidation. The majority of patients (27/52 [61.4%]) received IDAC consolidation. The median time between AML diagnosis and Oral-AZA ATU request approval was 6.8 months [range: 1-98]. Because of the limited time frame of the ATU, follow-up is available for 14/52 patients, and the median follow-up is 21.8 days [range: 1-35]. During the follow-up period, one patient had a temporary interruption of Oral-AZA treatment due to grade 4 neutropenia. There was no reported permanent discontinuation of treatment related to an adverse event. Summary/Conclusion: The characteristics of the patients included in the Oral-AZA Early Access Program in France are in line with European label. These real-life results bring new insights in this population of patients who are not eligible to HSCT with high unmet need to prolong CR1. No unexpected safety signal was registered. Updated results will be presented at the meeting.