NPM1 mutations are among the most frequent genetic alterations in acute myeloid leukemia (AML) and have been associated with several immunophenotypic features. This study aims to characterize the immunophenotypic profile of this entity at diagnosis using multiparametric flow cytometry and to evaluate the impact of phenotype classifications on prognosis. Immunophenotypic analysis enabled the identification and characterization of various populations previously described in this entity, including immature (CD117+ HLA-DR+), neutrophil-committed (CD117+/heterogeneous HLA-DR-), and monocytic (with variable CD117 expression, HLA-DR+, and CD64+) leukemic cells, which were identified as leukemic expansions, as well as populations presenting immunophenotypic alterations. Cases were distributed in seven immunophenotypic patterns based on R-classification that considers the presence of the three previously described leukemic cell populations but independently of their proportion and relative distribution. Most of the patients included in this study (30, 33%) exhibited an immature and monocytic leukemic cells population (pattern 4), followed by those patients (16, 18%) with a predominant expansion of immature leukemic cells (pattern 1), and those (16, 18%) characterized by a neutrophil-committed leukemic population (pattern 2). Less frequent patterns included (11, 12%) neutrophil-committed and monocytic cells population (pattern 6), (7, 8%) coexistence of the three populations (pattern 7), (6, 7%) immature and neutrophil-committed leukemic cells population (pattern 5), and (5, 5%) predominant expansion of monocytic leukemic cells population (pattern 3). Our analysis indicated that cases with monocytic leukemic cells population predominance exhibit a trend towards a lower cumulative incidence of relapse compared to other leukemic populations, either as the predominant population or across different immunophenotypic patterns. However, differences did not reach statistical significance. These findings help us to contribute with additional information about the biological and immunophenotypic signature of NPM1-AML.

Introduction: Most patients with acute myeloid leukemia (AML) who receive palliative best supportive care (BSC) alone experience poor outcomes, with reported median overall survival (OS) below two months. However, a subset of these patients not deemed for active therapy may survive significantly longer (i.e, more than those receiving non intensive chemotherapy approaches), suggesting the presence of a clinically indolent AML (iAML) phenotype. Identifying such patients could have meaningful implications for therapeutic decision-making and trial design. Objectives: We analyze clinical and biological characteristics of patients aged ≥60 years with indolent AML (i.e, receiving BSC only and surviving ≥9 months), comparing them with other AML patients aged ≥60 years receiving BSC only and surviving <9 months. Methods: We conducted a retrospective analysis of the PETHEMA epidemiological AML Registry (NCT02607059), including patients aged ≥60 years diagnosed between 1990 and 2024 who received BSC only. BSC included transfusions and other supportive measures, with or without oral cytoreductive agents (e.g., hydroxyurea, melphalan, mercaptopurine or thioguanine). iAML was defined as OS ≥9 months. Patients alive at last follow-up with <9 months of observation were excluded. Baseline characteristics and outcomes were compared between iAML and non-iAML groups (i.e, those aged ≥60 years receiving BSC only and surviving <9 months). A multivariate logistic regression model was used to identify independent predictors of iAML. Results: Of 2,506 eligible patients (i.e, aged ≥60 years receiving BSC only and follow-up ≥9 months), 192 (7.6%) met criteria for iAML (survival ≥9 months). Median OS was 14.8 months (95% CI, 13.2–16.4) in iAML vs. 0.85 months (95% CI, 0.78–0.93) in non-iAML patients (p<0.001). Compared with non-iAML patients, the iAML group had lower leukocyte counts (median 4.4 vs. 12.5 ×10⁹/L, p<0.001), higher platelet counts (median 82 vs. 49 ×10⁹/L, p<0.001), lower peripheral blood blast percentage (median 14% vs. 29%, p<0.001) and lower bone marrow blast percentage (median 35% vs. 56%, p<0.001). They also showed lower lactate dehydrogenase (LDH) levels (median 360 vs 535 U/L, p<0.001) and higher serum albumin levels (median 3.72 vs. 3.30 g/dL, p<0.001), reflecting a less proliferative disease profile. Performance status was better among iAML patients, with 52.9% having ECOG <2 compared to 32.6% in the non-iAML (p<0.001). Secondary and/or therapy-related AML was more frequent in the iAML group (48.7% vs. 36.7%, p=0.001). Fever at diagnosis, was more frequent among non-iAML patients (37.0% vs 18.4%, p<0,001). No significant differences were observed in sex distribution, creatinine levels, or bilirubin levels. Baseline karyotype was available in 68.5% of iAML patients and 63.5% of non-iAML patients, with no significant difference in the frequency of normal karyotypes (51.1% vs. 60.8% among evaluable patients; p=0.063). Among patients with available molecular data, NPM1 mutations were less frequent in the iAML group (11.9% vs. 23.7%; p=0.078), and FLT3-ITD positivity was low and similar between groups (8.7% vs. 14.6%; p=0.268). In multivariate analysis the following variables were independently associated with iAML: bone marrow blasts <50% (OR 3.36; 95% CI, 1.60–7.06, p=0.001), platelets ≥50 ×10⁹/L (OR 2.64; 95% CI, 1.31–5.32, p=0.007), and albumin ≥3.5 g/dL (OR 2.21; 95% CI, 1.15–4.28, p=0.018). Conclusions:Approximately 8% of elderly AML patients treated exclusively with BSC show unexpectedly long survival, consistent with an indolent clinical course, reflecting that in the absence of more efficacious therapeutic regimens, some patients could benefit from less invasive approaches. Easily measurable clinical parameters such as bone marrow blasts, platelet count, and serum albumin may help identify these patients. Further prospective and molecular studies are warranted to validate these findings and elucidate the biological underpinnings of iAML.

Background/Objectives: The incidence of cardiac morbimortality in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) is unknown. Methods: We analyze the characteristics, incidence, risk factors, and outcomes of cardiac events in AML patients treated for second-line (2L) or third-line (3L) episodes. Results: Among 327 2L AML patients (median age 62 years old), 135 experienced cardiac events, with an incidence of 38.6% non-fatal and 1.3% fatal events at 6 months. The grade 1–2 incidence was 16.8%, and the grade 3–4 incidence was 23.5% at 6 months. Overall, 207 cardiac events occurred in the 2L cohort, the most frequent being hypertension (n = 45), bradycardia (n = 39), QTc prolongation (n = 35), heart failure (n = 33), syncope/presyncope (n = 22), arrhythmia (n = 18), and myocardial ischemia (n = 8). Median OS in the 2L cohort was 9.4 months, 21.4 months in patients with grade 1–2, 8.8 months in patients without a cardiac event, 7.6 months in grade 3–4 patients, and 2.1 months with in 5 patients (p = 0.0035). The multivariate analysis showed prior cardiologic antecedents (p = 0.013), intensive 2L chemotherapy (p = 0.01), and inclusion in a 2L clinical trial (p < 0.001) as independent risk factors for non-fatal cardiac events. Among 189 patients of the 3L cohort, the incidence of non-fatal and fatal cardiac events was 49.2% and 0% at 6 months, respectively. Non-fatal cardiac events were more frequent in patients with prior cardiac antecedents (p = 0.004). Conclusions: In summary, cardiotoxicity is a frequent and challenging complication in R/R AML patients. We identified the risk factors that could be relevant to implementing risk-adapted management guidelines, aiming to reduce morbi-mortality in this difficult-to-treat setting.

Background: The therapeutic landscape of acute myeloid leukemia (AML) has evolved substantially over the past three decades. While intensive chemotherapy (IC) was the mainstay until the mid-2000s, the advent of hypomethylating agents (HMA), venetoclax-based regimens, and targeted therapies (e.g., FLT3 or IDH1 inhibitors) has changed clinical practice, especially in older or unfit patients. However, population data describing the evolution of patient characteristics, treatment allocation, and outcomes remain limited. Methods: Out of 21,371 patients, we retrospectively analyzed 17,908 evaluable adult patients with newly diagnosed AML (non-APL) reported to the PETHEMA epidemiologic registry (NCT02607059) between 1990 and 2024 (Spain, Portugal, Colombia, Chile, Mexico, and Uruguay). Patients were grouped into three eras based on major therapeutic changes: 1990–2006 (one size fits all), 2007–2016 (tailored therapies), and 2017–2024 (targeted therapies). Variables included baseline characteristics, treatment and outcomes. Survival analyses used Kaplan-Meier and Cox regression. Results: Median age at diagnosis increased over time, from 62 years in 1990–2006 to 65 years in 2017–2024 (p<0.001), with patients aged ≥80 increasing from 6.9% to 14%. Despite this, baseline ECOG ≥2 decreased from 31% to 21% (p<0.001). Secondary AML increased from 20% to 31%, while extramedullary disease declined from 25% to 16% (p<0.001). No significant differences were observed in sex distribution. Hemoglobin levels declined slightly (median 9.0 to 8.8 g/dL; p=0.019), while median white blood cell and platelet counts remained stable through eras. Serum creatinine and bilirubin slightly decreased (p<0.001), and albumin increased modestly (p<0.001), suggesting improved baseline condition at diagnosis. Frontline treatment strategies evolved markedly. IC remained predominant but declined from 80% (in 1990-2006) to 67% (in 2017-2024), p<0.001. Non-intensive therapies rose from 1.1% to 23% (p<0.001), while best supportive care (BSC) declined from 20% to 10%, indicating broader access to active treatment. Within the IC group, conventional 7+3-like regimens remained dominant until 2016 (around 90%) but decreased to 71% in 2017–2024, with increasing use of CPX-351 (5.2%), IC+FLT3 inhibitors (10%), and IC+gemtuzumab ozogamicin (2.7%). In the non-intensive setting, venetoclax + HMA combinations emerged as a key component (31% in 2017-2024), although HMA monotherapy remained the most frequently administered option (48%). In contrast, low-dose cytarabine-based regimens declined from 65% to 16%. CR/CRi rates remained stable in the three periods for IC (65% vs. 61% vs. 63%%). The proportion of patients transplanted in first CR/CRi remained stable (23% vs. 18% vs. 20%). A shift from autologous to allogeneic transplant was evident: autologous transplant use declined from 15% to 3%, while allogeneic transplant increased from 8% to 17% (p<0.001). Among 17,908 patients, median overall survival (OS) improved significantly from 9.3 months in 1990–2006, 9.3 months in 2007-2016, and 12.8 months in 2017–2024 (p<0.001). In univariate analysis, OS improved in most subgroups during the last diagnostic period, including all age categories, both sexes, patients with ECOG <2, de novo AML, those treated with front-line IC (from 12.9 to 20.4 months), those who underwent allogeneic or autologous transplantation, and even among non-transplanted patients. However, no significant gains were observed in patients with ECOG ≥2, secondary AML, or those treated with non-intensive therapies or BSC. Median OS among patients aged <50 increased from 27.2 to 65.8 months, from 5.8 to 10.3 months among those aged 65–74, and from 3.0 to 6.1 months among those aged 75–79. Median OS for ECOG ≥2 patients remained poor across all periods (approximately 3 months). Survival in the BSC group declined from 1.6 to 0.6 months. In multivariate analyses, the diagnostic period remained independently associated with OS after adjusting for age, sex, AML type, ECOG status, transplant, and treatment strategy (p<0.001). Conclusions:This large real-world study spanning more than three decades highlights substantial improvements in survival and evolving treatment patterns in AML. Despite an older population, better functional status and supportive care, and increased use of both intensive and non-intensive active therapies likely contributed to improved outcomes.

BackgroundLAMVYX was a multicenter, single-arm, phase 2 trial designed to validate the safety and efficacy of CPX-351 in patients aged 60-75 years with newly diagnosed, secondary acute myeloid leukemia and to generate evidence on key issues not addressed in the preceding regulatory pivotal trial.MethodsThe primary end point of the study was the complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate after induction. Eligible patients were recommended to undergo allogeneic hematopoietic stem cell transplantation after the first consolidation cycle. Alternatively, patients could undergo up to six maintenance cycles with CPX-351.ResultsTwenty-nine patients (49%; 95% exact confidence interval [CI], 37%-62%) patients achieved a CR/CRi after one or two cycles of induction, with a measurable residual disease negativity rate of 67% as assessed by centralized, multiparameter flow cytometry. Among patients who had serial next-generation sequencing analyses available, clearance of somatic mutations that were present at diagnosis was achieved in 7 (35%). The median follow-up among survivors was 16.8 months (range, 8.7-24.3 months). The median event-free survival was 3.0 months (95% CI, 1.4-7.3 months), and the median overall survival was 7.4 months (95% CI, 3.7-12.7 months). In landmark analyses at day +100 from diagnosis, the 1-year overall and event-free survival rate among patients who underwent allogeneic hematopoietic stem cell transplantation was 70% (95% CI, 47%-100%) and 70% (95% CI, 47%-100%), respectively. The corresponding values were 89% (95% CI, 71%-100%) and 44% (95% CI, 21%-92%), respectively, for patients who entered the maintenance phase. No significant longitudinal changes were observed in severity index or quality-of-life visual analog scale scores.ConclusionsThe current data provide novel insights that might inform the clinical positioning and optimal use of CPX-351, complementing previous results (ClinicalTrials.gov identifier NCT04230239).

Background Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia. Methods The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0-2. In the dose escalation portion of the trial, patients received a starting dose of iadademstat at 90 mu g/m 2 per day (with de-escalation to 60 mu g/m 2 per day and escalation up to 140 mu g/m 2 per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m 2 subcutaneously, for seven of 28 days. The primary objectives were safety (analysed in the safety analysis set; all patients who received at least one dose of study treatment) and establishing the recommended phase 2 dose; secondary objectives included response rates in the efficacy analysis set (all patients who had at least one efficacy assessment). This study is registered on EudraCT (EudraCT 2018-000482-36) and has been completed. Findings Between Nov 12, 2018, and Sept 30, 2021, 36 patients with newly diagnosed acute myeloid leukaemia were enrolled; the median age was 76 (IQR 74-79) years, all patients were White, 18 (50%) were male, and 18 (50%) were female, and all had intermediate-risk or adverse-risk acute myeloid leukaemia. The median follow-up was 22 (IQR 16-31) months. The most frequent (>= 10%) adverse events considered to be related to treatment were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3-4) and anaemia (15 [42%]; of which ten [28%] were grade 3-4). Three patients had treatment-related serious adverse events (one fatal grade 5 intracranial haemorrhage, one grade 3 differentiation syndrome, and one grade 3 febrile neutropenia). Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 mu g/m 2 per day with azacitidine. 22 (82%; 95% CI 62-94) of 27 patients in the efficacy analysis set had an objective response. 14 (52%) of 27 patients had complete remission or complete remission with incomplete haematological recovery; of these, ten of 11 evaluable for measurable residual disease achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an objective response. Interpretation The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid leukaemia, including those with high-risk prognostic factors.

Background: FLT3 mutations occur in approximately 30% of AML patients and are associated with aggressive disease. Despite the approval of midostaurin and gilteritinib, the prognosis for FLT3+ patients with relapsed or refractory disease is poor. NMS-088 is a novel, potent FLT3, KIT and CSF1R inhibitor with superior preclinical activity compared with approved FLT3 inhibitors in different FLT3-driven models. In addition, NMS-088 is active on FLT3 resistance mutation F691L. Dose escalation results from a Phase I/II study to establish safety, dose selection and preliminary clinical activity for NMS-088 in patients with R/R AML and CMML are described. Methods: In the Phase I 3+3 escalations, NMS-088 is administered daily for 21 of 28 days (schedule A) or continuously (schedule B). Patients must have R/R AML or CMML unsuitable for standard therapy. The primary objective is the MTD or MAD as assessed by DLTs. Secondary endpoints include safety, PK and ELN response. Results: as of January 26, 44 R/R AML or CMML patients were treated at doses from 20 to 360 mg/day in A or from 120 to 250 mg/day in B. Median age was 64 yrs, 41 pts had AML and 3 pts had CMML, median number of prior lines was 2 (range 1 to 10). FLT3 mutations were present in 24 out of 41 AML pts (20 FLT3-ITD, 2 FLT3 D835 and 2 FLT3-ITD and D835). The majority of pts with FLT3+ AML had received prior FLT3 inhibitors (86.4%). NMS-088 showed manageable safety with no MTD characterized. One pt had DLT (abnormal posture, decreased activity, dyspnea G3 and eyelid ptosis G1) at 360 mg in A (at day 21) and one pt had DLT (eyelid ptosis G3) at 180 mg in B (at day 29), both suggestive for myasthenic syndrome. Three additional pts experienced possible myasthenic syndrome at doses ≥ 180 mg. Overall the most frequent treatment emergent related adverse events (≥10%) were nausea (any grade 20.5%), vomiting (13.6%), asthenia (11.4%). Discontinuations due to related AEs were as follows: 2 DLT pts per protocol, 2 pts due to nausea (G1; day 161 at 270 mg) and myasthenia gravis (G3; day 39 at 300 mg in a pt with baseline AChR antibodies). There was a dose-dependent trend for response. A total of 5 out of 12 evaluable pts with FLT3+ AML treated at dose ≥ 300 mg achieved a response with 2 CRi, 1 CRi/MLFS and 2 MLFS. Remarkably, all these pts had received prior midostaurin and 2 pts received both midostaurin and gilteritinib. Two pts with response withdrew from treatment to receive HSCT (DoR 1.0+ mos each). For other responding pts DoR was 1.3, 2.8 and 7.9 mos. Conclusions: NMS-088 showed clinical efficacy in pts with FLT3+ R/R AML, including pts who have failed prior FLT3 inhibitors. Together with the manageable safety observed, these results warrant further development of this drug including potential as a novel valuable therapeutic option for pts who have exhausted available treatments. The trial is currently opened for enrollment (NTC03922100). Citation Format: Antonio Curti, Alessandro Rambaldi, Chiara Cattaneo, Roberto Cairoli, Matteo Della Porta, Patrizia Chiusolo, Federico Lussana, Marta Ubezio, Valentina Mancini, Isabel Cano, Carmen Besliu, Christian Hove Claussen, Rosalinda Gatto, Patrizia Crivori, Elena Colajori, Alessio Somaschini, Cristina Davite, Antonella Isacchi, Elena Ardini, Lisa Mahnke, Pau Montesinos. NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT025.

Background: Natural killer (NK) immune status in Acute Myeloid Leukemia (AML) could influence therapeutic results and natural history of the disease. Objectives: In the phase I/II VEN-A-QUI (Clinical trials NCT04687761) clinical trial for unfit newly diagnosed AML patients (venetoclax+Quizartinib+azacytidine or low-dose cytarabine), it was planned a prospective study of NK populations and their influence in the main clinical outcomes. NK cells were analyzed at the diagnosis in a central laboratory. Material and methods: We analyzed NK cell subpopulations based in the expression of DNAM-1, TIGIT, TACTILE, CD8, PD-1, TIM-3, LAG-3, NKp44, NKp46, NKp30, CD16, CD85j,KIR2D, NKG2C, NKG2A, CD57, CD6, CD244, NKp80, Perforin, Granulolysin and Granzyme B. We compare composite Complete Remission (CRc) results of the Venetoclax/Quizatinib with Aza or Cytarabine vs. not achieving CRc using t Student. MaxStat statistics was used to test the significant limit of those populations with a significant difference (R-statistics version 4.2.2). Survival analysis comparing significant differences between patients in CRc was performed using LogRank test and Kaplan Maier. Cox survival analysis was performed to evaluate if the presence of this populations could be an independent factor against the European Leukemia Net classification of 2017 and p53. Data of molecular characteristics were obtained with an NGS panel of 40 genes. RESULTS: The trial included 76 ineligible patients for intensive chemotherapy (37 and 39 were in Aza and LDAC arms respectively). cCR was obtained in 39 patients (51.3%). ELN2017 risk was favorable in 8, intermediate in 15, and Adverse in 53. In 70 patients NK cell populations were analyzed (4 patients with very low percentage of NK cells, 2 with no sample at diagnosis were excluded from the study). There were significant differences between patients who achieve CRc and those who did not, according to DNAM-1 (74.4% vs 61.9, p=0.0018) and TACTILE (62% vs. 72%, p=0.02) expression on NK cells. The rest of antigens analyzed on NK cells were not significant. We found a cutoff of 62% of DNAM-1+ and less than 81% of TACTILE to differentiate populations in terms of survival using long-rank test. The number of DNAM-1 positive was 47 (60%) and TACTILE- was 55 (78%). The median OS of DNAM-1+ was better than DNAM-1− (18.4 vs 4.7 months, p=0.0001), and between TACTILE− vs TACTILE+ (17,36 vs. 4.6 months, p=0.005). Using an Cox model comparing karyotype, p53 and DNAM-1+ and TACTILE-, only DNAM-1+ was associated with better outcome (HR:0.33 (0.17-0.66) and TACTILE+ with worse (HR: 2.44 (1.20-4.99) in multivariate analysis. Conclusions: DNAM-1(CD226) positive and TACTILE (CD96) negative NK cell populations are associated to CR and better OS. These findings need to be confirmed in larger studies. Interestingly, DNAM-1 is an activating receptor and TACTILE is an inhibitory receptor for NK cells that share the same CD155 ligand but display opposite function.

The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1–2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4–5 events. The 9-year CI of grade 1–2 cardiac failure was 1.3%, grade 3–4 was 15%, and grade 5 was 2.1%; of grade 1–2, arrhythmia was 1.9%, grade 3–4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3–4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.

Background: The incidence of cardiac morbidity and mortality in acute myeloid leukemia (AML) population is not well known. AML patients (pts) receive potentially cardiotoxic drugs such as anthracyclines, QTc prolonging drugs such as FLT3 inhibitors, azoles, among others. Cardiac events can emerge in pts with previous cardiac diseases, or due to the toxicity of chemotherapy and other concomitant medications. So far, no previous studies have provided a holistic view of cardiac issues in a real-world series of AML pts. Aims: To estimate the cumulative incidence (CI) of cardiac events in a large series of unselected pts with AML in a single Spanish institution, and to identify risk factors associated with their development. Methods: Between January 2011 and June 2020, 571 pts were consecutively diagnosed with AML in Hospital La Fe, Valencia. The median follow-up of alive patients was 33 months. Clinical records were reviewed from diagnosis to death/last follow-up. Cardiac events were coded according to CTCAE. There were 525 treated pts, 285 (54%) with intensive chemotherapy and 240 (46%) with non-intensive therapy. Results: Among 46 untreated pts, 7 (15%) died due to cardiac events. Median age of 525 treated pts was 65 years, 331 (58%) male, and 73 (13.9%) had prior relevant cardiac comorbidities; 77 (14.7%) had FLT3-ITD mutation and 38 (7.2%) received front-line FLT3 inhibitors. Overall, 488 cardiac events were recorded, 19 (3.6%) pts had fatal cardiac events and 288 (54.9%) had any grade of non-fatal cardiac events. The 9-years CI of grade 1-2 QTcF prolongation was 11.2%, 2.7% pts had grade 3 QTcF prolongation >500ms, and no patient had grade 4 o 5. The 9-years CI of grade 1-2 cardiac failure was 1.3%, grade 3-4 15%, and grade 5 2.1%. The 9-years CI of grade 1-2 arrhythmia was 1.9%, grade 3-4 9.1%, and no pts had grade 5. Among 307 pts with cardiac events, 38 (12%) pts developed the first event before starting treatment, 132 (43%) during first cycle, 31 (10%) during consolidation, 55 (18%) during non-intensive further cycles, 14 (5%) during hematopoietic cell transplantation and 37 (12%) during follow-up. In the univariate analysis, pts with prior cardiac antecedents had increased incidence of fatal cardiac events compared with pts with no prior cardiac disease (CI at 9 years 20.1% vs 4.9%, p<0.001). Pts older than 65 years of age (64.4% vs 49.9%, p<0.001), prior cardiac disease (73% vs 54.6%, p=0.004) or included in clinical trial (65.2% vs 50.8%, p<0.001) had increased CI of non-fatal cardiac events. Multivariate analysis showed that prior cardiac disease was associated with increased incidence of fatal cardiac events [Hazard Ratio (HR) 1.9, p<0.001]. Age >65 (HR 2.2, p<0.001), prior cardiac disease (HR 1.4, p=0.02) and non-intensive chemotherapy (HR 1.8, p=0.004) were associated with increased CI of non-fatal cardiac event. Median overall survival (OS) in the overall cohort was 11.4 months (9.6-13.4 months, IC 95%). Among 285 intensive therapy pts, median OS was 22 months, 34 months in pts without cardiac events (n=125), 43 months with grade 1-2 (n=52), 15 months with grade 3-4 (n=98), and 5.2 months with grade 5 (n=10) (p<0.001). Image:Summary/Conclusion: We observed a high CI of cardiac events (58.5%) in a real-world series of patients undergoing AML therapy, associated with significant mortality due to cardiotoxicity (3.6%), and decreased OS. Prior history of cardiac comorbidity was associated with an increased risk of fatal cardiac events. Older age, cardiac comorbidities, and non-intensive therapies were related to non-fatal events.

7024 Background: Mutations in the FLT3 tyrosine kinase are the most frequent ones that occur in adults with acute myeloid leukemia (AML) and can co-occur with mutations in IDH1 or IDH2 (collectively IDHm) in up to 30% of cases. SEL24/MEN1703 is an orally available, dual PIM/FLT3 kinase inhibitor. Preliminary results from the phase 1/2 first-in-human DIAMOND-01 trial (NCT03008187) evaluating single-agent SEL24/MEN1703 showed activity in adults with relapsed/refractory (R/R) IDHm AML, where 3/8 IDHm patients (pts) responded. Here we report the first safety and efficacy results from an additional expansion cohort of the DIAMOND-01 trial in 20 pts with R/R IDHm AML. Methods: Pts with IDHm R/R AML and no standard therapeutic options were eligible. The recommended dose of 125 mg SEL24/MEN1703 was given orally, once daily for 14 days over a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was safety; adverse events (AEs) were graded according to NCI-CTCAE v4.03. The secondary endpoint was anti-leukemic activity including overall response rates (ORR). Results: As of 10 Jan 2022, 14 pts were enrolled in the IDHm cohort. Median age was 68 years (range 37-79). Four pts had AML secondary to myelodysplastic syndrome and 7 pts had intermediate cytogenetic risk. The median number of prior lines was 2 (range 1-3). Seven pts had IDH2, 1 had IDH1/2, and 4 had IDH1 mutations. Concomitant mutations in FLT3/ITD were detected in 2 pts. Median duration of treatment was 2 cycles (range 1-8). Safety data (N = 12) showed that serious treatment-emergent AEs (TEAEs; ≥5%) were pneumonia (33%), and skin infection and gastroenteritis clostridial (8% each). These were all unrelated to study drug. Drug-related TEAEs were liver injury, overdose, and hyponatremia (8% each). The drug-related liver injury occurred in a pt who was concomitantly receiving other drugs with known hepatotoxic potential. Grade ≥3 TEAEs (≥10%) were pneumonia (33%) and asthenia (17%), both unrelated to study drug. No differentiation syndrome was observed. Of the 7 pts who completed ≥1 treatment cycle and had ≥1 post-baseline assessment or clear disease progression, ORR was 28.6%; 1 pt achieved CRi at cycle (C) 3 and underwent hematopoietic stem cell transplant, 1 pt had PR at C4 (confirmed at C7 and still on treatment), 4 had disease progression, 1 discontinued for AE not drug-related. Among the 7 remaining pts, 3 discontinued before completion of C1 without progression or response, while 4 pts were ongoing and have not yet had any post-baseline assessment. Conclusions: Preliminary results in the IDHm cohort confirm that SEL24/MEN1703, a first in class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in pts with R/R IDHm AML. Updated results will be presented at the congress. Clinical trial information: NCT03008187.

OPB-111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid leukemia (AML), in preclinical models. In the present study, a phase 1b, two-stage, 3+3 dose-escalation clinical trial [dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28-day cycles] was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB-111077 in patients with high-risk AML. A preliminary preclinical analysis evaluated the anti-proliferative activity of OPB-111077 in 19 patients with AML with a Vivia Biotech ex vivo PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB-111077. Dose-limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment-emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB-111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high-risk AML. A biomarker-driven design is useful for selecting the study population upfront.

SEL24/MEN1703 had a manageable safety profile and single-agent activity in adult patients with R/R IDHm AML and may be a feasible therapeutic option in this difficult-to-treat population.

Background: Acute myeloid leukemia (AML) is a heterogenous disease with a broad spectrum of cytogenetic and molecular aberrations. Emerging targeted therapies have improved overall survival (OS) for some specific subgroups. Outcomes, however, remain poor, particularly for patients (pts) with high-risk characteristics and not eligible for intensive treatments. Combinations with hypomethylating agents are the standard of care (SoC) for unfit patients. Azacitidine (aza) plus venetoclax has shown an OS of 14.7 months (mo) and a complete remission or complete remission with incomplete hematological recovery (CR/CRi) rate of 66% (VIALE-A trial). The presence of mutations in TP53 or FLT3-ITD predicts resistance to this combination. Overall, 50% of AML pts relapse after first line treatments, generally attributed to the persistence of leukemic stem cells (LSC) and/or their clonal evolution, emphasizing the need to develop new strategies targeting LSC, to improve outcomes. One such investigational strategy is iadademstat (iada), an oral, potent and selective inhibitor of the Lysine-Specific Demethylase 1 (LSD1/KDMA1) enzyme. This enzyme works as a master regulator of transcription by a double mechanism of action: 1) removing methyl groups from histone 3 lysines (epigenetic eraser); and 2) disrupting multiprotein transcriptional complexes on genes governing cell differentiation and stemness. In myeloid cells, LSD1 provides a scaffold for assembly of the GFI1/CoREST transcriptional repressor complex, which regulates hematopoietic differentiation. Iada-induced gene expression shifts from a proliferation to differentiation signature has been preclinically characterized in AML cells (Maes, et al., Cancer Cell 2018) and in the clinic in a Ph1 study in Relapsed/Refractory AML (Salamero, et al., JCO 2020). To date, iada has been administered to more than 100 oncology pts in Ph1 and Ph2 trials, showing manageable toxicity and encouraging preliminary activity. Herein, we present the results of the Phase 2 ALICE study (EudraCT 2018-000482-36) testing the combination of iada plus aza for the frontline treatment of unfit AML patients, with a median follow-up of 6.9 mo (range 0.7-41.9) (cut-off June 30, 2022). The final data (cut-off September 30, 2022) will be presented at the ASH meeting. Methods: Unfit adult patients with AML per WHO 2017 classification who had not received previous treatment were enrolled. Two cohort doses of iada at 60 or 90μg/m2/d (PO, 5d ON, 2d OFF weekly) were explored in combination with aza (75mg/m2 SC for 7d, either d1-5, 8-9, or d1-7 every cycle) in a 28d cycle. Primary endpoints are safety, tolerability, and establishment of the recommended phase 2 dose (RP2D); secondary endpoints include remission rates, time to response (TTR), duration of responses (DoR) and OS. Additional assessments include measurable residual disease (MRD), PK/PD determinations and molecular correlations with response. Results: Baseline characteristics for 34 per protocol pts out of 36 accrued are shown in Table 1. Safety and efficacy results are detailed in Table 2. Main safety events remain consistent with previous updates, with the most frequently reported adverse reactions (AR) being platelet reduction in 53% of pts (58% of pts entered the study with grade ≥3 thrombocytopenia). Only 2 drug-related SAEs have occurred to date. Of 27 pts evaluable for efficacy, 81% responded (64% of those with CR/CRi). Responses were rapid (91% by end of C2). 71% of CR/CRi pts became transfusion independent and 82% of CR/CRi pts evaluable for MRD were negative by flow cytometry. Mean/median DoR (CR/CRi) are 9.3 mo (SE: 1.0 mo) / NE (95% CI 10.1mo, NE). Mean/median OS are 8.2 mo (SE: 0.80 mo)/9.3 mo (95% CI 11.0 mo, NE). Median OS for pts achieving CR/CRi is ~14.3 mo. Based on PK/PD, safety and efficacy, iada at 90 μg/m2/d is the RP2D for the combination. Response assessment per specific mutations shows that 3 out of 3 (3/3) with FLT3 mutations, 7/7 with RAS pathway mutations, and 6/8 pts with TP53 mutations responded. Gene expression and cell differentiation analyses are ongoing and correlations with clinical responses will be presented. Conclusion: The combination of iada with aza produces robust, rapid and durable responses in previously untreated unfit AML patients, including those with high-risk features, with a manageable toxicity profile. Further research with iada in combination with SoC treatments for AML is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background: Acute Myeloid Leukemia (AML) is an hematological malignancy with highest incidence and lower survival rates in elderly. Previously reported ORR with hypomethylating agents such as azacitidine alone is less than 30%. Recently, combinations of hypomethylating agents with venetoclax have shown improved response ratios. However, refractoriness or relapse is still a challenge for most patients (pts), particularly in the elderly and the high-risk subpopulations. It has been shown that LSD1 is involved in malignant transformation in AML. Iadademstat (iada) is a potent and selective LSD1 inhibitor that has been administered to more than 100 oncology pts in Ph1 and Ph2 trials, showing manageable toxicity and signs of preliminary activity. Aims: ALICE (EudraCT 2018-000482-36) is a Phase IIa study to assess the safety, tolerability and the recommended Phase II dose (RP2D) of iada (PO 5d ON, 2d OFF every week in 28d cycles) in combination with azacitidine (sc., d1-5 and 8-9 every cycle) for the treatment of adult patients diagnosed with AML, as per WHO 2016 classification, who have not received prior treatment and are ineligible for intensive chemotherapy. We present an update of the ongoing study six months after completion of recruitment. Methods: Two doses of iada are studied in the trial: 60 and 90µg/m2/d. Besides the safety and tolerability primary endpoints, secondary endpoints investigate anti-leukemic activity including ORR according to ELN recommendations, time to response (TTR) and duration of responses (DoR). Additional assessments include residual detectable disease status, overall survival and PK/PD determinations. Results: At EHA 2021, ALICE data from 27 pts were reported. In October 2021, recruitment of the targeted 36 pts was completed. Patient baseline characteristics are shown in Table 1. Main safety events by the end of 2021 included 348 adverse reactions (AR). The most frequently reported AR was platelet reduction, observed in 44% of pts, however, Grade ≥3 thrombocytopenia was already present at baseline in 61% of pts (Table 1). Only three Grade 3-4 nonhematological treatment-related ARs were observed in two pts (asthenia, dysgeusia and weight decrease). Among the 71 serious AR reported, only 2 were considered as potentially related to iada, corresponding to a differentiation syndrome and a fatal intracranial hemorrhage, previously presented at EHA 2021. By the time this abstract is written, among the pts intended to treat (34), 27 have had at least 1 bone marrow evaluation after cycle 1 and are therefore evaluable for efficacy. 78% of them (21 of 27) achieved an objective response; of which, 62% were CR/CRi. Moreover, 80% of the CRi pts also achieved partial hematology recovery (CRh). Among CR/CRi pts, 5 out of the 8 already assessed by MRD presented no residual detectable disease by flow cytometry. DoR is encouraging with 77% of the CR/CRi lasting more than 6 months, with a mean DoR increasing as the study progresses, with the longest CR to date above 1,100 days. Iada at 90 µg/m2/d is the confirmed RP2D for the combination, showing deep responses with manageable toxicity. Image:Summary/Conclusion: ALICE data confirms that the combination of iada with azacitidine gives robust, fast and durable responses in unfit, previously untreated, AML patients. Considering iada’s efficacy, pharmacologic properties, its manageable toxicity and low anticipated drug-drug interactions, iada combinations may offer additional therapeutic options for AML patients in first line or in the R/R setting.

Background: Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce. Methods: A retrospective review of medical charts identified patients aged 60–75 years with sAML between 2010 and 2019. Patient information was collected from diagnosis to death or last follow-up. Outpatient resource use, reimbursement, frequency and duration of hospitalization, and transfusion burden were assessed. Forty-six patients with a median age of 64 years were included. Anthracycline plus cytarabine regimens were the most common induction treatment (39 patients, 85%). The ratio of the total days hospitalized between the total follow-up was 29%, with a sum of 204 hospitalizations (average four/patient; average duration 21 days). The total average reimbursement was EUR 90,008 per patient, with the majority (EUR 77,827) related to hospital admissions (EUR 17,403/hospitalization). Most hospitalizations (163, mean 22 days) occurred in the period before the first allogeneic hematopoietic stem cell transplant (alloHSCT), costing EUR 59,698 per patient and EUR 15,857 per hospitalization. The period after alloHSCT (in only 10 patients) had 41 hospitalizations (mean 21 days), and a mean reimbursement cost of EUR 99,542 per patient and EUR 24,278 per hospitalization. In conclusion, there is a high consumption of economic and healthcare resources in elderly patients with sAML receiving active treatments in Spain.

Background: Venetoclax (VEN) combined with Azacitidine (AZA) or Low Dose Cytarabine (LDAC) has emerged as new therapeutic option for unfit acute myeloid leukemia (AML) patients (pts), but primary resistance is observed in roughly 40% of them, while relapses occur in the vast majority. We speculate that adding a FLT3-ITD inhibitor could improve the complete remission (CR) and overall survival (OS) rates in this setting. Aims: To explore the safety and efficacy of VEN-AZA or VEN-LDAC regimens in combination with Quizartinib (QUI) (VEN-A-QUI trial; EUDRACT2020-000406-28). Methods: The target population comprised newly diagnosed pts aged ≥ 60 years old unfit for intensive treatment, including those with secondary AML, with or without prior exposure to AZA. The Phase I consisted in two arms, one with AZA (Arm A) and the other with LDAC (Arm B) plus VEN combined with QUI to establish the recommended phase 2 dose (RP2D) of both triplets. Phase 1 scheme was based in 3 + 3 cohorts of patients observing cycle 1 dose limiting toxicities. Once established the RP2D the phase 2 comprised randomized 1:1 assignment of 60 patients (48 FLT3 wild type and 12 FLT3-ITD mut) to VEN-AZA-QUI vs. VEN-LDAC-QUI, comparing the CR/CRi rate of both arms. Secondary objectives were to evaluate the CR/CRi after cycle 1 and 4, compare OS and RFS between both triplets, quality of life, medical resources, exploration of biomarkers, and immune recovery. Results: Data cut-off for preplanned interim analysis included 57 pts screened and 45 enrolled, 16 in phase 1 and 29 in phase 2. Median age was 76,5 years (range 67-87), males/females (28/23). Previous MDS or MPN was present in 28 pts (59%); and 22 (48%) had previous treatment with AZA for MDS or MPN phase. We included 16 pts in phase 1, 9 with AZA and 7 with LDAC. RP2D of QUI was 60 mg in AZA arm and 40 mg in LDAC arm. No DLT was observed in arm B, and in arm A a brain hemorrhage after more than 40 days of thrombocytopenia at dose of 60 mg. The safety committee recommended performing an early (day 14-21) bone marrow assessment in cycle 1, leading to VEN interruption in case of aplastic morphology with grade 4 neutropenia or thrombocytopenia. No grade ≥3 related non-hematological adverse events (AEs) were noted during phase 1. The most frequent non-hematological serious AEs during phase 1 were infections (n=23), and gastrointestinal (n=20). No grade 3 QTc prolongation was observed. Objective responses were CR+CRh+CRi 7 pts (44%), PR 1 (6%), death 4 (25%), and resistance/progression 4 (25%). Twenty-nine pts (4 with FLT3-ITD mut) were enrolled in the phase 2 (15 in AZA and 14 in LDAC Arm). A median of 1 cycle (range 1-4) was administered at data cut-off, with best response among 24 evaluable pts: CR+CRh+CRi 10 (42%), MLFS in 3 (12%), PR 5 (21%), death 4 (17%), and resistance/progression 2 (8%). The overall response (CR+CRh+CRi+MLFS) was 54%. The more frequent non-hematological AEs were infections (n=35) and gastrointestinal (n=31). Two cardiac failures, 1 chest pain and 1 atrial fibrillation were noted in phase 2 (all of them unrelated to VEN or QUIZ). No grade 3 QTc prolongation was observed. Summary/Conclusion: This interim report shows an overall response rate of 54% using triplets (VEN-AZA-QUI or VEN-LDAC-QUI) for newly diagnosed unfit AML pts. However, substantial toxicity and early death cases were observed. Of note, 59% of enrolled pts had secondary AML, and 48% was exposed to AZA before inclusion. Final analyses with more pts and follow-up will clarify the efficacy and tolerability of these triplets.

Objectives Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction. Methods Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients. Results The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013). Conclusions This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities.