Incomplete Recovery Research Articles

Venetoclax Combining with Homoharringtonine，Daunorubicin and Cytarabine (HAD) As Induction Treatment in Newly Diagnosed Adult Acute Myeloid Leukemia Patients

INTRODUCTION Venetoclax (Ven), a potent oral inhibitor of BCL-2, has improved clinical outcomes in acute myeloid leukemia. For chemotherapy-fit patients, Ven combined with intensive chemotherapy (IA, CLIA, FLAG-IDA and DA) achieves high complete response (CR) rate and measurable residual disease (MRD)-negative rates in de novo AML after one cycle of induction therapy. Homoharringtonine (HHT, omacetaxine mepesuccinate) is an alkaloid derived from trees of the genus Cephalotaxus. HHT, cytarabine (Ara-C) and daunorubicin (DNR) regimen (HAD) have been used as standard remission induction regimen in China. Here, we reported the data of 25 patients with newly diagnosed AML who were administered with Venetoclax combining with dose-reduced HAD as induction treatment in our hospital. The purpose of this study was to observe the efficacy and safety of the regimen. METHODS Between May 2022 and February 2023, twenty-five newly diagnosed AML who fulfilled the criteria of AML according to the 2016 World Health Organization (WHO) classification were treated with Ven combined with HAD as induction treatment. The induction regimen consisted of oral Ven (100mg Day -1; 200mg Day 0; 400 mg, Days 1-7), intravenous HHT (2mg/m 2/d, Days 2-6), DNR (45 mg/m²/d, Days 4-5), and Ara-c (100 mg/m 2/d, Days 2-6). After achieving CR, allogeneic hematopoietic stem-cell transplantation (allo-HSCT) were recommended according to ELN guidelines. Patients who could not or did not need allo-HSCT received consolidation ± maintenance therapy. The consolidation therapy included two cycles of Ven combining with intermediate-dose Ara-C (Ven 400 mg on Days 1-7, Ara-C 1 g/m 2/q12 h Days 2-4), two cycles dose-reduced DA (DNR 45 mg/m², Days 1-2 and Ara-C 100 mg/m², Days 1-5) chemotherapy and one cycle HA (HHT 2 mg/m², Days 1-5 and Ara-C 100 mg/m², Days 1-5). After completing consolidation treatment, patients (intermediate and adverse risk) entered maintenance therapy with AZA (100 mg/d, Days 1-5) every month for at least four cycles. The primary endpoints were the overall response rate (ORR), included of complete remission (CR), complete remission with incomplete blood cell count recovery (CRi), and partial response (PR). Secondary endpoints were overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and the safety of regimens. RESULTS Between May 2022 and February 2023, 25 patients who were enrolled in this study. Baseline characteristics of the twenty-five patients are shown in Table 1. After one cycle of induction therapy, twenty-one patients achieved CR, CR rate was 84.0% (21/25 95% CI, 68.6-99.4); one patient achieved PR. The ORR (CR+PR) was 88.0% (22/25 patients; 95% CI, 74.3-100). Three NR patients and one PR patient achieved remission after salvage therapy. For patients who achieved CR after one cycle of induction therapy, MRD was evaluated in 21 patients by flow cytometry and 17 patients attained MRD negative (81.0%; 95% CI, 61.6-96.7). None patient died before response evaluation . To June 20, 2023, with a median follow-up of 10.0 (4-13) months, 9 (36.0%) patients underwent allo-HSCT. The median OS, EFS, and DFS were not reached, and the estimated 1-year OS, EFS, and DFS rates were 100%, 94.7% (95% CI, 89.6-99.8%), and 94.7% (95% CI, 89.6-99.8%), respectively (Figure 1). The most frequent hematological adverse events were Grade 3 to 4 anemia, thrombocytopenia, and neutropenia during the induction treatment and occurred in all patients (25/25 100%). The most frequent grades 3-4 non-hematological adverse events were febrile neutropenia (25/25 patients, 100%). None of patients died during the induction therapy. Conclusion: Ven combined with HAD is an effective and safe induction regimen in de novo AML patients. It is worth and necessary to enroll more patients to further verify this regimen. 【Keywords】Venetoclax; HAD; AML; induction treatment

Optimization of Idarubicin and Cytarabine Induction Regimen with Homoharringtonine for Newly Diagnosed AML Based on the Peripheral Blast Clearance Rate: First Result of the Multicenter, Randomized, Phase 3 Trial (RJ-AML 2016)

Background: Combination of idarubicin and cytarabine (IA) is still the basis of induction treatment for acute myeloid leukemia (AML). As previous reported in RJ-AML 2014 trial [1], day 5 peripheral blast clearance rate (D5-PBCR) can be used as an indicator of early treatment response, and for patients in the D5-PBCR (+) group, addition of homoharringtonine (HHT) to traditional IA induction showed good efficacy and safety. To further verify the efficacy in long-term outcome, we designed the RJ-AML 2016 trial. Here we report the latest response and survival results. Patients and Methods: The RJ-AML 2016 trial is a multicenter, randomized, phase 3 clinical trial, conducted to evaluate the efficacy of HHT in newly diagnosed young AML. Patients in D5-PBCR(+) group was eligible for addition of HHT, and were assigned in a 1:1 ratio, either to the intervention or control group. The primary end point was event-free survival (EFS). The secondary end points were composite complete remission (CR or CR with incomplete hematologic recovery), early death rate, measurable residual disease, drug toxicity, and safety. We hypothesized the 3-year EFS rate may increase from 30% to 50%, therefore the sample size of patients who enter randomization should be 250. Based on historical data, the rate of D5-PRCR(+) was 43%. Assume that 10% of patients may lost to follow-up, at least 638 eligible patients were needed. All patients enrolled in this study received induction regimen same as the RJ-AML 2014 trial. D5-PRCR(+) patients who assigned to the intervention group received additional chemotherapy (HHT 2 mg/m 2 on days 6-10). Favorable cytogenetic/molecular risks group received four courses of the HiDAC for consolidation. Patients with intermediate and unfavorable risks were recommended for allogeneic hematopoietic stem-cell transplantation. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-OIC-16007764. Results: From December 7, 2016, through April 29, 2023, a total of 747 patients underwent screening, 649 were included in the intention-to-treat (ITT) population and received IA induction from 6 sites in China. D5-PBCR were analyzed in 647 patients and 275 (42.5%) had D5-PBCR (+). Of the 275 D5-PBCR (+) patients, 145 were allocated to the intervention group, while 20 patients withdraw, of which 4 patients received additional FLT3 inhibitor and 16 cases continued IA induction; of the 130 patients allocated to the control group, 5 discontinued the IA regimen on day 6 or 7. Of the 372 D5-PBCR (-) patients, 2 patients discontinued IA. Baseline characteristics, including age, sex, blast counts in bone marrow, and cytogenetic parameters, were similar between two groups. While patients in D5-PBCR (-) group had higher white blood cell counts before treatment. Patients with CBFβ- MYH11 fusion, NPM1 and CEBPA bZIP mutations were more sensitive to IA induction. Meanwhile, high-risk gene mutations including ASXL1, RUNX1, TP53 and U2AF1 were more common in D5-PBCR (+) group. Details were showed in table. The overall composite CR rate after one course of induction was 73.2% in the ITT cohort. For patients in D5-PBCR (-) and D5-PBCR (+) groups, the CR rates were 82.8% and 60.4% , respectively (P<0.001). In the ITT cohort of D5-PBCR (+) group, CR rates were 51.1% and 68.3% for control and intervention arm, respectively (P=0.0046). In the Per-Protocol (PP) cohort, CR rates were 52.8% and 71.2% for IA and IA+HHT arm, respectively (P=0.0027). The overall early mortality rate was 4.9% in whole cohort, which were similar between two treatment arms. The last follow-up time was April 2023. Patients in the PP cohort who enrolled before April 2022 were included in this survival analysis (n=486), and the median duration of follow-up was 23.4 months. The median EFS was 40.6 months in the PP cohort, which showed significant difference between D5-PBCR (-) and D5-PBCR (+) groups [D5-PBCR (-): not reached, D5-PBCR (+): 16.0±1.9 months, P<0.001]. For patients in the D5-PBCR (+) group, no significant difference was found in 3-year EFS till the latest follow-up. While, the 3-year EFS was improved from 34.0±5.5% to 47.1±6.1% with the addition of HHT ( P=0.086). Conclusion: Current analysis indicated that addition of HHT can benefit young AML patients in the D5-PBCR (+) group. Complete follow-up combining with cytogenetic-molecular information can provide more reliable results. 1. Zhang Y, et al. Am J Hematol. 2022;97(1):43-51.

Real-World Evaluation of T-Prolymphocytic Leukemia Outcomes Using the 2019 T-PLL International Study Group Criteria

Introduction: T-Cell Prolymphocytic Leukemia (T-PLL) is a rare, aggressive T-cell malignancy with very poor prognosis. CLL criteria have historically been used for diagnostic and response criteria for T-PLL, but due to the T-PLL's distinct biology and clinical features in 2019 the International Study Group (TPLL-ISG) developed the first consensus criteria for diagnosis and response assessment to harmonize clinical research in T-PLL (Staber et al, Blood, 2019). Diagnostic criteria included both major and minor criteria, while standardized criteria were developed for complete response (CR), complete response with incomplete marrow recovery (CRi), partial response (PR), and stable disease (SD). While the TPLL-ISG consensus criteria are an important step towards uniformity in diagnosis and response assessment, the applicability of these criteria has not been assessed in a real-world population. We evaluated the diagnosis and clinical responses of the OSU T-PLL population using the TPLL-ISG criteria to evaluate the concordance of historical outcomes with previous diagnostic/response criteria. Methods: We retrospectively evaluated all patients diagnosed with T-PLL at The Ohio State University between 2009-2022. Diagnosis and response were evaluated utilizing the TPLL-ISG criteria. Overall survival (OS), progression-free survival (PFS), and duration of response (DOR) were assessed using Kaplan-Meier methods and log-rank test. Results: A total of 32 patients, with an average follow-up time of 23 months were evaluated. All patients met the TPLL-ISG criteria for the diagnosis of T-PLL with 29 (91%) meeting major criteria and 22 (69%) meeting both major and minor criteria; concordant with prior studies. 23 patients (72%) were TCL1A positive (by cytogenetics or FISH) and 18 patients (56%) had nodal involvement via PET or CT scan. For all patients, median OS and PFS were 20 months (95% CI 6-45) and 4 months (95% CI 2-17), respectively. Using TPLL-ISG criteria, the overall response rate (ORR) (CR/CRi/PR) to first line treatment was 63% with a median OS of 45 months (95% CI 8-88) and PFS of 26 months (95% CI 4-46). Median DOR was 16 months (range 1-36). The median OS and PFS for patients who achieved a CR were 45 months and 37 months, respectively. For those with a Cri, the OS/PFS was not reached and for those with PR, OS was 7 months and PFS 3 months. The median OS and PFS for patients treated with frontline alemtuzumab (n=26) was 20 months and 4 months and 8 months and 4 months for patients treated with a combination of alemtuzumab/pentostatin (n=4). The ORR for patients treated front-line with alemtuzumab or alemtuzumab/pentostatin was 63% (19/30), with a median OS of 41 months and PFS of 26 months. One patient responded to frontline pentostatin with a DOR of 16 months. The median DOR for any second line treatment (n=7) was 4 months. One patient had a DOR of 4 with alemtuzumab retreatment. Second line pentostatin (n=4) had an ORR of X, and median DOR of 3 months. Patients with CD4+CD8- disease (n=24) had a median OS of 20.4 months and a median PFS of 6 months, while CD4-CD8+ patients (n=3) had an OS of 8 months and PFS of 3 months, and CD4+CD8+ patients (n=4) did not reach median OS or PFS. Nine patients (28%) proceeded to allogeneic stem cell transplantation (allo-SCT). Patients treated with alemtuzumab first line who received allo-SCT had a significantly longer median OS (88 months vs 40 months; p=0.01) and PFS (46 months vs 9 months; p=0.04) compared to those that did not receive an allo-SCT. Response rates in this cohort were similar to published results (Table 1) suggesting no substantial difference between previously utilized response criteria and TPLL-ISG criteria (Table). Conclusions: No substantial differences in T-PLL response rates or survival were observed when using the TPLL-ISG criteria when compared to historical reports. Patients who had a CR or CRi to alemtuzumab that proceeded with allo-SCT had a significantly prolonged OS and PFS. Patients with CD4-CD8+ T-PLL had inferior survival , but this will need to be validated in a larger sample set. Consistent with previous studies, alemtuzumab produced the best responses, particularly for frontline treatment. Pentostatin provided transient responses as second line treatment but patients inevitably relapsed. Our results confirm the utility of the 2019 consensus criteria and set the basis for larger real-world studies to further assess the outcomes of patients with T-PLL.

A Systematic Review of Venetoclax and Azacitidine: Effectiveness and Safety for Newly Diagnosed and Relapsed Acute Myeloid Leukemia Patients

Introduction: Acute Myeloid Leukemia (AML) remains the most prevalent acute leukemia in adults, often associated with a bleak prognosis. Current treatment recommendations for elderly AML patients incorporate a combination of venetoclax (Ven) and azacitidine (AZA) following trials that underscored Ven's efficacy. This review seeks to analyze and summarize the literature concerning the effectiveness and safety of the Ven + AZA regimen for adult patients with newly diagnosed (ND) and relapsed/refractory (R/R) AML, and those unsuitable for intensive chemotherapy. Materials and Methods: Following PRISMA guidelines, a comprehensive electronic literature search was conducted across PubMed, Embase, Clinicaltrials.gov, Cochrane Library, and Web of Science from inception to 2023. MeSH terms and relevant keywords for (Leukemia, Myeloid, Acute) AND (Venetoclax) AND (Azacitidine) were used. From 327 initially identified articles, 12 studies were selected for inclusion, and citation searching further added 2 studies, summing up to 14. We analyzed data from a combined patient pool of 1256. Results: The review encompassed 13 non-randomized and 1 randomized clinical trials. The median patient age was 75.2 years. Primary outcomes comprised complete remission (CR) and complete remission with incomplete count recovery (CRi), yielding a pooled CR/CRi of 57.8%. Secondary outcomes included an overall response rate (ORR) of 61.1%, and a median overall survival (mOS) of 8.94 months with a median follow-up duration of 13.25 months (Table 1). Notably, high-grade adverse effects were predominantly hematological (anemia, neutropenia, thrombocytopenia, febrile neutropenia) while low-grade effects primarily involved gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation, decreased appetite, etc). Conclusion: The current data suggest that the Ven + AZA regimen is both efficacious and well-tolerated for treating newly diagnosed and relapsed/refractory AML. Cytopenias across all three cell lines emerged as the most reported adverse effects of Ven + AZA therapy. Ongoing Phase III clinical trials are expected to enhance our understanding of this regimen's efficacy and safety profile, solidifying its role in standard AML therapy.

Venetoclax Combined with Hypomethylation Agents As Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia - Priliminary Results from a Real World Study in China

Introduction: Venetoclax in combination with hypomethylation agents (HMAs) is a first-line induction regimen recommended by NCCN guidelines for patients aged older than 75 years or unfit for intensive chemotherapy. Since December, 2020, venetoclax has been approved in China for the treatment of AML patients who are older or unfit for intensive chemotherapy, and is gradually being used in an increasing numbers of hospitals in China. However, the efficacy and safety of venetoclax plus HMAs for the treatment of newly diagnosed adult AML patients, especially AML patients fit for intensive chemotherapy. Since January 2022, we have initiated a multicenter, prospective, observational study (No.2022219) to investigate the efficacy and safety of venetoxlax-based AML induction therapy in a real world setting. Here, we report the primary results of this study. Methods: A total of 25 sites in 19 provinces or municipalities across China participated in this study. The study population consisted of adult patients with newly diagnosed acute myeloid leukemia who had received venetoclax and HMA induction therapy and were available for evaluation. Diagnosis was based on the 2016 World Health Organization criteria. Risk stratification was performed according to the 2017 ELN recommendations. Clinical data were retrospectively collected from the electronic healthcare system and reviewed by the principal investigator of the lead site (The First Affiliated Hospital of Soochow University). The primary endpoint was composite complete remission (CRc, including complete remission, CR, and complete remission with incomplete hematologic recovery, CRi). Statistical analyses were performed using SPSS version 26.0 (Illinois, USA) and R4.0.4 (R Foundation for Statistical Computing, Vienna, Austria). Comparisons of categorical variables between groups were performed using the chi-square test or Fisher's exact test, and the Mann-Whitney U test and the Kruskal-Wallis test were used for continuous variables. P-values less than 0.05 were considered statistically significant. Results: Clinical data were collected from a total of 418 patients with newly diagnosed AML between January, 2022 to February, 2023. The minimum dose of venetoclax were 14 days. The baseline characteristics of all patients were shown in Table 1. The median age of all the patients were 64 (53-70 years). The was no difference in the gender distribution of patients (male to female ratio = 1.25:1). 231/418 (55.3%) patients had an ECOG score of ≥ 2 at the time of initiation of the induction treatment. 327 (80.9%) patients were considered unfit for intensive chemotherapy. 350/418 (83.7%) patients received azacitidine and venetoclax, and 12.3% of the patients received decitabine and venetoclax. Five patients were treated with specific targeted drugs along with decitabine and azacitidine, one patient was treated with flumatinib, two patients were treated with gititinib, and one patient was treated with sorafenib. A total of 384 (91.9%) de novo AML and 34 (8.2%) secondary AML patients were included in this study. According to the 2017 ELN criteria, 60 (14.4%), 114 (27.3%), and 244 (58.4%) patients were grouped to favorable, intermediate, and adverse risk groups, respectively. The overall response rate (ORR) for all patients was 77.5% (324/418). The composite complete remission (CRc) rate was 80% (48/60), 86% (98/114) and 73% (178/244) in the favorable, intermediate and adverse-risk group respectively (Figure 1A). There was no difference in CRc rates in patients with de novo AML or secondary AML(79% vs 65%, P=0.0699) (Figure 1B). Treatment responses varied among different sites (Figure 1C). The median amounts for platelet infusions and red blood cell infusions were 6.0 U (3.0-11.0 U) and 4.0 U (1.0-8.0 U). The median time of hospitalization during the induction treatment was 31 days (26-37 days). The median cost of induction treatment were $14,755 ($8,654- 22,991). Conclusion: In this study, venetoclax in combination with a hypomethylation agent showed comparable responses across all genetic subgroups in this real-world study of China，which was compared to the results of clinical studies conducted primarily in Western countries. Currently, we have collected 800 samples in this study. We will analyze and report the short- and long-term efficacy of venetoclax plus hypomethylating agent for the treatment of newly diagnosed AML in the near future.

Venetoclax Exposure Reduction in Venetoclax-Hypomethylating Agents Combination Is Feasible and Has the Same Efficacy in Patients with Acute Myeloblastic Leukemia. Experience of a Single Center

BACKGROUND The combination of venetoclax (VEN) and azacitidine (AZA) is the actual standard of care for patients with acute myeloid leukemia (AML) not eligible for intensive treatment ( Di Nardo et al. N Engl J Med 2020; 383:617-629). Despite being considered a low-intensity treatment, dose adjustments are frequently needed in this group of patients due to prolonged myelosuppression and increased incidence of infection. Reducing the duration of VEN administration might improve the safety profile, although its efficacy is still unknown in this setting. AIM We present the experience of the Institut Català d'Oncologia-Hospital Duran i Reynals in patients with AML treated with VEN in combination with hypomethylating agents (HMA) to evaluate the efficacy of VEN exposure reduction in patients who require VEN adjustment due to myelotoxicity. METHODS We retrospectively analyzed 68 patients with AML treated with VEN+HMA as a first-line or as salvage therapy between May 2019 and April 2023. We specifically evaluated patients in complete remission (CR) after 1 to 3 cycles of VEN combination who require VEN scheme shortening to 7 (low dose) or 14-21 (intermediate dose) days every 28 days cycle due to myelotoxicity. Response to treatment was defined according to ELN2022 criteria. RESULTS Median age at diagnosis was 75 years (range 33-85 years). Forty-seven (69%) were male. Twenty-eight (41.2%) were classified according to the 2022 ELN classification as an adverse risk, 33 (48.5%) as intermediate risk and 7 (10.3%) as a favorable risk group. The median number of cycles was 7 (range 1-23). ORR of the whole series was 76.5%. Forty-six (67.6%) patients achieved a composite complete response (CRc) (CR, CR with partial hematologic recovery, and CR with incomplete hematologic recovery). Among the 46 responding patients, seven of them (15.2%) discontinued treatment because of patient's decision after achieving CR and they were not considered for further analysis. The remaining 39 patients reached the best response in the first 2 cycles. Twenty-eight (71.8%) patients received VEN+HMA as first-line treatment and 11 (28.2%), as salvage therapy. No significant differences were found between these two groups regarding sex, age or ELN2022 risk. Nine out of these 39 patients (23.1%) received VEN for 28 days every 28 days cycle (VEN28 group), 21 (53.8%) patients received VEN for 14 or 21 per cycle (VEN14-21 group), and 9 (23.1%) patients received VEN for 7 days per cycle (VEN7 group). With a median follow-up of 18.8 months (range 14.6-23.1), the median OS of the VEN14-21 group was 15.9 months but it was not reached for the VEN7 group. Regarding EFS, the median EFS of the VEN14-21 group was 11.4 months though it was not reached for the VEN7 group. No statistically significant differences were found comparing OS and EFS between the VEN14-21 group and the VEN7 group nor were both of them with the VEN28 group (Figure 1). CONCLUSION Shortening VEN exposure to 14-21 or 7 days per cycle with concomitant HMA administration seems to induce a similar response rate and is likely to have comparable efficacy to the 28-day cycle. Among responders, VEN dose reduction seems to be associated with favorable outcomes. Prospective clinical trials that further evaluate the efficacy and safety of shortened VEN administration are required.

Psychiatric and Substance Use Disorders Are Independent Predictors of Treatment Response and Outcomes in United States Veterans with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Combinations

BACKGROUND: Venetoclax (VEN) combinations have become the standard frontline therapy for patients with newly diagnosed acute myeloid leukemia (AML) who are deemed unable to tolerate intensive induction chemotherapy, either due to age or comorbidities. However, outcomes in the real-world setting have been inferior to those observed in clinical trials. Preexisting psychiatric diagnoses and substance use disorders (SUDs) have previously been associated with increased mortality in patients with cancer, but their prognostic influence in veterans with AML is unclear. The aim of this study was to measure the prevalence of psychiatric and SUDs in veterans with AML treated with VEN combinations, determining the impact of these conditions on treatment response and outcomes. METHODS: This was a retrospective cohort study of veterans with newly diagnosed AML who received frontline therapy with VEN combinations within the national Veterans Affairs (VA) Healthcare System. To measure the prevalence of psychiatric and SUDs, we used the Centers for Medicare and Medicaid Services (CMS) Chronic Conditions Data Warehouse algorithm, which tracks health conditions by administrative claims data with International Classification of Diseases (ICD) diagnostic and procedural codes. Our endpoints were rates of complete remission or complete remission with incomplete marrow recovery (CR/CRi), early mortality (EM, or death within 60 days of treatment initiation), intensive care unit (ICU) admissions, and overall survival (OS). We evaluated the relationship between comorbid medical conditions and outcomes using Kaplan-Meier analysis and Cox proportional hazards regression models, first unadjusted, and then adjusted for all covariates. Patients who underwent allogeneic stem cell transplantation (HSCT) were excluded from statistical analyses. RESULTS: We identified 452 veterans treated with VEN up to April 1, 2022 (Table 1). In combination with VEN, 60% (n=270) received azacitadine, 37% (n=168) received decitabine, and 3% (n=14) received low-dose cytarabine. Median age was 74.3 years (IQR: 71.2-78.5) with 52% ≥75 years. By European LeukemiaNet (ELN) 2017 risk classification, 61% (n=274) were classified as adverse risk. Forty-six percent (n=206) of veterans had a preexisting psychiatric diagnosis, and 19% (n=84) had SUDs; 11% (n=49) had both comorbidities. Psychiatric disorders were significantly more prevalent in younger veterans (68% in <65 years vs 50% in 65-74 years vs 39% in ≥75 years, p<0.003); same was true for SUDs (38% in <65 years vs 26% in 65-74 years vs 9% in ≥75 years, p<0.001). For the entire cohort, CR/CRi was achieved by 57% (n=257), and only 3% (n=12) received HSCT. Zero veterans with SUDs and 8 with psychiatric diagnoses were transplanted. At the end of study period, 69% (n=310) had died. Median OS was 216 days (95% CI: 195-254). The 60-day mortality rate was 20% (n=87), of which 8 veterans had primary refractory AML. ICU admissions after treatment initiation was significantly higher in veterans with SUDs compared to those without history of SUDs (5.0 versus 2.2 per 5 person-years, p<0.001). On multivariable analyses (Table 2), both psychiatric and SUDs were independently associated with decreased odds of CR/CRi. Veterans with psychiatric disturbances had a 1.97 times higher hazard of EM (95% CI: 1.16-3.39, p=0.01) and a 1.28 times higher hazard of death (95% CI: 1.00-1.64, p=0.05) compared to veterans without concurrent psychiatric disorders. CONCLUSION: Psychiatric diagnoses and SUDs were not only prevalent among veterans with AML, but they also negatively impacted treatment response, EM, and OS-independently of age, sociodemographic variables, markers of disease risk, and VEN combination. Veterans with SUDs also had significantly higher ICU admissions after treatment initiation for AML. Compared to published clinical trials data, veterans experienced inferior outcomes. Veterans with psychiatric and SUDs may have difficulty adhering to regimens, reemergence of their mental instability and illness that is triggered by AML diagnosis and its treatment, or biologic mechanisms associated with these comorbidities. Better understanding of these factors contributing to health disparities and targeting these comorbidities with supportive care interventions alongside AML-specific therapy may improve outcomes and warrant further study.

Efficacy and Tolerance of Brexucabtagene Autoleucel in Adults with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia : A Graall Study from the Descar-T Registry

Background : Brexucabtagene autoleucel (brexu-cel) was recently approved for adult patients with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on the results of the ZUMA-3 phase 2 study. After a median follow-up of 39 months, brexu-cel showed a complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 71% and a median overall survival of 26 months (Shah B, et al. ASCO 2023). In the present study, we aimed at investigating the efficacy and safety of brexu-cel in a real-life cohort of adult BCP-ALL patients included in the French early access program. Methods : In this Group for Research on Adult Acute Lymphoblastic leukemia (GRAALL) study, we performed an analysis of the DESCAR-T registry which collects real-life data of patients treated with CAR T-cells since July 2018 in France. All patients who underwent a leukapheresis with an intent to manufacture brexu-cel were included (N=80). Efficacy and safety analyses were performed in the 64/66 infused patients with available response assessment after infusion. The data cut-off was June 2023. The present study reports on best overall response, overall survival (OS), relapse-free survival (RFS), as well as immune effector cell-associated neurotoxicity syndrome (ICANS), and cytokine release syndrome (CRS) incidence and grading (according to ASTCT Consensus). Results : Between May 2019 and February 2023, 80 adults with R/R BCP-ALL from 22 French centers had a leukapheresis for brexu-cel. Among them, 14 patients (18%) were not infused because of death (8 pts), progression (1 pt), manufacturing failure (2 pts), or other causes (3 pts). Among the 64 infused patients with available response assessment, median age was 43.5 yrs (range, 22-69). A Philadelphia(Ph)-chromosome was found in 20/64 (31%). Patients had received a median of 3 (range, 1-6) prior lines of treatment including blinatumomab, inotuzumab ozogamicin and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 67%, 19% and 70% of patients respectively. Twelve patients (19%) had an active CNS disease (CNS2/3) prior to apheresis and 18/40 (45%) had bone marrow blasts ≥ 25% before lymphodepletion (LD). ECOG before infusion was ≥2 in 6/64 (9%) patients. All patients received fludarabine and cyclophosphamide as LD. Median time from apheresis to infusion was 40 days (range, 27-99). CRS and ICANS occurred in 48/64 (77%, grade 3+ in 6%) and 28/64 (45%, grade 3+ in 8%) of patients respectively and were reversible. A CR was achieved in 49/64 patients (77%) of whom 23/25 (92%) were MRD-negative. An older age, a prior allo-HSCT, and the occurrence of CRS were associated with significantly higher CR rates. The median follow-up was 13 months. Three patients were bridged to an allo-HSCT in continuous complete remission (second allo-HSCT for 2 of them). The median RFS and OS were 12.9 months and 15.6 months respectively (Figure). In patients who achieved a CR, median OS was 25.8 months (Figure). Patients with CNS involvement before leukapheresis had a significantly shorter RFS (HR 5.4, 95%CI 1.9-15.8, p=0.002) and OS (HR 3.3, 95%CI 1.4-8.2, p=0.008). Number of prior treatment lines, prior inotuzumab, prior blinatumomab, or pre-LD BM blast% were not associated with outcome. A better OS was observed in patients with prior allo-HSCT (HR .4, 95%CI 0.2-0.9, p=0.04). Conclusion : This multicenter real-life study confirms the efficacy and acceptable safety profile of brexu-cel in adult patients with R/R BCP-ALL. It also suggests that patients with CNS involvement, that were not eligible to ZUMA-3 study, have a limited benefit of brexu-cel when compared to other patients.

Improved Survival with Venetoclax in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Cohort Study

Background: Venetoclax in combination with azacitidine or low-dose cytarabine has become standard treatment for newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML). Since approval of venetoclax in 2020 in Japan, venetoclax combination therapy have been also used for relapsed or refractory patients although its role in relapsed or refractory disease is not well defined. The survival impact of chemotherapy with venetoclax combination therapy compared with that without venetoclax combination therapy on AML patients in a real-life setting is scarcely reported. Objective: The aim of this retrospective study was to evaluate chemotherapy with or without venetoclax combination therapy in patients with newly diagnosed AML in our institution. Patients and Methods: This study included 234 non-M3 newly diagnosed AML patients who were treated with or without venetoclax combination therapy between February 2008 and July 2023 in our hospital. We evaluated overall survival and composite complete remission (complete remission or complete remission with incomplete hematologic recovery). Overall survival was compared with the use of a cox proportional-hazards regression model adjusted for age (1-year increase) and cytogenetic risk (favorable or intermediate vs. adverse). Composite complete remission was compared between the treatment groups with the use of a logistic regression model adjusted for the same prognostic factors. Subgroup analyses of overall survival was performed according to variables based on disease characteristics at baseline to assess whether the beneficial effect of venetoclax combination therapy varied among specific patient subgroups. Results: We identified 41 patients who were treated with venetoclax as first-line or later treatment and 193 patients who were treated without venetoclax. In the venetoclax group, 26 (63.4%) received venetoclax combination therapy as first-line and 15 (36.6%) as second- or later-line treatement. Twenty (48.8%) were treated with venetoclax combined with azacitidine, 12 (29.3%) with low-dose cytarabine and 9 (22.0%) with both in their course of treatment. Patients in the venetoclax group was older than those in the non-venetoclax group (median age, 76 years vs. 67 years, respectively; P<0.001). FLT3, NPM1, TP53 and IDH1/2 mutational status was comparable between groups. The percentage of patients classified as poor cytogenetic risk category according to the NCCN guidelines for AML, 2021 was higher in the venetoclax group than that in the non-venetoclax group (51.2% vs. 28.0%, respectively; P=0.005). The percentage of patients who umderwent allogeneic hematopoietic stem cell transplantation was lower in the venetoclax group than that in the non-venetoclax group (2.4% vs. 16.6%, respectively; P=0.014). Composite complete remission was achieved in 46.3% (95% CI, 30.7 to 62.6) of the patients in the venetoclax group and 54.4% (95% CI, 47.1 to 61.6) of the patients in the non-venetoclax group (P=0.199). In a Cox model adjusting for age and cytogenetic risk, the 1-year overall survival rate was 79.4% (95% confidence interval [CI], 66.5 to 87.8) in the venetoclax group, as compared with 68.0% (95% CI, 59.6 to 75.0) in the non-venetoclax group (adjusted hazard ratio, 0.64; 95% CI, 0.41 to 1.00; P=0.049). Subgroup analysis of overall survival showed a greater survival benefit in the venetoclax group than in the non-venetoclax group in patients who were 70 years of age or older (P=0.003 for interaction) and in patients with de novo AML (P=0.022 for interaction) after adjustment for age and cytogenetic risk. Conclusions: These real-world data suggested that incorporation of venetoclax combination therapy into existing therapies improved survival in patients with AML. The survival benefit of venetoclax combination therapy was greater in elderly patient and in de novo AML patients than secondary AML patients. Interpretation of the results must be careful because the sample size in the venetoclax group was small. To confirm our findings, further investigation in a larger patient population is required.

Only FLT3-ITD Mutation Did Not Have a Deleterious Effect on Acute Myeloid Leukemia Patients with NPM1 Mutation, but Concomitant with DNMT3A Mutation or a＜3log Reduction of MRD2 Predicted Poor Survival

Background Co-occurring mutations were observed in NPM1-mutated acute myeloid leukemia (AML) frequently, and the measurable residual disease (MRD) for NPM1 is effective for the prognosis of NPM1-mutated AML. However, the combined effects of co-occurring gene mutation at the baseline and MRD on survival are unclear. We investigated the impact of gene mutation status and NPM1 MRD on predictive value of AML patients with NPM1 mutation. Methord A single-center, retrospective cohort study was carried out in patients diagnosed as AML with NPM1 mutation in Peking University Peoples'hospital. Patients were treated by an anthracycline and cytarabine-based or homoharringtonine and cytarabine-based induction chemotherapy regimen and followed by high dose cytarabine as consolidation therapy. Patients who had the indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) underwent allo-HSCT. A small part of patients with FLT3-ITD mutation received FLT3 inhibitor. Targeted next-generation sequencing (NGS) were analyzed at diagnosis, and quantitative NPM1 mutation (A, B, and D type) were detected at diagnosis and each end of chemotherapy cycle. As MRD for NPM1 rare type (NPM1 RT) was not available, MRD, relapse free survival (RFS) or overall survival (OS) analysis were conducted in patients received chemotherapy only (NGS chemo), excluding harboring NPM1 RT. Results A total of 234 patients, with NGS results, diagnosed as NPM1-mutated AML were included. 68.4% (160/234) patients including 17 patients with NPM1 RT received chemotherapy only, and NGS chemo patients were 143. After chemotherapy, 31.6% (74/234) patients underwent allo-HSCT. 1.7% (4/234) patients died of infection or hemorrhage during induction therapy. 15.8% (37/234) patients received FLT3 inhibitor，and 92.2% (212/230) patients achieved complete remission rate (CR) or incomplete hematologic recovery (CRi). During median follow-up time of 24.9 [interquartile range (IQR) 11.6-47.8] months, 40.6% (95/234) patients died. Median transcription of NPM1 at diagnosis was 31.13 (IQR 17.23-56.91)%, and would take a median time of 4.1 (IQR 2.6-5.6) months to converted to negativity.Reduction of MRD at the end of second cycle of consolidation (MRD2) ≥3log associated with higher RFS (3-year RFS rate 66.3% vs. 11.1%, p＜0.001) and OS (3-year OS rate 78.4% vs. 32.4%, p＜0.001) than reduction＜3log, and consistent negativity of MRD also predicted higher RFS (3-year RFS rate, 98.1% vs. 42.3%, p＜0.001) and OS (3-year OS rate, 100% vs. 67.7%, p＜0.001) than those whose MRD turned from negativity to positivity. 9 genes were mutated in＞10% in 234 patients, and DNMT3A and FLT3-ITD were the most prevalence (Figure 1). Univariate analysis showed FLT3-ITD, DNMT3A and reduction of MRD2＜3log were associated with poorer RFS and OS in 143 NGS chemo patients. But In multivariate analysis, only DNMT3A mutation [RFS, hazard ratio (HR)=1.9, p =0.023; OS, HR=2.1, p =0.032] and reduction of MRD2 ≥3log（RFS, HR=0.1; OS, HR =1.9, both p＜0.001）were independent prognostic factors for survival. Four subgroups were divided by different status of DNMT3A and FLT3-ITD, that were both FLT3-ITD and DNMT3A negative, FLT3-ITD positive and DNMT3A negative, FLT3-ITD negative and DNMT3A positive, and both FLT3-ITD and DNMT3A positive. The concurrence of FLT3-ITD and DNMT3A was associated with lowest RFS and OS (3-year RFS rate 29.2%, p＜0.001; 3-year OS rate 53.5%, p＜0.001). However, patients with only FLT3-ITD mutation did not contribute to poor survival compared with patients without FLT3-ITD mutation (3-year RFS rate 71.4% vs. 74.4%, p＜0.843; 3-year OS rate 74.5% vs.75.8%, p = 0.759). Three risk group were re-stratified by the gene mutation and gene reduction of MRD2 (Figure2), and the RFS and OS of the poor risk group, defined by patients with ＜3log reduction of MRD2, or with both FLT3-ITD and DNMT3A mutation, could be improved by allo-HSCT(3-year RFS rate, 56.4% vs. 29.2%, p = 0.015; 3-year OS rate, 72.0% vs. 31.6%, p = 0.001). Conclusion In AML patients with NPM1 mutation, the deleterious effect of FLT3-ITD could be pronounced in patients concomitant with DNMT3A mutation. A＜3log reduction of MRD2 was also another independent poor prognostic factor for survival, which could be improved by allo-HSCT. Meanwhile, the conversion of MRD for NPM1 from negative to positive might be a poor prognostic factor, but it requires to be validated by multivariate analysis.

Selinexor and Chidamide in Patients with Relapsed/Refractory Acute Myeloid Leukemia Exposed to Venetoclax: A Single-Arm, Phase 2 Study

Background: Novel therapies for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are imperative, particularly those who have experienced relapse or resistance to multiline chemotherapies or venetoclax-based regimens, thereby underscoring the need for more innovative therapies that are both effective and well-tolerated. Chidamide and Selinexor have shown potential synergistic anti-leukemia effects by targeting NF-Κb /c-FLIP signaling via suppressing HDAC1/XPO1 activity. Therefore, the aim of this study was to investigate the activity and tolerability of chidamide combined with selinexor regimen for R/R AML. Methods: We report the findings of a phase 2 study in patients with relapsed/refractory AML that combined chidamide with selinexor. Selinexor was administered orally twice weekly for 4 weeks at a dose of 40/60 mg, depending on the patent's weight (over or under 70 kg). Chidamide was taken orally once a day at a dose of 10mg for 28 days. The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 1 cycles of treatment. The secondary endpoints include safety and survival. Results: Between December 2022 and April 2023, a total of 11 patients, median age 40 years (range, 22-54) were enrolled in the trail (ClinicalTrials.gov number, NCT05951855.). 8 out of 11 (72.7%) patients with R/R AML had received more than three prior lines of treatment. All of patients were previously exposed to venetoclax or hypomethylating agents (HMAs). Key baseline and clinical characteristics are summarized in Table 1. 10(90.9%) patients received the initial dose of 40 mg of selinexor twice a week, while one (9.1%) received 60 mg. Chidamide was administered to all patients at a daily dose of 10 mg daily. Five (45.5%) patients achieved a CRc (with 3 CR and 2 CRi), two (18.1%) achieved Partial remission (PR), and 5 (45.5%) had progressive disease for an overall response rate (ORR) of 63.6%. With a median follow-up of 147 days（range 59-234）, the median event-free survival (EFS) was 75 days and median overall survival (OS) was not yet reached (Figure 1). Among the seven patients who achieved CRc or PR, all proceeded to transplant after responding. One relapsed on day 56 following response and died 20 days later. Another patient died from an infection during the allogeneic hematopoietic stem cell transplantation (allo-HSCT). The remaining 5 patients are currently alive as of July 2023. No dose-limiting toxicities were observed. Common adverse events included neutropenia (72.7%), thrombocytopenia (63.6%), nausea/vomiting (63.6%), fatigue (45.5%), diarrhea (18.1%), bacteremia (9%). Conclusion: In this study, the combination of Selinexor and chidamide was administered as salvage treatment for R/R AML patients, resulting a high response rate and favorable safety profile. This offers a potential way for patients to bridge to transplantation. However, future studies with larger sample sizes and longer follow-up periods are needed to further validate its efficacy.

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Background and Significance Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment. CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition. CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211-2.). This abstract details a second study with CTX-712 that has just been initiated. Study Design and Methods A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

Gene-Edited Universal CD7 Chimeric Antigen Receptor T Cells for Pediatric T-Cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Background: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are highly aggressive T-lineage malignancies characterized by an infiltration of immature T cells in the bone marrow (BM) and peripheral blood (PB) or extramedullary organ involvements. Effective treatments were elusive, and the long-term survival of patients with refractory/relapsed (R/R) T-ALL/LBL remains poor despite allogeneic hematopoietic stem cell transplantation (allo-HSCT). CAR-T therapies for T-cell malignancies remain underdeveloped due to the shared antigenicity between normal and malignant T cells. CD7 is highly expressed on the surface of T-ALL/LBL T cells and is considered a viable CAR-T therapeutic target. However, CD7-targeting immunotherapies may be compromised by T-cell fratricide and extermination. And one of the biggest challenges with autologous CAR-T cell therapy is to isolate a sufficient number of healthy T cells from malignant T cells. Thus, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR9-associated protein 9 (Cas9)-mediated gene ablation has been used to produce universal CD7-targeted CAR T cells (UCD7-CAR) from suitable healthy donors that no longer express CD7 and TCR. In vitro killing tests, animal tests, and phase 1 clinical trials have preliminarily verified the efficacy and safety of universal CD7 CAR-T cells. Here we investigated the safety and efficacy of the universal CD7 CAR-T therapy in phase 2 clinical trial(NCT05454241) for pediatric R/R T-ALL/LBL patients. Aims: To investigate the efficacy and safety of the universal CD7 CAR-T therapy for pediatric R/R T-ALL/LBL patients. Methods: Patients over three years of age whose disease failed ≥ 2 lines of therapies and had ≥ 80% CD7 expression were eligible, including those who relapsed within 12 months after complete response or relapsed more than 12 months after complete response and failed to achieve remission induced by one or more courses of standard treatment; and patients with recurrence after hematopoietic stem cell transplantation. A lymphodepletion regimen was administered to all patients using fludarabine (30 mg/m2 per day) and cyclophosphamide (500 mg/m2 per day) for three consecutive days (day -5 to day -3) before CAR-T infusion. Patients received one single infusion of UCD7-CAR T cells at a median dose of 2.0×10^6/kg. Consolidative allo-HSCT after remission was allowed after day 28 after UCD7-CART infusion at the discretion of the physician and patient preference. All surviving patients were followed until July 15, 2023; the median follow-up was 109 days (54 to 117 days). Results: Five eligible children, 1 with r/r T-LBL and 4 with r/r T-ALL, were enrolled between December 2022 and April 2023 (Table 1). The median age of the patients was 5 (4-11) years. One girl(Patient 04) had a history of allo-HSCT before enrollment. Patients were heavily pretreated with a median of 3(2-6) lines of therapies. At registration, the median proportion of blasts in 4 T-ALL patients was 47.275% (6.0%-56.0%) in BM by FCM along with CNS(n=2) or testis(n=1) involvement. In contrast, 1 T-LBL patient(patient 02) did not have BM blasts but with bulky mediastinal masses ≥7 cm in diameter. All five patients had no or mild CRS (no CRS, n=1; grade 1, n=3; grade 2, n=1), and most(n=4) did not show symptoms of neurotoxicity. Patient 04, who received a prior allo-HSCT approximately seven months before CAR-T therapy, had a Herpes virus 6 (HHV-6B) encephalitis on day 17 after CAR-T infusion, but no GVHD was observed. On day 28, 4 of 5 (80.0%) patients who had BM involvement achieved MRD-negative complete remission (CR; n=2) or CR with incomplete hematologic recovery (CRi; n=2); but patient 02 with bulky mediastinal masses did not have an obvious response. Until the cutoff date, patient 04 still kept a sustained MRD negative CR; patient 05 relapsed again 49 days after CAR-T infusion, and the other three patients received a subsequent allo-UCBT with a CR state. All the children are still alive. Conclusion:UCD7-CAR T therapy is a safe and highly effective pediatric T-ALL/LBL treatment. More patients and longer follow-ups are needed for validation.

Association of Hypomethylating Agents + Venetoclax in the Real-Life Treatment of Myeloproliferative Neoplasms in Blastic Phase

Background Association of hypomethylating agents (HMA) and venetoclax (VEN) is widely used in elderly patients (pts) with de novo Acute Myeloid Leukemia not eligible for intensive chemotherapy, with improvement of survival. However, very few data are available in pts with Myeloproliferative Neoplasms evolved in blastic phase (MPN-BP). In this setting, the survival is dismal and at present no therapy seems to have a role. Methods Data of 54 pts with MPN-BP treated frontline with HMA+VEN in 19 hematologic Centers in Italy outside clinical trials from 11/2018 to 3/2023 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematologic improvement (HI)], duration of response and overall survival (OS) were assessed. Results: Baseline features at evolution and starting treatment are reported in the Table. Median interval from initial MPN diagnosis to evolution was 38.4 months [interquartile range (IQR) 15.4-124.5]. Pts were treated for a median of 3 courses (IQR 2-7): HMA were administered at standard dosage, VEN daily doses in the 1 st cycle are reported in the Table. On the whole, 40 pts (74.1%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN < 0.5 x 10 9/l) was reported in 37 pts (68.5%). Thirty pts (55.5%) had at least one infective episode during the treatment: pulmonary infections were reported in 13 pts (24.0%). Response to treatment is shown in the Table: ORR was 62.7%, with a median response duration of 9.4 months (95%CI 5.8-12.9). After a median follow-up of 6.7 months (IQR 3.2-12.1), 35 pts (64.8%) died, 2 (3.7%) were lost to follow-up and 17 (31.5%) were alive. Median OS of the whole cohort was 10.6 months (95%CI 5.8-15.3), Pts with any response to HMA+VEN had a significantly longer OS compared to pts with progressive/stable disease [11.6 (95%CI 9.4-13.7) versus 5.4 (95%CI 2.1-8.6) months, respectively (p=0.002)] (Figure). Conclusions: Our real-life data confirm that HMA+ VEN combination could have a role in MPN-BP, with ORR > 50% in pts unfit for intensive approaches: however, this treatment is affected by severe hematologic and infective toxicities and the response duration is short, with a persistently poor median OS. Larger cohorts of pts and a longer follow-up are needed to assess factors predictive of CR/iCR achievement, while addition of other targeted therapies should be explored.

Phase 1 Trial Results for Patients with Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT with Orca-T Donor Cell Therapy Product and Single Agent Tacrolimus

Introduction: Reduced intensity conditioning hematopoietic bone marrow stem cell transplantation (HSCT-RIC) is the only curative option for many hematological malignancies in older/unfit patients. Strategies to minimize complications such as graft versus host disease (GVHD) in HSCT include donor graft engineering but this approach has not been widely tested to the RIC setting due to a potential trade-off between engraftment and reduced GVHD with T cell depletion strategies. Here we present the interim results of our single center Phase I trial evaluating the T cell reduced Orca-T cell therapy product and single agent tacrolimus in the RIC setting. Methods: The trial is a single-center open-label phase 1 feasibility and safety study for dose escalation of conventional T cell (Tcon) infusion. Primary objectives included measuring the incidence of grade III-IV acute GVHD, time of engraftment and donor T cell chimerism at day +30. Secondary objectives are measuring relapse free survival, severity of GVHD and incidence of serious infections. While the study has three independent trial arms depending on donor type (HLA matched related and unrelated, 9/10 HLA matched or haploidentical matched), accrual has focused on the HLA-matched cohort which is reported here. The first 11 patients on this arm were conditioned with fludarabine 40mg/m 2, melphalan 50 mg/m 2 and 4 Gy of total body irradiation (TBI), an additional 4 patients have been treated with thiotepa 10 mg/kg replacing the melphalan. All patients received single agent tacrolimus with a target goal of 6-8 ng/ml. Results: A total of 15 HLA-matched patients have been recruited thus far in this interim dose escalation analysis. The median patient age is 68.0 years (range 62 to 72), with 73% male (11/15) patient distribution. Pre transplant, 53% had acute myeloid leukemia (8/15), 20% had myelodysplastic syndrome (3/15), 13% had acute lymphoblastic leukemia (2/15) and 13% had a myeloproliferative neoplasm (2/15). Prior to transplant, all acute leukemia patients were in complete remission (CR) or CR with incomplete count recovery. Median follow up was 10.4 months for the entire cohort (range 2 to 20 months). 14/15 patients had engraftment by day 20 and 1/15 at day 39 post-transplant. Based on these findings, no dose escalation of Tcon infusion was needed. None of the patients had infusion reactions on day of transplant nor engraftment syndrome. Median percent donor chimerism for CD15 was high, with 100% at day 30 (15/15, range 94% to 100%) and 99% (13/15, patients with available data, range 98% to 100%) at day 90. Median CD3 chimerism at days 30 and 90 of transplant were also high at 99% (15/15, range 68% to 100%) and 99% (for 13/15 patients with available data, range 78% to 100%) respectively. No patients developed grade III-IV acute GVHD ( Fig.), defined <100 days post-transplant. One patient developed grade II aGVHD. In 12 months, the incidence for moderate to severe chronic GVHD was 7%. The 12-month relapse free survival (RFS) is thus far 79% ( Fig.). The cumulative incidence for grade 2 and 3 infections in the first 90 days was 26.7%, where 2 patients died. One patient died at day 180 from liver biopsy complications for late onset hepatic sinusoidal obstruction syndrome. No surviving patient has had disease relapse. Conclusions: These early results demonstrate that Orca-T is a safe and feasible transplant strategy in the RIC setting for patients with advanced hematological malignancies. Patients showed robust and early donor myeloid and eventual full donor T cell engraftment. The low incidence of acute and chronic GVHD with low rates of disease relapse, suggest retention of graft versus leukemia effect. Few studies of donor graft-engineered products have been successfully evaluated in the RIC setting and merits larger multicenter studies evaluatingGVHD-free and RFS post-transplant to validate these findings.

Decitabine/Cedazuridine (ASTX727) Combined with a Molecularly-Targeted Agent (Venetoclax, Gilteritinib, Ivosidenib, or Enasidenib) As Personalized Maintenance Therapy in Acute Myeloid Leukemia: First Results from a Phase 1b Study

Background: Disease relapse is the major cause of treatment failure and death in acute myeloid leukemia (AML). Currently, oral azacitidine (CC-486) is the only drug approved in the maintenance setting in patients with AML who are unable to complete standard therapy. The ECOG ACRIN E2906 trial suggested an overall survival (OS) benefit with 3-day IV decitabine maintenance. Decitabine/cedazuridine (ASTX727) is an oral formulation of decitabine that achieves systemic exposures as seen with IV decitabine. Multiple small-molecule agents are now available targeting key leukemic drivers (BCL-2, FLT3, and IDH1/IDH2 inhibitors). We developed a multi-arm phase 1b study (NCT05010772) to evaluate an oral maintenance regimen composed of an ASTX727 backbone combined with a molecularly-targeted agent (venetoclax, gilteritinib, ivosidenib, or enasidenib). Methods: Patients ≥ 18 years with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) not currently eligible for stem cell transplantation (SCT) and unable/unwilling to complete standard therapy were eligible. Patients having received either intensive induction (at least 2 cycles of therapy based on intermediate to high dose cytarabine) or low-intensity induction (at least 3 cycles based on low-dose cytarabine or a hypomethylating agent) were permitted. Other inclusion criteria were ECOG ≤ 3, adequate hepatic/renal function, absolute neutrophil count > 0.5 x 10 9/L, and platelets > 50 x 10 9/L. Patients were enrolled in one of five arms per physician choice based on molecular profile. Arm A consisted of ASTX727 35/100 mg PO on D1-3. All other arms combined this ASTX727 backbone with either venetoclax 400 mg (adjusted for azoles) PO on D1-5 (arm B), gilteritinib 120 mg PO on D1-28 (arm C), enasidenib 100 mg PO on D1-28 (arm D), or ivosidenib 500 mg PO on D1-28 (arm E). Treatment was administered in 4-week cycles, up to 24 cycles. Each arm initially consisted of a safety lead-in cohort with predetermined dose reductions for dose-limiting toxicity (DLT) per a 3+3 dose de-escalation design. Prophylactic antibiotics, antifungals, and antivirals were encouraged. The primary objective was safety and tolerability. Secondary objectives included relapse-free survival (RFS) and OS. Patients becoming eligible for SCT were taken off study and censored at the time of SCT for time-to-event endpoints. Results: 23 patients, with a median age of 68 years (range 33-83), have been enrolled (3 on arm A, 19 on arm B, and 1 on arm C). 12 (52%) were enrolled following intensive induction and 11 (48%) after low-intensity induction. 16 (70%) had prior venetoclax. Best response at enrollment was CR in 22 (96%) patients and CRi in 1 (4%). 6/22 (27%) patients with available testing were measurable residual disease (MRD)-positive. 2 (9%) patients had antecedent myelodysplastic/myeloproliferative neoplasms and 1 (4%) had therapy-related AML. ELN 2022 risk was favorable in 10 (43%), intermediate in 3 (13%), and adverse in 10 (43%) patients. The most common grade 3/4 adverse events were neutropenia (96%), thrombocytopenia (74%), anemia (39%), lung infection (22%), hypertension (17%), and neutropenic fever (17%). Cycle 2 dose reductions due to myelosuppression occurred in 5/23 (22%) patients. No DLTs were observed. No deaths occurred on protocol. Two patients died in remission from SCT-related complications after going off maintenance. The current median follow-up time is 5.3 months (m). The median number of cycles given is 3 (1-15). Three relapses have occurred to date (1 in arm A, 2 in arm B). The median RFS for the full cohort is not reached (NR, 1-year 71%). The median OS for the full cohort (figure 1A) is NR (1-year 100%). The median RFS for arms A, B, and C are NR (1-year 67%), NR (1-year 84%), and NR, respectively (figure 1B). The median RFS is 14.5 m (1-year 50%) for patients who received intensive induction and NR (1-year 75%) for those who received low-intensity induction. The median RFS for patients who were MRD-negative and MRD-positive at enrollment were NR (6-month 93%) and NR (6-month 75%), respectively (p=0.50). Of the 6 MRD-positive patients, 2 (33%) cleared their MRD while on maintenance (both patients in arm B). Conclusions: A fully oral, targeted maintenance regimen is feasible in AML. Early results show encouraging RFS and OS. Further enrollment and follow-up are required to better assess the safety and efficacy of these regimens.

Efficacy and Safety of Asciminib in Chinese Patients with Philadelphia Chromosome(Ph)-Positive Leukaemias

Background Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) tyrosine kinase inhibitor (TKI). Its efficacy and safety profile in patients with chronic-phase chronic myeloid leukaemia (CML) have been shown in the Phase 3 ASCEMBL study, comparing asciminib 40 mg twice daily versus bosutinib 500 mg once daily. However, asciminib use in Chinese patients has hitherto not been reported. Moreover, the safety of high-dose asciminib (≥150 mg twice daily) in the Asian population is yet to be addressed. Here we present the real-world clinical outcomes of Chinese patients with Ph+ leukaemias in Hong Kong who received asciminib through a Managed Access Program (MAP). Methods Queen Mary Hospital (QMH) is a university-affiliated tertiary hospital in Hong Kong. Patients with Ph+ leukaemias under the care of QMH for whom asciminib was requested through MAP were included. Details on patient demographics, disease history, prior treatment lines, asciminib usage, adverse events, efficacy and death were collected. Results At data cut-off for analysis on 30 June 2023, 13 patients for whom asciminib was approved had data available. One patient passed away before the commencement of asciminib, and thus was excluded (Table 1). There were 7 patients with CML, who on diagnosis were all in chronic phase at a median age of 53 (22-70) years. All had received imatinib and at least one newer generation TKI, with 5 patients (71%) having received ponatinib. The majority (5 patients, 71%) received asciminib because of lack of efficacy of prior treatment, with 4 patients also having the T315I mutation. The median age at asciminib treatment (median dose: 400 mg, 80-400 mg) was 64 (28-76) years, with a median time from diagnosis of 81 (13-314) months. Two patients received imatinib concomitantly. The median duration of treatment was 12 (6-38) months. Two patients were already in at least major molecular response (MMR) before treatment, and have maintained that response. Two patients had ≥ 1-log reduction of BCR::ABL1 transcript level. Three patients had stable disease. There was one death unrelated to CML (Figure 1). There were 5 patients with Ph-positive acute lymphoblastic leukaemia (ALL), at a median age of 57 (18-68) years at diagnosis. All had received prior chemotherapy in combination with a TKI (imatinib, N=3; dasatinib, N=5; ponatinib, N=5), with 3 patients having undergone allogeneic haematopoietic stem cell transplantation (allo-HSCT). Three patients had detectable kinase domain mutation (T315I, N=2; E255K + E459K, N=1). The majority (3 patients, 60%) received asciminib because of lack of efficacy of prior treatment. The median age at asciminib treatment (median dose: 240 mg, 80-400 mg) was 58 (19-72) years, with a median time from diagnosis of 22 (7-47) months. The median duration of treatment was 16 (2-19) months. Four patients received another ATP-competitive TKI concomitantly (imatinib, N=1; dasatinib, N=1; ponatinib, N=2). For patients receiving asciminib due to prior treatment failure (N=3), complete molecular response (CMR) was achieved in 2 patients with measurable residual BCR:: ABL1; 1 patient with frank leukaemia achieved complete remission with incomplete hematologic recovery with molecular response at 0.06%. For two patients receiving asciminib because of intolerance to prior treatment, one further improved from MR4 to CMR while pre-existing CMR was maintained in the other patient. There were 3 deaths; 2 due to COVID-19 and 1 due to refractory leukaemia (Figure 1). Asciminib showed an acceptable safety profile, with raised lipase leading to dose reduction only in 1 patient. Grade 3 or above toxicities were all haematological, observed in 5 patients, 2 of whom had previous allo-HSCT. One patient on asciminib-ponatinib treatment developed grade 2 renal impairment. Conclusion Asciminib demonstrated promising clinical efficacy with satisfactory tolerance in this cohort of Ph+ leukaemias failing multiple lines of therapy. Further investigation of its therapeutic role in Ph+ ALL is warranted.

Response to Subsequent Novel Therapies and Time to Second Progression-Free Survival Event in the MURANO Trial in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Previously Treated with Fixed-Dose Venetoclax Plus Rituximab

Background: The randomized Phase III MURANO trial (NCT02005471) assessed fixed-duration treatment with venetoclax (Ven) plus rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Despite improved clinical outcomes (progression-free survival [PFS], overall survival [OS] and time-to-next-treatment [TTNT], as well as minimal residual disease conversion and progressive disease [PD] association [Seymour et al. Blood 2022]) for pts randomized to VenR compared with bendamustine-R (BR), most pts will ultimately require subsequent therapies. However, the efficacy of subsequent treatment after relapse remains largely unexplored. This study was conducted prior to the widespread availability of other targeted therapies, so pts were not previously exposed to targeted therapies prior to MURANO treatment allocation. Here we report response rates to follow-up therapy with Ven-based regimens, or Bruton tyrosine kinase inhibitor (BTKi) therapy, as well as time to the second PFS events from the final analysis of the MURANO trial. Methods: Overall, 389 pts were randomized to VenR (2 years of Ven, with R for the first 6 months) or 6 months of BR. Pts in either arm with PD were followed for disease response to any subsequent anti-CLL therapeutic regimens, PFS and OS. A sub-study, introduced in 2018, allowed pts who developed PD following treatment with VenR or BR to receive the MURANO VenR regimen. Pts who initiated new anti-CLL therapy without a response assessment reported by the investigator, were considered unevaluable. Results : At the final clinical cutoff date of August 3, 2022, all pts had ceased study-specified treatment and the median follow-up of the main study was 85.7 (range: 0-99.2) months. PFS and OS benefits were maintained at the 7-year follow-up (Kater et al. EHA 2023). Overall, 73/194 (37.6%) pts in the VenR arm had not received a next-line therapy at the final cutoff, and 26 pts had died without subsequent therapy. Median TTNT or death with VenR was 63.0 months vs 24.0 months with BR (hazard ratio: 0.30). Following PD, 95/194 (49.0%) pts randomized to VenR and 131/195 (67.2%) pts randomized to BR had received subsequent anti-CLL therapy; the median (range) time off therapy in these pts was 28.3 months (-0.1-68.6) and 17.9 months (0.7-82.4), respectively. Of the 95 VenR pts receiving subsequent anti-CLL therapy, 30 (32.3%) received BTKi therapy (ibrutinib [n=25], acalabrutinib [n=4] and zanubrutinib [n=1]), with 18 ongoing at the time of the final cutoff; 47 (51.6%) received Ven-based therapy, with 12 ongoing at the time of the final cutoff; and 16 (17.2%) received chemoimmunotherapy (CIT). Two pts received a non-CLL therapy for another malignancy so were excluded from the subsequent analysis. Of the 131 BR pts receiving subsequent therapy, 79 (60.3%) received BTKi therapy (ibrutinib [n=69], acalabrutinib [n=6] and zanubrutinib [n=4]), with 20 ongoing at the time of the final cutoff; 17 (13.0%) received Ven-based therapy, with 3 ongoing at the time of the final cutoff; 24 (18.3%) received CIT; and 11 (8.4%) received other novel agents. Median time from randomization to second PFS event was 85.9 months (95% confidence interval [CI]: 81.8-88.2) in pts randomized to VenR and 48.4 months (95% CI: 44.5-56.6) in pts randomized to BR; p<0.0001 ( Figure). Best overall response (BOR; defined as complete remission [CR], CR with incomplete count recovery, partial remission [PR] and nodular PR) rates to first subsequent anti-CLL therapy for pts with evaluable responses were 75/93 (80.6%) for VenR and 85/107 (79.4%) for BR. Among evaluable pts previously treated with VenR and BR, the BOR rate to subsequent BTKi therapy was 19/22 (86.4%) and 51/65 (78.5%), respectively, while BOR rate to subsequent Ven-based therapies was 32/42 (76.2%) and 15/17 (88.2%), respectively. Conclusions: Final data from MURANO demonstrate that, despite the majority of BR pts receiving novel therapies after relapse on MURANO, there was a significantly prolonged time to second PFS event observed in favor of the VenR arm. Pts who had relapsed and received retreatment or crossed over to Ven-based regimens or subsequent BTKi therapy also demonstrated high response rates. These results indicate that early intervention with fixed-duration VenR in R/R CLL is an effective approach and does not compromise subsequent therapy response.

A Phase 2 Study with Volasertib for Ven-HMA Relapsed/Refractory Acute Myeloid Leukemia Patients Guided By a Predictive Precision Medicine Platform

Introduction Acute myeloid leukemia (AML) represents a significant clinical challenge, with complex genetic heterogeneity that underlies the variable patient response to existing treatment modalities. While molecular features and novel therapeutic options offer promising solutions, their effectiveness is often compromised by inter-patient and intra-leukemia variability, coupled with an overall lack of biomarkers that can reliably inform therapeutic benefit. Consequently, these therapies yield clinical responses limited to only a subset of patients. Predicting a patient's response before initiating therapy optimizes treatment selection by improving the benefit/risk ratio (therapeutic index) and increasing response rates. This helps avoid treating non-responding patients, thereby reducing the occurrence of adverse effects and minimizing the costs associated with ineffective care. Here, we present an actionable strategy in AML that employs an automated, high-throughput, multi-color flow cytometry-based predictive precision medicine platform (PPMP) offering a genetic biomarker-agnostic approach to identify responders to standard-of-care (SOC) treatments and the polo-like kinase 1 (PLK-1) inhibitor volasertib. Clinical validation of the PPMP To date, we have conducted four studies evaluating the PPMP's predictive performance in myelodysplastic syndromes, adult AML, and pediatric AML with several SOC agents. For all studies, pre-induction blood or bone marrow samples were collected from patients then ex vivo treatment responses of individual leukemic cells were assessed using multi-color flow cytometry. The results were validated with the patient's actual clinical response as reported by physicians and indicated high precision-with positive predictive values (PPVs) of 83-100%. These findings help establish a PPMP-based pursuit of investigational therapies to enhance their therapeutic utility in distinct response groups. Case study: Volasertib One application of this approach involves the revival of volasertib, a PLK-1 inhibitor with demonstrated activity in AML, that was discontinued by Boehringer Ingelheim (BI) after failing its Phase 3 study. A BI Phase 2 study showed volasertib combined with low-dose cytarabine (V+LDAC) delivered a complete response (CR) + CR with incomplete count recovery (CRi) rate of 31.0% compared to 13.3% from LDAC monotherapy, and higher overall survival (OS). Similarly, in a global Phase 3 study a CR + CRi rate for V+LDAC (27.7% overall response) compared to Placebo+LDAC (17.1%) was reported. However, the Phase 3 study showed a higher frequency of fatal events with V+LDAC, especially in non-responders, resulting in lower median OS. By accurately pinpointing clinical responders, the integration of PPMP aims to identify those patients deriving clinical benefit (CR or CRi) from volasertib. Clinical trial design We plan on initiating a Phase 2a single-arm, open-label clinical trial in AML with volasertib in Ven-HMA relapsed or refractory patients, while co-developing PPMP as a companion diagnostic to selectively enroll predicted responders in a follow-up Phase 2b study (Figure 1). Intially, 20-30 patients will be enrolled. Once sufficient responders are achieved and certain performance thresholds of the drug sensitivity platform are met, an additional 20-30 patients will be enrolled, utilizing the companion diagnostic to selectively enroll predicted responders. The primary objectives will be focused on efficacy and safety of intravenous volasertib (possibly in combination with another drug) in patients with relapsed/refractory AML. Secondary objectives will include ex vivo response data collection to optimize the diagnostic parameters for the Phase 2b study. Primary Phase 2a endpoints include AML disease response assessment per pre-specified criteria. Secondary endpoints include an assessment of the diagnostic performance characteristic of Notable's drug sensitivity score in predicting in vivo volasertib clinical response. Specific strategies, including tailored dosing, robust infection control, and carefully selecting drug combination partners are designed to mitigate the adverse events observed in BI's Phase 3 trial and maximize volasertib's therapeutic impact regarding both efficacy and safety.

Tyrosine Kinase Inhibitors with Intensive Chemotherapy in AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1: Time to Reconsider Prognostic Risk? a Study from the Dataml Registry

Introduction De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is now a distinct entity of the ICC and WHO 2022 classifications within the group of AML with defining genetic abnormalities. This entity is distinguished from cases with history of chronic myeloid leukemia (CML) and ≥ 20% blasts, which are classified as CML in myeloid blast phase (CML-BP), although the distinction between both entities could be challenging. In the 2022 ELN classification, AML with BCR::ABL1 belong to the adverse risk group. However, this entity is very rare and generally excluded from clinical trials. Thus, there is little data on outcome especially since the era of BCR::ABL1 inhibitors (Orsmark-Pietras C et al.). In this study, we thought to describe treatments and outcome of patients (pts) with de novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 in comparison with CML-BP and ELN 2017 intermediate (Int) or adverse (Adv) risk AML. Methods Inclusion criteria were: pts aged ≥ 18y, included in the DATAML registry between 2000 and 2021, with either de novo BCR::ABL1 AML defined as no previous history of CML, no previous treatment with TKI and ≥ 20% blasts in bone marrow/blood or CML-BP defined as the occurrence of ≥ 20% blasts following the diagnosis of CML in chronic phase. Outcomes of pts with de novo BCR::ABL1 AML were compared with those of CML-BP pts and AML with ELN 2017 Int (n=643) or Adv (n=863) risk treated with intensive chemotherapy (IC) over the same period. A 50-gene NGS panel was retrospectively performed on available samples. Results We identified 20 pts with de novo BCR::ABL1 AML among 5819 AML (0.3%). We only studied the 18 pts who received IC. Their main characteristics were: female to male ratio (55.6%), median age (54y), extramedullary disease (47%) including splenomegaly (35%); high WBC at diagnosis; isolated t(9;22) (67%); p210 isotype (78%), mutations in ASXL1, RUNX1, NPM1, TET2, BCOR, BCORL1, DNMT3A, EZH2, IDH1, KDM6A, NF1, SMC1A, SRSF2, WT1. Comparisons with the 24 pts CML-BP who were treated with IC are shown in the Table. The main differences between both groups was a higher WBC and the presence of NPM1 mutation in de novo pts whereas ABL1 mutations were found in CML-BP only. Induction chemotherapy was mainly cytarabine and daunorubicin (45-90 mg/m²) combined with imatinib (median dose 600 mg, range 400-800). Only 2 patients did not receive imatinib because the drug was not available in 2000-2003. Those 2 pts achieved complete remission (CR) but subsequently relapsed and died from progression. Overall, 17 pts (94.4%) achieved CR or CR with incomplete hematologic recovery (CRi) after one or two induction cycles, one pt failed and there was no early death. Consolidation was mainly high dose cytarabine with imatinib and 12 pts received an allogeneic hematopoietic cell transplantation (alloHCT) in first CR/CRi with myeloablative or reduced intensity conditioning in 7 and 5 pts, respectively. Five pts received maintenance therapy with imatinib (n=4) or nilotinib (n=1). Of note, 4 of the 5 CR/CRi pts who were not transplanted in CR1 did not relapse. With a median follow-up of 76.3 months, median RFS was not reached and 2y-RFS was 82.4% (95%CI, 55-94). Median OS was not reached and 2-y OS was 77.4% (95%CI, 50.3-90.9). Of note, there were 3 late deaths at 48, 60 and 84 months unrelated to AML (1 lung cancer, 1 pancreatic cancer, 1 infection). CR/CRi rate was significantly higher in pts with de novo BCR::ABL1 AML(94.4%) compared with CML-BP (79.2%), AML with ELN 2017 Int (83.4%) or Adv (68.5%) risk (P<0.0001). RFS (median, CML-BP: 100.5 months, IQR 19.7-NR; ELN-Int: 20.6 months, IQR 7.2-115.3; ELN-Adv: 10.3 months, IQR 4.4-48.1; P<0.0001) and OS (median, CML-BP: 33.9 months, IQR 14.6-NR; ELN-Int: 26.9 months, IQR 10.3-117.3; ELN-Adv: 11.8 months, IQR 4.7-40.0; P<0.0001) were also significantly improved. 2-y OS was 77.4%, 57.0%, 53.7% and 33.4% in de novo BCR::ABL1 AML, CML-BP, AML with ELN2017 Int and Adv, respectively (P<0.0001) (Figure). Conclusion De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is a very rare event in AML classifications (<1%) with particular features. Pts treated with IC and imatinib have a high rate of CR, very low incidence of relapse and a remarkable OS rate that do not support the ELN2022 risk classification . Pts may have prolonged RFS and OS without alloHCT. Further studies are needed to confirm these results and reclassify these AMLs in the intermediate or even favorable group of the ELN 2022 classification.