Intermediate-risk Acute Myeloid Leukemia Research Articles

Limited efficacy of 3 + 7 plus gemtuzumab ozogamycin in newly diagnosed fit intermediate genetic risk acute myeloid leukemia patients.

Gemtuzumab-ozogamycin (GO) is approved in combination with high-dose chemotherapy for treatment-naïve low- and intermediate-risk acute myeloid leukemia (AML). In this retrospective real-life multicenter study, we reported efficacy and safety of GO plus high-dose chemotherapy in newly diagnosed AML patients. A total of 31 fit low- and intermediate-risk AML patients treated with GO-based regimens were retrospectively included in this real-life multicenter study, and results were compared with a control cohort treated with 3 + 7 alone. Complete remission (CR) rate after induction was 77%, and most responders (45%) underwent two GO-based consolidation, and minimal residual disease (MRD) negativity was observed in 17 cases (55%) after the end of consolidation. Low genetic risk was associated with increased CR rate compared with intermediate-risk AML (88% vs. 33%; p < .001), as well as prolonged overall survival (OS; hazard ratio, 0.16; 95% confidential interval, 0.02-0.89; p < .001). GO addition resulted in a survival benefit for low-risk AML (median OS not reached vs. 25 months; p = .19) while not for intermediate-risk subjects (10 vs. 13 months; p = .92), compared with the control group. Moreover, GO-treated patients experienced fever of unknown origin or sepsis in 42% or 36% of cases, respectively, with one death during induction due to septic shock, with similar rates compared with the control group (p = .3480 and p = .5297, respectively). No cases of veno-occlusive disease after allogeneic transplantation were observed. Our real-life multicenter study confirmed GO-based treatment efficacy with high MRD negativity rates in fit newly diagnosed AML patients, especially in those with low genetic risk and core binding factor, while limited benefits were observed in intermediate-risk AML. However, further validation on larger prospective cohorts is required.

Trajectories of physical well-being among adults with acute myeloid leukemia

AbstractPatients with acute myeloid leukemia (AML) often undergo physical decline leading to negative outcomes. Identification of distinct trajectories may help guide clinical decision-making and supportive care interventions. We built group-based trajectory models (GBTM) to find trajectories of change in the Functional Assessment of Cancer Therapy Physical Well-Being (FACT-PWB) subscale (up to 5 time points over 0 to 200 days of follow-up) using data from adults with newly diagnosed AML in 4 supportive care studies. We also estimated the association of baseline characteristics (age, marital status, education, AML risk, baseline FACT-PWB, depression, and anxiety) with group membership. Among 343 patients with ≥2 FACT-PWB scores, mean age was 69.6 years (standard deviation, 12.1); most had intermediate-risk AML (n = 178 [51.8%]), received intensive treatment (n = 244 [71.1%]), and died during follow-up (n = 199 [58.0%]). The GBTM with 4 distinct trajectories showed the best fit. The largest group (n = 153 [45.0%]) showed slight improvement, whereas the smallest (n = 8 [2.4%]) experienced early decline with later improvement. Baseline FACT-PWB was the only characteristic statistically significantly associated with group membership. Adults with AML show distinct trajectories of physical well-being, and many experience some decline. Exploring trajectories of self-reported and objective physical function may inform decision-making and interventions. These trials were registered at www.ClinicalTrials.gov as #NCT02975869, #NCT03310918, and #NCT03372291.

Real-world treatment outcomes from a retrospective cohort of patients with acute myeloid leukemia from an urban safety net hospital.

While continual advancements in acute myeloid leukemia have augmented response rates and survival, outcomes in clinical trials may not correlate with real-world practice as trials may underrepresent individuals with comorbidities, decreased performance status, and older age. Additionally, clinical trials may underrepresent certain ethnicities, and disparities based on ethnicity, socioeconomic status, and insurance have been demonstrated in acute myeloid leukemia. We performed a retrospective chart review of adult patients with acute myeloid leukemia who were treated at Harbor-UCLA from 2014 to 2022 to examine patient characteristics, management patterns, and outcomes in a safety net hospital setting. The median age was 56 years old (range 18-84). In regards to risk stratification, 22%, 33%, and 41% had favorable, intermediate, and adverse risk acute myeloid leukemia, respectively. The most common induction regimens included 7 + 3 (55%), azacitidine (10%), azacitidine + venetoclax (7%), and 7 + 3 + midostaurin (7%). The complete remission rate was 51%. Among patients who received intensive induction chemotherapy, 15% underwent re-induction with a second cycle, 51% received consolidation therapy, and 5% received maintenance therapy with a targeted agent. Overall, 12% of patients received allogeneic stem cell transplant. Median overall survival was 12.2 months, and 5-year overall survival was 18%. Suboptimal response rates and survival in this population may be related to low rates of re-induction and allogeneic transplant in addition to high rates of adverse cytogenetics, secondary acute myeloid leukemia, and supportive care only. Efforts to increase access to clinical trials, novel therapies, and transplants for diverse and underinsured populations are essential.

Flow cytometry-based measurable residual disease (MRD) analysis identifies AML patients who may benefit from allogeneic hematopoietic stem cell transplantation.

Measurable residual disease (MRD) monitoring independently predicts long-term outcomes in patients with acute myeloid leukemia (AML). Of the various modalities available, multiparameter flow cytometry-based MRD analysis is widely used and relevant for patients without molecular targets. In the transplant (HCT) setting, the presence of MRD pre-HCT is associated with adverse outcomes. MRD-negative remission status pre-HCT was also associated with longer overall (OS) and progression-free survival and a lower risk of relapse. We hypothesize that the combination of disease risk and MRD at the time of first complete remission (CR1) could identify patients according to the benefit gained from HCT, especially for intermediate-risk patients. We performed a retrospective analysis comparing the outcomes of HCT versus non-HCT therapies based on MRD status in AML patients who achieved CR1. Time-dependent analysis was applied considering time-to-HCT as a time-dependent covariate and compared HCT versus non-HCT outcomes according to MRD status at CR1. Among 336 patients assessed at CR1, 35.1% were MRD positive (MRDpos) post-induction. MRDpos patients benefitted from HCT with improved OS and relapse-free survival (RFS), while no benefit was observed in MRDneg patients. In adverse-risk patients, HCT improved OS (HR for OS 0.55; p = 0.05). In intermediate-risk patients, HCT benefit was not significant for OS and RFS. Intermediate-risk MRDpos patients were found to have benefit from HCT with improved OS (HR 0.45, p = 0.04), RFS (HR 0.46, p = 0.02), and CIR (HR 0.41, p = 0.02). Our data underscore the benefit of HCT in adverse risk and MRDpos intermediate-risk AML patients.

Outcomes of allogeneic stem cell transplantation in acute leukemias – single centre study

Aim: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended in first complete remission (CR) for adverse and intermediate-risk acute myeloid leukemia (AML) and not recommended for AML patients with favourable disease. Allo-HSCT is standard of care in high-risk acute lymphoblastic leukaemia (ALL) and relapsed ALL but is not indicated for standard-risk ALL. Even though in many studies benefit for survival was proven for these patients, relapse rates (RR) at one year (32.9% for LAM and 34% for LAL) remains problematic. We want to report the outcomes of patients treated for acute leukaemia in our centre. Materials and methods: We conducted a retrospective descriptive analysis of 215 patients with acute leukaemia treated with allo-HSCT between 2017 and 2022 in Fundeni Clinical Institute. Data analysis aimed the overall survival (OS) rate, progression free survival (PFS) and RR at one year based on genetic risk, number of CR, minimal residual disease (MRD) status and conditioning regimen used. Results: At one year evaluation we observed OS rate of 64% and a 34% RR for ALL patients, while AML patients had a 74% OS rate and 13% RR. Conclusions: The results obtained in our centre are similar to the ones reported in literature. The highest risk of relapse and smallest rate of survival are registered for patients who present with negative risk factors. The multifactorial influence over OS and RR impose the need for future studies in which different patient categories can benefit from an optimal therapeutic management.

Efficacy and Prognostic Factors of Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia

To retrospectively analyze the efficacy and complications of our institution's modified nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) in treating intermediate-risk acute myeloid leukemia (AML) - first complete remission (CR1) and prognostic factors. Clinical data of 50 intermediate-risk AML-CR1 patients who underwent matched related NST at the Fifth Medical Center of Chinese People's Liberation Army General Hospital from August 2004 to April 2021 were collected, the hematopoietic recovery, donor engraftment and complications were observed, and overall survival (OS) rate, leukemia-free survival (LFS) rate, treatment-related mortality (TRM), and cumulative relapse rate were calculated. Statistical analysis of factors affecting prognosis was also preformed. The median times for neutrophil and platelet recovery after transplantation were 10 (6-16) and 13 (6-33) days, respectively. One month after transplantation, 22 patients (44%) achieved full donor chimerism (FDC), and 22 patients (44%) achieved mixed chimerism (MC), among whom 18 cases gradually transited to FDC during 1-11 months, 4 cases maintained MC status. The overall incidence of acute graft-versus-host disease (aGVHD) was 36%, with a rate of 18% for grade II-IV aGVHD and a median onset time of 45 (20-70) days after transplantation. The overall incidence of chronic GVHD (cGVHD) was 34%, with 20% and 14% of patients having limited or extensive cGVHD, respectively. The incidence rates of infections, interstitial pneumonia, and hemorrhagic cystitis were 30%, 10%, and 16%, respectively. The 5-year OS rate, LFS rate, TRM, and cumulative relapse rate were 68%, 64%, 16%, and 20%, respectively. The increase of the number of CD34+ cells infused had shortened the recovery time for neutrophils and platelets (r =0.563, r =0.350). The number of CD34+ cells infused significantly influenced the occurrence of extensive cGVHD (OR =1.36, 95%CI : 1.06-1.84, P =0.024). Modified NST is effective in treating intermediate-risk AML-CR1 patients, however, further expansion of sample size is needed to study prognostic factors.

Relationship between Mitochondrial Oxphos Kinetics and Response to Induction Chemotherapy in Patients with Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy carrying a poor prognosis. Relative to non-leukemic myeloid progenitors, AML cells present with elevations in mitochondrial metabolism driven by higher mitochondrial content. Despite having more mitochondria per cell, AML cells are inefficient at coupling respiration to ATP synthesis, indicative of intrinsic deficiencies in oxidative phosphorylation (OXPHOS) flux. The present study aimed to determine the relationship between mitochondrial OXPHOS kinetics and chemotherapy response in a clinical cohort of AML patients by comparing mitochondrial bioenergetic profiles between responders to induction chemotherapy with those who have persistent disease, and between adverse risk and intermediate risk AML. Methods: In this prospective study from January 2020 to February 2023, we collected bone marrow aspirate samples from patients with new diagnosis of AML on day 1 to evaluate the bioenergetic phenotype of the AML cells. We collected data on primary induction therapy, response to induction therapy, relapse, and other clinical features. We compared the bioenergetic phenotypes between the responders to primary induction chemotherapy and non-responders who had persistent disease post induction chemotherapy. We did the same comparison between patients with adverse risk and intermediate risk AML per European LeukemiaNet (ELN) 2022 risk stratification. Mitochondrial bioenergetic profiles were generated via high resolution respirometry using freshly isolated mononuclear cells from each patient's bone marrow aspirate. The Fisher exact test was used for categorical variables and the Wilcoxon Rank Sum for continuous variables. Results: In 18 AML patients included in the study, median age was 64 years (range 30-85 years), 67% (N=12) were male, 33% female, 61%(n=11) were Caucasian and 39%(n=7) were African Americans. Day 1 median blast count was 57% (range 20-92%). Initial induction therapy with cytarabine/daunorubicin (standard 7+3) with or without midostaurin (in patients with FLT3 mutations) was done in 12 (67%) patients and hypomethylating agent/venetoclax was used in 5 (28%) patients. One patient was managed with azacitidine only. Seven (39%) patients had persistent disease after induction and others responded to the initial induction. Relapsed disease after achieving remission with initial induction was seen in 8 (44%) patients. No patients had favorable risk cytogenetics/molecular findings, 10 had adverse risk AML and 9 had intermediate risk AML. TP53 mutation was observed in 4 patients, FLT3 mutation in 5 patients, IDH1 mutation in 4, and IDH2 mutation in 3 patients. The fraction of the respiratory network capable of performing OXPHOS (i.e., Fractional OXPHOS) was 0.426 in responders and 0.629 in non-responders (p=0.93). In responders, basal respiration in intact cells was non-significantly (p=0.54) lower ( JO2 9.838 pmol/s/million cells) compared to non-responders ( JO2 11.52 pmol/s/million cells). Adverse risk patients had lower fractional OXPHOS, and higher basal and maximal respiration rates as compared to intermediate risk AML patients (Table 1). Conclusion: While Fractional OXPHOS and basal respiration were lower in the patients who had remission after induction therapy, this difference was not statistically significant. We did not find a clinically significant correlation in the bioenergetic profile of AML cells; however, our study is limited by small sample size. Further research is warranted to investigate the role of OXPHOS kinetics in patients of AML that can translate into clinically meaningful outcomes.

Venetoclax in Combination with Intermediate Doses of Cytarabine in Consolidation Phase for Acute Myeloid Leukemia Patients in First Complete Remission; Results of the Part 1 of the Phase 1/2 Multicentric Covenidac Study

For authors: Please: L Gastaud and P Peterlin: co-primary, H dombret et C Recher: co-last Background: The French ALFA-FILO AML intergroup launched the BIG-1 trial (EudraCT No.: 2014-000699-24) in 2015 to evaluate different intensive chemotherapy (ICT) strategies aiming at improving the survival of younger adults with acute myeloid leukemia (AML). All patients (pts) with previously untreated non-APL and non-CBF AML aged 18-60 years were eligible for this trial. The trial design included several randomization types. Results of the R1 and R2 randomizations, namely idarubicin vs daunorubicin for induction and IDAC vs HDAC for consolidation, will be reported at this meeting. In patients who achieved first complete remission (CR), randomizations R4 consisted of nested randomized Phase 2 or 1/2 studies evaluating the addition of new drugs to the IDAC/HDAC consolidation cycles. The protocol was designed to allow several sequential multicenter R4 evaluations of various new agents over the trial period. Venetoclax (VEN) has proved its efficacy when combined to azacitidine or low dose cytarabine in unfit AML pts (DiNardo et al. 2020; Wei et al. Blood 2020). Its role in fit patients treated with ICT is still under investigation. The COVENIDAC Phase 1/2 R4 sub-study is evaluating the safety and efficacy of VEN added to IDAC during the consolidation cycles of CR pts. We report herein the result of the Phase 1 part. Methods: The primary objective of this Phase 1 study was to determine the maximum tolerated dose (MTD) of VEN in combination with IDAC during the consolidation cycles, which will be the recommended dose for the Phase 2 (RP2D). Dose limiting toxicities (DLTs) were assessed during the first cycle of consolidation (C1) according to a 3+3 design. A maximum of 3 consolidation cycles was planned depending on the AML risk group. Hematological DLT was defined as no peripheral blood count recovery within 56 days from day 1 of the cycle. Non-hematological DLTs were defined as Grade ≥4 toxicities or Grade ≤3 toxicities which have not recovery by day 56 and deemed related to VEN per investigator opinion. VEN was started at dose level (DL) 1: 100 mg/d from day 1 to 8. In the absence of DLTs at DL1, 3 others DL were planned: 200 mg/d from day 1 to 8 (DL2); 400 mg/d from day 1 to 8 (DL3), and 400 mg/d from day 1 to 14 (DL4). IDAC was administrated at 1.5 gr/m² twice daily on day 1/3/5 for DL1, DL2 and DL3 pts, then on day 1/2/3 for DL4 pts after a protocol amendment. Main inclusion criteria were: pts in first CR following 1 or 2 courses of induction chemotherapy fit for further ICT; favorable and intermediate risk AML as defined by the protocol; ECOG PS ≤2; written informed consent. Measurable residual disease (MRD) was assessed by multiparametric flow cytometry (MFC) in all pts as well as NPM1-qPCR in NPM1-mutated pts. Results: Between 06/2021 and 04/2022, 15 pts from 9 centers were screened and enrolled. Pt characteristics were as follows: median age, 42 years (IQR, 30-49); 2 males/7 females; ECOG-PS, 0 in 10 pts and 1 in 5 pts; favorable/intermediate/adverse ELN-2017 risk, 9/2/4. Neutropenia and thrombocytopenia durations are shown in Table 1. Only 1 hematological DLT was observed at DL3 (platelet count of 96 giga/L at day 56 in a patient who was infected by Covid-19). Overall, there were very few non hematological AEs ( Table 2, no grade 4) and only 4 SAEs (1 related to IDAC/VEN during C1, 3 non-related). No non-hematological DLT was observed. No patient died during the DLT observation period, 1 experienced a septic shock (C2, DL2). One pt received only C1 (due to DLT), 7 received 2 cycles, and 7 received 3 cycles. Median time between initiation of subsequent consolidation cycles was 37.5 days (IQR, 35-41) for C1/C2 and 40 days (IQR, 35-43) for C2/C3. One pt had to stop VEN during C3. Six pts received an allogeneic HSCT (5 in CR1, 1 after salvage). With a median follow-up of 13.5 months, 3 pts relapsed and 2 died. MRD results will be presented. Conclusion: VEN/IDAC combination appears to be feasible and safe as consolidation therapy, with expected thrombocytopenia and neutropenia durations. These durations appeared even shorter at DL4, when IDAC was given on 3 consecutive days. VEN at 400 mg/d from day 1 to 14 combined with IDAC on day 1/2/3 was thus retained as RP2D for the randomized Phase 2 with RFS as primary endpoint. This phase 2 has already recruited 29 of the 200 pts planned.

The ELN 2022 Risk Stratification Has No Impact on the Dismal Prognosis of Patients with Acute Undifferentiated Leukemia

Introduction: Acute undifferentiated leukemia (AUL) is a rare subtype of acute leukemia. It is characterized by lack of expression of myeloid or lymphoid lineage markers, frequently expressing CD56 or CD7. The dismal prognosis of AUL was reported in small studies; the largest previously reported group with this disorder included 24 patients (Weinberg, Mod Pathol, 2019). Furthermore, data are lacking regarding cytogenetic and molecular patterns of AUL. In this study, the cytogenetic and molecular changes of AUL patients are described, together with the clinical outcome. Methods: AUL was defined, in accordance with the WHO classification, as an acute leukemia that does not qualify for myeloid, B- or T-cell lineage. Immunophenotyping of BM cells at diagnosis was performed using 8-color flow cytometry. Multi-parameter Cytognos acute orientation tube (ALOT) and the combination of the following antigens were used: CD34/CD117/CD14/CD56/CD36/CD123/HLA-DR/CD45/CD64/CD11c. (Weinberg, Mod Pathol, 2019). Results: Three hundred and eighty-five patients with acute myeloid leukemia (AML) were diagnosed at Rambam Health Care Campus in Haifa, Israel between April 2015 and April 2021, of whom 30 (8%) were defined as AUL. The baseline characteristics are presented in Table 1. The median age was 62 years, none of the patients harbored NPM1 mutation, with 1 patient expressing FLT3-ITD mutation. Cytogenetic analysis was completed for all patients: 9 (30%) had adverse-risk cytogenetics by ELN 2022 criteria. A comprehensive molecular study using molecular inverted probe was performed on all patients, with final results available on 17. Nine of these 17 (53%) had high-risk mutations; RUNX1 was found in 4 patients. Notably, 4 other patients had JAK2 mutation, with or without previous myeloproliferative neoplasm. Only 3 patients had mutations characterizing secondary AML (Lindsley, Blood, 2015). Only 2 patients in this cohort had TP53 mutation or del17p. Fourteen patients were classified as adverse-risk AML by ELN 2022 using cytogenetic and molecular markers, while 15 were classified as intermediate risk. Only 4 patients in this adverse-risk cohort were not allogeneic hematopoietic stem cell transplant (HSCT) candidates due to age or comorbidity limitations. The outcome of the cohort is presented in Table 2. Twenty-two fit patients received 7+3 intensive chemotherapy, of whom 10 achieved complete remission (CR) after induction. Four of the 10 patients needed reinduction chemotherapy due to a high blast count on the bone marrow performed at day 14. Five patients were treated with low-intensity therapies such as hypomethylating agents ± novel agents; 2 achieved CR. One patient received FLAG-Ida chemotherapy and another patient was treated with ECOG1910 protocol due to clinical presentation more compatible with acute lymphoid leukemia; both achieved CR. Of the 14 patients achieving CR, 4 relapsed before HSCT and needed further salvage therapy. Eventually, 13 (50% of the transplant-eligible candidate cohort) patients proceeded to HSCT. Relapse occurred in 14 patients (10 post-HSCT and 4 before HSCT), none of them achieved long-term survival. Four of the 30 patients are alive, all in remission. The median overall survival of the entire cohort is 1 year (Fig 1). The outcome of patients with adverse or intermediate risk according to the ELN risk classification did not differ. The CR rate and relapse rate and median overall survival (OS) were similar in both groups (Table 2; Fig 1). Discussion: These data emphasize the dismal outcome of patients diagnosed with AUL, with the 5-year OS of 7.5%, far lower than the survival of other types of acute leukemia. In this cohort, 15 patients were classified as intermediate risk AML; yet, their CR rate and long-term survival were not different from the whole cohort. The CR rate achieved with the widely used 7+3 protocol, was inferior, raising the question whether this protocol should be the “standard of choice” in such patients. A limitation of this study is that not all patients were evaluated by the NGS panel, bringing about the issue whether more patients had high-risk mutations, who would then be classified as adverse risk. Conclusion: The unique subtype of AUL is associated with a particularly adverse risk genotype, irrespective of known prognostic determinants, as in the 2022 ELN classification.

Influence of Bone Marrow Blast Enumeration and Co-Occurring Myelodysplasia Related Gene Mutations in NPM1-Mutated Myeloid Malignancies

Introduction Both World Health Organization (WHO 5th) and International Consensus Classification (ICC) guidelines recognize mutations in nucleophosmin 1 ( NPM1mut) as a class defining molecular event in acute myeloid leukemia (AML). WHO 5th omitted the blast percentage requirement and ICC lowered the blast threshold to 10%. NPM1mut AML without FLT3 ITD or adverse risk cytogenetics is considered favorable risk in European LeukemiaNet (ELN) 2022, however co-occurring adverse-risk myelodysplasia related mutations (MR mut) do not influence ELN 2022 risk stratification. This analysis addresses the prognostic impact of blast enumeration in NPM1mut myeloid neoplasms (MN) with &amp;lt;10% blasts and influence of co-occurring mutations in NPM1mut AML. Methods We interrogated publicly available data from adult (≥18 years) patients (pts) with chronic myeloid neoplasms included in the International Working Group for Prognosis in MDS (N= 3,323; Bernard et al. NEJMEvid 2022) and two independent AML cohorts (AMLSG [N=1540] Papaemmanuil et al. NEJM 2016; UKNCRI [N=2,113] Tazi et al. Nat. Commun. 2022). Between group differences were assessed using the Wilcoxon rank-sum test or Fisher's exact test as appropriate. Time to event endpoints were analyzed using the log-rank method. Multivariate analysis (MVA) used cox proportional hazards regression. Results NPM1 mut was identified in 17% (N=1148) of pts (AML: 30% [1109/3653], MN with &amp;lt;20% blasts: 1.2% [39/3,323]). Compared to pts with NPM1mut AML, pts with NPM1mut MN (MDS, CMML, aCML) with blast &amp;lt; 20% were older (median age 65 vs. 55 years, p &amp;lt; 0.001), had a lower median total WBC count (5 vs. 32 x10 9 /L, p &amp;lt; 0.001) and bone marrow (BM) blast percentage (8% vs. 76%, p &amp;lt; 0.001). No significant difference was observed between NPM1mut AML and MN with &amp;lt;20% blasts in median hemoglobin (9.1 vs. 9 x10 9, p: 0.44), platelets (62 vs. 66 x10 9 /L, p: 0.55), or NPM1mut variant allele frequency (VAF; 35% vs. 37%, p: 0.64). After a median follow up of 4.7 years (range: 0-12), no difference in overall survival (OS) was observed between pts with low blast (LB; &amp;lt;10%) NPM1mut MN (N=19) vs. ≥10% blasts (N=18) (median OS: 0.64 years [95% CI: 0.31-3.0] vs. 1.1 years [95% CI: 0.95-NR], p=0.32). Median leukemia free survival (LFS) was 0.81 years (95% CI: 0.67-1.5) and not significantly different between NPM1mut MN pts with &amp;lt;10 vs. ≥10% blasts (median LFS: 0.55 vs. 0.91 years, p=0.27). In pts with NPM1mut AML (N=1109), 52% (N=581) were ELN 2022 favorable-risk; 15% (N=92) had MR mut including SRSF2 (51%, N=47), STAG2 (21%, N=19), ASXL1 (9%, N=8), BCOR (9%, N=8), RUNX1 ( 8%, N=7), EZH2 (5%, N=5), SF3B1 (5%, N=5), U2AF1 (1%, N=1), and ZRSR2 (1%, N=1). Pts with MR mut were older (median age 62 vs. 53 years, p &amp;lt; 0.001), had higher BM blasts (80% vs. 72% p=0.019), and lower platelets (45 vs. 77 x10 9/L p &amp;lt; 0.001) compared to pts with NPM1mut AML without MR mut. No significant difference in NPM1mut VAF was observed (34% in both groups). After a median follow up of 3.5 years (range: 0-15), median OS was 6.2 years in pts with NPM1mut AML (95% CI: 4.2-9.7). Inferior OS was observed in ELN favorable risk NPM1mut pts with vs. without MR mut, respectively (2 vs. 8.4 years, p=0.0001). When stratified by age &amp;lt; 60 vs. ≥ 60 years, younger pts with MR mut had an increased risk of death (HR 1.7 95% CI: 1.1-2.8, p: 0.02). No OS difference was observed in older pts with or without MR mut (HR: 1.2, 95% CI: 0.80-1.68, p=0.44), however OS was significantly shorter in older pts with NPM1mut compared to younger pts (median 1.7 years vs. NR, p &amp;lt; 0.001). Patients with NPM1mut /MR mut AML had survival comparable to patients with ELN 2022 intermediate risk AML (2.0 vs. 2.1 years, p=0.35). In MVA of NPM1mutAML adjusted for MR mut, BM blast percentage, age, performance status, baseline WBC, hemoglobin, platelet count, NPM1mut VAF, and treatment setting (AMLSG or UKNCRI), the presence of an MR mut (HR 1.39 [95% CI: 1.0-1.9], p=0.04), age &amp;lt; 60 (HR 0.43 [95% CI: 0.32-0.56], p &amp;lt; 0.001), and performance status (HR 1.35 [95% CI: 1.14-1.60], p=0.0004) retained statistical significance. Conclusion Pts with low blast NPM1mut MN have outcomes similar to pts with NPM1mut AML, supporting NPM1mut as an AML defining event irrespective of BM blast enumeration. In patients with ELN favorable risk NPM1mut AML, co-occurrence of MR mut is independently associated with inferior survival, comparable to ELN intermediate risk AML. These results may inform future refinements of current consensus guidelines.

The Efficacy of Modified Melphalan and Busulfan-Based Conditioning Regimen for Autologous-HSCT in Low-Risk and Intermediate-Risk AML Patients

Abstract: Background: Treatment options for patients with low-risk and intermediate-risk acute myeloid leukemia (AML) patients (non-M3) who achieved complete response (CR) after one course of induction chemotherapy include consolidation chemotherapy, autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Compared with chemotherapy, auto-HSCT could significantly reduce relapse rate, as was associated with significantly lower transplant-related mortality compared with allo-HSCT, but relapse rate was relatively high. The selection of conditioning regimen was crucial to reduce relapse rate after transplantation. In this study, we made refinements in the conditioning regimen with two alkylating agents, namely MCBA (the combination of melphalan, cladribine, busulfan, and cytarabine). We aim to investigate the efficacy of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. Methods: This prospective multi-center clinical trial was conducted in 5 tertiary hospitals in China, and enrolled low-risk and intermediate-risk AML patients (non-M3) who achieved CR after one course of induction chemotherapy, followed by 1-3 courses of high-dose cytarabine consolidation chemotherapy, and underwent auto-HSCT from May 2021 to June 2023 (ChiCTR Registration ID: ChiCTR2200056167). The MCBA conditioning regimen consists of melphalan 70mg/m 2/d, day -6~-5, cladribine 5mg/m 2/d, day -4~-2, busulfan 3.2mg/kg/d, day -8~-7, cytarabine 2g/m 2/d, day -4~-2. Results and Discussion: This study included a total 21 AML patients, 14 males, 7 females, with median age 41 years (ranged 20-56 years). There were 8 of low-risk and 13 of intermediate-risk. The median infused mononuclear cell and CD34+ cell counts were 12.22×10 8/kg (ranged 1.79-34.68×10 8/kg) and 2.28×10 6/kg (ranged 1.05-17.15×10 6/kg) respectively. Neutrophil and platelet engraftment were achieved in all patients, with a median time of 13 days (ranged 11-27 days) and 32 days (ranged 12-150 days) respectively. On the day of reconstitution, all patients exhibited good responses, including hematologic CR and minimal residual disease (MRD) negativity rates of 100%. 11 (52.4%) patients received maintenance therapy after auto-HSCT, with a median time of 3.5 months (ranged 1-9 months). Azacytidine, venetoclax or geritinib were the main maintenance therapies. With a median follow-up of 306 days（ranged 43-798 days）, the estimated 1-year overall survival (OS) and 1-year disease-free survival (DFS) were 80.4±13.4% and 70.9±12.8%, respectively. 4 patients relapsed within 1year, and the median time from HSCT to relapse was 240 (101-314) days. The probability of relapsed rate was 29.1±12.8%. Mucositis was the main reported regimen-related toxicity, mostly were mild and well tolerated. Severe mucositis included grade Ⅱ liver damage (4.8%), grade Ⅱ oral mucositis (4.8%) and grade Ⅲ-Ⅳ diarrhea (9.5%), respectively. Conclusion: The preliminary data demonstrated the efficiency of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. The regimen-related toxicity was well tolerated.

Development of a Stacked Ensemble Model for Risk Stratification of Chronic Gvhd after Allogeneic HSCT: Trump Cohort Study

Background Effective risk stratification is vital for selecting donors and developing treatment strategies for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several pretransplant risk models have been proposed to predict post-transplant patient outcomes from pretransplant risk factors. However, it is still challenging to predict mid-to-long-term prognosis. To establish a novel and user-friendly tool for predicting chronic graft-versus-host disease (cGVHD), non-relapse mortality (NRM) and overall survival (OS), we used a Stacked Ensemble Model (SEM) designed to handle right-censored data and competing risk events (Iwasaki et al., 2021). Methods Using Japanese registry data, the Japanese Transplant Registry Unified Management Program, we analyzed 21,840 patients who underwent their first allo-HSCT between 2010 and 2018 for hematologic malignancies. Of these, 14,430 patients were alive without cGVHD and relapse on day 100 post-transplantation. Primary endpoint was cGVHD and secondary endpoints were NRM and OS. Data were randomly split into the training set (70% of the dataset) and the validation set (30%). We treated patient age and time from diagnosis to transplant as continuous variables and performance status, ABO type matching, sex matching, disease/status groups based on refined Disease Risk Index, Hematopoietic Cell Transplantation-specific Comorbidity Index, usage of total body irradiation, conditioning intensity, T cell depletion in vivo, human leukocyte antigen (HLA) locus matching, the number of HLA mismatching and CMV serostatus as categorical variables. To evaluate predictive accuracy at day 30, 60 and 100 posttransplant, we considered acute graft-versus-host disease (aGVHD) and its treatment, including grade 2 to 4 aGVHD occurrence, grade 3 to 4 aGVHD occurrence, stage of aGVHD before and after treatment, corticosteroid treatment, anti-thymocyte globulin treatment and treatment response of 1 st line therapy for aGVHD. Results The median age of the patients at transplantation was 51 years (inter quartile range (IQR): 39 - 60). The sources of stem cells were HLA-matched related bone marrow (BM) in 967 patients, HLA-matched related peripheral blood (PB) in 1,998 patients, haploidentical BM in 172 patients, haploidentical PB in 778 patients, unrelated BM in 5,539 patients, unrelated PB in 366 patients, and cord blood in 4,237 patients. Myeloablative conditioning was administered in 9,390 patients and reduced-intensity conditioning in 5,040 patients. The most common indication of HSCT was intermediate-risk acute myeloid leukemia (AML) in complete remission (CR, n=3,233) followed by acute lymphoblastic leukemia in first CR (n=2,164) and intermediate-risk AML in non-CR (n=1,618). Median follow-up period of survivors was 2.2 years (IQR: 0.9-4.5). The overall performance of SEM was superior across the endpoints evaluated, cGVHD, NRM and OS, while XGBoost showed a slightly higher C-index for cGVHD, demonstrating its robustness and reliability (Table 1, the C-index for cGVHD/NRM/OS-SEM: 0.567/0.635/0.607, Cox-PH: 0.550/0.624/0.602, Random Survival Forest: 0.555/0.632/0.597, XGBoost: 0.573/0.624/0.604, and Dynamic Deephit: 0.549/0.614/0.589). C-index of SEM for cGVHD, NRM, and OS were gradually improved as time goes by (Table 1, the C-index for cGVHD/NRM/OS: at day 30-0.589/0.643/0.635, at day 60-0.598/0.655/0.640, at day 100-0.598/0.688/0.640). Kaplan-Meier curves 100-day post-transplantation confirmed the accuracy of our predictions, effectively stratifying patients into four risk groups (Figure 1). SHapley Additive Explanations showed contribution of variables for predicting specific outcomes. Grade 3 to 4 aGVHD and stage of aGVHD after treatment influenced non-relapse mortality. Particularly, grade 3 to 4 aGVHD showed significant impact on OS in line with pretransplant risk factors including sex matching, donor source and disease/status groups. Grade 2 to 4 aGVHD and treatment response of 1 st line therapy for aGVHD influenced cGVHD. Conclusion Our study emphasizes the importance of aGVHD events in mid-to-long-term post-transplantation outcomes and presents SEM-based prediction models that account for early-phase post-transplantation events. We are currently developing a user-friendly web application tool for cGVHD, aiming to enhance post-transplant risk stratification and preemptive therapy for cGVHD.

Microcosting Analysis of Hematopoietic Stem Cell Transplantation and Chemotherapy with Intermediate Doses of Cytarabine in the Treatment of Acute Myeloid Leukemia

Adult patients with Acute Myeloid Leukemia (AML) are stratified according to clinical and laboratory features at diagnosis into favorable-, intermediate-, or unfavorable-risk groups and may be treated differently according to risk. The European LeukemiaNet panel of experts' recommendation for the post-induction treatment of the favorable subgroup is either chemotherapy with intermediate doses of cytarabine (IDAC, e.g. 1.5 g/m2 q12h for 3 days) or autologous hematopoietic stem-cell transplantation (auto-HSCT). Both alternatives are costly and few studies have compared health economics aspects, which are particularly relevant in source-restrained regions. Moreover, AML treatment in low- and middle-income countries was associated with a higher frequency of invasive fungal diseases (IFD) and infections by multi-resistant bacteria compared to high-income countries and this may directly affect the treatment cost. Studies comparing IFD incidence in patients with hematological malignancies showed lower rates in patients treated with auto-HSCT compared to intensive chemotherapy. Material &amp; Methods: we performed the micro-costing analysis patients with intermediate-risk AML who received auto-HSCT (n=5) or IDAC (n=4) as post-induction treatment at University of Sao Paulo Hospital, Ribeirao Preto, Brazil. For cost analysis, we collected information about all resources and services consumed by patients such as medicines, materials, laboratory analysis, units of blood transfusion components, apheresis, hospital admissions, and outpatient care, in the period that began on the date of diagnosis until the end of treatment. The two groups had similar clinical and laboratorial characteristics at diagnosis and were treated according to the ICAML2015 protocol, in which induction (ID-1) is based on daunorubicin + standard-dose cytarabine (‘3+7‘), followed by a second cycle (ID-2) with daunorubicin + IDAC and, for those patients that achieved CR, consolidation was done with two cycles of IDAC (CONS-1 and CONS-2) or one cycle of IDAC followed by auto-HSCT (CONS-1 and auto-HSCT). The choice between the two alternatives of post-induction regimens was pre-defined by the participating center of the ICAML2015 study. Results: the mean cost of auto-HSCT and IDAC was US$ 4,188.12 and 2,368.22, respectively. Patients who received auto-HSCT stayed longer in-hospital compared to those in the IDAC group (21.8 versus 12.5 days). When the whole treatment is analyzed, the mean cost of the treatment with four cycles of chemotherapy was US$ 121,980.93 and that with three cycles followed by auto-HSCT was US$ 84,619.16. The most costly phase of treatment was the ID-1 (US$ 9,690.10). Regardless of the type of treatment, we observed that the inputs with the greatest economic impact were hospital admissions, which represented 51.2% of the total costs. . The second input with the greatest economic impact was drugs, and in that regard, treatment of infections played an important role in increasing the use of supplies in general. All patients in the study had febrile neutropenia that required hospital admission. Three patients were treated for IFD episodes, all of them were considered to be probable according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group, and the most frequently used antifungals were amphotericin B (deoxycholate) and voriconazole. All patients received prophylaxis with fluconazole. The frequency of IFD considering the whole treatment was 19.4 % (7/36 episodes of febrile neutropenia) and, there was no significant difference between patients who received auto-HSCT or IDAC. In conclusion, our results show that the cost of the post-induction treatment using auto-HSCT was higher than with IDAC and that cost with hospital stay.

Comparison of Autologous, Matched Sibling, and Alternative Donor Stem Cell Transplant Outcomes for Acute Myeloid Leukemia Patients in First Remission: A Propensity Score Matching Study

Introduction Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). Auto-HSCT is more commonly administered in favorable- and intermediate-risk AML with good remission, while MSD-HSCT and AD-HSCT are suggested for patients with high-risk factors. In the present study, we aim to retrospectively compared auto-HSCT with MSD-HSCT and AD-HSCT in de novo AML patients who are in first complete remission (CR1) with favorable or intermediate risk, according to 2022 ELN criteria. Methods We conducted a single-center retrospective comparative analysis, comparing auto-HSCT and allo-HSCT for favorable and intermediate-risk de novo AML in CR1. Patients with secondary AML, acute promyelocytic leukemia, poor-risk AML, those receiving syngeneic HSCT, those not in CR1 before HSCT, or those who achieved CR1 with ≥ 3 cycles of induction chemotherapy were excluded from the study. A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Persistent undetectable MRD (uMRD) was defined as uMRD after one course of chemotherapy without recurrent positive MRD before HSCT, while non-persistent uMRD was characterized by the presence of detectable MRD at least once before HSCT. The variables used for propensity score matching included induction chemotherapy cycles, consolidation chemotherapy cycles, and measurable residual disease (MRD) measurement by flow cytometer before HSCT. A caliper width of 0.2 was used. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Results After applying propensity score matching, a final cohort of 126 patients was available for analysis. This cohort consisted of 42 patients in each group: auto-HSCT, MSD-HSCT, and AD-HSCT. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT (haplo-HSCT). All patients received myeloablative conditioning regimen. There were no significant differences observed in the 3-year overall survival (OS) and disease-free survival (DFS) among the auto-HSCT, MSD-HSCT, and AD-HSCT groups [3-year OS: 79.5% (95% CI, 67.8-93.3%), 83.0% (95% CI, 72.2-95.3%), and 65.7% (95% CI, 50.5-85.5%), respectively; P=0.21. 3-year DFS: 72.6% (95% CI, 59.9-87.9%), 83.0% (95% CI, 72.2-95.3%), and 67.5% (95% CI, 54.2-84.1%), respectively; P=0.32]. The cumulative incidence of 3-year NRM was 2.7% (95% CI, 2.0-12.5%), 7.3% (95% CI, 1.8-17.9%), and 21.9% (95% CI, 10.7-35.6%), respectively (P=0.008). The 1-year probability of OS after relapse was higher in the auto-HSCT group (44.4%; 95% CI, 21.4-92.3%) compared with MSD-HSCT (0.0%) and AD-HSCT (37.5%; 95% CI, 8.4-99.9%) (P=0.0017). The MRD status before HSCT had an impact on DFS (persistent uMRD versus non-persistent uMRD: HR=0.29; 95% CI 0.09-0.94, P=0.04) and relapse (persistent uMRD versus non-persistent uMRD: HR=0.17; 95% CI 0.05-0.66, P=0.01) following auto-HSCT. The subgroup analysis was then performed based on MRD status before HSCT. In patients with uMRD before transplant (n=83), OS was similar across the groups. However, auto-HSCT showed a trend of increased DFS compared to AD-HSCT (HR 2.85, P=0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (n=38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, P=0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first two years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P=0.015) and AD-HSCT (P&amp;lt;0.001). Conclusions Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.

The Benefit of Allogeneic Transplant in 1 st Complete Remission in NPM1 Mutated AML with or without FLT3 ITD Is Restricted to Those Testing MRD Positive after Induction - an Analysis of the UK NCRI AML17 and AML19 Studies

Background While there is accumulating evidence that measurable residual disease (MRD) negative patients with intermediate risk AML may not benefit from allogeneic transplantation in 1 st complete remission (CR1-allo), many consider the presence of a FLT3 Internal Tandem Duplication (ITD) an indication for this procedure. However, the studies supporting this practice were mainly performed before the development of sensitive molecular MRD techniques (Schlenk NEJM 2008).The UK NCRI AML17 and AML19 trials studied, then incorporated, MRD by RT-qPCR into the management of patients with NPM1 mutated AML. Methods NCRI AML17 (April 2009 to December 2014) and AML19 (November 2015 to November 2020) were sequential prospective randomised trials for younger adults (18 - 60 years) with newly diagnosed AML. In AML17, decisions regarding CR1-allo were made using a validated risk score incorporating baseline factors and response to induction. In AML19, for patients with NPM1 mutated AML ( NPM1mut) the protocol recommended CR1-allo only in patients testing MRD positive in the peripheral blood (PB) post cycle 2 (PC2), regardless of other baseline risk factors such as FLT3 ITD, based on findings from AML17 (Ivey et al, NEJM 2016). Both trials were performed prior to the availability of midostaurin and FLT3 ITD MRD assays. Here we compare the outcomes of patients with NPM1mut in these trials and assess the benefit of CR1-allo according to FLT3 ITD and molecular MRD status. Time-to-event variables are analysed using the Kaplan-Meier method, and the impact of alloSCT assessed using time-dependent Cox regression and visualised with Simon-Makuch plots. Molecular relapses were included as relapse events, and alloSCT performed after molecular relapse was not considered as CR1. Results 737 patients with NPM1mutAML who achieved CR/CRi and had a valid PC2 PB MRD result were included in the analysis. 60/348 (17%) patients from AML17 and 83/389 (21%) from AML19 tested PB PC2 MRD positive. Overall, CR1-allo was performed in 20% of patients in AML17 and 25% in AML19. Of the MRD positive patients CR1-allo was performed in 16/60 (27%) in AML17 compared to 50/83 (60%) in AML19 where these patients were recommended for transplant. CR1-allo was performed in 18% and 16% of MRD negative patients in AML17 and AML19 respectively. In AML17, as previously reported (Ivey et al, NEJM 2016), patients who were MRD+ had poor outcomes, with 3-year cumulative incidence of relapse (CIR) of 84% and overall survival (OS) of 25%. These outcomes were improved in AML19, with 3y CIR 50% and 3y OS 51%. Across both trials, CR1-allo was associated with a significant survival benefit in MRD+ patients (3y OS 61% vs 24%, HR 0.42, 95%CI 0.26-0.69, p&amp;lt;0.001, Figure A). Patients who were MRD negative had excellent outcomes in both trials (3y CIR 33% and 24% and 3y OS 75% and 83% for AML17 and AML19 respectively). AlloSCT in CR1 provided no survival advantage for MRD- patients (HR 0.83, 95%CI 0.51-1.34, p=0.4). There were a total of 286 patients with NPM1mutFLT3 ITD mut AML with a PC2 PB MRD result across both trials. 81/286 (28%) were PB PC2 MRD+ of whom 32/81 (40%) received CR1-allo (28% in AML17 and 49% in AML19). Outcomes in these high-risk patients were improved in AML19, with 3y CIR 91% vs 68% and 3y OS 22% and 31% for AML17 and AML19 respectively. Those who received CR1-allo had improved outcomes (3y OS 45% vs 18%, HR 0.52, 95% CI 0.29-0.93, p=0.03) consistent with the overall MRD+ population. In the 70% of NPM1mutFLT3 ITD mut AML patients who achieved PB PC2 MRD-, outcomes were encouraging in both AML17 (3y CIR 37%, 3y OS 75%) and AML19 (3y CIR 27%, 3y OS 80%). CR1-allo was performed in 20% (19% in AML17, 21% in AML19), with no survival benefit for transplant (HR 0.80, 95% CI 0.37-1.72, p=0.6, Figure B). There remained no benefit when restricted to those with high (&amp;gt;0.5) FLT3 ITD allelic ratio (HR 0.63, 95% CI 0.2 - 2.23, p = 0.50) and there was also no evidence of an interaction between allelic ratio and benefit from transplant for MRD negative patients (p=0.86). Conclusion Molecular MRD can be used to stratify decision making concerning post remission therapy in patients with NPM1mut AML. Patients who achieve MRD negativity in the peripheral blood by the end of course 2 are at low risk of relapse and we found no evidence of benefit from allogeneic transplant in CR1, including in the subset with FLT3 ITD. This finding contrasts with MRD+ patients where there was a significant survival benefit for CR1 transplant.

Outcomes of Extramedullary Acute Myeloid Leukemia with Gemtuzumab Ozogamicin: Real-World Experience

Introduction: Extramedullary AML (EM AML) is characterized by the presence of leukemic cells in organs or tissues outside of the blood or bone marrow and remains a therapeutic challenge with dismal response rates to standard chemotherapy and short overall survival. Gemtuzumab Ozogamicin (GO) is an anti-CD33 antibody drug conjugate currently approved for single-agent therapy or in combination regimens for CD33+ relapsed/refractory (R/R) or newly diagnosed (ND) AML, respectively. Although GO is an active drug in AML, the optimal employment of this agent for treatment of EM AML at initial diagnosis, or at relapse, remains to be defined. Methods: A retrospective chart review on outcomes of GO in adults with EM AML at our institute from 2000 to 2023 was performed. Variables collected included age, sex, type of myeloid malignancy, and European LeukemiaNet (ELN) risk, bone marrow, peripheral blood and radiographic involvement, Response Evaluation Criteria in Solid Tumors (RECIST), prior lines of treatments, including stem cell transplant, next-generation sequencing (NGS), cytogenetics, mutational profile, and overall survival (OS). We screened patients with a diagnosis of EM AML who received GO at any point during their EM AML therapy. Patients with only CNS involvement as the extramedullary site were excluded. The aims of this study were to characterize responses and potential clinical benefit of EM AML to GO based regimens in the upfront and R/R settings. Results: 32 patients(pts) with EM AML received GO: 8 (25%) were ND and received GO-based induction regimen, while 22 (68.75%) received GO for R/R AML, and 2 (6.25%) patients received GO both at initial diagnosis and relapse. The median age of patient with ND EM AML was 66 years (y) (range: 28-84), and 60.5 (43-73) y in R/R EM AML. Twenty-four (75%) were men. One (12.5%) ND EM AML and 5 (10.1%) R/R EM AML had &amp;gt;1 extramedullary sites involved. The most frequent sites of EM-AML were skin (25%), lymph nodes (25%), soft tissues (25%), solid organs (25%), and visceral body cavity fluids (12.5%). Based on ELN 2022 risk group criteria, 17 patients were adverse, 8 with intermediate, and 3 with favorable risk. Next-Generation Sequencing (NGS) available for 21 patients identified mutations in TP53 (14.28%), FLT3 (19.04%), NPM1 (19.04%), KMT2A (19.04%), and ASXL1 (19.04%) as the most common mutations. Normal karyotype was noted in 6 (25%) R/R EM AML, while complex karyotype was present in 1 (12.5%) ND EM AML and 10 (41.67%) of R/R EM AML. While none of the ND pts had prior myeloid malignancy, R/R pts had prior AML (15), MDS (2), MDS-EB (1), CMML (1), therapy-related AML (1), myelofibrosis (1), and myeloid sarcoma (1). Concomitant bone marrow involvement at identification of EM AML was present in most ND cases (7/8, 88%) and R/R settings (16/23, 69.56%) (Table 1). Combination 7+3 plus GO was most frequently administered for ND EM AML (3/8) and R/R EM AML (8/24, 33%). Eleven patients had measurable radiologic findings prior to and following GO. Median OS was 10.91 months (m) (range: 0.2 to 27.1) for ND EM AML and 1.58 m (range: 0.7 to 7.5) for R/R EM-AML (Figure 1). 3 of 8 newly diagnosed EM-AML underwent allogeneic bone marrow transplant (AlloBMT) after GO based induction, followed by relapsed EM AML in 1 patient. Despite 50 percent of R/R EM AML pts undergoing prior AlloBMT, none had a durable disease-free response and received GO after relapse. Based on RECIST criteria, 7 of 11 (63.63%) pts achieved a response including 1 Complete Response (disappearance of all target lesions), 6 Partial Response (at least a 30% decrease in the sum of target lesions), and 2 Stable Disease (neither sufficient shrinkage nor increase). The 30-day mortality for ND and R/R were 12.5% and 8.33%, respectively. The 60-day mortality for ND and R/R were 25% and 50%, respectively. Conclusion: Our real-world single-institute experience in patients with EM AML suggests that GO combined with chemotherapy in the upfront setting results in promising outcomes with high overall response rates (CR 50%, PR 13%) by RECIST criteria, durable remissions, and prolonged overall survival in largely favorable and intermediate risk AML. However, despite high partial response rates (4% CR, 50% PR) following GO-based therapy in R/R EM AML, survival was less than 2 months likely due to the high proportion of patients in this cohort with poor risk disease. Further investigations and larger studies are warranted to establish the optimal use of GO in EM AML.

Comparing the Efficacy and Safety of Venetoclax Combined with Decitabine Versus Conventional Chemotherapy As Induction Therapy for Young Adults with Newly Diagnosed Acute Myeloid Leukemia - Interim Analysis of a Multicenter, Randomized, Phase 2b Trial

Introduction: Venetoclax in combination with hypomethylating agents (HMAs) is a first-line induction regimen recommended by NCCN guidelines for older or unfit AML patients. In a phase 2 study (NCT04752527) from our group, venetoclax plus decitabine (VEN-DAC) resulted in a 93% of response rate in young adult patients with newly diagnosed (ND) ELN adverse-risk AML. Currently, there is a lack of data on the VEN-DAC regimen in ND young adults with favorable or intermediate risk AML who are fit for intensive chemotherapy. There are also no studies directly comparing the VEN-DAC regimen with intensive chemotherapy in patients with ND AML. Here, we report the results of an interim analysis of a multicenter, randomized, phase 2b trial (NCT05177731) , which explored the efficacy and safety of VEN-DAC versus intensive chemotherapy (idarubicin and cytarabine) in ND AML patients. Methods: Adult patients with newly diagnosed AML aged between 18 and 59 years were enrolled. The diagnosis was made according to the WHO 2016 criteria. Risk stratification was performed according to the 2017 ELN recommendations. Eligible patients were randomized in a 1:1 ratio to the VEN-DAC group (decitabine 20mg/m 2 on days 1-5 and venetoclax at an escalated dose of 100mg, 200mg and 400mg by day 28) or the IA-12 group (idarubicin 12mg/m 2 on days 1-3 and cytarabine 100mg/m 2 on days 1-7). Patients who did not respond to the treatment were allowed to receive another cycle of the original induction regimen. Intermediate-dose cytarabine (2g/m 2, q12h, days 1-3) were applied as consolidation therapy. The primary endpoint was the composite complete remission (CRc, including complete remission, CR and complete remission with incomplete hematologic recovery, CRi). The secondary endpoints included measurable residual disease (MRD) negative remission (defined as &amp;lt;1×10 -3 by flow cytometry), event-free survival (EFS) , overall survival (OS) and adverse events. Results: Since March, 2022, a total of 163 patients with AML were screened and 116 patients were randomized. Sixty patients received the VEN-DAC regimen and 55 patients received the IA-12 regimen. There were no differences in baseline characteristics between the two groups of patients (Table 1). Bythe cut-off date of July 11, 2023, a total of 102 patients have been evaluated, 55 in the VEN-DAC group and 47 in the IA-12 group. The overall CRc rate in the VEN-DAC group was 85.5%, which was comparable to that of the IA-12 group (78.7%, P=0.37). The MRD-negative CR rate in the VEN-DAC group was 67.3%, which was much higher than that in the IA-12 group (53.2%) ( P=0.147). According to univariate analysis, efficacy of the VEN-DAC regimen did not differ from that of the IA-12 regimen with respect to sex, age, initial bone marrow blast count, genetic risk category, and major molecular markers (Figure 1A). Notably, the CRc rate and MRD-negative CR rate were significantly higher in the VEN-DAC group than in the IA-12 group for intermediate-risk and adverse-risk patients, especially those with adverse risk ( P=0.031 for CRc, P=0.029 for MRD-negative CR) (Figure 1A). At median follow-ups of 7.8 months (range, 0.9-16.6), the EFS and OS were not reached in both groups. The median time for platelets to recovery to 20×10 9/L or above in the VEN-DAC group was 12 days after induction in the VEN-DAC group, which was shorter than that in the IA-12 group (21 days) ( P&amp;lt;0.01). In addition, patients in the VEN-DAC group required fewer platelet (5 U vs 7 U, P&amp;lt;0.01) and red blood cell infusions (3 U vs 5 U, P=0.023) during induction as compared with that in the IA-12 group. In addition, the incidence of grade 3 or higher febrile neutropenia (41.8% vs. 83.0%), infection (27.3% vs. 72.3%) and sepsis (5.5% vs. 31.9%) were all significantly lower in the VEN-DAC group than in the IA-12 group ( P&amp;lt;0.01) (Figure 1B). Conclusion: In newly diagnosed young AML patients, venetoclax in combination with decitabine as an induction regimen had comparable efficacy and a higher safety profile compared to IA-12 regimen. In particular, patients with adverse-risk AML showed higher and deeper remission rate in the venetoclax plus decitabine group as compared with the IA-12 group.

Daunorubicin/Cytarabine Liposome +/- Gemtuzumab Ozogamicin for Adult Patients with Newly Diagnosed, Low-Intermediate Risk, FLT3-Wild Type, AML: A Pilot Study

Introduction: Liposomal-encapsulated cytarabine and daunorubicin (CPX-351 or Vyxeos) has been approved by the Food and Drug Administration (FDA) for use in the treatment of newly diagnosed therapy-related AML (tAML) and AML with myelodysplasia-related changes (AML-MRCs). This was based on results of a phase III study conducted in patients with secondary AML (Lancet JE et al. JCO 2018). Despite data that highlighted the advantage of CPX-351 for sAML, it is intuitively likely that this powerful drug is also suitable for non-sAML. The mechanism of action is applicable for every AML. The aim of this study is to evaluate the role of CPX-351 for patients with de novo low/ intermediate risk, FLT3-negative AML. While a definitive phase III study is planned, herein is described the pilot forerunner study. Methods: This pilot multi-center study is planned to recruit 20 patients, ages 18-70 years, with low-intermediate risk FLT3-negative AML. Induction therapy is with CPX-351 on days 1,3,5. One dose of gemtuzumab ozogamicin (GO) can be added on day 1, at the discretion of the treating physician. Re-induction with CPX-351 on day 1,3 is permitted based on the results of day 14 bone marrow examination and at the discretion of the treating physician. Post-induction therapy followed the practice of the participating institutions. The primary endpoint was response rate. A key secondary endpoint was MRD evaluation, after induction, by multi-parameter flow cytometry with a threshold of 0.1%. As the initial genetic evaluation at diagnosis takes time, it was assumed upfront that an adverse risk may only become apparent in some patients with AML after initiation of therapy. Such subjects would ultimately be excluded from the study analysis. Results: Between August 2022 and June 2023, 20 patients were recruited and received the CPX-351 but 4 were finally diagnosed as high-risk and were excluded. The median age of the 15 patients that were included in the analysis was 56 years (range: 21-70), 53.3% were females. Eight of 15 patients (53.3%) were categorized as intermediate risk, according to the 2016 ELN guidelines, and 46.6% as favorable. Four patients (26.6%) received GO in addition to the CPX-351. None of the patients needed to receive re-induction. 100% of the patients achieved CR. Five of 13 evaluable patients (38.4%) achieved MRD-negativity post induction. No unfamiliar or severe adverse events were reported, even among patients who received GO. One patient died from sepsis after hematopoietic stem cell transplant. The median time from day 1 of treatment to neutrophil recovery (ANC≥500/µL) and platelet recovery (≥50,000/µL) was 29 and 24 days, respectively, for the entire cohort and 27 and 24 days, respectively, for those who also received GO. Discussion: The hallmark of this study is reflected by the focus on patients with the low and intermediate-risk AML and not tAML and AML-MRCs, as was approved by the FDA. It includes also young patients (≥18 years), and not only those≥ 60 years. In addition, the CPX-351 was only given as induction therapy (with an option for re-induction) but not after achieving CR. The combination of CPX-351 with GO, although not previously reported, was based on current practice of adding GO to standard induction in some patients, allowing for a realistic future true comparator with standard 7+3 induction. In addition, MRD assessment post induction with CPX-351 has not been previously reported. The CR rate was 100% and the MRD results were a basis for subsequent studies. Finally, this is a pilot study that precedes a definitive planned phase III study that will compare standard induction with 7+3 versus CPX-351, with post-induction MRD monitoring and GO optional in both arms. Such a study may ultimately lead to a paradigm shift in the initial induction therapy of non-adverse risk patients with AML.

Current Results of Intensive Therapy in Younger Adults with Acute Myeloid Leukemia (AML): The Large Randomized French Backbone Intergroup (BIG)-1 Study on Behalf of the Filo, ALFA, and SFGM-TC Study Groups

Introduction. This multicenter study randomly explored various standard intensive chemotherapy (ICT) strategies in adults with AML, namely higher-dose idarubicin (IDA) vs high-dose daunorubicin (DNR) and intermediate-dose (IDAC) vs high-dose (HDAC) cytarabine. The study was planned large enough to allow patient subgroup analysis. Treatments. Eligible patients (pts) were randomized (R1) to receive an induction course with either DNR at 90 mg/m 2/d for 3 days or IDA at 9 mg/m 2/d for 5 days combined with cytarabine at 200 mg/m 2/d CIV for 7 days. Since 09/2018, FLT3-mutated AML pts may also receive midostaurin 100 mg/d d8-21. Then, all pts alive without contra-indication for further ICT were randomized (R2) to receive a first consolidation (C1, if in CR/CRp/CRi) or salvage (if induction failure) with either HDAC (3g/m 2/12h) or IDAC (1.5g/m 2/12h) cytarabine at day 1, 3 and 5. Pts in CR/CRp/CRi after C1/salvage received two additional HDAC/IDAC cycles (C2, C3), according to R2 arm. In intermediate (int) or adverse (adv) risk AML pts as defined in the protocol, allogeneic HSCT from sibling or 10/10 (or even 9/10 if adv-risk) matched donors was offered after C1 (adv-risk) or C2 (int-risk). Conditioning regimens were myeloablative (MAC; Bu-Cy ± ATG) if age&amp;lt;45y or reduced-intensity (RIC; Bu-Flu-ATG) if age≥ 45y or HCTCI&amp;gt; 2 in int-risk pts, and sequential FLAMSA/Bu-Cy-ATG in adv-risk pts. Fav-risk pts were also eligible for HSCT if late CR/CRp/CRi or suboptimal NPM1 MRD response. Alternative stem cells sources and conditioning regimens might also be offered to adv-risk pts. Patients &amp; Methods. Pts aged 18-60y with de novo, post-MDS or therapy-related AML (CBF, APL, Ph+, and post-MPN excluded) were eligible if ECOG-PS ≤3, no active infection or neoplasia, no organ contra-indication, and a health insurance. Patient characteristics are shown in Table 1. Between 01/2015 and 05/2019, 1405 pts were enrolled and 1357 were evaluable. Among them, 1159 were randomized in R1 with the primary objective to increase 3-year OS from 45% in the DNR to 55% in the IDA arm. A total of 1221 pts were randomized in R2, including 198 pts after the end of the R1 inclusion period (they received DNR or IDA according to centers' preferences). Primary R2 objective was to show OS non-inferiority after IDAC vs HDAC in a per protocol (PP) set, defined as pts who received the planned HDAC/IDAC dose ± 20% during C1/salvage. The non-inferiority boundary was an upper limit of the hazard ratio [HR] CI below 1.25. Analysis of R1 and R2 effects was adjusted on ELN-2022 risk groups, the other randomization/treatment arms, and time-dependent HSCT in first remission. Median follow-up was 5.4 years. Results. Overall, 1148 (84.6%) pts achieved CR/CRp/CRi and 564 (41.6%) received HSCT in first remission ( Table 1). At 6 years, OS was estimated at 53.4% (95% CI, 50.6-56.2). In the R1 population, IDA did not prolong OS (adjusted HR, 1.04 [0.88-1.23]; p=0.67). This lack of effect was observed in the three ELN-2022 risk groups. During induction, IDA was associated with longer neutropenia and antibiotic administration durations, more RBC/platelet transfusions, more mucositis and fungal infections. Remission and induction death rates were similar in both arms. In the R2-PP set that excluded 39 R2 pts, OS was significantly non inferior in the IDAC as compared to the HDAC arm (adjusted p-value, 0.004) and this was observed in the three ELN-2022 groups ( Figure 1). During the first C1/salvage cycle, IDAC was associated with less CNS toxicity and less RBC/platelet transfusions. Only 2 pts died during this cycle. Neither responses, HSCT rates, relapse incidence, nor RFS were significantly impacted by R1 or R2. With respect to the OS endpoint, no interactions were found between induction anthracycline and R2. In pts in induction failure at R2, the salvage rate was 51.6% after HDAC vs 39.5% after IDAC (adjusted p-value, 0.081). As expected, time-dependent HSCT in first remission significantly prolonged RFS (adjusted HR, 0.41 [0.32-0.52]; p&amp;lt;0.0001) and OS from remission (adjusted HR, 0.65 [0.50-0.83]; p=0.001) in int/adv-risk AML pts. In these pts, no interaction was found between the effect of HSCT and the R2 arm (HDAC or IDAC). Conclusions. In younger adults with non-CBF AML, benefit/risk analysis favors high-dose DNR vs IDA for remission induction and confirms IDAC as the standard for consolidation. The high overall transplant rate may have contributed to the good results of this study.

Clinical and Prognostic Implications of WT1 Mutations in De Novo and Relapsed Acute Myeloid Leukemia

Introduction Wilms Tumor 1 ( WT1) is integral to cell proliferation and survival and is mutated in up to 10-15% of patients (pts) with acute myeloid leukemia (AML). WT1 mutated ( WT1 m) AML frequently co-occurs with fms-like tyrosine kinase 3 ( FLT3) and nucleophosmin 1 ( NPM1) mutations, and is generally thought to impart poorer outcomes, however the impact of WT1 m remains incompletely understood. Methods We analyzed 307 pts with WT1 m AML, identified through next generation sequencing panels of recurrently mutated myeloid genes performed at two large academic cancer centers between 2015 - 2022. Of the 307 pts, 161 (52%) had WT1 m at AML diagnosis (ND) and 146 (48%) were identified at relapse (RR). Here we describe the baseline characteristics and outcomes in pts with WT1 m AML with emphasis on co-mutated FLT3 and NPM1. Results In pts with ND WT1 m AML, the median age was 59 years (range,22-87). Pts most commonly had intermediate (41%) or adverse (43%) risk disease by ELN 2022 criteria. 51% (n=82) had co-mutated FLT3 (ITD or TKD). Among pts with FLT3 mutated AML, 30% (37%) also had co-mutated NPM1. 10 (7%) pts had co-mutant NPM1 m without FLT3 m. Median OS in the ND cohort was 19.8 months. Variant allele frequency (VAF) ranges of WT1 m were 1-98 (median 27) and 1-97 (median 13) in the ND and RR cohorts respectively. OS was affected by mutational profile (table 1) with triple mutated NPM1/FLT3/WT1 exhibiting worse OS compared to others. 68% of ND pts received intensive chemotherapy (+/- venetoclax (VEN)) at time of diagnosis with mOS of 26.5 mos vs. 11.1 mos (p = &amp;lt;0.0001) for pts treated with lower intensity therapy (+/- VEN). Improved OS was observed in pts with ELN2022 favorable risk disease (mOS not reached (NR)) and in pts receiving an allogeneic hematopoietic stem cell transplant (SCT). Pts with ND AML and ELN2022 intermediate-risk disease who underwent SCT had significantly longer OS of 47.9 mos vs. 11.8 mos (p&amp;lt;0.0001, figure 1). In the ND cohort, pts had significantly improved OS if they underwent SCT after achievement of CR1 compared to SCT after first relapse, mOS NR vs. 38 months (p=0.00039), respectively. Notably, the median age of pts who received SCT was 50 (22-74) with 16% having secondary (s-AML) or therapy related (t-AML). Of those who did not undergo SCT median age was 63 (23-87) and had with 28% of pts with (s- or t-AML). Within the RR cohort, 44 (30%) pts acquired WT1 mutation post SCT. 56 (38%) were FLT3 m (25 pts with co-mutated NPM1) and 10 (7%) NPM1 m mutated (without FLT3 m). The mOS in the RR cohort (from time of WT1 m acquisition) was shorter in pts with co-mutated FLT3/WT1 without NPM1 (table 1). Pts who underwent SCT after WT1 macquisition had mOS of 25.7 mos (95% CI 23.8-38.7) compared to 18.3 mos (95% CI 13.2-21.2) (p=0.001) in those who did not undergo SCT. 28% of pts received intensive therapy (+/- VEN) as salvage after acquisition of WT1 mwithout difference in OS compared to those receiving low intensity therapy (66% with VEN). mOS (11.1 vs. 7.8 mos, p=0.12) . In pts ND AML and co-mutant NPM1/WT1, WT1 m was frequently (75%) subclonal to NPM1 m with a mOS NR. However, in pts who initially had NPM1 m disease and acquired a WT1 m at relapse, WT1 m was more clonally co-dominant with NPM1 mwith a mOS of 15.9 mos (p=0.11). Amongst both cohorts, there was no difference in survival based on sex. Conclusion WT1 mutations are enriched in intermediate and adverse risk AML, frequently acquired at relapse, and are associated with overall poor OS in the absence of SCT. Our data suggests that pts with WT1m AML benefit from high intensity induction regimens and SCT at CR1 should be considered in all WT1 m pts with ELN2022 intermediate or adverse risk disease. WT1 mutations should also be considered for inclusion into ELN risk stratification given poor overall survival without SCT.