Intermediate-risk Acute Myeloid Leukemia Patients 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.

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.

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.

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.

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.

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.

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). 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. 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. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT. In patients with persistent undetectable measurable residual disease (uMRD) before transplant (n=83), overall survival (OS) was similar across the groups. However, auto-HSCT showed a trend of increased disease-free survival (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 2years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P=0.015) and AD-HSCT (P<0.001). 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.

Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT

In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p < 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p < 0.001), similar LFS (65.9% vs 63.8%; p = 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p = 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p = 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p = 0.007) and similar OS (73.5% vs 61.9%; p = 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.

Analysis of epigenetic modification gene mutations among patients with acute myeloid leukemia

To investigate the carrier rate and clinical characteristics of epigenetic modification gene mutations (EMMs) among patients with acute myeloid leukemia (AML). One hundred seventy two patients who were initially diagnosed with AML at the First People's Hospital of Lianyungang from May 2011 to February 2021 were selected as the study subjects. Next-generation sequencing was carried out to detect variants of 42 myeloid genes among these patients. Clinical and molecular characteristics of patients with EMMs and the effect of demethylation drugs (HMAs) on their survival were analyzed. Among the 172 AML patients, 71 (41.28%) were found to harbor the EMMs, and carrier rates were TET2 (14.53%, 25/172), DNMT3A (11.63%, 20/172), ASXL1 (9.30%, 16/172), IDH2 (9.30%, 16/172), IDH1 (8.14%, 14/172), EZH2 (0.58%, 1/172). Patients with EMMs (+) had lower peripheral hemoglobin compared with those with EMMs(-) (72 g/L vs. 88 g/L, Z = -1.985, P = 0.041). The proportion of EMMs(+) among elderly AML patients was significantly higher than that of young AML patients[71.11% (32/45) vs. 30.70% (39/127), χ² = 22.38, P < 0.001]. EMMs(+) were significantly correlated with NPM1 gene variants (r = 0.413, P < 0.001), while negatively correlated with CEPBA double variants (r = -0.219, P < 0.05). Compared with conventional chemotherapy regimens, HMAs-containing chemotherapy regimens have improved the median progression-free survival (PFS) and median overall survival (OS) among intermediate-risk AML patients with EMMs(+) (PFS: 11.5 months vs. 25.5 months, P < 0.05; 12.5 months vs. 27 months, P < 0.05). Similarly, Compared with conventional chemotherapy regimens, chemotherapy with HMAs had increased median PFS and median OS in elderly AML patients with EMMs(+) (4 months vs. 18.5 months, P < 0.05; 7 months vs. 23.5 months, P < 0.05). Patients with AML have a high rate of EMMs carriage, and HMAs-containing chemotherapy regimens can prolong the survival of elderly patients with AML with poor prognosis, which may provide a reference for individualized treatment.

Measurable residual disease-guided therapy in intermediate-risk acute myeloid leukemia patients is a valuable strategy in reducing allogeneic transplantation without negatively affecting survival.

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Individualized busulfan dosing improves outcomes compared to fixed-dose administration in pre-transplant minimal residual disease-positive acute myeloid leukemia patients with intermediate-risk undergoing allogeneic stem cell transplantation in CR.

Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in acute myeloid leukemia (AML). Therapeutic drug monitoring by calculating area under the curve (AUC) was developed to optimize busulfan (Bu) exposure. Here, we compared post-transplant outcomes after individualized versus fixed busulfan dosage in intermediate-risk AML who achieved CR prior to allograft focusing on pre-transplant flow-MRD. Eighty-seven patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. Thirty-two patients received individualized busulfan; 54 fixed dosages. Individualized dosage was adjusted in 25/32 patients: increased, n= 18/25 (72%); decreased: n= 7/25 (28%). After median follow-up of 27 months, we observed lower 3-year relapses (6%, 2%-19% vs. 35%, 23%-49% p= 0.02), improved 3-year leukemia-free survival (LFS) (78%, 54%-91% vs. 55%, 40%-70% p= 0.009) and - overall survival (OS) (82%, 60%-93% vs. 69%, 54%-81% p= 0.05) after individualized compared to fixed Bu. Non-relapsed mortality (NRM) and acute graft versus host disease (GvHD) were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (hazard ratio [HR] 4.6, p= 0.044), LFS (HR 3.6, p= 0.018) and relapses (HR 3.6, p= 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1-12.6, p= 0.041) in pre-transplant MRD-positive patients. Individualized, AUC-based, busulfan is associated with lower relapses in intermediate-risk AML patients allografted in CR and may overcome pre-transplant MRD-positivity.

MYC Influences mRNA Processing and Nuclear Export to Initiate Acute Myeloid Leukemia

Background: Although MYC is a potent oncogene that is frequently associated with poor outcomes in many solid tumors, its precise role in Acute Myeloid Leukemia (AML) pathogenesis and outcomes are not clear. We recently discovered that intermediate-risk AML patients with long first remissions with standard chemotherapy have an unexpectedly high frequency of pathogenic MYC mutations in the dominant leukemia clone at diagnosis (6 of 26 [23%] cases, versus 1.8% of all AML patients, p=0.002). An analysis of all MYC mutations reported in AML, revealed that they are nearly always single base substitutions that localize to a hotspot in the MYC Box I domain (MBI - AAs hotspot 73-74); this stands in distinct contrast to other hematopoietic malignancies, where MYC mutations are scattered throughout the entire gene. In this study, we engineered mouse hematopoietic stem and progenitor cells (HSPCs) to express AML-associated MYC missense mutations and characterized their in-vitro and in-vivo cellular and molecular phenotypes. Results: We observed that constitutive expression of MYC MBI mutant proteins in mouse HSPCs significantly prolonged Myc half-life and conferred different degrees of growth advantage over both wild type MYC overexpression and overexpression of non-MBI mutant proteins. To determine whether these mutations are AML drivers, HSPCs expressing MYCWT or the MBI mutants MYCP74Q and MYCT73N were transplanted into lethally irradiated syngeneic recipient mice, which were then evaluated for the development of leukemia. Primary recipient mice transplanted with MYCWT-expressing cells developed leukemia with a median survival of 58 days for whereas mice transplanted with MYCP74Q- or MYCT73N-expressing cells displayed a median survival of 42 and 41.5 days, respectively (p<0.001). Furthermore, secondary recipient mice transplanted with MYCWT-, MYCP74Q- or MYCT73N-expressing AML cells from primary recipient mice also developed AML, indicating that expression of WT and MBI-MUT Myc leads to the development of frank leukemia in mice. Next, we investigated the impact of these point mutations on the transcriptional targets of Myc by comparing single-cell RNA-seq profiles of murine HSPCs expressing wild type, P74Q, or T73N Myc versus an empty vector control. From these analyses, we found that while each of these mutants retain many of the transcriptional activities of wild type Myc, they also display unique transcriptional signatures. To better understand how these mutations affect the transcriptional output of MYC, we performed ChIP-seq analysis of primary murine HSPCs expressing MYCWT-, MYCcP74Q- or MYCT73N. Despite MBI mutations causing persistent MYC protein expression (due to prolonged half-life), we detected an overall decrease in chromatin binding of MBI-MUT MYC, with preserved binding to transcriptional start sites of a core sets of genes involved in splicing and translation. Importantly, MBI mutations did not affect the canonical E-box Myc binding site, nor create novel binding sites, indicating that these mutations lead to an overall decrease in Myc occupancy at target promoters. Immunofluorescent staining for WT vs. MBI mutant MYC showed that despite their overall decrease in chromatin binding, Myc mutant proteins localized predominantly to the nucleus. However, a substantial number of nuclei showed a ring-like morphology of MBI-MUT MYC, suggesting that MBI mutations might enrich protein localization at the nuclear periphery. To determine whether the changes in staining pattern observed for MBI-MUT were associated with alterations in the ability of MYC to interact with its regulatory proteins, we employed a modified BioID proximity labeling system, "TurboID", to screen for differential protein interactions in murine HSPCs. This analysis showed that MBI mutations resulted in several gained interactions over WT MYC - most prominently with components of the nuclear pore complex (NUP98, NUP107, NUP133, XPOT, RAE1) supporting the idea that MBI-MUT might accelerate transformation by controlling translation and mRNA nuclear export. Conclusions: Collectively, these data indicate that AML-associated MYC mutations support leukemogenesis through non-canonical (transcription-independent) MYC proprieties. More broadly, these data suggest that aberrant mRNA processing and nuclear export might play an important role in the initiation of AML by MYC mutations.

Prognostic Impact of WT1 Mutation on AML of Different Risk Groups Based on 2022 European Leukemianet (ELN) Risk Classification

Background The Wilms tumor 1 (WT1) gene, located on chromosome 11p13 exists in multiple isoforms. It has been implicated in the regulation of cell survival, proliferation and differentiation, and may function both as a tumor suppressor and an oncogene. Approximately 15% of acute myeloid leukemia (AML) patients carry WT1 mutations, and WT1 mutation have been shown to be independent predictor of worse clinical outcome in some but not all adult AML studies. Some studies suggested that NPM1-AML & AML with CEBPA double-mutation accompanied with WT1 mutation can alter their original favorable prognosis. Recently, a revised European LeukemiaNet (ELN) genetic risk classification has been published and the prognostic significance of WT1 mutation in three risk groups according to this 2022 ELIN risk classification is still unclear. Objective To investigate the prognostic significance of WT1 gene mutations in acute myeloid leukemia (AML) patients with different risk of the 2022-ELN risk classification. Methods 502 patients de novo AML diagnosed between March 2015 and July 2021 who underwent next-generation sequencing (NGS) tests and had MICM precise typing at the Peking University Institute of Hematology were enrolled in this study. The patients received chemotherapy ± hematopoietic stem cell transplantation (HSCT), and they were stratified into three groups according to the 2022 version of ELN-AML risk stratification. Results Among 502 patients, a total of 71 (14.1%) patients carried WT1 mutations, of which 57 patients had mutations at a single locus, 8 patients had mutations at double sites, 5 patients had co-mutations at 3 sites in the WT1 gene, and 1 patient had mutations at 4 sites. Comparing the incidence of AML-related mutations between the WT1 mutation group and the wild-type group, the results showed that the concomitant rate of NPM1 mutations was lower in the WT1 mutation group than in the WT1 wild-type group (14.1% vs 27.1%, p=0.028), and the concomitant rate of CEBPA-bZIP mutations was higher in the WT1 mutation group than in the WT1 wild-type group (29.6% vs 10.9%, p<0.001). The concomitant rate of CEBPA double mutation was also higher in the WT1 mutation group than in the WT1 wild-type group (29.6% vs 10.4%, p<0.001), and the concomitant rate of GATA2 mutation was higher in the WT1 mutation group than in the WT1 wild-type group (14.1% vs. 4.4%, p=0.004). In addition, the WT1 gene expression level (WT1/ABL1) was higher in the WT1 mutation group than in the WT1 wild group at diagnosis (22.0% vs 13.5%, p=0.004). All patients were further divided into 6 groups based on 2022 ELIN risk classification and whether they received HSCT. There were 158 (31.5%) patients in the low-risk chemotherapy group, 73 (14.5%) in the low-risk transplantation group, 72 (14.3%) in the intermediate-risk chemotherapy group, 58 (11.6%) in the intermediate-risk transplantation group, 78 (15.5%) in the high-risk chemotherapy group, and 63 (12.5%) in the high-risk transplantation group. Univariate and multivariate COX regression analyses were performed including WT1 mutation, FAB classification, age, sex, and karyotype stratification indicators. In 58 patients who were intermediate-risk and received HSCT, patients with WT1 mutation resulted in higher cumulative incidence of relapse(CIR) in compared with those without WT1 mutation (52.3% vs 33.5%, HR=9.28, p<0.001). In the remaining 5 groups of patients, WT1 mutation seemed have no significant effect on overall survival(OS), event-free survival (EFS), or CIR in patients (p-values were all less than 0.05). Conclusion Among intermediate-risk AML patients in the 2022 version of ELN stratification who received transplantation, the CIR after transplantation was higher in AML patients with WT1 mutation. It seemed that WT1 mutation was an independent risk factor for post-transplantation recurrence, and allogeneic HSCT cannot efficiently overcome the poor prognosis of WT1 mutation in the intermediate-risk group. Intermediate-risk AML with WT1 mutations still requires more active strategies to prevent relapse. Of course, the impact of WT1 mutation on prognosis needs to be further confirmed by expanding the sample size.

Extracellular Vesicle-Based Liquid Biopsy Shows Clinical Relevance and Reveals Links with Single-Cell Metabolic Signature in Acute Myeloid Leukemia

Background. Acute myeloid leukemia (AML) is an aggressive disease that shows dysregulated cell metabolism and a high relapse rate. To date, less invasive tools are urgently needed to explore disease dynamics in AML. In this regard, Extracellular Vesicles (EV) from plasma represent a promising tool for liquid biopsy. Also, the material extracted from blood (including circulating leukemic stem cells, LSC) can be used for clinical purposes revealing clinically relevant (metabolic) vulnerabilities. Along with EV profiling in AML patients, we explored the clinically relevant (metabolic) signature carried by CD34+ cells in circulation. Methods. Peripheral blood (PB) was collected from AML patients at diagnosis (n=70) and healthy donors (HD, n=20). EVs were purified from platelet-poor plasma by size exclusion chromatography and ultrafiltration. Quantitative lipidomic profiling was performed by Liquid Chromatography coupled with High-Resolution Mass Spectrometry (LC/HRMS). Single Cell ENergetic metabolism by Profiling Translation inhibition (SCENITH) has been performed in fresh whole blood. Results. We profiled the surface protein of isolated circulating EVs by AML patients at diagnosis. Compared to EV from HD, leukemic EV from newly diagnosed AML patients were mainly enriched in cancer stem cell marker, CD44. Intriguingly, the area under the curve (AUC) confirmed a reliable performance for employing this marker on EVs to discriminate EVs from AML patients. Among other 36 markers explored, CD4 (immune marker), CD105 (mesenchymal stromal cell marker), CD14 (monocyte marker), and CD133-1 (stem cell marker) were highly expressed only in leukemic EVs. In particular, CD11c as the well-known dendritic marker was solely expressed in EVs from some AML patients and totally absent in healthy EVs. By contrast, in circulating leukemic EVs, we observed depletion in markers such as CD62P, CD41b, and CD41a suggesting an impaired function in leukemic megakaryocytes and platelets. From the clinic point of view, according to European LeukemiaNet (ELN) 2017 risk classification, we observed that CD9, CD29, CD31, and CD42a were enriched in the favorable AML group in comparison with adverse/intermediate-risk AML patients. Notably, non-survivor AML patients showed a significant reduction in the expression of EV markers including CD11c, CD69, and ROR-1. Then, to further highlight crucial characteristics in EV composition, we performed an untargeted lipidomic analysis on circulating EVs. Fatty acids (FA) and Diacylglycerols (DG) were significantly overexpressed in leukemic EVs compared to healthy EVs. Leukemic EVs were depleted in Cholesteryl ester (CE) suggesting an increase in membrane stiffness. Interestingly, the lipid CE18:2 was found high in adverse-risk AML patients encouraging further studies on EV lipidomic profiles for better AML stratification. An in-depth investigation of the metabolic dependencies of leukemia (stem) cells from blood might be crucial for detecting novel metabolic vulnerabilities in AML patients. Thus, we applied the innovative SCENITH approach in fresh blood from AML patients at diagnosis. We found that circulating AML CD34+ cells were highly dependent on glucose oxidation and less prone to use fatty acids and amino acids as sources for ATP production when glucose oxidation was inhibited. Also, AML CD34+ cells in circulation reported a higher glycolytic capacity compared to mitochondrial dependence. Towards a clinically relevant implication, SCENITH analysis showed that mitochondrial dependence was solely increased in adverse and intermediate-risk AML patients compared to favorable AML patients. Interestingly, the percentage of mitochondrial dependence in AML CD34+ was positively correlated to the expression of CD24 (cancer stem marker) observed on leukemic EVs suggesting a novel potential link between EV profiling and energy metabolism for leukemia. Conclusion. Overall, these results demonstrate that an abnormal signature characterizes the phenotype of circulating EVs in AML patients. Indeed, the depletion of selected EV markers could be associated with high-risk AML disease and supports their prognostic relevance. This work might reveal novel metabolic vulnerabilities in the AML scenario by exploiting both EV-based liquid biopsy and single-cell metabolic phenotyping.

5'-nucleotidase, cytosolic II genotype, and clinical outcome in patients with acute myeloid leukemia with intermediate-risk cytogenetics.

Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: .003; HR 2.16, 95% CI 1.29-3.61) and lower disease-free survival (DFS) (p: .002; HR 2.45, 95% CI 1.41-4.27), associated to a higher relapse incidence (p: .010; HR 2.23, 95% CI 1.21-4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.

Prognostic factors of autologous hematopoietic stem cell transplantation in intermediate-risk acute myeloid leukemia patients with minimal residual disease negativity

To explore prognostic factors in intermediate-risk acute myeloid leukemia (AML) patients with minimal residual disease (MRD) negativity (MRD<0.1%,MRD-)receiving autologous hematopoietic stem cell transplantation (auto-HSCT).A total of 59 intermediate-risk AML patients with MRD-were treated with auto-HSCT from January 2015 to September 2021 at Affiliated People's Hospital of Ningbo University. The clinical data and laboratory results were collected retrospectively. Efficacy, clinical outcome and prognostic factors were analyzed. Univariate analysis was conducted by using log-rank test, the multivariate analysis by Cox proportional risk model.Among 59 patients, there were 27 males and 32 females with median age of 55 (31-69) years old.The median follow-up was 761(317-1 861)days. The 2-year overall survival (OS) rate and event-free survival (EFS) rate were 76.1%±11.4% and 73.4%±11.6% respectively.The univariate analysis showed that age older than 50 years, TET2 gene mutation (TET2+), achieving MRD negativity over 30 days (MRD30+) were unfavorable factors of OS (χ2=6.20, 33.20, 7.18;P=0.013,<0.001, 0.007). TET2+, WT1 gene mutation (WT1+), CD34+cells<2×106/kg, MRD30+were negative factors of EFS (χ2=17.29, 4.47, 3.94, 9.393;P<0.001, 0.035, 0.047, 0.002).Multivariate analysis showed that MRD30+, TET2+ were independent prognostic factors of OS and EFS (OS:HR=9.251, 25.839, P=0.036, 0.001;EFS:HR=5.851, 9.199, P=0.043, 0.002). Intermediate-risk AML patients with MRD30+or TET2+ have very poor prognosis after auto-HSCT. Alternative regimens should be investigated.

The importance of genomic predictors for clinical outcome of hematological malignancies

The importance of genomic predictors for clinical outcome of hematological malignancies

Mutations in DNMT3A, U2AF1, and EZH2 Identify Intermediate-Risk Acute Myeloid Leukemia Patients with Poor Outcome after CR1

Introduction: Intermediate-risk acute myeloid leukemia (IR-AML) is a clinically heterogeneous disease, for which optimal post-remission therapy has been debated. Several studies using next-generation sequencing have identified important prognostic information and led to modifications in risk stratification. However, the utility of this genetic information in decision making for IR-AML has yet to be elucidated. We investigated the clinical relevance of recurrent driver gene mutations in a well-characterized cohort of IR-AML patients in first complete remission (CR1) after induction chemotherapy.Methods: A total of 1,589 AML patients treated at the Cleveland Clinic (CC) between 2002 and 2016 were screened for eligibility, of whom 825 were in European Leukemia Net (ELN) IR category. Of them, 100 IR-AML patients, who had mutational information at diagnosis and achieved CR after ≥ 1 round of intensive induction were included. CR was defined as <5% bone marrow blasts, absolute neutrophil counts ≥ 1x109/L, and platelet counts ≥ 100x109/L. CR with inadequate count recovery (CRi) was same as CR, except for residual neutropenia or thrombocytopenia. The induction regimen was 7+3, and patients with persistent disease at day 14 marrow were re-induced with 7+3 or 5+2. Patients who did not receive intensive therapy or achieve CR/CRi were excluded. A TruSeq Custom Amplicon panel targeting exons of 62 genes was used for deep sequencing at diagnosis. We used The Cancer Genome Atlas (TCGA) data for validation of our findings.Results: In the CC cohort, median age was 58.5 (24-75) years, 64% had normal cytogenetics, and 31% required >1 induction cycles to achieve CR1. DNMT3A and FLT3-ITD mutations were the most common (19%), followed by RUNX1 (15%), TET2 (12%), IDH2 (12%), NPM1 (12%), ASXL1 (11%), and U2AF1 (11%). The frequency of persistent disease after initial induction was higher in patients with mutations in DNMT3A (47% vs 27%, p= .03) and U2AF1 (55% vs 28%, p= .01), while CRi was more common in patients with BCOR mutation (50% vs 8.5%, p= .02). In univariable analysis, patients with mutations in DNMT3A, U2AF1, and EZH2, and patients who achieved CRi after induction had worse overall (OS) and relapse-free survival (RFS). Patients who had hematopoietic cell transplant (HCT) in CR1 achieved better OS (HR, 0.4; 95% CI, 0.2-0.7; p=0.003) and RFS (HR, 0.3; 95% CI, 0.1-0.6; p< 0.001) than those who did not. Other clinical factors analyzed, such as age, sex, cytogenetics, and the number of induction courses to achieve CR1 were not significant predictors for survival after CR1. To evaluate the impact of these three mutations on risk stratification, we compared patients whose AML harbored any of the mutations with those who did not. The median OS and RFS for patients with mutations were 13 and 9 months, respectively, compared to 41 and 16 months in patients without (p< 0.0001 and p= .003). Similarly, TCGA patients with mutations had significantly poorer OS (median, 9.8 vs 46.8 months, p= .0002) and RFS (median, 9.3 vs 17 months, p= .02). In multivariable analysis, mutations maintained an independent effect on survival (Table 1).Since mutations and HCT were the major predictors of outcome after CR1, we analyzed the outcomes of patients harboring mutations in relation to HCT (Figure 1). In both cohorts, patients who did not have the mutations and underwent HCT had the best outcomes. In the CC cohort, median OS and RFS for patients who had mutations and HCT were 14 and 11 months, respectively, compared to 7.5 and 5 months in patients who did not undergo HCT (p= .04 for OS and p= .002 for RFS). In the TCGA cohort, patients who harbored mutations and did not undergo HCT had significantly worse OS (median, 6.3 vs 24.6 months, p= .001) and RFS (median, 7.8 vs 12.5 months, p= .003). In view of the recently proposed ELN 2017 criteria that place IR patients with RUNX1 or ASXL1 mutations into the adverse risk, we explored outcomes of these patients at the time of CR1. Presence of these mutations did not predict OS and RFS in our cohort, and performance of HCT did not confer a significant survival benefit in patients with these mutations.Conclusions: In two independent cohorts, DNMT3A, U2AF1, and EZH2 mutations were predictors of relapse and OS in IR-AML at CR1, and performance of HCT translated into survival benefit. Our results provide evidence of clinical utility in considering mutation screening to stratify IR-AML patients to guide therapeutic decisions. [Display omitted] DisclosuresSekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Gerds:CTI BioPharma: Consultancy; Incyte: Consultancy. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Ra Pharma: Consultancy; Apellis Pharmaceuticals: Consultancy. Advani:Pfizer: Consultancy; Takeda/ Millenium: Research Funding.

An Integer Weighted Genomic Mutation Score (GMS) Using Next Generation Sequencing Is Predictive of Prognosis in Intermediate Risk AML Patients

Introduction: The genomic heterogeneity in Acute Myeloid Leukemia (AML) has been shown to affect the overall prognosis and should be taken into account to decide the best course of treatment. Study of AML genomic landscape by The Cancer Genome Atlas (TCGA) research network by Ley, et.al, analyzed the genomes of 200 patients (pts) with de-novo AML and showed at least one potential driver mutation in nearly all AML samples and further classified these mutation in 9 functional categories: Myeloid transcription factor and fusion genes, Tumor suppressor genes, gene encoding Nucleophosmin, Activated signaling genes, DNA methylation related genes, Chromatin modifying genes, Cohesion complex genes and Spliceosome complex genes . The availability of Next Generation Sequencing (NGS) has allowed easy characterization of patient samples. However, this has now became increasingly important to prioritize the influence of different mutations clones so as to give actionable and prognostic information. We developed an Integer Weighted Genomic Mutation Score (GMS) to address this in the context of the TCGA data and applied this to a retrospective cohort of pts with AML. The goal was to meaningfully stratify the Intermediate risk AML patients per current ELN criteria based identified by NGS technique into low and high risk group and correlate this with clinical outcome.Study Method: We screened 1200 AML patients at our institution from 2010 to 2016 and identified 111 patients from our hospital database who had information on both cytogenetics and gene mutation detected by NGS. We queried for the diagnosis of AML and demographics, Cy, NGS and OS. We divided the patients into 3 groups according to their cytogenetic risks- Favorable (FCy), Intermediate (ICy),Poor (PCy). Mutations in 54 genes associated with myeloid disorders were tested in NGS by using the TruSight Myeloid Sequencing Panel (Illumina) (Table1). We also performed flow cytometric evaluation on a BD FACSCantos™ II 3-laser (405, 488, 630 nm excitation sources), 8-color flow cytometer (BD Biosciences, San Jose, CA, USA) and data analyzed using BD FACSDiva software. We then utilized the TCGA data by Leyet.al and developed a system of Integer Weights forthe Genomic Mutation Score (GMS) obtained by targeted NGS at Houston Methodist Hospital mentioned below. GMS was designed by assigning a score for each genomic mutation between the range of negative 2 (-2) for good risk to positive 2 (+2) for each of 9 TCGA mutation categories .The total IWGMS for each patient was calculated by the sum of mutation scores in each 9 categories. A score of 3 or greater than 3 was defined as high risk. We then performed a retrospective analysis of 111 AML patients to correlate the GMS with 2 year mortality and survival outcome. Statistical Analysis was done using multivariate logistic regression method.Results: Pts were grouped into 51 intermediate risk and 60 poor risk cytogenetics. Median age of the pts was 66 years and 57.6% were male. Immunophenotyping of CD34 and CD38, and CD117 did not emerge as significant predictors of survival when adjusting for covariates. 32% of patients underwent allogeneic stem cell transplant as consolidation therapy. Median overall survival for the entire study population was 24 months with a median follow up time was 20.01 months (95% CI; 15.77 - 25.17). Univariate analysis using cox proportional hazard method showed age and cytogenetics risk as a statistically significant predictor of overall survival as shown in Fig: 1. Overall survival in all AML patients and Intermediate risk patients showed a trend toward better OS with lower GMS but no such trend was seen in poor risk AML patients as shown in Fig: 2-4.Conclusion: We have developed an GMS system to further stratify Intermediate Risk AML patients into high and low risk groups. Age and cytogenetics risk per ELN criteria were independent prognostic factor for overall survival in our study cohort as expected. Patients with lower GMS in our study cohort had a trend towards better OS but patients with high GMS had a trend towards worse OS in intermediate risk AML patients. Larger size prospective study is required to validate this scoring system; it has a great potential to identify high risk patients among Intermediate risk group and plan different consolidation therapies to further improve their outcomes.Further treatment related analysis will be presented at ASH,Atlanta 2017. [Display omitted] DisclosuresIyer:Takeda: Research Funding; Genentech: Research Funding.

Outcomes of Intermediate Risk Acute Myeloid Leukemia in First Remission Undergoing Autologous Stem Cell Transplantation Compared to Allogeneic Stem Cell Transplantation and Chemotherapy Consolidation: A Retrospective, Propensity-Score Adjusted Analysis

Introduction: Post-remission therapy (PRT) for acute myeloid leukemia (AML) remains an area of debate. Autologous stem cell transplantation (AutoSCT) is listed as a possible PRT in patients with intermediate risk AML in the 2017 European Leukemia Network Recommendations. Our center has frequently performed AutoSCT for patients with AML and we aimed to retrospectively compare this strategy with allogeneic SCT (AlloSCT) and consolidation chemotherapy (CMT).Methods: We compared overall survival (OS) and leukemia free survival (LFS) using propensity score (PS) adjusted analysis of patients receiving PRT with: AutoSCT, matched sibling (Sib) AlloSCT, unrelated/mismatch (UD/MM) AlloSCT and CMT. We included patients diagnosed between 1984-2003 (period of AutoSCT at our centre) in first complete remission (CR1) following induction CMT. The 2010 Medical Research Council cytogenetic classification [Grimwade D. Blood 2010;116(3):354-65] was used to define intermediate risk patients. PS-adjusted analysis was performed with marginal mean weighting through stratification (MMWS) method [Hong G. Psych Methods 2012;17(1):44-60.], accounting for sex, de-novo vs. secondary, year of diagnosis, age, chromosome, performance status and high risk features based on prior institutional guidelines (monocytic subtypes, white blood cell > 50x109/L and > 1 cycle to CR1). In brief, log(PS) were calculated from multinomial regression. We excluded cases with log(PS) outside common support area (20% standard deviation from minimum and maximum of each group). Log(PS) were then stratified into 6 strata. MMWS weight was the product of inverse proportion of treatment in each stratum multiplied by proportion of treatment in the whole population. Data was censored at failure or at 10 years. Unadjusted survival analysis was performed using Kaplan Meier method and multivariate logistic regression, and adjustment was also performed by MMWS weight.Results: We identified 259 patients (62 Sib-AlloSCT, 18 UD/MM-AlloSCT, 30 AutoSCT and 149 CMT). Baseline pre-PRT characteristics were used for PS calculation before and after weight adjustment (Table). All SCTs were performed with myeloablative conditioning regimens, most being busulfan-cyclophosphamide based. Median follow-up time for patients who survived beyond 1 year was 6.5 years. Unadjusted OS and LFS were as shown in Figure panel A and B. We excluded 38 patients (2 Sib-AlloSCT, 3 AutoSCT and 33 CMT) based on the PS calculation. The pre-PRT characteristics were well balanced after PS adjustment. Adjusted OS at 2 and 5 years were: Sib-AlloSCT 75.3% and 65.5%; UD/MM-AlloSCT 38.2% and 38.2%; AutoSCT 60.7% and 46.0%; CMT 48.0% and 30.4% (Figure panel C). Adjusted LFS were: Sib-AlloSCT 71.4% and 65.5%; UD/MM-AlloSCT 38.2% and 38.2%; AutoSCT 50.8% and 46.0%; CMT 21.9% and 17.4%, respectively (Figure panel D). Adjusted cumulative incidence of relapse and non-relapse mortality (considered as competing risks) at 5 years were: Sib-AlloSCT 17.2% and 20.9%; UD/MM-AlloSCT 32.6% and 33.3%; AutoSCT 48.4% and 10.8%; CMT 80.5% and 10.9%. Adjusted multivariate HR, 95% confidence interval (CI) and p-value for OS, considering CMT as reference, were: Sib-AlloSCT [0.34, 0.19-0.61, <0.001], UD/MM-AlloSCT [1.03, 0.40-2.66, 0.953] and AutoSCT [0.71, 0.33-1.51, 0.374], respectively. Adjusted multivariate HR, 95%CI and p-value for LFS were Sib-AlloSCT [0.22, 0.13-0.37, <0.001], UD/MM-AlloSCT [0.62, 0.27-1.43, 0.262] and AutoSCT [0.45, 0.21-0.96, 0.038], respectively.Conclusion: Our results show that intermediate risk AML patients who underwent Sib-AlloSCT in CR1 had the best outcomes. AutoSCT significantly improved LFS, in comparison to CMT. However, this benefit did not result in a significant improvement in OS, possibly due to subsequent SCT in the CMT group after relapse. Limitations of our findings include a lack of molecular data and the older time period of our cohort. In a more contemporary cohort, we anticipate that advancements in donor selection and supportive care might improve outcomes with AlloSCT, particularly for the unrelated donor group. Despite this, our results support AutoSCT as a valid option for intermediate risk AML patients who lack an HLA-matched sibling. Further studies integrating molecular genetics and minimal residual disease are needed to guide the selection of patients for AutoSCT who are likely to gain the greatest benefit. [Display omitted] DisclosuresHogge:Novartis, Roche, and Sanofi: Consultancy. Sutherland:Janssen: Honoraria. Gerrie:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding.

Comparison of Autologous Stem Cell Transplantation Versus Haplo-Identical Donor Stem Cell Transplantation for Favorable- and Intermediate-Risk Acute Myeloid Leukemia Patients in First Complete Remission

BackgroundFor favorable- and intermediate-risk AML patients who lack of an available HLA-matched donor, the post-remission treatment is controversial. Autologous stem cell transplantation (auto-SCT) and haplo-identical stem cell transplantation (haplo-SCT) are widely used alternative options, both of which revealed promising data according to recent studies. However, few data have been published on the direct comparison between these two transplant types.Patients and MethodsThis is a retrospective study based on the transplantation database in our center. The inclusion criteria were: a) patients who were definitely diagnosed as de novo AML without extramedullary disease; b) who achieving complete remission (CR) after induction chemotherapy of no more than 2 cycles; c) who had results of cytogenetic and molecular genetic detections suggesting a favorable- or intermediate-risk according to the NCCN guideline of AML; and d) who received auto-SCT or haplo-SCT in CR1 before January 2014. Myeloablative conditioning applied in this cohort was Bu/Cy-based regimen (with ATG for haplo-SCT recipients), and a minority of auto-SCT patients received a nonmyeloablative conditioning of BEAM regimen.ResultsTotally 196 cases were recruited in this study, in which 88 cases received auto-SCT and 107 cases received haplo-SCT (Table 1). There are statistical differences of age, risk stratification, ratio of CBF-AML, induction cycles, interval from diagnose or CR1 to transplant, conditioning and graft type between the two groups. After SCT, neutrophil recovery was earlier in auto-SCT group with a median time of 11 days comparing to 12 days in haplo-SCT group (P = 0.004). Survival, relapse and NRM were shown in Table 2. For the whole cohort and favorable-risk patients, impact of high relapse incidence in auto-SCT group was compensated by low NRM, which resulted in a comparable survival comparing to haplo-SCT group (Fig 1A and 1B). However, for intermediate-risk patients, NRM was similar between the two groups and haplo-SCT exhibited superior survival (Fig 1C).Thirty-six cases relapsed after SCT with a median time of 9 months post-SCT, in which 28 cases received auto-SCT and 8 cases received haplo-SCT. Estimated OS at 3 years for relapsed patients was 38.7 ± 9.0%, without notable difference between auto-SCT and haplo-SCT (37.9 ± 9.9% versus 40.0 ± 20.3%, P = 0.823). Instead, patients with intermediate-risk showed markedly inferior 3-year OS comparing to the ones with favorable-risk (23.3 ± 9.8% versus 60.8 ± 14.3%, P=0.011) (Figure 1D). For intermediate-risk patients, only 5 out of 20 (25.0%) cases who relapsed post-SCT could achieved constant remission again. Contrarily for favorable-risk patients, 11 out of 16 (68.8%) cases achieved remission again (P = 0.017), and 10 cases in whom remained survival at the end of follow-up.In the multivariate analyses, MRD measured by FCM and gene mutation status before transplant were independent predict factor for both OS and RFS. Interestingly, intermediate-risk independently led to an inferior OS rather than RFS, probably due to the poorer survival of post-SCT relapse for intermediate-risk cases. Transplant type had no independent impact on OS and RFS, but haplo-SCT could result in higher risk of NRM and lower risk of relapse. In addition, myeloablative conditioning and longer interval from diagnosis to transplant will increase the risk of NRM, while positive gene mutation before transplant will increase the risk of relapse post-SCT.ConclusionBoth auto-SCT and haplo-SCT were acceptable option as post-remission treatment for favorable- and intermediate-risk AML patients. For intermediate-risk cases, haplo-SCT revealed better survival but the relapse after SCT still led to a poor outcome. Clearance of MRD before SCT could improve the prognosis after transplantation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.