Acute Myeloid Leukemia Pts Research Articles

Frailty risk assessment and impact on acute myeloid leukemia outcomes (FRAIL-AML): A population-based study from Ontario, Canada.

6506 Background: In acute myeloid leukemia (AML), treatment decisions, specifically intensive versus non-intensive approaches, depend on the clinician’s assessment of patient fitness. Frailty as a measure of fitness is a broader concept than commodities and is associated with worse outcomes in many cancers. Frailty assessment is incorporated to provide the precision to oncology treatment selections in addition to disease-related factors. The impact of frailty on outcomes in AML is not well studied. Methods: This retrospective cohort study from population-based health administrative databases in Ontario, Canada (ICES) included all patients (pts) ≥18 years diagnosed with AML between 2006 and 2021, treated within 90 days after diagnosis. Frailty was measured using McIsaacs’s frailty index (MFI)- a validated tool. Progressively increasing tertiles of MFI were categorized as fit (FT), pre-frail (PFR), or frail (FR). Treatment intensity was classified as intensive (IT) or non-intensive (NIT) based on standard practices. The primary outcome was overall survival (OS). Association of frailty with OS was measured using Cox regression separately for IT and NIT AML. Results: Out of 5450 pts, with a median age of 65 (IQR 54-74), 55.8% were males and 44.2% were females. 65% (n=3543) received IT, out of which 29.4% and 35.5% pts were FR and PFR respectively. Remaining 35% (n=1907) received NIT, with 41.1% and 32.3% pts being FR and PFR. Median overall survival in months (OS, 95% CI) for the entire group, IT, and NIT were 12.5 (12.0-13.2), 16.7 (15.7-18.2), and 7.6 (7.0-8.2), respectively. OS (table) was notably lower in FR pts compared to fit pts (p<0.0001) in both IT and NIT. Univariate and multivariate analyses identified frailty, advanced age, and previous non-AML malignancy as risk factors associated with worse OS in both IT and NIT groups (table). Conclusions: Higher frailty is independently associated with worse OS in AML pts after adjusting for advanced age. A substantial proportion of AML pts in both IT and NIT groups exhibit a mismatch in treatment intensity assignments based on their frailty status, with about 30 % FR pts receiving IT and over 25 % FT pts receiving NIT. This study sheds light on the need for frailty evaluations using standardized tools to optimize treatment decisions in AML pts. [Table: see text]

A phase 1 single-arm, open-label study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in patients (pts) with acute myeloid leukemia (AML) in complete response (CR) with measurable residual disease (MRD).

TPS6587 Background: Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these 3 onco-proteins by emavusertib may address the unmet need for novel therapies in AML. Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses in pts with relapsed or refractory AML (Metzeler 2022). Azacitidine + venetoclax (aza+ven) is an approved therapy for newly diagnosed pts with AML, unfit for intensive chemotherapy. Pre-clinical studies have demonstrated that emavusertib in combination with aza+ven has synergistic and antileukemic effects. In the VIALE-A study, composite CR (CRc) (CR, CRh, or CRi) in the absence of MRD of <1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS) compared with AML pts who achieved CRc but were MRD+ (Pratz, 2022). Therefore, adding emavusertib to aza+ven in CR or CRh, MRD+ pts may convert MRD status without significant toxicity and become a potential new regimen in front-line therapy. Methods: This is a single-arm, open-label Phase 1 study of emavusertib in combination with first line aza+ven in AML pts ≥60 years of age who achieved CR or CRh with MRD+ status based on local testing. The primary objective is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include determining the MRD conversion rate, pharmacokinetics, DOR, and OS. The study will enroll approximately 24 pts at 5 to 10 sites globally. Pts will have received aza+ven as first line therapy and achieved CR or CRh after 1-6 cycles of aza+ven. If MRD status remains positive, emavusertib will be added to the existing aza+ven regimen. Key exclusion criteria include residual toxicities and significant comorbidities. In the first cohort, the starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. The duration of emavusertib treatment will extend to 14 and 21 days, in subsequent cohorts. The pts will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- after 6 cycles of treatment. Enrollment to cohort 1 began in December 2023. (EU CT Number 2023-505828-58). Clinical trial information: 2023-505828-58.

Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor, in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia.

6541 Background: Investigational agent lisaftoclax (Lisa) was shown in preclinical findings to synergistically induce apoptosis in acute myeloid leukemia (AML). Here, we present follow up safety and efficacy data from a phase 1b/2 study evaluating Lisa + azacitidine (AZA) in adults with AML. Methods: Elderly (≥ 75 years)/unfit treatment-naïve (TN) and relapsed or refractory (R/R) AML (≥ 18 years) patients (pts) were enrolled. Lisa (400/600/800 mg) was administered orally once daily in 28-day cycles (a daily ramp up schedule was used for Lisa to prevent tumor lysis syndrome, TLS) combined with AZA (75 mg/m2/day on D1-7). Results: As of January 25, 2024, 76 AML pts were enrolled (R/R [n = 37]; elderly/unfit TN [n = 39]). The median (range) age was 66 (20-81) years and 61.8% of pts were male. All pts treated with Lisa + AZA reported TEAEs, with 89.5% Grade 3/4 AEs; and 43.4% SAEs. Common TEAEs (≥ 30%) included neutropenia (60.5%), thrombocytopenia (60.5%), diarrhea (42.1%), hypokalemia (40.8%), pyrexia (35.5%), and vomiting (30.3%). Grade ≥ 3 TEAEs reported in ≥ 10% of pts were neutropenia (57.9%), thrombocytopenia (50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia (10.5%). No TLS was reported, and the 30-/60-day mortality rates were 1.3% and 3.9%, respectively. In pts with R/R AML treated with Lisa + AZA, the overall response ([ORR] = CR + CRi + morphologic leukemia-free state [MLFS] + PR) and composite complete remission (CRc = CR + CRi) rates were 72.7% and 45.5%, respectively. In the 600 mg cohort (n = 30), ORR and CRc were 76.7% and 50.0%; the median (range) duration of treatment (mDoT), 3.8 (0.8‒15.4) month (mo); median time to CRc (mTTCRc), 2.5 (95% CI, 1.5-6.1) mo; median PFS was 10.2 (95% CI, 6.5-NR) mo; and median OS was 14.7 (95% CI, 7.8-NR) mo. Among 39 pts with TN AML treated with Lisa + AZA, ORR and CRc were 64.1% and 51.3%, respectively (Table). In the 600 mg cohort (n = 29), mDoT was 3.3 (1.0- 9.9) mo; mTTCRc was 1.9 (95% CI, 1.2-3.3) mo; median PFS was not reached (3.5, NR). 600 mg of Lisa + AZA was established as the recommended phase 2 dose. Conclusions: Our data support an emerging role for this new BCL-2 inhibitor Lisa combined with AZA for the treatment of elderly/unfit TN and R/R AML pts, especially with low early mortality and promising mPFS. A phase 3, randomized, double-blind clinical study is in progress to determine whether Lisa + AZA improves OS in elderly/unfit pts with AML. *HW, XW, and YL are co-first authors. Clinical trial information: NCT04501120 . [Table: see text]

Patient-Associated Survival Modulators in Adolescent and Young Adult (AYA) Patients (Pts) with Acute Myeloid Leukemia (AML)

Background: AML is a highly aggressive hematologic malignancy, but the AYA pts [aged 18-39 years (y)] have improved survival, with ~50% of pts achieving long-term cure. Pt outcomes are known to be affected by disease-related factors including cytogenetic findings and gene mutations, which were established in large genomic studies. In addition, pt-related factors, such as self-reported race and socioeconomic contributors have been found to affect survival in population-based studies. Whereas population-based studies are performed on large pt cohorts to establish meaningful conclusions, they usually lack details with respect to additional pt-related factors, including complete comorbidities, insurance status as well as information on disease presentation, such as time from the first provider contact to confirmation of AML diagnosis (time to diagnosis) and treatment, which might also influence pt survival. Rationale and Methods: Thus, we set out to establish recent survival rates of AML AYA pts at the population level using pts reported to one of 12 Surveillance Epidemiology End Results (SEER) Program registries of the National Cancer Institute [n=1119; median age, 30 y,1992-2014; n=239; median age, 29 y, 2015-2020], and analyze possible factors influencing survival. In parallel, we performed an in-depth analysis of treatment response and survival, including time to diagnosis, and additional pt-associated variables pertinent to AYA pts (employment status, housing, insurance, comorbidities, distance to treatment center, research study enrollment, biobanking) based on retrospectively collected data of AYA AML pts cared for at a major US Comprehensive Cancer Center (CCC) in 2015-2020 (n=96, median age, 31 y), for whom detailed clinical information was available. Results: Generally, overall survival (OS) of AYA AML pts significantly improved over time, with a marked improvement of 3-y OS rates from 47% in pts diagnosed prior to 2009, to 63% in pts diagnosed in 2010-2014 and 69% in pts diagnosed in 2015-2020. Analysis of possible associations between demographic parameters and risk of death among AYA AML pts reported to SEER Program registries did not show any statistically significant impact of sex, age, county-level median household income or metro/rural status. The only factor affecting OS of AYA AML pts was race. Specifically, Black AML pts had a higher risk of death compared with that of White AML pts [HR 2.13 (95% CI 1.03 - 4.39)], with 3-y OS rates of 47% and 80% ( P=.04), respectively. Survival disparities did not improve over time. CCC AYA AML pts had similar OS rates to those seen in the population-based analyses, with a 3-y OS rate of 70%. Ninety-three percent of pts achieved a complete remission, and 31% of pts relapsed. Analyses of CCC AML pts allowed for preliminary assessment of additional parameters. Ninety-one percent of pts (77/85) received a diagnosis in ≤2 weeks after first provider contact. Although pt numbers were small, there was a trend for a longer diagnosis time in Black pts, 27% (3/11) of whom were diagnosed >2 weeks after first presentation, compared with only 8% (5/61; P=.10) of White pts. Interestingly, analysis of possible additional outcome modulators in CCC AYA pts suggested that presence of other medical conditions at diagnosis associated with lower relapse rates (16% vs 34%, P=.04), and unemployment tended to associate with higher relapse rates (34% vs 17%, P=.06). In addition, of pts approached for biobanking, fewer Black pts consented to sample collection than White pts (60% vs 87%, P=.06). Conclusion: Survival of AYA pts with AML significantly improved over time, likely driven by availability of allogeneic stem cell transplantation and improved supportive care. Black race still represents the most important negative survival prognosticator, without marked signs of improvement. An exploratory analyses of additional pt-associated variables suggested less recognized factors that may impact survival, such as trends for longer time to diagnosis and reduced participation in biobanking protocols in Black pts compared with White pts, and a higher relapse rate in pts who are unemployed. Although these differences were not yet statistically significant , we are currently in the process of increasing the sample size to further evaluate these potentially important trends. Support: American Cancer Society, Leukemia Lymphoma Society

Different Epidemiology and Characteristics of Invasive Pulmonary Aspergillosis in Acute Lymphoid Leukemia in Comparison with AML: Results of a Prospective Multicentric Observational Study of the Rete Ematologica Lombarda (REL)

Introduction. Invasive pulmonary aspergillosis (IPA) still affects the outcome of acute leukemia (AL) patients (pts). Although this aspect is better defined in acute myeloid leukemia (AML) ( Candoni et al, Mycoses 2020), some reports show a dismal impact also in acute lymphoid leukemia (ALL) ( Cattaneo et al, Leuk Lymphoma 2019). However, data concerning the epidemiology of IPA in adult ALL patients, as well as the best antifungal prophylaxis strategy, are still lacking. Therefore, to describe the incidence of IPA in AL pts and their clinical characteristics, as well as the predisposing factors, we carried out a prospective multicentric observational study within the Rete Ematologica Lombarda (REL). Methods. All consecutive AL patients diagnosed during a 3-year period and treated with curative intent were recorded. Diagnosis of IPA was defined according to EORTC/MSG criteria ( Donnelly et al, Clin Infect Dis 2020). Data concerning age, gender, AL type, chemotherapy (cht) received, complete remission (CR) achievement, antifungal prophylaxis, duration of neutropenia and 30-day mortality were collected. Patient's characteristics were analysed by standard descriptive statistics. The Student's t-test was used to compare continuous values; the Fisher's exact test was used to compare differences in percentage. P values below 0.05 were considered statistically significant. Results. Between 2018 and 2020, 207 AL pts (AML: 165, ALL: 42) were evaluated in five Hospitals participating to the REL. Median age of the whole cohort was 58y, and M/F ratio 112/95. After induction treatment, CR was achieved in 153 of the 200 evaluable pts (76.5%), more frequently in ALL (38/42, 90.5%) than in AML pts (115/158, 72.8%) (p=0.0146). During induction cht, proven/probable (p/p) and possible (poss) IPA were diagnosed in 32/207 pts (15.4%), equally divided in p/p and poss (16 each, 7.7%). P/p IPA were more frequent in ALL than in AML (ALL: 7/42, 16.6% vs AML: 9/165, 5.4%; p= 0.0235); similarly, considering also poss IPA, incidence was higher, even if not significantly (9/42, 21.4% vs 23/165, 13.9%; p=0.2374). Among ALL pts, IPA was more frequent in pts not achieving CR (2/4, 50%) than CR pts (7/38, 18%), whereas in AML CR achievement did not influence IPA frequency (CR group: 15/115, 13%; no CR group: 7/43: 16.5%). ALL pts were uniformly treated with pediatric-like protocols; in AML pts no statistically significant differences in IPA incidence were observed according to cht received (3+7/like: 13/81, 16%; 3+7+midostaurin: 2/27, 7.4%; FLAG-Ida: 3/21, 14.3%; CPX-351: 4/19, 21%). Antimould prophylaxis was protective against IPA in 202 evaluable pts (Yes: 22/171, 12.9%; No: 10/31, 32.3%, p=0.0134). Among ALL pts only 1 out of 15 (6.7%) receiving antimould prophylaxis developed IPA, as compared to 8/27 (29.6%) of those not receiving antimould prophylaxis (p=0.1235). All but two AML pts developing IPA were on posaconazole prophylaxis. Both mean age and duration of neutropenia were significantly lower in ALL than in AML pts (46.02y vs 57.75y, p<0.0001 and 16.66d vs27.96d, p<0.0001); however, an impact of mean duration of neutropenia on IPA incidence was observed only in ALL pts (IPA group: 24.38d; no IPA group: 14.79d, p=0.0359). Only 2 AML pts died at 30d: 1 (3.1%) out of 32 pts with IPA and 1 (0.6%) out of 175 pts without. No early death was observed in ALL pts. Table 1 summarizes the clinical characteristics of AL pts in relation to IPA. Conclusions. Despite younger age, shorter duration of neutropenia and higher percentage of CR achievement, IPA, particularly p/p, was more frequently observed in ALL pts than AML during induction cht. High dose induction cht seems to have no impact in IPA incidence in AML pts. On the other hand, intensive cht ALL protocols, including high doses of dexamethasone, could have a role in IPA development, as well as the lack of antimould prophylaxis, which is confirmed as a predictive factor for IPA. Therefore, studies with antimould agents as prophylaxis against aspergillosis in ALL pts during inductions would be desirable.

Single-Center Experience of Decitabine/Venetoclax in Newly Diagnosed Older AML Patients with Non-Favorable Genetics: Bridging to Allo-HCT or Treatment Continuation

Background DNA-hypomethylating agents (HMAs) have improved the prognosis of patients (pts) with acute myeloid leukemia (AML) unfit for standard induction chemotherapy. AML pts aged >60 years eligible for allografting (HCT) can be effectively bridged to HCT by HMA monotherapy. This was demonstrated in the EORTC randomized phase III trial AML21 (NCT02172872) comparing 10-day decitabine (DEC) to “7+3” induction (Lübbert et al., EHA 2022, S125), with similar transplant rates and post-HCT outcomes in both arms. Also the combination of an HMA with venetoclax (VEN) is not only effective in pts unfit for more intensive treatment (DiNardo et al., New Engl. J. Med. 2020) but also in pts fit for HCT (Pollyea et al., BMT 2021, Maiti et al., ASH 2022, #7725). A recent analysis demonstrated that HMA+VEN as pretransplantation therapy can attain post-HCT outcomes comparable to intensive chemotherapy regimens (Winters et al., TCT 2022). Patients and Methods We retrospectively analyzed 47 consecutive older AML pts receiving firstline treatment with DEC+VEN. DEC was administered on five consecutive days per cycle. VEN was administered up to 28 days per cycle (see Table 1). All pts who had received at least one dose of DEC and VEN were included. Data on all pts were retrospectively collected as reported in the medical charts. Written informed consent of all pts to analysis of their records for scientific purposes was provided. Key parameters captured and analyzed were: age, ECOG performance status (PS), ELN 2017 risk, number of cycles of DEC+VEN administered, response rates and overall survival (OS). Common safety parameters (e.g., prolonged neutropenia, tumor lysis syndrome, etc.) were assessed. Results Between 2/2019 and 2/2023, 47 pts with AML received DEC+VEN as firstline treatment. Of those, 18 pts (38%) proceeded to HCT, 29 (62%) did not (ineligibility for HCT, wish of pt, intercurrent events etc.). Median follow-up was 25.0 (HCT) and 14.8 months (no HCT). Key pt characteristics in the two groups were i. median age: 69 and 79 years, ii. ECOG PS 0: 50 and 27%, iii. de novo AML: 39 and 72%, iv. ELN 2017 adverse risk: 67 and 59%, median number of treatment cycles administered were 2.0 and 3.0. Safety data are shown in Table 1. A hematologic response before HCT (CR, CRi, MLFS) was attained in 8/18 pts (44%), with only 2/18 receiving >2 cycles. Median time from treatment start to HCT was 2.5 months (for transplant details, refer to Table 1). For non-transplanted pts, CR, CRi, MLFS as best response were attained in 16/29 (55%), 13/29 receiving >4 cycles. In pts receiving HCT, graft-versus-host-disease occurred in 10/18 pts (56%), median OS was not reached (16/18 pts alive; Fig. 1). In pts not receiving HCT, median OS was 9.0 months. A direct comparison of treatment outcomes between the two groups is not possible, given the different selection factors operative for pts attaining HCT or not. Conclusions Among these older AML pts with non-favorable genetics, administration of a limited number of DEC+VEN cycles followed by HCT was well feasible in almost 40% of pts (median age 69 years) and resulted in very encouraging post-HCT OS in this first analysis. In pts not able to receive HCT (median age 79 years), DEC+VEN resulted in response rates, treatment continuation and OS comparable to “real-world” older AML pts treated with AZA+VEN, suggesting equivalent efficacy of both regimes.

The Ancestry-Related Landscape of Long Non-Coding RNAs (LncRNAs) in Acute Myeloid Leukemia (AML) and Its Impact on Patient (Pt) Survival

Background In addition to molecular genetic and cytogenetic findings, gene expression profiles provide independent prognostic information in AML. Aberrant expression of non-coding RNAs, including lncRNAs, further inform pt prognosis. However, non-coding expression profiles and their clinical relevance in AML almost exclusively stem from studies of pts of European ancestry (hereafter referred to as White). Given the inferior survival of African-American (hereafter referred to as Black) AML pts, we hypothesized that aberrant, possibly ancestry-associated lncRNA expression may contribute to survival disparities. Hence, we set out to (1) characterize the lncRNA landscape of African-American ancestry, (2) delineate associations of lncRNAs with clinical and molecular characteristics and (3) assess the prognostic significance of ancestry-associated lncRNAs in AML. Methods We used diagnostic samples from 681 adult AML pts (<60y) treated similarly on Alliance frontline protocols (White, n=616; Black, n=65) for RNAseq, mutational profiling and centrally reviewed karyotyping. A negative binomial model was fit to identify lncRNAs differentially expressed between Black and White pts. To determine prognostic relevance of identified lncRNAs, 10-fold cross-validation repeated 1000 times was performed on LASSO penalized Cox proportional hazards model to overall survival (OS). LncRNAs appearing in at least 900 of the 1000 models were retained and coefficient estimates were averaged then applied to form the “lncRNA score.” Ancestry-associated SNPs in regulatory regions of select lncRNAs were identified using the ENCODE registry for cCREs, SNP2TFBS and population allele frequency data from NCBI ALFA. Results Comparing Black and White AML pts, 135 lncRNAs were upregulated and 55 lncRNAs were downregulated. The differentially expressed lncRNAs were equally distributed throughout the genome and no lncRNA was ancestry-exclusive in its expression, indicating high conservation. lncRNAs with the highest differential expression include several lncRNAs previously implicated in cancer/leukemia, but also thus far unstudied lncRNAs. Using the 190 aberrantly expressed lncRNAs identified from comparison of Black and White pts, we derived a prognostic score (lncRNA score) consisting of 13 lncRNAs. LncRNA High strongly associated with inferior OS in all pts ( Fig. 1). In all pts combined, presence of lncRNA High positively associated with several adverse-risk features, and negatively associated with core-binding factor AML and CEBPA bZIP mutations. Notably, select genetic features differed in their lncRNA score associations based on ancestry, including a relative paucity of cytogenetically normal AML (29% vs 57%), NPM1 (13% vs 40%) and CEBPA bZIP (8% vs 17.5%) mutations in Black pts compared to White pts in the lncRNA Low group. lncRNA score was an independent prognosticator of worse OS in both Black and White pts that refined the prognostication of the European LeukemiaNet 2022 Favorable (P=.004) and Intermediate (P<.001) genetic risk groups. It also provided further prognostic information to the LSC17 score in both low (P<.001) and high (P<.001) LSC17 groups. Examination of the genomic context of regulatory regions within the 13 lncRNAs revealed multiple ancestry-associated SNPs that putatively altered transcription factor / chromatin regulator binding sites in cis-regulatory regions, including rs58515841 (MAF White vs Black, 24% vs 9%, CTCF binding site within ENSG00000284052) and rs1400262 (MAF, 62% vs 10%, REST binding site upstream of NCK1-DT). Conclusions We show an ancestry-related landscape of lncRNAs in AML, including an ancestry-associated expression profile of lncRNAs and evidence of ancestry-associated SNPs as expression modulators. A prognosis-associated lncRNA score based on differentially expressed lncRNAs in Black versus White AML pts carries prognostic significance irrespective of ancestry and refines both mutation/cytogenetically-based (ELN 2022) and gene-expression-based (LSC17) prognostic algorithms. Our findings highlight the importance of ancestry-diverse populations in the establishment of prognostic scoring systems to provide ancestry-connected survival prediction. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org. Clinicaltrials.gov Ids: NCT00048958, NCT00899223, NCT00900224

Evaluation of Neddylation and Apoptosis-Related Gene Expression in Patients with Acute Myeloid Leukemia

Introduction Regulated cell death (RCD) is a process commonly dysregulated in patients (pts) with acute myeloid leukemia (AML), resulting in the survival of genetically unstable cells. Apoptosis, as the best-known form of RCD, interacts with neddylation, a process that contributes to tumorigenesis and apoptosis resistance. Aims This study was conducted to determine the expression of the selected genes involved in the neddylation pathway and to assess their clinical importance along with selected interacting proapoptotic genes. In addition, we correlated the expression levels of these genes with known prognostic factors in AML and determined their impact on the survival of AML pts. Methods The expression of selected proapoptotic genes BIK, BAX, BAK, BCL2L11, BBC3 , PMAIP1 CASP3, CASP7, and neddylation-related genes: CUL1, CUL2 , CUL4A, CUL5, CUL7, CUL9, NEDD8 was determined in duplicates in bone marrow samples of newly diagnosed AML pts. Real-Time PCR was carried out using the TaqMan chemistry and the QuantStudio7 thermal cycler (Applied Biosystems-Thermo Fisher Scientific). Gene expression was normalized using reference genes selected by the Normirazor tool. The normalization was performed by ∆Ct = Ct (reference) - Ct (mRNA of interest). This approach results in higher values for higher mRNA expression. Differential expression analysis was performed using a Welch t-test. Kaplan-Meier method with the log-rank test was used to assess overall survival (OS). Results In a prospective study, we included 40 newly diagnosed AML pts (mean age 62; range 26-87) with a median (m) follow-up of 6.7 months (95% CI: 4.5-9.1). High-risk AML was present in 52.5%, intermediate-risk in 32.5%, and low-risk in 15% of pts, according to European LeukemiaNet (ELN) 2022 risk stratification. NPM1 mutation was present in 23%, whereas FLT3 ITD or TKD mutation in 25% of pts. Intensive treatment was introduced in 43% of pts, while 25% were treated with azacitidine+venetoclax. Non-intensive treatment with azacitidine in monotherapy was administered to the remaining pts. BAK expression was detected in 70%, BIK in 98%, while expression of the other genes was found in all pts. In the high-risk group, we detected lower expression of both proapoptotic BAX (fold change - FC=0.7, p=0.01) and BIK gene (FC=0.4, p=0.01), as well as lower expression of CUL9 (FC=0.7, p=0.03). Accordingly, in pts with NPM1 mutation we revealed upregulation of BIK (FC=6.1, p=0.001), and CUL9 (FC=1.6, p=0.01). Whereas pts with FLT3 mutation had lower expression of proapoptotic BBC3 (FC=0.5, p=0.01), and neddylation-related CUL1 (FC=0.6, p=0.01). In cases of initial bone marrow blasts infiltration above median value (>49%) BCL2L11 CUL5 , NEDD8 and PMAIP1were downregulated ( p=0.001-0.02), while CUL7 ( p=0.00) and CASP3 ( p=0.04) were upregulated. Patients with initial white blood cell count >20 G/l had lower expression of BCL2L11 ( p=0.005), and CUL4A ( p=0.02), while higher expression of CASP7 ( p=0.04). The mOS in the study cohort was not reached. OS was longer in pts with higher (> -2.061, cutoff was determined with CutOff Finder) BAX expression (log-rank: p=0.03) [Figure 1]. The mOS was not reached in this group, whereas the mOS in pts with lower BAX expression was 1.3 months (95% CI: 0.6-1.3). In univariate Cox regression analysis, higher BAX expression (HR 0.31, 95%CI: 0.11-0.84, p=0.022), higher albumin level (HR 0.13, 95%CI: 0.04-0.41, p=0.0004), and intensive treatment (HR 0.18, 95%CI: 0.04-0.69, p=0.012) were factors influencing the outcome. In the multivariate model for OS, higher expression of BAX (HR 0.03, 95%CI: 0.003-0.33, p=0.004) retained its significant protective effect in the context of established prognostic factors [Table 1]. Conclusions To our knowledge, we were the first to evaluate such a complex spectrum of neddylation and apoptosis-related genes in AML. We revealed dysregulation of these genes in AML. Our data indicate that upregulation of BAX at the diagnosis is associated with longer OS. Moreover, we reported significantly lower BAX expression in ELN high-risk group. Thus, indicating BAX may be a potential prognostic factor in AML. Our preliminary results did not prove significant differences in the effect of neddylation gene expression levels on the prognosis of AML patients. As studies are emerging on the potential of neddylation-targeted therapies, we are conducting further research to verify the effect of neddylation on AML.

Is Allogeneic Hematopoietic Stem Cell Transplant (HCT) in First Remission Beneficial to Acute Myeloid Leukemia (AML) Patients with Isocitrate Dehydrogenase(IDH) Mutations?

Introduction Somatic mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are relatively frequent in acute myeloid leukemia (AML) but with heterogeneous prognoses. The prognostic impact of this AML subtype with IDH mutations may be influenced by the comutational status with other somatic mutation, the specific types of IDH1/2 mutation (ie, IDH1 R132, IDH2 R140, and IDH2 R172). Allogeneic stem cell transplant allogeneic HCT represents a curative option for subgroups of AML patients (pts), but not for all subtypes. Transplant referral is made based on the ELN risk group classified into favorable, intermediate, and adverse risk. Although many AML pts with IDH1/2 mutations are referred to allogeneic hematopoietic stem cell transplantation (HCT) and transplanted, however it is not fully elucidated whether allogeneic HCT brings definite survival benefit to this group of the pts. Statistical attention is to be paid to the time to HCT from CR1 achievement. Before HCT, the case should be counted as a case of no HCT, while after HCT this case can be accounted as the case received HCT using the Mantel-Byar test (MBT). To handle immortal time bias, the Mantel-Byar method was used to depict outcomes during the follow-up period. Kaplan-Meier curves were avoided as they can introduce immortal bias, considering the period of time before treatment as part of the treatment arm. Instead, the MBT and landmark methods were employed to address this issue. Allogeneic HCT was treated as a time-dependent variable to prevent immortal bias. The aim of the present study is to identify if AML pts with IDH mutations obtain survival benefit from allogeneic HCT in CR1 using HCT as a time-dependent covariate with using Mantel-Byar test. Patients & Method We conducted a retrospective study that included 1,228 adult pts who were diagnosed with AML and achieved CR1 in 5 centers (Toronto, Vancouver, and Montreal, Canada; Hwasun and Seoul, South Korea) from January 1997 to January 2020. Next-generation sequencing was performed in each institution according to their own standard targeted sequencing panel. We considered allogeneic HCT in CR1 as a time-dependent covariate and used a Mantel-Byar test to avoid immortal bias. Relapse-free survival (RFS) was selected for the primary endpoint, defined as the time from CR1 to relapse or death from any cause. EZR software version 1.41 was used throughout the study for statistical analysis. Results Out of 1228, a total of 238 pts (19.4%) was found to have IDH1/2 mutation, among whom 92 pts (38.6%) had isolated IDH1 mutations, 140 pts (58.8%), isolated IDH2 mutations, and 6 pts (2.5%) having coexistence of IDH1 and IDH2 mutations. With a median follow-up duration of 20.8 months (mo) (1-194.3 mo) among survivors after achieving CR1, 91 pts died while 115 pts experienced relapse. One hundred twenty-one pts received HCT in CR1, and 44 pts relapsed after HCT. The 2-year overall survival of those 238 pts was 58.9% (51.3-65.6), and 2-yr RFS was48.9% (41.6-55.8) Between the HCT (n=121) vs non-HCT group (n=117), there were no differences in sex, cytogenetic risk or other somatic mutation except NPM1 mutation which was more frequently detected in the non-HCT group (p =0.002). As expected, the HCT group was younger (55 years (15-74 yrs)) than non-HCT group (62 years (27-82 yrs), p<0.001). First, the RFS and OS was compared between HCT vs non-HCT groups considering HCT as non-time dependent covariate. The 2-year RFS rate was higher in the HCT group (61.0%) compared to the non-HCT group (37.0%, p= 0.0002). However, it was not translated into superior OS in the HCT group: 2-year OS rate, 64.4% in the HCT group vs 53.7% in the non-HCT group, p=0.1). We have conducted time-dependent analysis taking taken HCT in CR1 into account as a time-dependent (td) covariate using MBT. The trend of superior RFS in HCT group was reproduced in MBT: HCT in CR1 was found to improve RFS (Hazard ratio [(HR) of 0.62, (95% C.I. [0.42-0.92]; p=0.02)] as shown in Fig.1B utilizing Simon-Makuch plot. However, Multivariate analysis (MVA) for RFS did not confirm HCT in CR1 as an independent prognostic factor for RFS, while Following factors were found to be associated with RFS adversely: age > 60 years, presence of DNMT3A mutation, and presence of IDH1 mutation. Conclusion Allogeneic HCT in CR1 could bring some survival benefit on RFS in AML pts with IDH1/2 mutation, but not confirmed in MVA. Further study is warranted to reach a clearer conclusion with larger number of

A Novel and Cost-Efficient Measurable Residual Disease (MRD) Detection Assay Using a Single Molecule Molecular Inversion Probe-Based Next Generation Sequencing (NGS) Assay Predicts Overall Survival in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction Relapse remains the main reason for poor outcomes of patients (pts) with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred post-remission treatment in pts at high risk of relapse. The presence of measurable residual disease (MRD) after intensive frontline treatment or before or after HSCT has emerged as an important predictor of relapse. Various methods are used for MRD detection, including flow cytometry and molecular assays detecting individual gene mutations (mut) such as NPM1mut. Next generation sequencing (NGS)-based assays covering multiple genes commonly mutated in AML may allow sensitive MRD detection in a broad range of pts with diverse genetic characteristics. Methods We established a targeted, error corrected NGS MRD assay utilizing single-molecule molecular inversion probes (smMIPs). The smMIP protocol uses a hybridization-capture approach to selectively enrich and amplify both DNA strands of 92 regions in 32 genes in a single reaction. Unique molecular identifiers (UMIs) facilitate computational correction of sequencing errors to enable reliable detection of variants ≥0.5% variant allele frequency (VAF), with the additional advantage of relatively low reagent and sequencing costs of < $100 per sample. The smMIP assay was used to evaluate MRD status on pre-HSCT bone marrow samples from 98 AML pts who received an HSCT in first (n=83) or second (n=15) complete remission with or without count recovery. Median age at HSCT was 59 (range 20-75) years, 42% were female; 70% had de novo AML, 19% had an antecedent myeloid neoplasm and 11% had AML post cytotoxic therapy. European LeukemiaNet (ELN)-2022 risk groups at diagnosis were favorable in 11%, intermediate in 33%, adverse in 20% and unknown in 22%. All pts had received intensive induction chemotherapy. Twenty-nine percent received a myeloablative conditioning regimen (MAC), while 23% received reduced intensity conditioning (RIC) and 48% a non-myeloablative (NMA) conditioning regimen. Donors were matched related (18%), haploidentical (6%), or matched (55%) or mismatched (21%) unrelated. The median follow-up for pts alive was 34.8 months. Results Overall, we detected 190 variants in 71 (72%) of 98 pre-HSCT remission samples. The most commonly affected genes were DNMT3A (in 37% of pts), TET2 (21%), PPM1D (12%), IDH2 (10%) and TP53 (5%). Twenty-nine percent of pts had only variants affecting the clonal hematopoiesis-related genes DNMT3A, TET2 or ASXL1 (‘DTA‘), while 44% of patients had ≥1 variant involving a non-DTA gene. MRD-positive pts, defined as those with ≥1 non-DTA variant, had similar baseline and HSCT-related characteristics (includingage, sex, ELN risk group, de novo vs. secondary AML) compared to pts without non-DTA variants. Overall survival (OS) was significantly inferior in NGS MRD-positive pts compared to those with no non-DTA variant (Figure A, 5-year OS, 49% vs. 85%, P=.011). MRD-positive pts also had a non-significant higher cumulative incidence of relapse at 5 years (46% vs. 24%, P=.14), while non-relapse mortality was similar in both groups (P=.72). We next performed multivariable analyses, considering variables associated with OS at an univariable P<.10 (MRD status, patient sex, therapy-related AML, conditioning intensity), and using stepwise backward variable selection to identify factors significantly associated with OS (Figure B). In the final multivariable model, pre-HSCT MRD detection remained associated with inferior OS (hazard ratio 2.51; 95% confidence interval, 1.07 - 5.91; P=.035). Female sex associated with favorable OS, while myeloablative conditioning (MAC) showed a borderline significant association with superior OS. Of note, we did not detect an interaction between conditioning intensity and detection of MRD with regard to OS, i.e. the prognostic association of MRD detection was not different between pts receiving myeloablative or less-intensive conditioning. However, this analysis was limited by the small patient number. Conclusion Detection of MRD by targeted NGS using the smMIPs approach provides prognostic information in pts undergoing allogeneic HSCT, including those without established molecular markers such as NPM1mut. This method is applicable to a large proportion of AML pts and is cost-efficient for broad clinical use. S.M.K. and T.H., and M.J. and K.H.M. contributed equally to this abstract.

Safety, Pharmacodynamic, and Anti-Tumor Activity of SL-172154 As Monotherapy and in Combination with Azacitidine (AZA) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Patients (pts)

Background: CD47 blocking antibodies and SIRPα-Fc fusion proteins have demonstrated activity in combination with azacitidine (AZA) in previously untreated (UnTx) HR-MDS and AML pts. SL-172154 (SIRPα-Fc-CD40L), a hexameric, bi-functional fusion protein consisting of SIRPα domains linked to CD40L domains through an inert Fc linker demonstrated improved anti-tumor activity in comparison to naked CD47 blocking antibodies in pre-clinical studies [de Silva et al. Cancer Immunol Res 2020]. SL-172154, as a CD47 inhibitor, requires combination with AZA to enhance pro-phagocytic signals on leukemic stem cells/blasts thereby potentiating macrophage phagocytosis in AML/HR-MDS. Here we report the results from the Phase 1 Dose Escalation. cohorts for SL-172154 monotherapy [SL-mono] and for SL-172154 + AZA combination [SL-AZA] in pts with HR-MDS or AML. Methods: The objectives of the dose escalation cohorts include evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic effects and efficacy per IWG 2006 for MDS and ELN 2017 for AML. SL-172154 was administered IV weekly of a 28-day cycle as monotherapy or with AZA 75 mg/m 2 for 7 days per cycle. mTPI-2 was used for dose escalation with a DLT threshold of 20%. Pts ≥ 18 years old with R/R HR-MDS or R/R AML were eligible for dose escalation cohorts. In addition, UnTx pts with TP53 mutant (TP53m)-MDS were eligible for SL-AZA cohorts. Results: As of May 25, 2023, 37 pts were enrolled (19 in SL-mono; 18 in SL-AZA cohorts): 14 women; median age 70 years [range 44-81]. 27 pts had R/R AML (16 de novo; 11 secondary), 5 had R/R MDS, and 5 were UnTx TP53m-MDS. 23 (85%) of 27 R/R AML pts had adverse genetic abnormalities per 2017 ELN classification, including 9 (33%) with TP53m or del 17. The median number of prior lines of AML therapy was 2 [range 1-4]; 25 (93%) had received venetoclax (VEN) and 23 (85%) had received a hypomethylating agent (HMA). All 5 pts with R/R MDS had previously received HMA and 2 pts were previously treated with VEN. SL-172154 was dose escalated as monotherapy or with AZA as shown in Table 1. Infusion-related reactions (IRRs) were the most common SL-172154-related treatment-emergent AEs (TEAEs) reported in 13 (68%) and 8 (44%) pts in SL-mono and SL-AZA cohorts, respectively. IRRs (51 events) were Grade (G) 1 or 2 except for 3 G3 events (1 each at 6 mg/kg SL-mono and SL-AZA; 1 at 3 mg/kg SL-mono). Other SL-172154-related TEAEs observed in ≥ 3 pts were AST increased (4; 21%), ALT increased (3; 16%) and nausea (3; 17%) in SL-mono cohorts, and nausea (3; 17%) in SL-AZA cohorts. All events of AST/ALT increased were transient. Only one DLT (G3 IRR in the 6 mg/kg SL-AZA cohort) was reported, which required a dose reduction to 3 mg/kg. As of July 10, 2023, in SL-mono cohorts, 1 pt with R/R AML post 7+3, FLAG and VEN/AZA achieved Morphologic Leukemia-Free State (blast reduction from 19% to <5%) after 1 cycle of 6 mg/kg SL-172154 and proceeded to allogeneic hematopoietic cell transplant (allo-HCT) after cycle 2. In 12 evaluable pts with R/R AML receiving SL-AZA, although no objective responses (OR) were observed, relative reduction in bone marrow (BM) blasts from baseline was reported in 2/5 pts at 1 mg SL-AZA (-50%, -75%) and 5/7 pts at 3 mg SL-AZA (ranging from -35% to -90%). One pt underwent an allo-HCT. In 4 evaluable pts with UnTx TP53m-MDS, the ORs were 1 complete remission (CR), 1 marrow CR, and 2 stable disease. 2 of them proceeded to allo-HCT. SL-172154 induced elevations in serum IL-12p40, IP-10, IL-8, IL-10, MIP3α and MCP1: greater response at 3 mg/kg compared to 1 mg/kg while similar between 3 and 6 mg/kg. In the BM, SL-172154 induced a dose-dependent increase in phagocytic cells (CD11b, HLA-DR, CD16, CD36 and CD64) within mature myeloid immune cell compartments (CD45highCD34-). Reduction in leukemic blasts (CD45lowCD34+) was associated with an increase in mature myeloid and phagocytic cell phenotypes (3 mg/kg SL-AZA > 1 mg/kg SL-AZA). Conclusions: SL-172154 was well tolerated up to 3 mg/kg as monotherapy and in combination with AZA. Preliminary efficacy signals were detected in UnTx TP53m-MDS and R/R AML. A response to SL-172154 monotherapy, dose-dependent increases in serum cytokines and accumulation of mature myeloid cells in BM suggest a potential role for CD40 stimulation. Based on the safety, preliminary efficacy and pharmacodynamic activity, 3 mg/kg SL-172154+ AZA is being evaluated in treatment naïve pts with TP53m AML and HR-MDS.

MYC Pathway Upregulation Identified in Non-Responders to Hypomethylating Agents and Presents a Therapeutic Target in Acute Myeloid Leukemia

Background: In the current era of acute myeloid leukemia (AML) management, hypomethylating agents (HMAs) remain as the backbone of combination regimens for front-line treatment of elderly or unfit patients (pts) and/or as salvage therapy in relapsed/refractory pts. Data on biological predictors of HMA response are limited. Our previous work explored cytidine deaminase (CDA), known to inactivate HMAs, and nucleophosmin 1 (NPM1), determined by core pathway analysis to indirectly influence CDA expression. No clear correlation was identified in pt samples between CDA protein expression and NPM1 status or response, and pharmacogenomic analysis showed no CDA single nucleotide polymorphisms were predictive of response to HMAs. We aimed to expand prior findings using RNA sequencing (RNA seq) and gene set enrichment analysis (GSEA) to identify gene signatures predictive of HMA response and propose potential therapeutic targets. Methods: AML pts with banked samples who received frontline, bridging, or salvage HMA-based therapy between January 2014 to December 2018 were reviewed. Responses following at least 2 cycles of HMA were categorized as complete response (CR), CRi (CR with incomplete hematologic recovery), morphologic leukemia-free state (MLFS), complete hematologic response (CHR), or refractory. Pts were categorized as responders (CR, CRi, MLFS, CHR) or non-responders (refractory). Tumor cells were purified using immunomagnetic selection from bone marrow aspirates collected at diagnosis (dx). RNA seq was performed on 20 available pt tumor samples. Unsupervised clustering was performed and GSEA was completed to compare identified clusters using a false discovery rate (FDR) cut-off of less than 25%. GSEA-derived gene pathway scores were assessed by Wilcoxon rank-sum test. To evaluate AML cell lines to explore the non-responder phenotype, viability of AML cell lines was assessed following treatment with HMA azacitidine (Aza) and MS177 (a proteolysis targeting chimeric EZH2 degrader, also known to degrade MYC). Immunoblotting was used to assay proteolysis targeting chimeric (PROTAC)-induced MYC degradation. Results: Unsupervised clustering of RNA seq from 20 tumor samples at dx, labeled for response and NPM1 status, revealed 3 distinct groups: a non-responder group, a responder group, and a mixed response group ( Figure 1A). GSEA comparing the non-responder group to the responder group revealed several enriched genes in the non-responder group, including MYC targets (FDR <0.001), E2F targets (FDR <0.001), and G2M checkpoint (FDR=0.244). Upregulation of MYC targets was confirmed by enrichment profiling. Application of enrichment pathway scores revealed significant differences between non-responders and responders for E2F targets (p=0.026), G2M checkpoint (p=0.026), and MYC targets (p=0.0022). To explore MYC as a therapeutic target, we assayed MYC degradation in leukemia cells treated with two PROTAC degraders. The PROTAC MS177 induced marked MYC degradation in HL-60 cells ( Figure 1B). Cytotoxicity assays showed that in Kasumi-1 cells, the 50% inhibitory concentrations (IC50) for Aza and MS177 were 2.9 µM (responder phenotype) and 1.1 µM, respectively ( Figure 1C); in HL-60 cells the IC50 for Aza and MS177 were 10.9 µM (non-responder phenotype) and 0.06 µM, respectively ( Figure 1D). MS177 also showed efficacy in cytotoxicity assays using pt derived tumor samples. Conclusions: Using tumor samples from AML pts receiving HMAs, we identified a non-responder gene phenotype enriched with MYC upregulation. GSEA-derived pathway scoring differentiated non-responders from responders in our dataset. To further evaluate whether the enrichment pathway score is predictive for response across other AML cohorts, we are applying enrichment scores to publicly available AML datasets. With MYC upregulation identified as a potential driver of HMA failure, MYC degradation or inhibitory targets are recognized as potential therapeutic targets for pts with a non-responder gene signature. We established the HL-60 AML cell line, found to be less sensitive to Aza than the Kasumi-1 cell line, demonstrated greater sensitivity to MYC degradation compared to Kasumi-1 cells and may reflect the non-responder phenotype. Further in vitro efforts are ongoing to evaluate MYC targets for the HMA non-responder phenotype.

Differences within the Immune Microenvironment May Account for Poorer Outcomes in African American AML Patients Compared to European American Patients with AML

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from an immature myeloid progenitor with notoriously poor outcomes. A critical factor responsible for the difficulty in treating this disease evasion of the host immune system by AML. Both the innate and adaptive immune systems have been shown to be dysfunctional in AML with poor type I interferon responses, decreased STING signaling and increased populations of granulocytic and monocytic myeloid derived suppressor cells ultimately leading to poor adaptive response. Studies in solid tumors have demonstrated that variation in immunity contributes to racial disparities in cancer and outcomes. This is felt to be due to variation in geographic ancestry leading to differences in the innate immune genome required due to the need for protection against environmental pathogens. However, no data exists comparing innate and adaptive immunity by race in patients (pts) with AML. Here we sought to characterize the immune microenvironment with treatment outcomes in racially diverse AML pts. Methods: Adults with newly diagnosed AML were identified who had corresponding cryopreserved bone marrow mononuclear cells available within Roswell Park Hematologic Procurement bank. Pts were matched as closely as possible for age, gender, cytogenetic risk per ELN 2017 and molecular profile. Transcriptional differences between African American (AA, n=26) and European American (EA, n=26) AML pts and healthy controls (n=10) were analyzed using transcriptomics data from NanoString Pan Cancer Immune Profile panels. AA and EA AML samples were compared to each other, as well as their race-matched healthy controls. The ‘Limma’ package in R was utilized for differential gene expression analysis. Research was conducted according to the Declaration of Helsinki in accordance with the Institutional Review Board regulated protocol. Results: The median age of the entire cohort (n=52) was 65 years (range: 28-92), with 28 female patients (53.8%) ( Table 1). Within the AA cohort, the majority of pts had intermediate risk cytogenetics per ELN 2017 (n=19; 73.1%, and 6 pts had FLT3 mut (26.1%). Three pts (11.5%) underwent allogeneic stem cell transplant, with a median overall survival (OS) censoring for transplant of 5 months (range; 0.5-68 months) ( Figure 1). Within the EA cohort, most pts had poor risk cytogenetics (n=15; 57.7%). Six pts had FLT3 mut (26.1%), and three pts had TP53 mut (12%). Five pts underwent allogeneic stem cell transplant (19.2%), with a median OS of 16.4 months (range; 0.8-67 months). Sixty-nine significantly (p<0.05, |logFC|>1.5) differentially expressed genes in AA vs. EA pts were identified. Gene set enrichment analysis (GSEA) revealed alterations to Interferon, Jun kinase and STAT signaling pathways in AA pts. In contrast, EA pt samples were enriched for pathways related to amyloid metabolism and other T and B cell immune pathways. Master regulator analysis using LISA highlighted transcriptional dysregulation attributed to PDGB5, CTCF, AR, and NOTCH in AA pts and to GLIS2, SMAD1 and NFE2 in EA pts. Conclusions: As previously reported, we found that a clinically matched cohort of AA AML patients experienced significantly worse OS as compared to EA counterparts. We have identified several significant alterations within the immune microenvironment between cohorts, which may potentially explain this discrepancy in survival in AA patients. These differences could potentially serve as targetable alterations for therapeutic purposes. This work represents the first of its kind evaluating the immune microenvironment by race in AML patients and are awaiting confirmation in a larger cohort.

T-Cells Immune Cluster Analysis Using Cytof Identifies Unique Patient Subgroups with TP53 Mutation and Predicts Complete Remission (CR) in Patients with Acute Myeloid Leukemia (AML) Receiving Venetoclax Plus Hypomethylating Agent Therapy

Introduction The advent of venetoclax (VEN) based chemotherapy has revolutionized the treatment of elderly acute myeloid leukemia (AML), with improvement in remission rates from historical 10%-20% to 60%-70%. However, remission duration is short-lived in patients (pts) with high-risk AML with consequent dismal outcome. As our knowledge of genomic landscape of AML expands and more immunotherapies become available, exploration of the immune tumor microenvironment (TME) of AML may allow identification of subsets of pts that may benefit from immune based therapy. We conducted an investigator initiated prospective study to evaluate TME of pts receiving VEN plus hypomethylating agent (HMA; azacitidine or decitabine) combination. We hypothesize that these pts will cluster into immune-infiltrated vs. immune-depleted sub-types by high-definition immune cell profiling. Methods In 26 newly diagnosed AML pts, who were planned to receive VEN plus HMA therapy, we isolated bone marrow (BM) and peripheral blood (PB) derived mononuclear cells (MC) by density gradient centrifugation and cryopreserved. We performed CyTOF (cytometry time-of-flight) analysis to study their immune signatures. Thawed cells were labeled with metal-conjugated antibodies that bind CD33, CD196, CD19, CD127, CD11b, CD4, IgD, CD11c, CD14, CD56, CD123, TCRgd, CD185/CXCR5, CD45RA, CD27, CD28, CD66b, CD183 (CXCR3), CD161, CD45RO, CD197 (CCR7), CD8a, CD25, CD3, CD20, CD38, HLA-DR, CD194 (CCR4), CD57, CD16 and CD45. We performed a Rphenograph clustering on 25 paired BMMC and PBMC samples (one patient only had PBMC) to create 35 unique clusters for each ( Figure 1). Then we broke down the distribution of cluster by two different groupings: pts with TP53 mutation (m) and those who achieve complete remission. Statistical significance of clusters calculated using t-test. We performed Pearson correlation test on the paired BMMC and PBMC samples to assess correlation between BMMC and PBMC samples. Results Baseline characteristics The median age of the pts was 74 years (range, 53-88), and 17 (65%) pts were male. Ten (37%) pts had secondary AML, and 12 (46%) pts had ELN adverse risk disease (n=6; TP53m). There was no significant difference in median age (p= >0.99), proportion of pts with secondary AML (p= 0.64), acute myelomonocytic leukemia (p= 0.14) white blood cell count (WBC) ≥ 100 (10 9/L) (p= >0.99), and frequency of commonly occurring co-mutations ( ASXL1 [p=0.35]), FLT3 ITD [p=0.54], splicing [p=0.29], IDH1/2 [p=0.28], DNMT3A [p=0.29], NPM1 [p=0.29], TET2 [p=0.35]) in TP53m and TP53 wild-type group. Response 12/20 (60%) evaluable pts achieved complete remission with or without count recovery (CR/CRi). There was no significant difference in median age (p= 0.06), proportion of pts with secondary AML (p= 0.16), therapy related AML (p= 0.60) WBC ≥ 100 (10 9/L) (p= 0.40), and frequency of commonly occurring mutations ( TP53 [p=0.60], ASXL1 [p > 0.99]), FLT3 ITD [p=0.54], splicing [p > 0.99], IDH1/2 [p=0.60], DNMT3A [p=>0.99], NPM1 [p=0.61], TET2 [p >0.99]) in CR/CRi and no-CR/CRi group. CyTOF analysis and Rphenograph clustering on 25 paired BMMC and PBMC samples We found significant clustering with high expression of B-cell activated (cluster 2; p= 0.005), NK cell rich (cluster 1; p= 0.005, cluster 35; p= 0.0009), CD8 T-cells (cluster 31; p= 0.01) and CD4 effector cells (cluster 17; p= 0.005) phenotype among TP53m AML ( Table 1). Among pts who achieved CR/CRi, significant clustering with low expression of B-cell activated (cluster 29; p= 0.01), CD8 cytotoxic (cluster 14; p= 0.01) CD4 activated (cluster 21; p= 0.03) phenotypes observed. Correlation between BMMC and PBMC clustering Among clusters which showed significance for a particular phenotype, we performed Pearson correlation (R 2) and observed strong correlation between BMMC and PBMC samples clustering in cluster 1 (R 2 = 0.99), cluster 2 (R 2 = 0.95), cluster 17 (R 2 = 0.96), cluster 21 (R 2 = 0.99) and cluster 29 (R 2 = 0.93). Conclusion In this single institutional study using CyTOF analysis we have identified novel clustering with immune- infiltrated phenotype among pts with TP53m AML and conversely immune-depleted phenotype among AML pts who responded to VEN plus HMA. Moreover, we found strong correlation in CyTOF analysis conducted from BMMC and PBMC samples. Future studies with larger sample size needed to validate our findings.

Ubtf- Tandem Duplications Are Recurrent Somatic Genetic Events in Adult AML and Associate with Additional Structural Variants and a Distinct Gene Expression Profile (Alliance)

Background The gene upstream binding transcription factor ( UBTF ) encodesa nucleolar protein that is a key regulator of the epigenetic status of ribosomal DNA and RNA transcription. Tandem duplications (TDs) of the UBTF gene have been initially identified in pediatric patients (pts) with acute myeloid leukemia (AML) and were recently also reported as relatively rare, but recurrent genetic events in adult AML based on targeted re-sequencing efforts (1.2%-3%). Their presence was associated with dysplastic bone marrow features, and co-occurrence of select genetic features, including FLT3-internal tandem duplications (ITDs) and WT1 mutations, and inferior outcome. However, associated biologic features and affected pathways have not yet been thoroughly investigated, and may provide further insights into leukemogenesis and identify potentially targetable vulnerabilities. Thus, we set out to assess the frequency of UBTF-TDs in a large cohort of adult AML pts (n=807) treated on frontline protocols of the Alliance for Clinical Trials in Oncology with complete RNA sequencing data, comprehensive targeted mutation profiling, centrally reviewed cytogenetic data and clinical information available, and to gain further insights into UBTF-TDs via comprehensive integrated genomic profiling. Methods UBTF-TD detection was performed via the RNAseq-based RNAmut and EnFusion algorithm. To gain insights into associated molecular features, all UBTF-TD + pts underwent paired tumor-normal whole-exome sequencing. To understand associated pathways and downstream effects, differential gene expression (DGE) and gene set enrichment analyses (GSEA) were performed. Results UBTF-TDs were detected in 6/807 pts (0.7%). In line with previous studies, these 6 UBTF-TD + pts were young, with a median age of 35y (range: 19-59y). Three pts had extramedullary disease, 2 with skin and 1 with gingival involvement. All but 1 of the 6 pts were cytogenetically normal. Clinically, pts did poorly after treatment with intensive chemotherapy induction, with a CR rate of only 33%. No pt was alive 2.5 y after diagnosis. In paired tumor/normal exome sequencing, UBTF-TD + pts had a median mutation burden of 21 non-synonymous variants in coding genes (range: 17-27), with a notable presence of larger insertions/deletions (indels), loss of heterozygosity (LOH) or TDs as co-occurring somatic genetic lesions (median: 4, range: 2-5). There was a 100% co-occurrence of UBTF-TDs with FLT3-ITDs. In addition, pts harbored larger indels in WT1 (n=2), BPTF, CEBPA, Corf53, KRTAP5-7, NFE2, PTPRN2, RNF144B, SOWAHC and ZCCHC14. Also, analysis of copy-number variations and LOH revealed LOH in 5 pts, in chromosomes 13 (n=3), 15 (n=1) and 18 (n=1), suggestive of a propensity to the acquisition of structural variants. In unsupervised clustering analysis of the RNAseq data, UBTF-TD + pts clustered with FLT3-ITD + pts but formed a relatively distinct subcluster in principal component and t-distributed stochastic neighbor embedding analyses. In supervised clustering comparing 6 UBTF-TD +/ FLT3-ITD + and 196 UBTF-TD -/ FLT3-ITD + pts, 2 UBTF-TD - pts clustered together with the UBTF-TD +/ FLT3-ITD + group, suggesting either presence of an undetected TD or genetic phenocopy. UBTF expression was higher in UBTF-TD pts. DGE analysis of UBTF-TD +/ FLT3-ITD + and UBTF-TD -/ FLT3-ITD + pts (Fig 1) showed distinct upregulation of the locus of the stem cell and chemoresistance marker ALDH1A3, including the associated long non-coding RNAs AC015712.7/AC015712.2 in UBTF-TD + pts, which was confirmed by a comparison of those pts to AML pts who had neither TD (n=605). GSEA indicated a downregulation of inflammation pathways and several metabolic pathways of UBTF-TD +/ FLT3-ITD + compared to FLT3-ITD + pts (Fig 2). Conclusions UBTF-TDs are rare, but recurrent genetic events in adult AML, associated with high chemotherapy resistance. Our results highlight a susceptibility of those pts to the acquisition of structural variants and suggest a distinct associated biology, with upregulation of ALDH1A3 as possible contributing resistance mechanism. Support: U10CA180821, U10CA180882, U24CA196171; Clinicaltrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00899223 (CALGB 9665), NCT00900224 (CALGB 20202); https://acknowledgments.alliancefound.org

Association between BMI and Survival in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia Treated with Intensive Chemotherapy

Introduction: Obesity is linked to a higher incidence of acute myeloid leukemia (AML) in older adults as well as B-cell acute lymphoblastic leukemia in children and adolescents and young adults (AYA). To date, however, the relationship between weight and clinical outcomes in AYA patients (pts) diagnosed with AML has not been clearly established. We hypothesized that obesity reflected by higher body mass index (BMI) would confer worse prognosis in AYA pts treated with intensive chemotherapy and/or allogeneic stem cell transplant (SCT) for AML. Methods: We conducted a single institute retrospective chart review of AYA patients aged 18 to 39 years diagnosed with AML between Jan 2006 and Oct 2022. All patients received intensive chemotherapy with cytarabine- and anthracycline-based induction and consolidation chemotherapy followed in some cases by SCT. BMI was calculated based on height and weight on the date of AML diagnosis. Additional information including European Leukemia Net (ELN) 2022 risk classification, therapy response (complete remission (CR), CR with incomplete count recovery [CRi]), receipt of SCT, relapsed disease, event-free (EFS), overall survival (OS) and percentage of pts alive at 2- and 5-years after diagnosis were collected. All data was de-identified and procured on an IRB-approved protocol. Results: Seventy-six AYA patients were identified. Median age was 25.2 (range 18-39) years. 39 (51%) were female. The majority (65, 86%) were Caucasian. Per ELN 2022 risk classification, 24 (32%) had favorable, 36 (47%) had intermediate, and 16 (21%) had adverse risk disease. The CR rates based on ELN 2022 risk classification were 86%, 72% and 50%, respectively. Median OS for all pts was 791 days and per risk group was 1379, 569, and 595 days, respectively. Pts were then categorized per initial BMI into 4 categories. The majority of pts (44, 58%) had above average BMI (≥ 25), with 21 (28%) considered overweight with BMI 25-29.9 and 23 (30%) obese defined as BMI >30. Only 3 pts (4%) were underweight with BMI <18.5 (Table 1). Of note, 43% of obese pts had ELN favorable risk vs 33% of overweight pts and 24% of normal weight pts. Overall response rates in each BMI category were similar, ranging from 96-100% except in overweight pts where only 6 of 21 pts (29%) obtained CR. Relapse occurred in approximately one third (29-35%) of pts in the three highest BMI categories. Two thirds of all pts with BMI ≥18.5 underwent SCT. Excluding underweight pts due to small numbers (n=3), there was a trend to decreased survival in pts with BMI ≥18.5. Median overall survival among normal, overweight, and obese pts was 1403, 1295, and 777 days, respectively, with a significant difference between healthy and obese pts (p-value 0.0274 by log rank test). The percentage of pts alive after 5 years was 41%, 29%, and 17%, respectively (Table 2). Conclusion: Our real-world single-institute retrospective analysis suggests that AYA pts aged 18-39 yrs old diagnosed with AML and with higher BMI have decreased overall survival following intensive chemotherapy and/or allogeneic transplant. Obese patients with the highest BMI (>30) had a markedly shorter overall survival (median 777 days) and lower percentage of pts (17%) alive after five years following therapy than AYA AML pts with normal BMI (median 1403 days, 41% 5-year survival). This was despite over 40% of obese pts having favorable ELN risk. Potential reasons for this include biological heterogeneity in BMI cohorts, chemotherapy dosing, weight-related medical co-morbidities (i.e. cardiovascular disease) and/or transplant-related complications leading to shorter survival. Additional analyses to rule out the contribution of these and other factors and to confirm these results in a larger cohort are ongoing.

Assessment of SIRT1-SIRT7 and TP53 Genes Expression in Patients with Acute Myeloid Leukemia

BACKGROUND Sirtuins ( SIRTs) are a family of histone deacetylases with 7 representatives ( SIRT1-7), which affect cell survival and metabolism. They influence gene expression by interacting with histones and transcription factors, or directly modulate pathways associated with cell survival, for instance by downregulating p53, thus potentially contributing to cancerogenesis. On the other hand, SIRTs may function as tumor suppressors depending on cellular context. While the role of SIRTs expression is widely discussed in solid neoplasms, they have not been comprehensively evaluated in acute myeloid leukemia (AML) yet. AIMS To investigate the prognostic importance of initial SIRTs expression in AML patients (pts) and its relationship with the expression of TP53. METHODS The study included 40 newly diagnosed AML pts (19 women, 21 men), with a mean age of 62 years (range: 26-87). Low-, intermediate- or high-risk AML according to European LeukemiaNet (ELN) 2022 stratification was diagnosed in 6 (15%), 13 (32.5%), and 21 (52.5%) of pts respectively. The expression of SIRT1-7 and TP53 was examined by real-time PCR using the TaqMan chemistry and the QuantStudio7 thermal cycler (Applied Biosystems-Thermo Fisher Scientific). The reference genes were selected using GeNorm and NormFinder. The mRNA levels were normalized by the formula ∆Ct = Ct(reference) - Ct(particular mRNA). Group comparisons were performed using Welch's t-test. Pearson correlation evaluated the relationship between individual gene expression. Overall survival (OS) was assessed by the Kaplan-Meier method with the log-rank test. Cox proportional hazard regression of clinical factors and genes expression for predicting OS was performed. RESULTS FLT3 ITDor TKD mutations were present in 10 (25%) of pts, NPM1 in 9 (23%), and IDH1 or IDH2 in 6 (15%). 14 (35%) of the study group were diagnosed with AML with myelodysplasia-related cytogenetic abnormalities, AML progressed from myelodysplastic syndrome, or therapy-related AML (secondary AML, sAML). Standard induction chemotherapy was given in 42.5% of pts, 25% were treated with azacitidine+venetoclax (Aza+Ven), and other non-intensive therapies were administered to 32.5%. SIRT4 expression was detected in 92.5% of pts, while expression of the other genes studied was found in all pts. There were no differences in SIRT 1-7 expression in terms of ELN2022 risk stratification. However, TP53 was downregulated in the high-risk group (fold change - FC=0.6, p=0.004). In pts with FLT3 mutation, SIRT7 was downregulated (FC=0.8, p=0.07), while in both NPM1 and IDH1/2 mutated groups, we showed upregulation of TP53 (FC=1.5, p=0.03, and FC=1.5, p=0.001, respectively). Moreover, in older pts (>60 years old) TP53 was downregulated (FC=0.7, p=0.02). In sAML group SIRT3 and TP53 were downregulated (FC=0.7, p=0.08, and FC=0.7, p=0.05, respectively). Significant positive correlations were shown between the expression of individual SIRTs, and it was most strongly expressed between SIRT2 and SIRT6 (r=0.85, p=0.00), SIRT2 and SIRT7 (r=0.81, p=0.00), and SIRT6 and SIRT7 (r=0.76, p=0.00). The median follow-up was 6.7 months (95% CI: 4.5-9.1). The median OS in the study cohort was not reached. There were no significant differences in treatment response or OS considering each SIRT expression level. However, pts with higher TP53 expression (> median) presented longer OS (median OS not reached vs 5.8 months (95% CI:1.3-5.8, p=0.05) [Figure 1]. In the multivariate Cox proportional hazard model for OS, upregulation of TP53 (HR 0.25, 95%CI: 0.08-0.60, p=0.01), age (HR 1.06, 95%CI: 1.01-1.12, p=0.03), as well as initial albumins (HR 0.01, 95%CI: 0.00-0.07, p=0.01), and LDH levels (HR 1.00, 95%CI: 1.00-1.01, p=0.01) were factors influencing the outcome [Table 1]. CONCLUSIONS The expression of SIRTs in AML presented no evident impact on treatment outcome. However, our study revealed that higher TP53 expression was associated with longer OS. Moreover, TP53 upregulation was found in pts with certain mutational profiles, while downregulation in the elderly and those with sAML. The analysis indicates that SIRTs expression may also vary markedly depending on the clinical and molecular context. The expression of individual SIRTs is closely correlated with each other, but these preliminary results did not show their direct relationship with TP53 expression. Further studies on SIRTs are needed to assess their impact on AML.

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.

Extended Nutritional Monitoring in Patients Undergoing Intensive Chemotherapy for Acute Myeloid Leukemia

Background Fit patients (pts) with acute myeloid leukemia (AML) are conventionally administered repeated cycles of intensive chemotherapy, often followed by allogeneic hematopoietic stem cell transplant. AML pts need to be long hospitalized in a protected setting, they are often prescribed a neutropenic diet and chemotherapy-induced gastro-intestinal toxicity is common. As a result, malnutrition is frequently observed, it sensibly reduces the quality of life and has the potential to undermine eligibility for intensive treatment, increase treatment-related toxicity, and ultimately reduce survival. Aims Aim of this study was to systematically assess the nutritional status of fit pts undergoing treatment for AML and to explore early predictors and associations with known nutritional risk scores and relevant clinical outcomes. Methods Nutritional Risk Screening 2002 (NRS) score was calculated for each patient at time of diagnosis (a score of 3 or more is considered high). Then, nutritional monitoring included standard anthropometric measurements (body weight, BW; body mass index, BMI) and a bioelectrical impedance analysis (BIA) performed by a registered dietitian to assess fat-free mass, body cell mass (BCM, the metabolically active component of body mass), fat mass and the phase angle. Variations in nutritional parameters between admission and day 7 (end of CHT, called “dif7”) or between admission and day 14 (called “dif14”) were calculated and tested for correlation with variations of the same parameter at discharge from the same cycle (called “dif30”) or at discharge after the first consolidation (called “dif60”). Results Up to now, 26 pts with newly diagnosed AML (median age 55y, range 21-74) were prospectively monitored during a total of 61 cycles of intensive chemotherapy (35 induction cycles, 26 consolidation cycles). Median NRS score at enrolment was 3 (range 2-6). Median follow up for surviving pts is 300 days. We observed a significant reduction in fat-free mass and body cell mass during induction cycles. Similar trends, although not significant, were observed for consolidation cycles as well. These trends were observed irrespectively of baseline NRS, disease response, or whether admission was complicated by a fever lasting more or less than 7 days. A high NRS score was only associated with a greater fat mass loss between diagnosis and discharge after first consolidation (FM dif60), but the score failed to predict any meaningful nutritional parameter variation. For fat-free mass, body cell mass and the phase angle (but not for BW or BMI), dif7 correlated with dif30 for induction and consolidation cycles. For body cell mass and the phase angle, both dif7 and dif14 also correlated with dif60. Only variations in body cell mass at day 7 (BCM dif7) correlated with cumulative weight loss at discharge after the first consolidation cycle (BW dif60). Reduction in BW, BMI and fat mass at day 7, and of phase angle at day 14, were associated with extended length of stay for consolidation chemotherapy cycles only. Conclusions In this study, pts intensively treated for AML suffered a significant reduction in the metabolically active component of body mass during admission for induction chemotherapy and, cumulatively, during the first two treatment cycles. Bioelectrical impedance analysis performed as early as seven days from admission could already reveal the first signals of nutritional deterioration: body cell mass loss between day 0 and day 7 correlated with both cumulative body cell mass loss and cumulative body weight loss after two cycles of chemotherapy. Notably, a commonly used nutritional risk screening tool failed to predict the risk of malnutrition in our cohort of patients. “NUTRIAMO” is a prospective, observational trial currently starting at our institution, where pts intensively treated for AML are monitored via known nutritional assessment tools, new biochemical markers (e.g., prealbumin and retinol-binding protein) and microbiome analysis and variations. Our aim is to find more sensitive nutritional triggers to activate earlier and more effective support measures (e.g., oral nutritional supplements, diet variations, psychological support) and ultimately improve AML patients' quality of life and survival beyond the cure of their disease.

Neighborhood Disadvantage Is Associated with Inferior Overall Survival for Acute Myeloid Leukemia Patients Treated with Standard Intensive Induction

Background: Identifying biologic and socioeconomic contributors to disparities in outcomes is critical for the management of acute myeloid leukemia (AML). Prior studies in AML revealed that Black patients (pts) have inferior survival compared to White pts, with more striking disparity for Black pts aged <60. We previously explored our large and diverse AML cohort from urban and large rural areas and did not identify inferior survival for pts with self-reported Black race or Hispanic ethnicity. Although no surrogates for social determinants of health (SDOH) or insurance status were recognized as contributing to survival differences, oncology nurse navigation (ONN) was associated with a survival benefit, with no significant difference in access to ONN among racial or ethnic groups. To further evaluate socioeconomic drivers of disparities in this population supported by ONN, we aim to use the Area Deprivation Index (ADI) to determine the impact of neighborhood disadvantage on survival in AML. Methods: AMLpts diagnosed at Levine Cancer Institute between 12/2015 and 12/2020 were included. Pts with acute promyelocytic leukemia (APL) were excluded from this analysis. Details regarding insurance coverage, ONN services, induction therapy, stem cell transplant (SCT) status, and survival outcomes were collected. Race and ethnicity were self-reported. European LeukemiaNet (ELN) 2017 criteria were used to assign AML risk. Pt and disease characteristics were summarized, described, and compared with Fisher exact tests and Wilcoxon rank-sum tests for categorical and continuous data, respectively. Pts were grouped into 4 quartiles based on ADI national percentile. Subsequent models were fit with ADI dichotomized at the median after adjacent ADI groups were removed with backward elimination. Associations between overall survival (OS) and pt and disease characteristics, insurance status, race, ethnicity, ONN services, and ADI were investigated. OS was defined as the time from diagnosis (dx) to death from any cause, with surviving subjects censored at the time of last follow-up. Kaplan-Meier methods were used to summarize OS and calculate landmark survival rates. Survival was compared with unadjusted log-rank tests. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) associated with OS. Results: Three hundred eighty pts with available baseline characteristics were included in our analysis ( Table 1) . For pts <60 who received intensive induction and had available ADI (N=86), there was a significant difference in OS amongst the quartiles of ADI (P=0.007), with differences even more pronounced with dichotomized ADI (P<0.001) ( Figure 1). With a median follow-up of 38.1 months for the intensively treated pts <60, the estimated two-year OS was 96.6% for more advantaged/low ADI pts and 55.4% for less advantaged/high ADI pts (HR 5.21; 95% CI 1.82 to 14.95). Within the cohort of pts <60 who received intensive induction, sixty-eight percent were Non-Hispanic White and 28% were Non-Hispanic Black. Many (66%) were privately insured at dx, with 24% uninsured or with Medicaid. ONN services were accessed by most (72%) pts with known ADI. Care barriers were expressed by pts of all ADI quartiles, with transportation being the only barrier most reported by pts of increased disadvantage (P<0.01). Forty-two percent of pts received SCT (N=38). Nearly 60% of socially advantaged pts (ADI≤51) received SCT versus 33% of socially disadvantaged pts (P=0.03). In univariate models, receipt of SCT (P=0.016) was associated with improved OS while receiving navigation services (P=0.32) was not. Conclusions: Higher ADI was associated with inferior OS in AML pts <60 who received intensive induction. Receipt of SCT was observed more often in pts with more neighborhood advantage, which is of great importance since SCT improved OS in this cohort. Although insurance status is often linked to SCT access, insurance status did not significantly impact OS. Of the ONN reported barriers to care, transportation issues had a greater impact on pts with more neighborhood disadvantage. Expanding access to SCT and addressing barriers to care, such as transportation, is necessary to overcome the detrimental impact of neighborhood disadvantage on survival in AML.