The LSC17 Score Correlates with the ELN 2022 Classification of AML and Is an Independent Predictor of Detectable Measurable Residual Disease after Induction Chemotherapy

Introduction: An emerging trend for targeted treatment in AML has led to increased treatment options, however variable outcomes remain even with a targeted approach suggesting novel approaches are needed. To date, risk stratification of AML patients has relied on cytogenetic and genomic data as there has been no CLIA-certified biomarker to assess how leukemia stem cells (LSC) contribute to disease resistance at a clinical level. The LSC17 score predicts risk based on stemness features in AML patients at diagnosis and is strongly associated with survival after standard induction therapy (Ng, Nature 2016). A NanoString clinical assay for the LSC17 score has recently been validated in a CLIA-certified laboratory (Ng, Blood Advances 2022) and can provide a rapid result within 72 hours of diagnosis for incorporation into upfront treatment decisions. Recent updates in AML have led to an improved risk stratification at cytogenetic and genomic levels (ELN 2022). Here we carried out a new analysis to assess the value of the LSC17 score as an independent predictor of outcomes in AML patients in the context of the updated ELN 2022 classification.

Methods: Data from recent validation and prospective feasibility studies were analyzed. Only patients that received induction chemotherapy were included in the analysis. Patients with a confirmed diagnosis of acute promyelocytic leukemia were excluded from analysis. In our studies the LSC17 score was measured in parallel with standard prognostic markers including cytogenetics, molecular studies and targeted sequencing using a standard myeloid panel. Patients’ ELN status was updated using the 2022 classification scheme and was correlated with treatment response and survival.

Results: 190 patients were included in our analysis. LSC17 scores ranged from 0 to 1.25, and were classified as high or low according to the median score of 0.51 from our reference cohort (Ng, Blood Advances 2022). Of the 190 patients, 84 had a low LSC17 score and 106 had a high LSC17 score. Patients received induction chemotherapy with three different protocols: standard 3+7 (n = 141), Flag-IDA (n =40) and CPX-351 (n = 9).

We first considered the impact of the ELN 2022 classification and how it altered prognostic categorization in our cohort. Using ELN 2017 criteria, 48 (27%), 51 (29%), and 77 (44%) of patients had favorable, intermediate and adverse risk disease, respectively. 14 patients were not classifiable as cytogenetic testing failed. Using the ELN 2022 hierarchical classification, patients were categorized into low (n=44), intermediate (n = 53) and high (n = 93) risk groups. Changes in prognostic classification were most evident in the intermediate risk category where 11 patients were upgraded to high-risk disease due to the presence of myelodysplasia-related disease mutations. When the LSC17 score was considered as a continuous variable, the median LSC17 score was statistically different between the three ELN 2022 risk groups (0.24 [range 0-0.8] vs 0.48 [range 0.04-1.13] vs 0.73 [range 0.14-1.25] for low, intermediate and high-risk, respectively; P<0.001, Figure 1).

Measurable residual disease (RD) is associated with poor clinical outcomes. Prediction of RD can identify patients who may benefit from alternative treatment approaches. We therefore assessed the ability of the LSC17 score to predict RD positivity after induction chemo in the context of ELN 2022. In our cohort, 141 patients (74%) had RD testing performed after induction. In univariate analysis, RD positivity was associated with both ELN 2022 high-risk disease (P=0.001, OR 12.7) and a high LSC17 score (P<0.001, OR = 7.7). In multivariate analysis incorporating both variables, both ELN high risk (P=0.02, OR 5.56, 95% CI 1.35 -22.85) and high LSC17 score (P=0.007, OR 3.98, 95% CI 1.44 -11.01) retained independent prognostic value.

Conclusion: The LSC17 score measured by the clinical NanoString-based assay correlates with the updated ELN 2022 risk classification and importantly is an independent predictor of RD positivity irrespective of mutational status. Measurement of the LSC17 score at diagnosis will enable identification of patients with high probability of treatment refractoriness. This study highlights the potential role of the LSC17 score in future risk-adapted clinical studies of novel induction candidates.

Murphy:Trilium therapeutics: Honoraria. Gupta:Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; Roche: Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; Novartis: Consultancy, Honoraria; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board. Schimmer:Otsuka Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Medivir AB: Research Funding; UHN: Patents & Royalties: the use of DNT cells to treat AML. Schuh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yee:Treadwell: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Geron: Research Funding; Forma Therapeutics: Research Funding; Astex: Research Funding; Abbvie: Honoraria; Takeda: Consultancy; TaiHo: Consultancy; Shattuck Labs: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; F. Hoffmann La Roche: Consultancy, Research Funding; Bristol-Myers Squibb/Celgene: Consultancy; Astellas: Consultancy. Khalaf:Novartis: Honoraria; Pfizer: Honoraria; Paladin: Honoraria; Astellas: Honoraria; Jazz: Honoraria; Taiho: Consultancy, Honoraria. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sabloff:Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Wang:Trillium Therapeutics/Pfizer: Patents & Royalties: patent licensing.