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4311 IL-1RAP Is a Targetable Surface Antigen in Relapsed/Refractoy AML

Program: Oral and Poster Abstracts
Session: 618. Acute Myeloid Leukemias: Biomarkers and Molecular Markers in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Translational Research, Diseases, Treatment Considerations, Biological therapies, Myeloid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Mohamad Sabbah, MD1*, Morgane Fontaine2*, Kim Pacchiardi3*, Alexis Delabrière4*, Stephane De Botton, MD, PhD5*, Catherine Lonchamp2*, Renaud Buffet, MD6*, Laure Farnault, MD7*, Jean-Baptiste Micol, MD8, Typhaine Dumas-Rivero, PharmD9*, Emmanuel Raffoux, MD10,11*, Lionel Ades, MD, PhD1, Nicolas Boissel, MD, PhD12, Juliette Lambert, MD, PhD13*, Kevin-James Wattebled, MD14*, Matthieu Duchmann, MD, PhD15*, Karine Celli-Lebras, RN16,17*, Alexandra Coelho18*, Hervé Dombret, MD, PhD19, Edouard De Dreuzy, PhD20*, Marina Deschamps, PhD21,22*, Christophe Ferrand, PhD22,23, Jens Hasskarl, MD, PhD24, Richard Sainson20* and Raphael Itzykson25,26,27

1Hopital Saint Louis, Paris, France
2Université Paris Cité, Génomes, biologie cellulaire et thérapeutique U944, INSERM, CNRS, Paris, FRA
3St Louis Hospital, INSERM U944, Paris, France
4Advesya, paris, France
5Department of Hematology, Institut Gustave Roussy, Villejuif, France
6Hospital Saint-Louis, Boulogne, FRA
7APHM Hopital La Conception, Marseille, FRA
8Hematology Department, Gustave Roussy Institute, Villejuif, France
9Université Paris Cité, Génomes, biologie cellulaire et thérapeutique U944, INSERM, CNRS, Paris, France., Paris, France
10Hematology Department, Saint Louis University Hospital, AP-HP, Paris, France
11Hematology Department, Saint Louis Hospital, Paris, France
12Hematology Adolescents and Young Adult Unit, Saint-Louis Hospital, APHP, Paris, France, Paris Cedex 10, Paris, France
13Clinical Hematology Department, Versailles Hospital, Le Chesnay-Rocquencourt, France
14CH Dunkerque, Dunkerque, FRA
15INSERM U944, Paris, FRA
16Hopital Saint-Louis, Paris, FRA
17ALFA Coordination, Hôpital Saint-Louis, Paris, France
18ALFA Project Manager, Paris, France
19Hôpital Saint-Louis, Hematology Department, AP-HP, Paris, France
20Advesya, Paris, France
21Hopital Jean Minjoz, Besancon, FRA
22ADVESYA, Paris, France
23University/INSERM UMR1098 RIGHT, Besancon Cedex, France
24ADVESYA, Paris, Cedex, FRA
25Unité 944/7212-GenCellDi, Saint-Louis Research Institute, INSERM, CNRS, Université Paris Cité, Paris, France
26Service Hématologie Adulte, Assistance Publique des Hôpitaux de Paris (APHP), Université Paris Cité, Paris, France, Paris, France
27Université de Paris, Unité 944/7212-GenCellDi, INSERM and Centre National de la Recherche Scientifique (CNRS), Paris, France, Paris, France

Context: Relapsed/Refractory (R/R) AML is an unmet medical need. Novel AML immunotherapies require surface antigens that have broad expression, both at the inter-individual level and intra-individual (blasts and leukemic stem cells [LSCs] levels, with minimal expression on healthy HSPCs. IL-1RAP, the accessory co-receptor of the interleukin 1, 32, and 33 receptors, is a promising target antigen with broad expression on AML cells at diagnosis (Boissel et al. EHA 2024 #P453, De Dreuzy et al. AACR 2024 #6322) and has been suggested as a potential Leukemic Stem Cell (LSC) marker (Askmyr et al. Blood 2013). Its expression in R/R AMLs eligible for early-stage trials is unknown.

Objective: To determine IL-1RAP expression on blasts and LSCs in a prospective cohort of R/R AMLs.

Methods: Peripheral Blood (PB) or Bone marrow (BM) from relapsed/refractory (excluding molecular relapse) AML patients ≥18 years old accrued to the ALFA PPP registry (NCT04777916) were collected and prospectively assessed for IL-1RAP expression (clone B-R58) in a 10-marker panel on an Ique3 high-throughput cytometer (Sartorius). Flow analyses were done on Kaluza (Beckman).

Results: From 26 July 2023 till 11 June 2024, we analyzed 38 patients (M/F 19/19, median age 67y), with primary refractory (26%) or relapsed (74%) AML, including 25% therapy-related and 17% secondary and 58% de novo AML. NPM1, FLT3 and IDH1/2 mutations were present in 25%, 29% and 17% of patients, respectively. Most (79%) had been previously exposed to intensive Cx, 58% to venetoclax and 21% had a previous allo-HCT. Peripheral blood (55%) or bone marrow (45%) samples (median blast % before gradient separation: 34%) were processed.

On a median of 20508 gated blasts (IQR 7796-31858), the median proportion of IL-1RAP+ cells was 24% (IQR 11-55, range 1-99) and the median Antibody Binding Capacity (ABC) was 970 (IQR 514-3722, range 35-3722). Based on IL-1RAP ABC distribution in CD45high/SSClow lymphocytes used as internal controls (median 38, IQR 16-96), we defined ABC 200 as the definition of IL-1RAP positivity in blasts; 34 (89%) patients had IL-1RAP+ blasts.

In univariable analyses, neither sample source (PB vs BM, p=0.06) nor processing method (fresh vs thawed, p=0.28) influenced IL-1RAP ABC on blasts. Neither age, sex, ontogeny nor disease status (relapse vs primary refractory), history of intensive Cx, hypomethylating agents, venetoclax or allo-HCT had impact on IL-1RAP ABC on blasts (all p>0.05). Ten (26%) pts had flow-defined monocytic differentiation. These pts had comparable IL-1RAP ABC in gated blasts to those without monocytic differentiation (p=0.17). Median IL-1RAP ABC of blasts was 1724 in NPM1mut pts vs 856 in NPM1wtpts (p=0.04) and 1878 vs 814 in FLT3mut vs FLT3wt pts (p=0.004) while IDH1/2 mutations had no impact (p=0.91). In a multivariable linear regression followed by backward variable selection and accounting for sample source, NPM1 and FLT3 status, after backward variable selection, only FLT3 status influenced IL-1RAP ABC (p=0.04). All (100%) FLT3mut pts had an ABC 200 vs 81% of FLT3wt pts (p=0.5). This was in agreement with FLT3-ITD being the main genetic biomarker associated with increased IL-1RAP expression (FC=1.68, q-val <10-20) in a public transcriptomic dataset of 1224 AML patients (Severens, Leukemia 2024).

A median of 2560 (IQR 542-9960) CD34+/CD38-/(CD97|TIM3|CLL1)+ LSCs were acquired. In the 29 pts with at least 200 gated LSCs, median IL-1RAP ABC in LSCs was 2,176 (IQR 1231-3059), representing a strong enrichment compared to the total blast population (p=0.006). IL-1RAP ABCs were significantly higher in FLT3mut vs FL3wt pts (p=0.01). All other demographic, treatment history or genetic variables had no impact on IL-1RAP ABC in LSCs.

Conclusion. IL-1RAP is expressed on blasts in 89% of relapsed/refractory AML patients regardless of disease ontogeny and treatment history. IL-1RAP is over-expressed in phenotypically-defined LSCs compared to blasts. FLT3mut pts have higher IL-1RAP expression in both blasts and LSCs. This data supports the use of IL-1RAP as a target antigen in R/R AMLs. The safety and clinical activity of the first in class, 3rd generation autologous IL-1RAP-directed CAR T cell therapy (CCTx-001) will be tested in the RESOLVE AML-001 study (NCT06281847).

Disclosures: Delabrière: ADVESYA: Current Employment. De Botton: Jazz Pharmaceuticals: Speakers Bureau; Astellas: Speakers Bureau; AbbVie: Other: travel, Speakers Bureau; Syndax: Consultancy; Servier: Consultancy, Other: travel, Speakers Bureau; Remix: Consultancy; GlaxoSmithKline: Consultancy; Forma: Research Funding; Auron: Research Funding; BMS: Consultancy, Speakers Bureau; Loxo: Honoraria. Micol: Jazz Pharmaceuticals: Honoraria; Astellas Pharma: Honoraria; SERVIER: Honoraria; AbbVie: Honoraria; Gilead Sciences: Honoraria. Ades: Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Boissel: Jazz Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. De Dreuzy: ADVESYA: Current Employment. Deschamps: ADVESYA: Current Employment. Ferrand: ADVESYA: Current Employment. Hasskarl: ADVESYA: Current Employment. Sainson: ADVESYA: Current Employment. Itzykson: Abbvie: Research Funding; Advesya: Research Funding.

*signifies non-member of ASH