<figure><img src="image_1.png" /></figure>

<figure><img src="image_2.png" /></figure>

(Patient-Derived Lymphoma Spheroids-PDLS) will allow us to confirm these results in relevant preclinical models.

As PD-1⁺LAG-3⁺ T cells predict a poor outcome in FL patients, our findings open encouraging perspectives for the use of new antibodies blocking both PD-1 and LAG-3 thus specifically targeting the exhausted T-cell population and may therefore represent a promising future treatment strategy in FL patients.

The research was funded by: This research collaboration was supported through the imCORE network on behalf of F.Hoffmann-La Roche.

Keywords: Immunotherapy, Indolent non-Hodgkin lymphoma, Risk Models

### Conflicts of interests pertinent to the abstract.

#### F. Bouquet

Employment or leadership position: Roche employee

#### C. Fonseca

Employment or leadership position: Roche employee

#### S. Herter

Employment or leadership position: Roche employee
Stock ownership: roche

#### L. Codarri

Employment or leadership position: Roche employee

#### R. McCord

Employment or leadership position: Genentech employee

#### E. Chiang

Employment or leadership position: Genentech employee

#### F. Morschhauser

Consultant or advisory role: Roche, Gilead, Genmab, Novartis, Abbvie
Honoraria: Chugai (scientific lectures)

#### C. Laurent

Educational grants: Janssen

## TRANSLATIONAL STUDIES, B-CELL LYMPHOMAS

### 199 | IDENTIFICATION OF AN ACTIVATED/MEMORY B-CELL SIGNATURE OF POOR OUTCOME AND SENSITIVITY TO LENALIDOMIDE IN FOLLICULAR LYMPHOMA PATIENTS

C. Laurent¹, P. Trisal², B. Tesson³, B. Lesne³, N. Van-Acker¹,
L. Chartier³, M. Stokes², C. Huang², S. Huet⁴, F. Morschhauser⁵,
A. K. Gandhi², L. Xerri⁶

¹CHU Toulouse, Institut Universitaire Cancer-Oncopole, INSERM U1037, Pathology, Toulouse, France, ²Translational Medicine, Bristol Myers Squibb, Summit, New Jersey, USA, ³LYSARC, Pierre Bénite, France, ⁴Hospices Civils de Lyon, CHU Lyon, Pierre Bénite, France, ⁵Hôpital Claude Huriez, CHU Lille, Lille, France, ⁶Institut Paoli-Calmettes, CRCM and Aix-Marseille University, Marseille, France
**Introduction:** The RELEVANCE randomized trial showed that the combination of lenalidomide + rituximab ($R^2$) has similar efficacy to rituximab + chemotherapy (R-chemo) in patients (pts) with advanced-stage, previously untreated follicular lymphoma (FL) after 6 years of follow-up. In this study, using RNA sequencing we identify high-risk patients benefiting from $R^2$.

**Methods:** RNAseq on FFPE biopsies was performed for 324 enrolled pts (grade 1–2 and 3A) at diagnosis. Using unsupervised clustering, gene signatures (GS) were identified, scored in individual pts and tested for their association with progression free survival (PFS).

**Results:** Of the total 46 identified GS, two GS displayed opposite and treatment-dependent associations with PFS. The first GS (179 genes) was enriched for genes expressed in ABC-subtype diffuse large B cell lymphomas and normal memory B cells; while the second GS (213 genes), strongly anti-correlated with the first one, was enriched for genes expressed in GCB-subtype DLBCLs.

We combined the two GS into a 20-genes based Linear Predictor Score (LPS20) which could classify pts into either an ABC/MEM-like FL subtype ($n = 160$ patients) or a GCB-like FL subtype ($n = 164$ patients). In the R-chemo arm, the 6 years PFS of ABC/MEM-like pts (45% [35–59]) was significantly shorter than GCB-like pts (67% [59–80]) (HR = 2.13[1.30–3.51], $p = 0.003$). In the $R^2$ arm, both subgroups had comparable PFS (65% vs. 62%; HR = 1.04[0.61–1.77], $p = 0.9$). In a multivariate model including FLIPI, the association between subtype and outcome remained significant for R-chemo pts (adjusted HR = 2.15[1.31–3.53], $p = 0.002$) and the treatment dependence as well (interaction subtype*treatment $p = 0.041$). A marked benefit of $R^2$

compared to R-chemo was observed (HR = 0.46[0.28–0.75], $p = 0.002$) for ABC/MEM-like pts with FLIPI $\ge 2$.

We validated these prognostic correlations in two independent R-chemo treated FL cohorts from the LYSA (PRIMA, $n = 134$) and BCCA (GSE119214, $n = 137$). In PRIMA, the ABC/MEM-like subtype was associated with a shorter PFS (vs GCB-like) but only among FLIPI $\ge 2$ pts ($n = 111$, HR = 1.72[1.01–2.93], $p = 0.044$). In the BCCA cohort, the ABC/MEM-like subtype was associated with inferior FFS (HR = 1.78[1.1–2.87], $p = 0.019$) and overall survival (HR = 2.13 [1.18–3.82], $p = 0.012$).

Exome sequencing data revealed that ABC/MEM-like FLs were enriched for mutations in genes from the mTOR/autophagic pathway, while GCB-like FLs were enriched for mutations in *EZH2* and *TNFRSF14*, hinting different genetic drivers.

**Conclusions:** These results confirm that FL tumors can be sub-categorized into cell of origin-based ABC/MEM- vs. GCB-like sub-types, as recently suggested (PMID 34991156). The herein described LPS20 predictor has theragnostic potential in identifying ABC/MEM-like FL pts as a high-risk subgroup with inferior outcome when treated with R-chemo, but the $R^2$ regimen overcame this poor prognosis.

CL, PT and BT contributed equally to this work. FM, AKG and LX contributed equally to this work

The research was funded by: Bristol Myers Squibb

Keywords: Diagnostic and Prognostic Biomarkers, Genomics, Epi-genomics, and Other -Omics, Indolent non-Hodgkin lymphoma

<figure><img src="image_3.png" /><figcaption>**Figure 1:** A Standardized expression of ICA consensus clustering derived GCB-like and ABC/MEM-like signatures in 324 patients from the RELEVANCE cohort. **B** Construction of a classifier using top 20 genes for predicting GCB-like vs ABC-MEM-like subtypes. **C** PFS according to subtype and treatment arm.</figcaption></figure>

<figure><img src="image_4.png" /></figure>
Conflicts of interests pertinent to the abstract.

C. Laurent

Research funding: BMS grant

Travel grants: Janssen

P. Trisal

Employment or leadership position: Translational Medicine, Bristol
Myers Squibb, Summit, NJ, USA

B. Tesson

Research funding: BMS grant

M. Stokes

Employment or leadership position: Translational Medicine, Bristol
Myers Squibb, Summit, NJ, USA

C. Huang

Employment or leadership position: Translational Medicine, Bristol
Myers Squibb, Summit, NJ, USA

S. Huet

Research funding: BMS grant

F. Morschhauser

Research funding: BMS grant

Travel grants: Janssen

A. K. Gandhi

Employment or leadership position: Translational Medicine, Bristol
Myers Squibb, Summit, NJ, USA

L. Xerri

Honoraria: EUSA pharma

Research funding: BMS grant

Travel grants: Janssen

**200** | A LOW LYMPHOCYTE-TO-MONOCYTE RATIO (LMR) PREDICTS PFS, POD24 AND OS IN PREVIOUSLY UNTREATED, HIGH TUMOR BURDEN FOLLICULAR LYMPHOMA (FL): AN ANALYSIS FROM THE RELEVANCE TRIAL

P. Mozas¹, R. Ould Ammar², L. Chartier², L. Nastoupil³, E. Bachy⁴,
S. M. Bezsera⁵, J. Barnes⁶, F. Bijou⁷, A. Goy⁸, H. Zerazhi⁹,
G. Cartron¹⁰, M. Ojeda-Uribe¹¹, S. Choquet¹², B. Joly¹³,
M. Cheminant¹⁴, A. Martín García-Sancho¹⁵, H. Eradat¹⁶,
R. Gressin¹⁷, P. Abrisqueta¹⁸, A. Parcelier¹⁹,
M. J. Rodríguez Salazar²⁰, C. Bonnet²¹, M. Crump²²,
A. López-Guillermo¹, F. Morschhauser²³

¹Hospital Clínic de Barcelona, Hematology, Barcelona, Spain, ²Lymphoma Academic Research Organization (LYSARC), Lyon, France, ³MD Anderson Cancer Center, Department of Lymphoma-Myeloma, Houston, Texas,

USA,⁴Centre Hospitalier Lyon Sud, Service d'Hématologie Clinique, Lyon, France,⁵Institut de Cancérologie et d'Hématologie Universitaire de Saint-Étienne, Service d'Hématologie, Saint-Étienne, France,⁶Mass General Cancer Center at Martha's Vineyard Hospital, Boston, Massachusetts, USA,⁷Institut Bergonié - Centre Régional de Lutte contre le Cancer, Service d'Hématologie, Bordeaux, France,⁸John Theurer Cancer Center at Hackensack University Medical Center, Oncology Service, Hackensack, New Jersey, USA,⁹Centre Hospitalier d'Avignon, Service d'Onco-Hématologie, Avignon, France,¹⁰Centre Hospitalier Régional Universitaire de Montpellier, Département d'Hématologie Clinique, Montpellier, France,¹¹Centre Hospitalier de Mulhouse - Hôpital Emile Muller, Département d'Hématologie, Mulhouse, France,¹²Hôpital de la Pitié-Salpêtrière, Service d'Hématologie, Paris, France,¹³Centre Hospitalier Régional Universitaire Sud Francilien, Service d'Hématologie, Corbeil-Essonnes, France,¹⁴Hôpital Necker, Service d'Hématologie, Paris, France,¹⁵Hospital Universitario de Salamanca, IBSAL, Servicio de Hematología, Salamanca, Spain,¹⁶Ronald Reagan and Santa Monica UCLA Medical Center, Santa Monica, California, USA,¹⁷Centre Hospitalier Universitaire de Grenoble, Service d'Hématologie Clinique, Grenoble, France,¹⁸Hospital Vall d'Hebron, Servicio de Hematología, Barcelona, Spain,¹⁹Centre Hospitalier Bretagne-Atlantique, Service de Médecine Interne - Hématologie, Vannes, France,²⁰Hospital Universitario de Canarias, Servicio de Hematología, Tenerife, Spain,²¹Centre Hospitalier Universitaire de Liège, Service d'Hématologie, Liège, Belgium,²²University Health Network - Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada,²³Centre Hospitalier Universitaire de Lille - Hôpital Claude Huriez, Service des Maladies du Sang, Lille, France

**Introduction:** The peripheral blood LMR has been postulated as an accessible piece of information about the composition of the tumor microenvironment. In a single-center, retrospective, unselected cohort of FL, a low LMR was shown to be associated with an older age and higher tumor burden and to predict for a shorter progression-free and overall survival (PFS, OS) and a higher risk of histological transformation and second primary malignancies (Mozas, Leuk & Lymph, 2020). We explored the impact of the LMR in patients included in the phase III RELEVANCE trial (Morschhauser, NEJM, 2018 and JCO, 2022), which compared rituximab-chemotherapy (R-chemo) with rituximab-lenalidomide (R²) in patients with previously untreated, high tumor burden FL.

**Methods:** Xtile and the maxstat package of R software were used to find the best LMR cutoff based on PFS data and then validated using a truncated power basis spline method. Baseline characteristics, PFS per investigator assessment, early relapse (POD24) and OS were compared between LMR risk groups. Multivariable Cox regression models including the FLIPI score and the treatment arm were built for survival analyses and uni/multivariable logistic regression was used for POD24 analysis.

**Results:** Among the 1030 patients included in the RELEVANCE study, 1018 had LMR data available. The median LMR was 2.5 (range, 0-93) and a LMR cutoff of 2 was found to best predict PFS. Patients with a LMR ≤2 (n = 372, 37%) were older and displayed higher-risk features (Figure A). In the global cohort, a LMR ≤2 was predictive of a shorter