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1644 Immune-Related Gene Expression Signatures Identify a Patient’s Subset Achieving Durable Complete Response to Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma

Program: Oral and Poster Abstracts
Session: 622. Lymphomas: Translational – Non-Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Hodgkin lymphoma, Biological therapies, adult, Antibody Therapy, Translational Research, Lymphomas, Clinical Research, health outcomes research, Diseases, immune mechanism, immunology, Therapies, Immunotherapy, Lymphoid Malignancies, Biological Processes, molecular biology, Study Population, Human, pathogenesis
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Paulina Nierychlewska, MD1*, Maria Rosaria Sapienza, MD2*, Alessandro Davini1*, Eugenia Montanari, MD3,4*, Anna Vanazzi, MD1*, Simonetta Viviani, MD1*, Valentina Tabanelli2*, Roberto Massimo Lemoli, MD5,6*, Corrado Tarella1*, Stefano Pileri2 and Enrico Derenzini, MD1,7*

1Oncohematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy
2Haematopathology Division, IEO European Institute of Oncology IRCCS, Milan, Italy
3IRCCS Ospedale Policlinico San Martino, Genoa, Italy
4Clinic of Hematology, University of Genoa, Genoa, Italy
5Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
6Clinica Ematologica, Dipartimento di Oncologia e Ematologia, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
7Department of Health Sciences, University of Milan, Milan, Italy

Background: In classical Hodgkin lymphoma (cHL), 20%-30% of patients experience relapse or progressive disease after standard chemotherapy, requiring salvage treatment strategies including targeted immunotherapy with brentuximab vedotin (BV). Molecular mechanisms underlying treatment resistance to BV in cHL are still poorly understood. The unique characteristics of cHL microenvironment, which represents >90% of the cellular infiltrate, make targeted gene expression profiling (T-GEP) a suitable technique to investigate immune-related determinants of BV sensitivity.

Methods: 31 consecutive patients (pts) affected by relapsed-refractory (R/R) cHL treated at 2 italian Institutions from 2013 to 2018 with available formalin-fixed paraffin embedded (FFPE) tissue collected right before the start of BV therapy, were included in this retrospective study. FFPE tissue was profiled by T-GEP on the Nanostring platform, using the PanCancer Immune Profiling panel, encompassing 730 genes regulating the most relevant immunologic pathways. Disease response after BV treatment was evaluated by FDG-PET after 4, 8, 12 and 16 cycles.


Median age of the whole cohort was 38 years (y) (range 18-76). 18 pts (58%) were male. Median number of BV cycles was 8 (range 2-16). After a median follow-up of 3.5 y from the start of Brentuximab treatment, the overall survival (OS) and progression-free survival (PFS) rates were 87% and 32% respectively. Pts were classified as BV-responders in case of complete metabolic response (CMR) lasting more than 6 months (m); pts achieving less than CMR or short lasting (< 6 m) CMR were classified as non-responders (NR). By applying these criteria, 12 pts (39%) were classified as responders and 19 as non-responders. Differential expression (DE) analyses were performed and differentially expressed (DE) genes were selected by applying two statistical filters: (log2FC > 1 and p-value < 0.05). 61 genes were differentially expressed between responders and non-responders. The 61-gene signature included genes involved in JAK-STAT signaling, IL-17 signaling and cytokine-cytokine receptor interaction. Unsupervised clustering analyses identified two different pts clusters with clearly different BV-sensitivity profiles: cluster1 (22 pts) and cluster2 (9 pts). Among the 22 pts of cluster 1, only 4 pts were responders while 18 were non-responders. As opposite, 8 of 9 patients of Cluster2 were responders, while only 1 was non-responder (p=0.0005).

In line with this, 4-y PFS rate of the 22 pts included in cluster1 was 19%, while the 4-y PFS rate of the 9 pts included in cluster2 was 66% (p=0.007). Median PFS of Cluster1 was only 5.7 months. The composition of the two clusters was not significantly different in terms of number of prior therapies and disease stage at the time of BV treatment.

After achieving a CMR 6 of 9 pts were consolidated with autologous stem cell transplantation (ASCT) in cluster2. In cluster1, 1 patient was consolidated with ASCT after CMR, and 2 pts received allogeneic stem cell transplantation (allo-SCT) after BV-failure.

Conclusions: With the limitation of the small sample size, these data suggest that the composition of cHL microenvironment could influence the activity of single agent BV. Pre-treatment microenvironment profiling with T-GEP could be a useful tool for selecting patients who may derive maximal benefit from BV in cHL.

Disclosures: Viviani: Takeda: Other: Travel and meeting accomodation; Beigene: Other: Travel and meeting accomodation. Tarella: ADC Therapeutics: Other: Advisory Board; CELGENE: Other: Advisory Board. Pileri: Stemline: Speakers Bureau; Lilly: Speakers Bureau; Diatech: Consultancy; Roche: Speakers Bureau; Beigene: Speakers Bureau; Nanostring: Speakers Bureau; Celgene: Speakers Bureau. Derenzini: TAKEDA: Other: advisory board, Research Funding; ADC Therapeutics: Research Funding; Incyte: Other: advisory board; BEIGENE: Other: Advisory board; ASTRAZENECA: Other: Advisory Board; ROCHE: Other: advisory board, Speakers Bureau.

*signifies non-member of ASH