Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL) are both B-cell malignancies that commonly arise in the mediastinum and have a peak incidence in the adolescent and young adult (AYA) age range of 15-39y. Advances in sequencing technology with low-input samples have allowed for recent advances in our knowledge of the key molecular alterations in these lymphoma subtypes. In this session, we will discuss the unique genomic features of HL and PMBCL and highlight what is known about differences across the age spectrum. We will also discuss how genomics can inform the use of novel therapies for HL and PMBCL.

Hodgkin lymphoma has traditionally been challenging to study by standard genomic platforms given the rarity of the Hodgkin Reed Sternberg (HRS) cell among the extensive inflammatory infiltrate. Recently, our group and others have utilized flow cytometry to sort HRS cells and intratumoral T and B cells for genomic analyses. Optimization of library preparation for ultralow (<5ng) input now allows for whole-exome characterization of classical HL. Sequencing of the first 10 HL exomes revealed inactivating mutations in β-2-microglobulin (B2M) in 7 of 10 cases. B2M alterations resulted in loss of MHC Class I expression, providing a potential mechanism of HRS cell immune escape (Reichel et al., Blood 2015). Other common alterations observed in this cohort were TNFAIP3 (in 6/10 cases) and HISTH1E (5/10 cases). More recently, a larger cohort of 23 cases of cHL was evaluated by whole-exome sequencing (Wienand et al., Blood Advances 2019). Here the most frequent alterations occurred in B2M (39%), NFKNIE (26%), and TNFAIP3 (26%). Further analysis of this cohort integrating genomic mutations, somatic copy number alterations, and structural variants identified key pathways that are altered in cHL including genomic mechanisms of immune evasion, enhanced JAK/STAT signaling, and alterations in NF-κB signaling. It is not known if differences in genomic alterations exist across the age spectrum in cHL and how this might guide therapy. For example, loss of B2M is associated with younger/AYA age range (median age of B2M negative (altered) vs. positive = 30y vs. 47y, p<0.001). Further studies are needed to fully characterize the HL genome and understand the implications of alterations for therapy in both pediatric and adult cohorts.

Primary mediastinal B-cell lymphoma is a rare subtype of non-Hodgkin lymphoma, accounting for 2% to 3% of NHL. The disease typically presents as a large mediastinal mass in patients in the AYA age range, with an increased incidence in females. Although previously considered a subtype of diffuse large B-cell lymphoma, PMBCL is now recognized as its own clinical and molecular/pathologic entity that shares many similarities with Hodgkin lymphoma. Recent genomic characterization of PMBCL has been performed using whole-exome sequencing (Mottok et al., Blood 2019; Chapuy et al., Blood 2019). These studies reported recurrent alterations in components of JAK/STAT and NF-κB signaling as well as genetic mechanisms of immune evasion similar to that observed in cHL including alterations in B2M, CD274, and CIITA. In addition, cases were observed to have high tumor mutational burden and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutation signature, which may confer sensitivity to PD-1 blockade.

In summary, recent genomic findings in HL and PMBCL demonstrate molecular similarities between these lymphoma subtypes and define the genetic basis for immune evasion sensitivity to PD-1 blockade. This has translated to national clinical trials for AYAs with HL and PMBCL. A randomized phase III trial of nivolumab + AVD vs. brentuximab + AVD for children and adults with advanced stage HL is currently ongoing (NCT03907488). In PMBCL, a randomized phase III trial evaluating nivolumab in combination with standard therapy for upfront disease is in development and will include pediatric and adult patients across NCTN sites.

Citation Format: Lisa G. Giulino-Roth. Genomics of common AYA lymphomas: Hodgkin lymphoma and primary mediastinal B-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA09.