Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial

Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets.

Positron Emission Tomography (PET) is a functional imaging technique that, combined with computerized tomography (PET-CT), is increasingly used in lymphoma. Most subtypes accumulate fluorodeoxyglucose (FDG) and the increased sensitivity of PET-CT, especially for extranodal disease, compared to CT, makes PET-CT an attractive staging tool. The availability of a staging PET-CT scan also improves the accuracy of subsequent response assessment. 'Interim' PET-CT can be used to assess early response and end-of-treatment PET-CT assesses remission. Clinical trials are currently seeking to establish whether the predictive value of PET-CT can be successfully used to guide individual treatment to reduce toxicity and/or to improve outcomes. Standardized methods for performing and reporting PET have been developed in the context of trials. The role of PET in transplantation selection is currently evolving, as it appears to be more accurate and prognostic than CT. The role of FDG PET-CT throughout the management course in patients with lymphoma is explored in this review, with areas discussed that may limit the use of PET-CT imaging which clinicians should be familiar with to inform practice.

Brentuximab vedotin (BV) is a key therapeutic agent for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The outcomes of patients experiencing disease progression after BV are poorly described.