9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial.

High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.

The histological and molecular spectrum of lipoblastoma: A case series with identification of three novel gene fusions by targeted RNA-sequencing.

Lipoblastoma is a rare benign mesenchymal neoplasm that typically occurs in infancy but may also occur in older age groups and various locations. Thus, there are often numerous clinical differential diagnoses. Moreover, lipoblastomas can show a broad histologic spectrum, which can hamper the correct diagnosis, particularly in small biopsies. At the genomic level, lipoblastomas are characterized by chromosomal fusions involving the PLAG1 gene. We investigated 11 lipoblastoma samples from 10 pediatric patients (age range five months to 12 years), including one patient with local recurrence, in view of their histopathological features, and performed targeted RNA sequencing. We found a broad histological spectrum with some tumors with prominent myxoid changes, but also tumors composed mainly of mature adipocytic cells, and classified the cases according to the literature as classic (mixed), maturing, or myxoid subtype. By targeted RNA sequencing analysis, we identified characteristic PLAG1 rearrangements in 70% of the investigated cases. Moreover, these analyses revealed three novel gene fusions, two affecting the PLAG1 gene and one involving HMGA2. Besides, we performed PLAG1 immunohistochemistry and identified positive cells, typically immature adipocytic cells and spindle cells, at various numbers in all cases. However, in the maturing areas, only very sparsely positive cells were found, limiting the value of the PLAG1 immunohistochemistry as an adjunct in the diagnosis of lipoblastoma, particularly for the maturing subtype and small biopsies. The presented case series confirms the broad morphological spectrum of lipoblastoma described in the literature and underlines the value of modern molecular diagnostic approaches as a supportive diagnostic tool in challenging cases and for gaining further insights into the molecular basis of this rare mesenchymal tumor.

Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns.

Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.