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Genetic alterations common defining features of classical Hodgkin lymphoma
PD-L1 and PD-L2 genetic alterations served as defining characteristics of classical Hodgkin lymphoma, according to study results published in Journal of Clinical Oncology.
Amplification of the chromosome 9p24.1 alteration appeared more commonly in patients with advanced-stage disease and was associated with poorer PFS, results showed.
Margaret A. Shipp
Classical Hodgkin lymphomas include small numbers of malignant Reed–Sternberg cells surrounded by an extensive yet ineffective inflammatory/immune cell infiltrate. Alterations of chromosome 9p24.1, PD-L1 and PD-L2 increase the abundance of PD-1 ligands, as well as their further induction through Janus kinase 2–signal transducers and activators of transcription signaling.
Due to the unique composition of classical Hodgkin lymphoma, which limits its analysis with high-throughput genomic assays, the precise incidence, nature and prognostic significance of PD-L1 and PD-L2 alterations remain largely unknown.
Margaret A. Shipp, MD, professor of medicine at Harvard Medical School and director of the lymphoma program at Dana-Farber Cancer Center, and colleagues used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in biopsy samples from 108 patients with newly diagnosed classical Hodgkin lymphoma (median age, 30 years; range, 18-69).
Thirty-three samples came from patients with early-stage favorable disease (stage I, n = 8; stage II, n = 25); 41 samples came from patients with early-stage unfavorable disease (stage I, n = 1; stage II, n = 40); and the remaining 34 samples came from patients with advanced-stage disease (stage III, n = 22; stage IV, n = 12).
All patients were treated with the Stanford V regimen, a combined modality treatment comprised of doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide and prednisone.
The researchers determined the frequency and magnitude of patients’ 9p24.1 alterations — including polysomy, copy gain and amplification — and their PD-L1 and PD-L2 expression by immunohistochemistry.
Nearly all patients (97%; n = 105) had concordant alterations of the PD-L1 and PD-L2 loci, and only one patient had normal 9p24.1 copy numbers.
Five patients (5%) had polysomy of 9p, whereas 61 patients (56%) had 9p24.1 copy gains and 39 patients (36%) had 9p24.1 amplification.
The researchers observed an association between PD-L1 and PD-L2 protein expression and 9p24.1 genetic alterations in Reed–Sternberg cells, as well as decreased residual 9p24.1 disomy and increased PD-L1 expression (P = .005).
Researchers then assessed the whether 9p24.1 alterations were associated with clinical factors, including staging and PFS.
Overall, patients with advanced-stage disease had inferior PFS outcomes compared with early-stage patients (P = .002). When assessed by genetic alteration, the researchers identified significant differences in outcomes among patients with 9p24.1 amplification (P < .001).
The poorer outcomes among patients with advanced-stage disease prompted the researchers to observe 9p24.1 alterations across risk categories. They found a significant increase in amplification by clinical risk group (early-stage favorable, 24%; early-stage unfavorable, 34%; advanced-stage, 50%; P = .024).
“Taken together, these data support a strategy for identifying lymphoid malignances with genetic bases for PD-1–mediated tumor immune invasion,” Shipp and colleagues wrote. “In classical Hodgkin lymphoma, the near-uniform alterations of the PD-L1/PD-L2 loci likely explain the remarkable activity of PD-L1 blockade in this disease.” – by Cameron Kelsall
Disclosure: Shipp reports honoraria, travel expenses and research funding from, as well as consultant roles with, Bayer AG, Bristol-Myers Squibb, Gilead Sciences, Merck and Takeda Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.