ORLANDO, FL—Research reported at the 57th American Society of Hematology (ASH) Annual Meeting has confirmed “the importance of genetically defined PD-1 mediated immune evasion in classical Hodgkin lymphomas.”1
“Near universal 9p24.1 genetic alterations likely explain the efficacy of PD-1 blockade in this disease,” said Margaretha G. M. Roemer, MS, of the Dana-Farber Cancer Institute in Boston, MA.
Recent pilot studies in patients with relapsed/refractory classical Hodgkin lymphoma have found that “PD-1 blockade was associated with high response rates and durable remissions,” she noted.
In classical Hodgkin lymphoma, the PD-1 ligands (PD-L1 and PD-L2) are known to be increased not only by chromosome 9p24.1 alterations, but by further induction via JAK2-STAT signaling. “Tumor cells expressing PD-1 ligands on their surface utilize the PD-1 pathway to evade an effective immune response,” Roemer said.
The challenge: to define the incidence, nature, and prognostic significance of PD-1 ligand alteration, given that “the unique composition of classical Hodgkin lymphomas limits its analysis with high throughput genomic assays.”
Roemer and colleagues used a recently developed fluorescence in situ hybridization (FISH) assay to characterize 9p24.1/PD-L1/PD-L2 alterations in 108 patients newly diagnosed with classical Hodgkin lymphoma. All patients were treated with a combined modality therapy regimen (Stanford V and field radiation), and followed long-term.
Results of FISH showed that almost all patients “had concordant alterations of the PD-L1 and PD-L2 loci; disomy was found in only 1% (1/108), polysomy in 5% (5/108), copy gain in 56% (61/108) and amplification in 36% (39/108),” she said. “There was a correlation between intensity of PD-L1 protein expression and relative genetic alterations.” Two additional patients had translocations of PD-L1 or PD-L2 (2%, 2/108). Only 1 case was without 9p24.1 alteration.
“We next assessed the association between specific types of PD-L1/PD-L2 alterations, clinical risk factors and outcome,” she outlined. Overall, progression-free survival was significantly lower for patients characterized as Ann Arbor advanced stage 3/4 compared with early stage 1/2 favorable risk or early stage 1/2 unfavorable risk (P = .002).
A model found that patients with amplification had significantly lower progression-free survival (P < .001), with incidence of 9p24.1 amplification increased by clinical risk group; in a multivariate model, genetic alteration further delineated progression-free survival (P = .075).
“PD-L1/PD-L2 alterations are a defining feature of classical Hodgkin lymphomas with rare polysomy and more frequent copy gain and amplification,” she concluded. “There is an increased incidence of amplification in patients with advanced stage disease and a highly significant association of PD-L1/PD-L2 amplification with progression-free survival.”
1. Roemer MGM, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting; December 6, 2015, Orlando, FL.