Early Evidence Suggests PD-1 Inhibitors May Be Effective in Relapsed/Refractory Mediastinal Gray-Zone Lymphoma

Mediastinal gray-zone lymphoma, nodular sclerosis classic Hodgkin lymphoma (cHL), and primary mediastinal B-cell lymphoma have overlapping clinical, histologic, and molecular features, including the frequency of 9p24.1 copy-number alterations associated with susceptibility to immune checkpoint inhibition. Such alterations occur in approximately 61 percent of patients with mediastinal gray-zone lymphoma, which is typically resistant to treatment.

In a Letter to the Editor published in the New England Journal of Medicine, Christopher Melani, MD, of the National Cancer Institute in Bethesda, Maryland, and colleagues noted “recent findings indicate that mediastinal gray-zone lymphoma may be more closely related to cHL than to primary mediastinal B-cell lymphoma” and therefore may respond to immune checkpoint inhibition.

Dr. Melani described three case studies that demonstrate “early evidence for using PD-1 inhibition [with agents like nivolumab and pembrolizumab] in relapsed or refractory mediastinal gray-zone lymphoma.”

  • Case 1: An 18-year-old woman with mediastinal gray-zone lymphoma (confirmed after a biopsy of a mediastinal mass showed an immunophenotype intermediate between diffuse large B-cell lymphoma [DLBCL] and cHL, which was positive for CD20, CD30, and CD15) experienced a partial response (PR) to dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R). However, six weeks after salvage radiotherapy, her disease progressed. She was then treated with pembrolizumab and had a complete metabolic response (defined as normalization of an abnormal positron emission tomography scan). After 235 days of treatment, she underwent allogeneic hematopoietic cell transplantation. Fluorescence in situ hybridization (FISH) detected rearrangement of the genes encoding the PD-1 and PD-2 ligands.
  • Case 2: A 76-year-old man with mediastinal gray-zone lymphoma (confirmed after a biopsy of a subcarinal mass showed DLBCL with an immunophenotype of cHL, which was positive for CD30 and PAX5 and negative for CD10, CD20, and CD15) also experienced a PR to DA-EPOCH-R, but his disease subsequently progressed. After treatment with pembrolizumab, he had a complete metabolic response and continues to be in remission after 381 days of treatment. FISH detected amplification of PD-L1/PD-L2, with 69 percent of cells having at least six copies per cell.
  • Case 3: An 80-year-old woman with mediastinal gray-zone lymphoma (confirmed after a biopsy of an axillary lymph node showed an immunophenotype intermediate between DLBCL and cHL, which was positive for CD20, CD30, and CD15) relapsed after dose adjusted EPOCH-R and experienced disease progression following treatment with brentuximab; a combination of rituximab, gemcitabine, and oxaliplatin; and mediastinal radiation. After receiving nivolumab, she had a complete metabolic response and continues to be in remission after 161 days of treatment. Immunohistochemical analysis showed focal membranous PD-L1 expression.

“These findings suggest that PD-1 inhibitors may be therapeutically important for mediastinal gray-zone lymphoma, which is more resistant to treatment than cHL or primary mediastinal B-cell lymphoma,” Dr. Melani wrote. “The high frequency of 9p24.1 copy-number alterations across mediastinal lymphomas suggests a disease-specific, genetically determined dependence on PD-1 for survival.”

Dr. Melani noted that these early findings warrant further testing in larger clinical trials.

Dr. Melani reports no conflicts.


Reference

Melani C. PD-1 blockade in mediastinal gray-zone lymphoma. N Engl J Med. 2017;377:89-91.

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