Targeted vitreoretinal lymphoma therapies mimic other approaches

Reviewed by Rajesh C. Rao, MD

Vitreoretinal lymphomas are both deceptive and deadly. While there are only about 350 cases reported annually in the United States, median survival is less than 5 years, said Rajesh C. Rao, MD.

“Vitreoretinal lymphoma is often difficult to diagnose,” said Dr. Rao, assistant professor of ophthalmology and visual sciences and pathology, University of Michigan, Ann Arbor. “There are no standardized therapies.

“While current intravitreous therapies-such as methotrexate and rituximab-can control intraocular disease, survival rates remain dismal due to central nervous system involvement,” he said.

Dr. Rao described a genetic approach based on precision-medicine strategies that have been used successfully in other cancers. His lab has identified genetic alterations that both identify vitreoretinal lymphomas and invite the kind of targeted therapies transforming treatments for other types of cancers.

Vitreoretinal lymphoma mimics forms of posterior uveitis, which are much more common than lymphoma. The gold standard for diagnosis is pathological confirmation of lymphoma cells, though this requires undiluted vitreous samples, and large-volume biopsies are seldom possible.

Vitreous is more viscous and difficult to process than serum and other liquid tissue biopsies. Diluted samples provide more material but make it harder to identify rare lymphoma cells. Adjunctive modalities, such as flow cytometry and interleukin-6/10 ratio testing, are of limited value without pathologic confirmation.

Genetic sequencing has identified multiple treatment targets in other cancer types. Breast cancers with ERBB2 amplifications are susceptible to trastuzumab. Non-small cell lung cancers with ALK translocations are sensitive to crizotinib, and chronic myeloid leukemias with BCR-ABL fusions respond well to imatinib.

Earlier research used polymerase chain reaction-based assays to probe the vitreoretinal lymphoma genome for IgH rearrangements and a single point mutation in the MYD88 oncogene.

Dr. Rao brought next-generation sequencing to the problem. Working with Scott Tomlins, MD, PhD, assistant professor of pathology and urology, University of Michigan, Dr. Rao analyzed vitreal samples from four patients with confirmed vitreoretinal lymphoma using a modified version of a panel currently used in the National Cancer Institute NCI-MATCH trial.

“We didn’t search for everything. We searched for actionable alterations,” Dr. Rao said. “Nearly every variant on this panel is linked to an agent that is either approved for other cancers or in development. The sensitivity of this assay is so high we could use as little as five nanograms of DNA in a 500 microliter sample.”

Initial results promising

Initial results promising

In addition to confirming a known MYD88 mutation, the group found a new mutation in MYD88 not yet linked to vitreoretinal lymphoma. All analyzed samples harbored copy number losses in the CDKN2A tumor suppressor gene, never before reported in vitreoretinal lymphoma. Some samples showed copy number losses in cancer-related genes PTEN and AKT1.

“There are already drugs being tested in cancers that contain alterations in these genes,” he said.

Clinical trials that enroll patients with vitreoretinal and CNS lymphomas harboring these genetic alterations are needed to determine whether these targeted agents may improve intraocular and/or CNS lymphoma outcomes.

“We are actively looking for collaborations with academic and private-practice retinal specialists, ocular oncologists, and pathologists to expand this work,” Dr. Rao said.

Panels can be used with undiluted and diluted fresh and frozen vitreous/retinal/choroidal samples, even samples that have been fixed and stored in paraffin for years.

The initial goal is to expand the findings using larger sample sizes. If the panel is shown to be highly sensitive and highly specific for vitreoretinal lymphomas that have been pathologically confirmed, the next step is look for lymphoma-associated genetic changes in samples with negative pathology but good cause for suspicion of cancer.

“We are trying to move this panel into a CLIA-certified environment to make it a useful clinical tool,” Dr. Rao said. “We want to do for vitreoretinal lymphoma what similar panels have done for other cancers.”

Rajesh C. Rao, MD

E: rajeshr@med.umich.edu

This article was adapted from Dr. Rao’s presentation during the Ocular Oncology and Pathology Subspecialty Day at the 2016 meeting of the American Academy of Ophthalmology. He has received grant support from the National Institutes of Health.