Immunotherapy Opens Up New Vistas in Rare Lymphoma

Checkpoint inhibitors, a form of immunotherapy, show promise in treating gray zone lymphoma, a rare form of lymphoma, according to three recent case reports.

Highlights:

Gray zone lymphoma is a very rare form of lymphoma that combines the characteristics of both Hodgkin’s Disease (HD) as well as non-Hodgkin’s lymphoma (NHL), two diseases with distinct pathogeneses.
Recent case reports in New England Journal of Medicine (NEJM) have suggested that treatment with checkpoint inhibitors such as nivolumab, pembrolizumab may be effective in gray zone lymphoma

Gray zone lymphoma, a rare form of lymphoma could respond to immunotherapy using checkpoint inhibitors, according to three case reports, one from University of Colorado Cancer Center using nivolumab, and two from the National Institutes of Health using pembrolizumab.

The Case Of Bobbie Flexer – Lack Of Response To Standard Lymphoma Treatments

Bobbie Flexer, an 80 year old retired mathematics education professor from CU Boulder, was diagnosed with mediastinal gray zone lymphoma, when her enlarged axillary lymph node biopsy demonstrated features combining the characteristics of both classical Hodgkin’s disease and mediastinal B-cell lymphoma (a subtype of non-Hodgkin’s lymphoma).
She was given conventional chemotherapy for B-cell lymphoma, namely the R-EPOCH regimen combining the antibody Rituximab along with four other agents. However, a post-chemotherapy PET-CT scan indicated disease progression.

"Given Bobbie's age and her resistance to chemotherapy it was difficult to simply increase her dose. Bobbie's tumor biopsy expressed a protein called CD30 and so we started her on brentuximab, which targets these CD30 cells," says, Manali Kamdar, MD, investigator at the CU Cancer Center and Clinical Director of Lymphoma Services at University of Colorado Hospital. Kamdar joined the Center in fall 2014 to establish the lymphoma program.

Unfortunately brentuximab was also not effective prompting the use of yet another chemotherapy regimen, namely gemcitabine with oxaliplatin.

However, Bobbie did not tolerate this regimen very well and in addition, a CT-PET scan again showed progression of disease, forcing the discontinuation of this treatment as well.

Presence Of PD-L1 Overexpression – Another Possible Treatment Target

In most situations, perhaps not always incorrectly, the physician would likely have recommended palliative management, given the age of the patient, and the possible side effects and toxicities of increasing the dose of available chemotherapy agents. The palliation would keep the patient comfortable and pain free without any active treatment of the disease per se.

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‘The success of checkpoint inhibitors in gray zone lymphoma paves the way for further trials to test these drugs in this particular condition, as well as similar conditions.’

However, Dr Kamdar did not give up, especially as Bobbie was an active and fit lady in spite of her age, before the diagnosis, and a fighter to the core.

"At that point, I knew that one recommendation was, 'Oh gosh, she's 80 years old, don't do anything. But Dr. Kamdar had to come up with something new," Bobbie says.

Genetic testing of Bobbie’s tumor cells showed that they were showing increased expression of PD-L1, which prevented the immune system from attacking the tumor.

This gave Dr Kamdar the idea to try out another angle of treatment, namely to try and use checkpoint inhibitor nivolumab, that targeted the overexpression of PD-L1 on the tumor cells.

Nivolumab Trial

Before the trial of Nivolumab, it was clearly explained to the patient and her family that nivolumab had never been used in gray zone lymphoma before. There was no data regarding its use in elderly patients or its safety profile in persons with gray zone lymphoma. It was more likely a last-ditch effort before giving up and suggesting palliation.

"This was a new drug and Dr. Kamdar explained very thoroughly that it would be an off-label use. She made it clear there aren't a lot of data where I am," Bobbie says. "Still, she thought it might be worth a try. We went for it."

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"For me, trying nivolumab was a binary choice: I could try the drug or I could give up," says Bobbie, who had not improved after multiple rounds of chemotherapy and radiation therapy.

Results Of The Nivolumab Trial

Within one dose of Nivolumab, Bobbie started to feel better and after six doses, a check CT-PET scan showed the disease to be in remission.

"It was a leap of faith when we started the drug," says Kamdar She explains that there are about 100 different types of lymphoma, one of which is gray zone lymphoma.

However the treatment was fraught with side effects including lung inflammation, that was treated with prednisolone and increased blood glucose levels managed with insulin.
Following a short drug holiday due to the side effects, Bobbie is back on Nivolumab and has now taken it for almost six months and is doing well.

Two More Success Stories With Checkpoint Inhibitors

Following Bobbie Flexer’s dramatic response, Dr Kamdar decided to report this case in the reputed medical, The New England Journal of Medicine.

Interestingly, the journal had just then received two similar case reports from the National Institutes of Health, that had employed the related immune therapy pembrolizumab to target the same condition in a similar manner. These included an 18 year old woman and a 76 year old man with a similar diagnosis of mediastinal gray zone lymphoma.

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Dr Kamdar opines that either of these reports submitted alone may not have received attention, but the separately recorded reports around the same time, raised the possibility of a new treatment strategy for gray zone lymphoma.

Mechanism Of Action Of Checkpoint Inhibitors

When the PD-L1 protein is displayed on the tumor cell, the host immune T cells surface protein PD-1 interacts with the PD-L1 and turns off the immune response against the tumor cell, preventing its destruction.

Nivolumab blocks PD-L1 from binding to PD-1 (inhibits this checkpoint) thus overcoming the immune system's blinders to cancer.

The drug is approved as a first-line therapy for metastatic melanoma, non-small cell lung cancer, renal cancer and Hodgkin disease. It had not previously been used to treat gray zone lymphoma.

The results do suggest that mediastinal gray zone lymphoma may share more characteristics of HD than NHL and the importance of accurate pathological diagnosis in determining lymphoma treatment.

In conclusion, these case reports highlight how an astute physician can correlate identified genetic mutations in lymphomas to treatments that target these mutations, notwithstanding the fact that they have never been used for that condition before, opening up new treatment vistas and offering hope to countless patients and their families in the future.

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