New Cancer Therapy Shows Promise to Treat a Rare Type of Lymphoma

A new treatment for cancer, called checkpoint inhibitors, are showing promise with several types of cancer, including a rare type of lymphoma, called gray zone lymphoma.

Immune checkpoint inhibitors are drugs produced by pharmaceutical companies that are often made of antibodies. Researchers are having success with these drugs in clinical trials focusing on various types of cancer.

They are used alone or in combination with other treatments, such as cancer treatment vaccines, to amplify the patient’s immune response.

What do these immune response drugs do?

Cancer cells often have proteins on them that appear to the immune system as representing normal, healthy cells. In this way, they block, or ‘deceive’ the immune responsive T-cells to leave the cancer cells alone.

Checkpoint inhibitors will block either these proteins, or the proteins found on the T-cells, in order to invoke an immune response on the cancer cell. They remove the immune system’s blinders to the cancer.

These proteins will typically keep the immune system in check by preventing overly intense responses, according to the National Cancer Institute.

About gray zone lymphoma

Lymphoma in general is a cancer of the immune system which exhibits uncontrollably dividing lymphocytes, or types of white blood cells.

There are many subtypes of non-Hodgkin lymphoma, so it is good to know about your subtype and what your treatment options are.

Gray zone lymphoma is such a rare type of cancer that is possible for a pathologist to not refer to it as gray zone lymphoma, because it is not a well-known disease.

There are no well-laid-out clinical characteristics or treatment plans for it, due to it being very rare and having been newly identified, according to the Genetic and Rare Diseases Information Center.

Because of the lack of information on this disease, it is wise to get a second opinion for diagnosis.

It can be easily misdiagnosed, and its signs and symptoms can be mistaken for other medical issues.

Some patients experience extreme itching as a symptom leading to diagnosis.

One patient was diagnosed as having scabies because of his itching. He was prescribed pesticide lotion to counter the itching.

After trying to eradicate his ‘scabies’ for several weeks, another doctor noticed his cough and gave him an x-ray which showed his tumors. He was finally given an accurate diagnosis of gray zone lymphoma.

Manali Kamdar, MD at the University of Colorado Cancer Center stated, “If you have a diagnosis of a rare subtype of lymphoma, it is pertinent to get a second opinion at an academic medical center to avoid misdiagnosis.”

Some doctors feel it should have a less benign name, as the disease itself can be quite aggressive and deadly.

It is named the gray zone because it has aspects of both primary mediastinal large B-cell lymphoma and classical Hodgkin’s lymphoma. Unfortunately, it is more aggressive than both.

No risk factors have yet been identified and the cause is unknown. As is the case for many cancers, certain genetic mutations have been implicated.

They say the average age of people who get this cancer of the lymph nodes is about 30; however, much older people are diagnosed with it also.

Patients with this disease many times experience breathing difficulties, chest pain, fatigue, fever, weight loss and appetite loss. In more advanced or severe cases, the heart and lungs may be afflicted.

Kamdar is Clinical Director of Lymphoma Services at the University of Colorado Hospital. She and colleagues led the treatment process in a study using checkpoint therapy on gray zone lymphoma.

The study results were so compelling that they were published in the New England Journal of Medicine.

An 80-year-old patient is treated

Kamdar said it was a “leap of faith” when they started using the drug on the study participant. The patient was an 80-year-old woman and had not responded to chemotherapy or radiation.

She had done 6 cycles of chemotherapy, and had started an older type of chemotherapy which was even tougher on her. Her body was just not tolerating it and the disease was progressing despite all the drugs.

Chemotherapy is only successful in about 50 percent of gray zone lymphoma cases.

Because of these unsuccessful and exhausting therapies, the patient felt she should either try this new therapy or realize that there were no more choices.

The oncologist did genetic testing on the patient’s tissue. She had over-expression of the protein PD-L1, the protein which blocks the immune system from targeting her cancer. The protein told her immune system’s cells not to attack the cancer cells.

The clinician was able to match the mechanism of the drug with the patient’s known molecular alterations.

The doctors started her on nivolumab, which is the generic name for the trade drug name Opdivo.

This checkpoint drug is already approved as a therapy for metastatic melanoma and has been used to treat renal cancer, Hodgkin disease and non-small cell lung cancer.

"Within one dose, she was in less pain and she looked much better," Kamdar said. A PET scan after six doses showed that the patient’s gray zone lymphoma was in complete remission.

This meant she was able to live longer and enjoy her family. She may live for months or years longer. The patient emphasized how important it was to her to have her family be so supportive during the whole process.

She has now been on nivolumab for 6 months and is still in remission.

Were there side effects?

The issue with this drug is that the immune system may attack other tissues that use that specific protein to protect themselves. So other organs may be at risk.

As a reaction to the drug, this patient developed pneumonitis when her immune system attacked her lungs. She also had an uptick in pancreas enzymes, causing high blood glucose levels, as well as some issues in her gut.

Her medical team has been able to address these issues. She treats her blood glucose problems with insulin and the pneumonitis was dealt with via prednisone on 2 different occasions. She had a nutritionist help her through her gut problems.

It is remarkable that she has come through this process after heavy doses of chemotherapy and radiation at such an advanced age, and stayed in remission of this aggressive cancer.

Her experience is the first successful use of immunotherapy in the gray zone lymphoma. This is the first step towards clinical trials, which could lead to the therapy being available to patients as a new treatment option.

Other successful cases

Two other patients were treated with a different but similar drug called pembrolizumab. They were treated at the National Institute of Health.

The first, an 18-year-old young woman, had been diagnosed with mediastinal gray zone lymphoma. She had a partial response to other cancer treatments, but her cancer was still progressing.

After treatment with the immunotherapy agent pembrolizumab, she showed a complete metabolic response, meaning the treatment worked just as it was intended to. Her positron-emission tomographic scan became normal.

Another patient, this time a 76-year-old man who had the same diagnosis, began treatment with pembrolizumab, and also went into complete remission. He too had experienced some success with prior treatment, but cancer had progressed anyway. After 381 days on the treatment he is still in remission.

These cases show early confirmation for using drugs that inhibit this particular protein, called PD-1, to encourage an immune response in gray zone lymphoma.

There are many more studies being done with the goal of the increasing immune response in cancer.

Immunotherapy, the treatment of diseases by stimulating an immune response, includes checkpoint therapy as well as other encouraging treatments.

Research is currently being conducted to:

• Determine why immunotherapy is effective in some people but not in others who suffer from the same cancer.
• Establish successful combinations of therapies and doses.
• Use immunotherapy on a wider variety of cancers.

FDA approval for a checkpoint drug

A checkpoint drug has been granted accelerated approval by the U.S. Food and Drug Administration (FDA) to treat classical Hodgkin lymphoma, as of May 14, 2017.

The Journal of Clinical Pathways has revealed that this approval came on the heels of a clinical trial with 210 adult participants with Hodgkin lymphoma. They had each had approximately 4 therapies previously.

After an average follow-up of 9.4 months, the overall response rate of Keytruda (pembrolizumab) was 69 percent. There was 22 percent of patients who experienced complete remission and 47 percent had partial remission of their cancer.

The drug had already been approved for melanoma, lung cancer, and head and neck cancer.

Treatment plans are changing

There have been other checkpoint inhibitors that have been approved for various cancers in the advancing field of immunotherapy.

With the kind of successes being seen in other cancers, this cancer therapy is looking like a potentially viable option for those suffering from gray zone lymphoma.

Clinical trials will need to come first, so safety and effectiveness can be confirmed with larger studies.

The medical community is very excited about the rapidly developing field of immunotherapy. Knowledge about checkpoint inhibitors, in particular, is growing quickly and on a day to day basis.