Treatment Update for Hodgkin Lymphoma

Over time, research has uncovered ways of treating Hodgkin lymphoma (HL) to produce an 80% to 90% cure rate. For the remaining 10% to 20% who are either resistant to the primary treatment or have relapsed, their cancer can still be fatal.

The standard care for those not yet cured has been a two-step process. First, the person with persistent HL receives what is referred to as salvage (or rescue) therapy.

Salvage therapy uses a combination of antiviral meds to suppress the resistant virus blocking the desired effects of the chemotherapy.

Then, the person receives an ‘autologous stem cell transplant’ (ASCT), using their own blood-forming stem cells.

With this intervention, approximately 50% enter prolonged remission.

“However, for patients who relapse within 3 to 6 months of ASCT, outcomes are “dismal”, revealed Ranjana H. Advani, M.D., of the Stanford Cancer Institute.

For this uncured ‘remnant’, research into other possible treatments has been ongoing.

Because of these studies, there are many new drugs researchers have been testing.

The results of a recent HL medication study bring encouragement to the medical field and also to those still struggling with the disease.

Drug treatments being researched for Hodgkin lymphoma

Among the pharmacologicals being tested include brentuximab vedotin (Adcetris), categorized as an antibody-drug conjugate (ADC).

According to Wikipedia, ADCs are a “class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of people with cancer; unlike chemotherapy, ADCs are intended to target and kill only the cancer cells and spare healthy cells.”

Biopharmaceutical drugs like Adcetris are manufactured products derived from ‘life forms’. (The first such drug approved for therapeutic use was in 1982: recombinant human insulin, trade name Humulin.)

Proposed uses for adcetris

Adcetris (brentuximab) was tested with 34 people who relapsed after their unsuccessful autologous stem cell transplants; 13 participants (38%) have been in complete remission for more than 5-years, and may be cured.

Brentuximab (Adcetris) has consequently been approved by the FDA for:

• Hodgkin lymphoma after failure of ASCT
• Failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates
• Treatments of patients at high risk of relapse
• Disease progression post-ASCT consolidation

Researchers also suggest the use of brentuximab as maintenance therapy for those with high-risk HL.

This suggestion comes after results of a study called the AETHERA trial.

Brentuximab and the AETHERA trial

In the AETHERA trial, entitled “A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant”, the purpose was “to evaluate the efficacy and safety of brentuximab vedotin (SGN-35) in the treatment of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT).”

The study is sponsored by Seattle Genetics. There are 329 enrolled participants. The research project began in 2010 and is ongoing.

In this study, consolidation with brentuximab after ASCT improved progression-free survival in Hodgkin lymphoma patients. (The term consolidation means “a therapy is used to kill any cancer cells that may be left in the body. It may include radiation therapy, a stem cell transplant, or treatment with drugs that kill cancer cells. It’s also referred to as intensification therapy and postremission therapy”.)

"The rate of 2-year progression-free survival was 65% with brentuximab vs 45% with placebo."

More clinical information on brentuximab

“Maintenance brentuximab is a reasonable approach in brentuximab-naive patients following ASCT, in selected high-risk patients,” said Dr. Advani.

In addition, Dr. Advani said, “Given its favorable toxicity profile and high efficacy in the posttransplant setting, brentuximab is an appealing candidate for consideration in first-line salvage therapy”.

Dr. Asco also spoke of current studies combining brentuximab with various chemotherapy regimens with some receiving high response rates.

The goal is to “see whether complete remission rates can be improved beyond brentuximab or chemotherapy alone.” However, as she noted, results will not be final for these attempts until the completion of randomized trials.

Testing the effectiveness of immune checkpoint inhibitors in lymphoma treatment

Immune checkpoint inhibitors are drugs, often made of antibodies, that unleash an immune system attack on cancer cells.

In the immune system, ‘T-cells’ are designated the function of attacking any infectious or cancerous cells in the body. Once they attack, a call goes out for other immune system cells to join with them.

In response, the body creates molecules to go to the defense of healthy cells. These molecules are referred to as ‘checkpoints’.

However, everything can become discombobulated by the cancer cells ‘outsmarting’ the T-cells by hiding within the molecules of normal cells, causing the T-cells to attack healthy cells as well.

Immune point inhibitors are designed to block the PD-L1 proteins to prevent this onslaught.

Dana-Farber’s Gordon Freeman, PhD led the lab that discovered the OD-L1 protein that resides on normal cells as well as some cancer cells, and that blocking it can provoke an immune system attack on tumors.

We are informed that checkpoint inhibitors are demonstrating exceptional success in the treatment of HL.

High response rates of immune point inhibitors in the treatment of HL

Checkpoint inhibitors have been shown to interfere with the proteins responsible for the massacre of healthy cells by cancer. These inhibitors intercept the process so that T-cells can appropriately identify and attack cancerous cells.

Two such medications recently approved by the FDA are Opdivo and Keytruda.

In a recent Hodgkin Lymphoma phase II trial, enrolled participants were some who failed to respond to both ASCT and brentuximab.

Results showed a 6-month progression-free survival of 76.9% with Opdivo. Similar results were seen in those with:

• Prior ASCT and brentuximab treatment
• ASCT-ineligible patients who failed to respond to salvage therapy and brentuximab
• Brentuximab-naive patients with prior ASCT

Keytruda demonstrated an overall response rate of 69.0% across all participants.

What are the implications for the treatment of Hodgkin lymphoma?

According to The Asco Post:

• Checkpoint inhibitors are effective and approved for relapsed Hodgkin lymphoma following ASCT and brentuximab vedotin
• The era of post–brentuximab vedotin therapies is rapidly developing
• Novel salvage approaches show a high overall response rate, but their optimal use depends on resources
• Targeted treatments that exploit certain genetic abnormalities may improve therapies, especially for older patients and for those with other serious medical conditions

Additionally, Brentuximab (Adcetris) has been approved by the FDA for use as outlined previously in this article.

It’s apparent there’s a new day dawning in the treatment of Hodgkin lymphoma.

According to Andrew D. Zelenetz, MD, PhD, Medical Director of Quality Informatics at Memorial Sloan Kettering Cancer Center, “We have a lot of new agents in Hodgkin lymphoma, but if we’re really going to make advances in the front-line setting, we need biomarkers to identify the 20% to 25% of patients who are going to do poorly for an intervention,” Dr. Zelenetz concluded. “That’s the major challenge we have today.”

References

http://www.ascopost.com/issues/november-25-2017/new-options-for-the-management-of-hodgkin-lymphoma/

https://www.cancer.org/cancer/hodgkin-lymphoma/about/new-research.html

https://www.cancer.net/cancer-types/lymphoma-hodgkin/latest-research

https://www.healthline.com/health/hodgkins-lymphoma

https://clinicaltrials.gov/ct2/show/NCT01100502

https://www.cancer.net/blog/2017-02/immunotherapy-20-2017-clinical-cancer-advance-year

http://blog.dana-farber.org/insight/2015/09/what-is-a-checkpoint-inhibitor/

https://www.gene.com/stories/understanding-pd-l1