Chemotherapy has been the backbone of treatment for both untreated and relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). But treatment paradigms for cHL are changing. Immunotherapies that unmask cancer cells and make them vulnerable to our immune system, called immune checkpoint inhibitors (ICIs), were recently approved for relapsed and refractory cHL. Examples include PD-1 inhibitors such as nivolumab and pembrolizumab.
Now data is showing that these drugs can improve outcomes for newly diagnosed patients. In June 2023, clinical researchers presented the results of a randomized phase 3 clinical trial for patients with newly diagnosed Hodgkin lymphoma. They found that the addition of nivolumab to chemotherapy had better results for patients compared with current standard therapy with brentuximab vedotin and chemotherapy.
The National Comprehensive Cancer Network (NCCN) guidelines have not yet been changed to reflect an update in standard first-line therapy for the disease, but if these results are maintained with longer follow-up, the guidelines will likely change.
“In a year or two, I suspect that many patients will receive anti-PD-1 therapy as part of initial therapy,” says Reid Merryman, MD, an oncologist in the Adult Lymphoma Program at Dana-Farber Cancer Institute.
More patients will likely be cured with these therapies, but some patients will still relapse. But what will doctors turn to for patients who have already been treated with an ICI?
“At Dana-Farber, we have multiple clinical trials that could be good options,” says Merryman.
A trial to postpone or avoid transplant
For patients who are relapsing for the first time but are reluctant to pursue a stem cell transplantation, Dana-Farber offers a phase 2 trial that combines brentuximab vedotin with nivolumab, an anti-PD-1 checkpoint inhibitor. The study is led by Philippe Armand, MD, PhD, chief of the Division of Lymphoma at Dana-Farber. The goal of the trial is to determine if there are patients who can be cured in a second line setting without a stem cell transplant.
Eligible patients are those who have classical Hodgkin lymphoma that has come back after initial treatment (relapsed) or has not responded to initial treatment (refractory). Patients can enroll even if they received brentuximab vedotin or a PD-1 inhibitor as part of initial therapy, provided that their last dose of these agents was at least 6 months earlier.
“This is an attractive trial for older patients, such as patients over 60, for whom you are more reluctant to pursue a transplant due to the potential for significant side effects,” says Merryman. “It’s also a good trial for patients who want to avoid or delay a transplant.”
Trials of ICI combinations to overcome immune evasion
For patients who have had anti-PD-1 therapy and relapsed, there are several trials that are exploring combinations of ICIs that target a range of immune checkpoints. Immune checkpoints are signaling pathways that prevent immune cells from killing healthy cells. But cancer cells often use these checkpoints in ways that enable them to evade immune detection.
PD-1 is one checkpoint exploited by Hodgkin lymphoma cells to evade immune destruction. Anti-PD-1 therapy unmasks the cancer cells and releases the brakes on the immune system. In early clinical studies, about 70% of patients with relapsed/refractory disease responded to treatment with anti-PD-1 therapy on its own.
Researchers have since found that Hodgkin lymphoma cells exploit other checkpoints used by T cells, including CTLA-4 and TIM-3. They also exploit the CD47 checkpoint on macrophages, white blood cells that eat and digest cancer cells and other pathogens.
Dana-Farber is offering three clinical trials that are investigating whether combining immune checkpoint inhibitors to release the brakes on the immune system in more than one way could be effective.
“Anti-PD-1 therapy works for many patients, but it might not work forever or for everyone,” says Merryman. “If we target two different signals that are allowing the Hodgkin lymphoma cell to evade the immune system, we think we can have better results.”
The trials include:
- A phase 2 study of magrolimab, an anti-CD-47 agent, with pembrolizumab, a PD-1 inhibitor, in patients with Hodgkin lymphoma. Magrolimab is an ICI that disables CD47, the “don’t eat me” signal some cancer cells use to avoid macrophages. Once unmasked, the cancer cells become visible and vulnerable to these cells.
Patients are eligible whether they have had previous anti-PD-1 therapy or not, though if they have had anti-PD-1 therapy, they must be six months out from their last dose. This trial is led by Merryman in collaboration with Stanford University.
- A phase 1/2 trial of a novel bispecific antibody for patients with relapsed or refractory Hodgkin lymphoma. This trial, led by Armand, is investigating the safety and efficacy of an agent that blocks both PD-1 and TIM-3 checkpoints simultaneously. This trial is also open to patients who have had previous anti-PD-1 therapy but no prior anti-TIM3 therapy.
“Both of these trials would be good options for a patient who relapsed after a transplant or who is not eligible for a transplant and needs a treatment option,” says Merryman.
- A third combination immunotherapy study is a phase 2 trial of ipilimumab with and without nivolumab in patients with relapsed or refractory classic Hodgkin lymphoma. Ipilimumab is an anti-CTLA-4 immune checkpoint inhibitor.
Research by Dana-Farber scientist Scott Rodig, MD, PhD, and colleagues found that Hodgkin lymphoma cancer cells exploit the CTLA-4 checkpoint on T cells, perhaps even more frequently than it exploits the PD-1 checkpoint. This finding provides the rationale for the ipilimumab trial. The trial, led by Merryman, currently has limited slots open.
Navigating decisions about stem cell transplant
Patients who relapse after stem cell transplant or who are ineligible for a transplant could benefit from a referral to Dana-Farber. The clinical trials listed above could be promising options. Our team can discuss treatment options with patients who may be considering a stem cell transplant or a clinical trial.
“These questions can be challenging to navigate,” says Merryman. “A referral to Dana-Farber can help patients navigate their options and find the best path forward.”
If you have questions about a clinical trial, contact our Clinical Trials information line at 877-338-7425.
About the Medical Reviewer
Dr. Merryman received his undergraduate degree from the University of Notre Dame and his medical degree from Harvard Medical School. He completed residency training in internal medicine at Brigham and Women's Hospital and fellowship training in hematology and oncology at Dana-Farber/Partners Cancer Care. He is an attending physician in the Lymphoma Program at Dana-Farber Cancer Institute. His research focuses on the development of immune-based therapies for patients with lymphoma.