‘Accelerated’ pace of targeted agent discovery in non-Hodgkin lymphoma spurs excitement
Click Here to Manage Email Alerts
Oncologists who treat non-Hodgkin lymphoma have increasingly become reliant on targeted treatment, with several new agents receiving FDA approval within the past 5 years.
Perhaps the best example of a non-Hodgkin lymphoma that has been increasingly treated with targeted therapy is mantle cell lymphoma, Brian T. Hill, MD, PhD, director of the lymphoid malignancies program and staff physician at Cleveland Clinic Taussig Cancer Institute, said during an interview with Healio.
“For patients with mantle cell lymphoma, [Bruton tyrosine kinase] inhibitors are preferred and best-in-class of targeted therapies in particular in the second line or beyond among those who have relapsed disease,” Hill continued.
The three currently approved and available targeted agents for mantle cell lymphoma are ibrutinib (Imbruvica; Pharmacyclics, Janssen), acalabrutinib (Calquence, AstraZeneca) and zanubrutinib (Brukinsa, BeiGene).
“These three agents have a high degree of activity and generally have favorable safety profiles,” Hill said. “We also have the option of [chimeric antigen receptor] T-cell therapy for mantle cell lymphoma, which might differ from traditional targeted therapies, but it is important to note that CAR T-cell therapy has now been approved for mantle cell lymphoma.”
Other types
In terms of the other non-Hodgkin lymphomas, chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia [SLL] are grouped together into the broad class of B-cell non-Hodgkin lymphoma, for which BTK inhibitors are used.
“For these patients, targeted treatment with BTK inhibitors have truly revolutionized treatment and are commonly used in the first-line setting,” Hill said. “The other targeted agent that is active and frequently used in both the front-line and second-line setting for CLL/SLL is the Bcl-2 inhibitor venetoclax [Venclexta; Genentech, AbbVie], which is typically used in combination with an anti-CD20 monoclonal antibody.”
As for the most common type of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, Hill said these patients for the first time in a long time have targeted therapies that were not available as of only a couple of years ago. “We have the option of CAR T-cell therapy for patients with relapsed diffuse large B-cell lymphoma that is now being used in the second-line setting.”
“Now there also are several no-cellular therapies for these specific patients, including polatuzumab vedotin [Polivy, Genentech], which is an antibody drug conjugate targeting CD79B,” he said. “It works very well in combination with chemoimmunotherapy in the relapsed setting and may soon be used in the front-line setting.”
Other antibody-drug conjugates include loncastuximab tesirine (Zynlonta, ADC Therapeutics), which targets CD19, and tafasitamab (Monjuvi, MorphoSys AG) —ahumanized Fc-engineered monoclonal antibody that is also directed against CD19.
“Tafasitamab is used most often in combination with lenalidomide [Revlimid, Celgene],” Hill said.
Adverse events
Similar to any other treatments, targeted therapies for non-Hodgkin lymphoma are associated with adverse events.
“However, in contrast to traditional chemotherapy treatment, the benefit of targeted therapies is that they are generally not associated with a significantly high rate of myelosuppression,” Hill said.
Some of the adverse events associated with these agents are class-specific.
“For example, covalent BTK inhibitors are associated with atrial fibrillation and other cardiovascular side effects that vary with each drug class and is something that is unique to this class of drug,” Hill said. “Similarly, neuropathy has been observed with some of the antibody-drug conjugates, such as polatuzumab vedotin. We also see this with some of the chemotherapies, but not all.”
Regarding CAR T-cell therapy, Hill said some of the associated adverse events may require hospitalization or very close outpatient monitoring daily.
“This can sometimes be a barrier to treatment as it requires a significant investment of time from patients,” he added. “Some of the other agents also have adverse events in terms of resistance, much like all the other cancer therapies that have come before — we know that resistance can develop with targeted therapies.”
Point mutations in BTK is also a well-characterized disease.
“These BTK point mutations render the covalent binding of ibrutinib, acalabrutnib and zanubrutinib to be unable to bind and inhibit the function of BTK,” Hill said. “In this setting, there is a new class of agents under development, known as noncovalent BTK inhibitors,’” Hill said. “The most well-developed of these is pirtobrutinib (LOXO-305; Eli Lilly, Loxo Oncology), which is an oral noncovalent BTK inhibitor that is very active in mantle cell lymphoma as well as CLL/SLL, including for those patients who develop resistance to covalent BTK inhibitors.”
On the horizon
The future of the targeted treatment landscape for patients with non-Hodgkin lymphoma appears bright, according to Hill.
“The targeted agents that are the most promising class of agents in the non-Hodgkin lymphoma space are bispecific antibodies,” Hill said. “This is a class of several new agents, which engage T cells to bring them in proximity of target malignant B cells by binding to CD20 on the target cells, which leads to immune-mediated cellular cytotoxicity by the T cells. These agents are administered either via IV or subcutaneously on an ongoing basis.”
Although there have been low rates of mild cytokine release syndrome with these agents, tolerability appears promising and they are clinically active in heavily pretreated patients with various B-cell non-Hodgkin lymphomas, Hill added.
“The pace of discovery for targeted agents in non-Hodgkin lymphoma has truly accelerated tremendously in recent years,” Hill said. “However, with new anticipated approvals of additional classes of therapeutic agents, it is increasingly challenging for practicing oncologists, particularly in the community setting where they may not be seeing a significant amount of patients with relapsed or refractory non-Hodgkin lymphomas.”
“It may become increasingly difficult to stay up to date on all of these developments,” he continued. “This is why partnerships are beneficial for both the clinician and patient in which opinions can be sought from specialist academic centers and then treatments may be better delivered into the community.”
For more information:
Brian T. Hill, MD, PhD, can be reached at hillb2@ccf.org.
Collapse
Click Here to Manage Email Alerts