Research Shows Promise for Directing Later Lines of Therapy for Hodgkin Lymphoma

New therapies have improved outcomes for patients in frontline treatment for Hodgkin lymphoma, and research now is addressing how subsequent therapies can meet needs of patients who progress after early lines of treatment.

“When a patient has progressed through chemotherapy…they’ve had a stem cell transplant, they’ve had brentuximab vedotin [Adcetris®; Seagen] and they’ve had PD-1 blockade, [physicians] are unsure of what treatments are available,” Alex F. Herrera, MD, associate professor in the Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation at City of Hope in Duarte, California, said in an interview with The SOHO Daily News before the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

Most patients with Hodgkin lymphoma can be cured by chemotherapy and radiotherapy, but the 20% to 25% of patients who do not respond can be as difficult to treat as those with other cancers, says Herrera. This means reducing the number of patients who relapse is crucial. Two major breakthroughs in this setting have been the introduction of brentuximab vedotin and PD-1 blockade, both of which have advanced to being used in the early lines of therapy in the United States. “As the standard becomes using novel agents like brentuximab vedotin in frontline therapy, and maybe someday PD-1 blockade in frontline therapy, it even makes this a more pressing need to find therapies that work after a patient has progressed on those therapies,” Herrera says.

Herrera’s presentation at SOHO 2022 discusses approaches to subsequent therapy for patients who have received brentuximab vedotin and PD-1 blockade. He says that although they have improved the outcomes of patients with Hodgkin lymphoma, patients who are not cured by initial therapies are now often resistant to these treatments as well. More durable responses are also needed for those who do benefit from these therapies, since it is a minority of patients who will have a long-term durable response from these immunotherapies when they are used alone.

“Hodgkin lymphoma is a disease that typically affects younger patients,” says Herrera. “If a patient is resistant to therapy, our goal is to be able to not just get a patient in response, but [to keep] a patient in response for as long as we can.”

A wide range of options could offer survival benefit to patients with relapsed disease. Because few new agents have been approved for patients with relapsed disease after brentuximab vedotin and PD-1 blockade, clinical trials play a major role in offering patients the best available care.

Emerging Therapies

New agents such as antibody-drug conjugates (ADCs) could offer a next-line approach. Whereas brentuximab vedotin targets CD30, camidanlumab tesirine (ADCT-301) is another ADC that targets CD25, which is also located on or around Hodgkin lymphoma cells. A phase 2 trial (NCT04052997) is investigating this ADC in patients who previously received brentuximab vedotin and an anti–PD-1 agent.

Extending the length of benefit from anti–PD-1 agents and overcoming resistance to immune checkpoint inhibitors is an important area of investigation due to the major role anti–PD-1 agents now play in treating Hodgkin lymphoma. One potential approach is combining PD-1 blockade with an epigenetic-based or other targeted therapy. These include hypomethylating agents such as decitabine and azacitidine as well as histone deacetylase inhibitors such as vorinostat (Zolinza®; Merck) and entinostat.

A study conducted in China (NCT03250962, NCT02961101) showed a significantly longer duration of response and favorable efficacy with the addition of decitabine to the anti–PD-1 agent camrelizumab for patients with Hodgkin lymphoma who were PD-1 naïve as well as those who were resistant to prior anti–PD-1 therapy.1,2 Herrera is helping lead a similar study (NCT05162976) at City of Hope evaluating azacitidine plus nivolumab (Opdivo®; Bristol Myers Squibb) to assess how a hypomethylating agent can improve response to immunotherapy. He is also the principal investigator of a phase 1 study (NCT03150329) of vorinostat (Zolinza®; Merck) combined with pembrolizumab (Keytruda®; Merck) in patients with Hodgkin lymphoma and other lymphoma types.

Herrera says targeted therapy that can extend the duration of benefit from immunotherapy would be an ideal approach in patients with low disease burden or fewer symptoms, because they are not in need of a fast-acting regimen and can benefit from the greater tolerability of immunotherapy. “When a patient is resistant to immunotherapy, if we can re-sensitize them with something that’s reasonably well tolerated and get them another year or two of response, [and] buy them that time, that might be a valuable option,” he says.

For patients with higher disease burden who are more heavily symptomatic, chemotherapy may be the best approach to get a strong, rapid response. Research has also shown that PD-1 blockade can cause patients to become more sensitive to subsequent treatments,3 meaning chemotherapy could be used in combination with immunotherapy or afterward in patients who previously progressed on therapies such as the ABVD combination regimen (doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine).

Drugs already in use such as lenalidomide (Revlimid®; Bristol Myers Squibb), everolimus (Afinitor®; Novartis), and temsirolimus (Torisel®; Pfizer) can also have a role as subsequent therapies when patients need to achieve a strong anticancer response to improve their outcomes, according to Herrera.

Cellular Therapies

Cellular therapies such as chimeric antigen receptor (CAR) T-cell therapy have made an impact in non-Hodgkin lymphoma and other hematologic malignancies, providing long-term durable remissions in many patients who had few options remaining. Herrera says CD30-targeted CAR T-cell therapies are promising for Hodgkin lymphoma, although they are not yet approved, and several CAR T-cell trials such as the phase 2 CHARIOT study (NCT04268706) are under way. A lingering question for him is whether CAR T-cell products will lead to durable responses in the relapsed population that is resistant to chemotherapy, immunotherapy, and CD30-targeted ADCs.

Herrera says he and his colleagues look for patients who may benefit from trials of cellular therapies that evaluate CAR T cells or natural killer T cells that can result in a durable response. “We are trying to refer patients [to trials] or give patients these types of cellular therapies when they are available,” he said.

Although the advances in the field have deemphasized the need for patients to receive an allogeneic stem cell transplant, Herrera anticipates it may still have a role as survival is now extended for patients who now may receive 5 or more prior lines of therapy. “Four or 5 years later, then you have all these patients who are now progressing on these later-line therapies and they need something else,” he says. “I think understanding the role allogeneic stem cell transplant may play is…a bit of an unresolved question that probably is going to need to be explored again.

“There is a range of options available to patients. There’s a lot of drug development happening. And I think that early results are promising and exciting,” Herrera says. “My talk is about just opening that door and showing folks that there’s a lot out there that we’re studying and that is possible.”

_REFERENCES:

_{1. Nie J, Wang C, Liu Y, et al. Addition of low-dose decitabine to anti-PD-1 antibody camrelizumab in relapsed/refractory classical Hodgkin lymphoma. J Clin Oncol. 2019;37(17):1479-1489. doi:10.1200/JCO.18.02151}

_{2. Liu Y, Wang C, Li X, et al. Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma. J Immunother Cancer. 2021;9(4):e002347. doi:10.1136/jitc-2021-00234}

_{3. Rossi C, Gilhodes J, Maerevoet M, et al. Efficacy of chemotherapy or chemo-anti-PD-1 combination after failed anti-PD-1 therapy for relapsed and refractory Hodgkin lymphoma: a series from Lysa centers. Am J Hematol. 2018;93(8):1042-1049. doi:10.1002/ajh.25154}