Novel Agents Continue to Transform Lymphoma Treatment

Gilles A. Salles, MD, PhD

While a number of active therapies are available to treat lymphoma, several new agents have been approved for this setting. There is a critical need to increase awareness of how these new agents fit into everyday practice and to discuss endpoints and goals of treatment.

At the 2015 ASCO Annual Meeting, physicians discussed some of the newer agents and described their personal experience with using them during a session called, “Incorporating Novel Agents Into Lymphoma Therapy: Value in Everyday Practice.”

Gilles A. Salles, MD, PhD, from the Hospices Civils de Lyon, Université Claude Bernard, discussed treatment regimens being developed for follicular lymphoma (FL).

Following the success of rituximab (Rituxan), several failed attempts at developing anti-CD20 antibodies have been made. Salles said that results from a phase II study of ofatumumab (Arzerra) in patients with rituximab-refractory FL were disappointing, with an overall response rate (ORR) of only 11%. A head-to-head study of rituximab versus obinutuzumab (Gazyva) showed no difference. Antibodies against other target proteins—CD22, CD80, CD74, and CD37—are also being developed, Salles noted.

A characteristic of FL, said Salles, is a defective immune response in tumors; specifically, tumor-infiltrating lymphocytes from FL have an impaired synapse formation. Treatment with lenalidomide (Revlimid) and IMiDs can eliminate this effect.

Using lenalidomide as a single agent in patients with relapsed/refractory FL resulted in a 27% ORR and a 9% complete response (CR) rate, said Salles; however, the treatment can cause neutropenia and may require a dose reduction of lenalidomide. Other commonly encountered side effects include rash, pain, and fatigue. A combination trial that evaluated lenalidomide and rituximab as frontline therapy in FL has yielded much better results: 98% ORR, with 85% of patients reaching CR and 13% of patients having a partial response.

Regarding immune checkpoint inhibition, Salles said that when the anti—PD-1 agent pidilizumab was combined with rituximab in FL, more than 50% of patients achieved ORR, which he described as very encouraging.

Some other signaling pathways being targeted in FL include PI3K and BTK, and inhibitors against these molecules are under clinical development. For example, Salles said that the PI3K-delta inhibitor idelalisib (Zydelig) demonstrated rapid, durable responses and acceptable safety in patients with highly refractory/relapsed FL in a phase II study. ORR was 56%, CR was 6%, and duration of response was 12.5 months. The most common adverse events were diarrhea, cough, pyrexia, fatigue, and nausea.

In everyday practice, however, Salles recommended caution when using these agents as first-line therapy. There are several options that can present good quality-of-life for patients, he said, adding that radiation is still an option for localized disease. But toxicity and the cost of these agents should be considerations when patients have a low tumor burden. For patients with a high tumor burden, he said, R-CHOP with chemotherapy is used.

Among relapsed/refractory patients, autologous and allogenic transplant is an option for younger patients, while for others, chemotherapy-free regimens are a definite option.

In a separate section of the presentation, Stephen M. Ansell, MD, PhD, professor of Medicine at the Mayo Clinic in Minnesota, discussed agents being developed for the treatment of Hodgkin lymphoma (HL). He began his talk on a very encouraging note, saying, “These are exciting times for Hodgkin lymphoma.”

HL, said Ansell, has a unique histology that provides multiple targeting options: signaling pathways, cell surface receptors, intratumoral immune cells, and intratumoral cytokines.

Ansell discussed use of the antibody-drug conjugate brentuximab vedotin (Adcetris) for the treatment of patients with HL. Brentuximab is currently approved by the FDA for the treatment of patients with HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not candidates for ASCT. The FDA has also granted a priority review to brentuximab as a consolidation therapy following ASCT in patients with HL at risk of relapse or progression. A final decision on this indication is scheduled by August 18, 2015.

Several studies have demonstrated the efficacy of brentuximab in patients with HL. One study found that brentuximab treatment resulted in 75% ORR and 34% CR, and the treatment was reasonably well tolerated. When brentuximab was incorporated into the ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) regimen a durable response rate was observed, and progression-free survival was about 80%, which is quite promising.

Use of anti—PD-1 agents is also a promising treatment approach in HL, said Ansell. Using nivolumab (Opdivo) in patients with HL resulted in a 70% PR and 17% CR. Overall, Ansell noted, nivolumab was well tolerated and a durable response was observed. When the PD-1 inhibitor pembrolizumab (Keytruda) was evaluated in a small study with 29 patients, the majority of patients had a good and durable response.

Ansell also discussed a few other promising agents being evaluated in the clinic, such as the HDAC inhibitor panobinostat (LBH589), which yielded an ORR of 27%.

“Multiple new approaches have promising activity in HL patients,” said Ansell. “The future, though, is in the use of combination treatment with standard chemotherapy.”