Choosing the Ideal Lymphoma Regimens

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 end points and goals of treatment. On the first day at the annual meeting of the American Society of Clinical Oncology in Chicago, physicians introduced some of the newer agents and described their personal experience with using them during the session, “Incorporating Novel Agents Into Lymphoma Therapy: Value in Everyday Practice.”

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

Following the success of rituximab, several failed attempts at developing anti-CD20 antibodies have been made. Salles said that a phase 2 study of ofatumumab in rituximab-refractory FL patients was conducted, but the overall response rate (ORR) was disappointing, with only 11% of patients responding. A head-to-head study of rituximab versus obinutuzumab (GA101) showed no difference, he explained. Antibodies against a few other target proteins—CD22, CD80, CD74, and CD37—are also being developed, he added.

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

Using lenalidomide as a single agent in patients with relapsed refractory FL resulted in 27% ORR and 9% complete response (CR), 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% patients reaching CR and 13% patients having a partial response.

Introducing the most sought after agents in oncology, Salles said that T-cell activity can be blocked by inhibiting the PD-1/PD-L1 interaction. When the anti-PD-1 monoclonal antibody 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, he showed, include PI3K and BTK, and inhibitors against these molecules are under clinical development. For example, Salles showed that idelalisib, which inhibits PI3K-d, demonstrated rapid, durable responses and acceptable safety in highly refractory, relapsed FL patients in a phase 2 study. ORR was 56%, CR was 6%, duration of response was 12.5 months, and 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.

To discuss Hodgkin lymphoma (HL) and agents developed to treat the condition was Stephen M. Ansell, MD, PhD, professor of medicine at the Mayo Clinic in Minnesota. He began his talk on a very encouraging note, saying, “These are exciting times for Hodgkin lymphoma.”

HL, said Ansell, has a unique histology which provides multiple targeting options: signaling pathways, cell surface receptors, intra-tumoral immune cells, and intra-tumoral cytokines.

Some of the novel agents currently being evaluated in the clinic, he said, include the monoclonal antibody brentuximab vedotin. One study found that brentuximab vedotin treatment resulted in 75% ORR and 34% CR, and the treatment was reasonably well tolerated. When brentuximab vedotin was incorporated into the A(B)VD (Adriamycin, bleomycin, vinblastine, dacarbazine) regimen—a first-line chemotherapy regimen used in HL—a durable response rate was observed, and progression free survival was about 80%, which is quite promising.

Use of PD-1 agents is a promising treatment approach in HL. PD-1 is expressed on activated T-cells in the tumor as well as intra-tumoral macrophages and monocytes, said Ansell. Using nivolumab in HL patients resulted in a 70% PR and 17% CR. Overall, said Ansell, nivolumab was well tolerated, and a durable response was observed.

When the other approved PD-1 inhibitor antibody, pembrolizumab, was evaluated in a small study with 29 patients, he said, the majority of patients had a good and durable response to treatment.

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

Lenalidomide, used to treat FL, is promising in HL as well. It targets the malignant cells, T cells, and other immune components, in addition to stromal effects.

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

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