Progress seen in indolent lymphoma treatment, experts say

The majority of patients with follicular lymphoma (FL) have excellent results when treated with chemotherapy so — even with evolving understanding of disease biology and availability of a parade of novel agents…

… the challenge is to improve on this impressive record of efficacy and tolerability or to change the natural history of the disease, an expert said here at the American Society of Hematology annual meeting.

Caron Jacobson, MD, assistant professor at the Dana-Farber Cancer Institute, pointed to recent data that suggest some progress is being made.

In one high-profile trial unveiled last year, Phase 3 RELEVANCE, both rituximab plus lenalidomide (R-lenalidomide) and rituximab plus chemotherapy produced similar confirmed or unconfirmed complete response rates at 120 weeks, with an almost identical 3-year progression-free survival. More patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia and any grade of febrile neutropenia, but a higher percentage of the R-lenalidomide patients had grade 3 or 4 cutaneous reactions. (1)

Officially, the study failed because it didn’t show superiority for R-lenalidomide, but the picture is more complicated than that, Dr. Jacobson said.

“Many felt the failure of this study was in designing it as a superiority rather than as a non- inferiority study,” she said. “If you see equivalent outcomes and the toxicity profile is similar, you can potentially consider using these therapies interchangeably.”

Other drugs to keep an eye on in follicular lymphoma include the PI3 kinase delta-inhibitors idelalisib, copanalisib and duvelisib; the EZH2-inhibitor tazemetostat; and antibody drug conjugates polatuszumab, which targets CD79b, and loncastuximab, which targets CD19.

Evaluation of single-agent immunomodulatory drugs in FL has been a perplexing exercise so far, she said.

“There is a large proportion of patients with follicular lymphoma that will have really excellent — and potentially permanent — long-term remissions with allogeneic stem cell transplant with reasonable transplant-related morbidity and mortality,” she said. “So, this is really proof of concept in support of this being an immune-sensitive disease. But despite this, the results of immunomodulatory drugs like the checkpoint inhibitors and the 4-1BB agonist antibodies as single agents, have so far yielded responses in very few patients.” For those who have responded to these agents, they’ve been durable responses, though, she added.

The results from those single-agent shows that scientists don’t understand the key relationships between the FL tumor cell and the microenvironment, “which are probably multi-layered,” she said.

Future trials should test combinatorial therapies and these agents, with analysis of patient samples before treatment and on treatment, with time of progression considered, “to understand what predicts response or lack thereof, so that future rational combinations can be developed.”

Autologous stem cell transplant or allogeneic stem cell transplant could make sense from a cost-perspective in the treatment of indolent non-Hodgkin lymphomas, even with the availability of new, targeted therapies, said Ajay Gopal, MD, director of clinical research in hematology at the Seattle Cancer Care Alliance.

He suggested autologous transplant can be considered in the case of chemo-sensitive disease in those who are medically fit for high-dose therapy and meet one of these conditions: relapse within 24 months of initial chemoimmunotherapy, relapse 3 or fewer times, the desire for more time off therapy, or short remission period after their last therapy.

Allo transplant could be considered for those with an ability to achieve low disease burden before transplant, have an appropriate donor available, and are medically fit, and who meet one of these conditions: ineligibility for or receipt of a previous auto transplant, relapse on 2 or more occasions, or short remission period after their last therapy.

Transplant in indolent non-Hodgkin lymphomas “may be economically sound compared with costly chronic treatments,” he said. “Improvements in conditioning regimes, donor options, and graft-versus-host-disease prevention have the potential to further improve outcomes.”

1) Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947.

2) Morschhauser F, Tilly H, Chaidos A, et al. 123 Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory Follicular Lymphoma. Abstract 123. Presented at the American Society of Hematology annual meeting. December 7, 2019.