Novel Nonchemo Combo (Len-R) Effective in Follicular Lymphoma

Nancy A. Melville

June 20, 2018

STOCKHOLM — A novel chemotherapy-free regimen of lenalidomide (Revlimid, Celgene) and rituximab (Rituxan, Genentech) showed efficacy in previously untreated follicular lymphoma that is similar to that of the standard of care of rituximab and chemotherapy followed by rituximab maintenance, but with significantly less toxicity.

The findings come from the phase 3 RELEVANCE trial and were presented here at the European Hematology Association (EHA) 2018 Congress.

Although this trial did not reach its primary endpoint of superiority over the conventional rituximab/chemo combination, the results nevertheless suggest a potentially important chemo-free alternative, first author Frank Morschhauser, MD, PhD, of the Hôpital Claude Huriez, in Lille, France, told Medscape Medical News.

"These findings are important, as lenalidomide/rituximab represents the first chemotherapy-free, immunomodulatory regimen to demonstrate comparable efficacy against the current standard of care of rituximab/chemo in the first-line treatment of follicular lymphoma in a large randomized phase 3 study," he said.

Lenalidomide, an immunomodulatory agent that activates natural killer cells and T cells and drives apoptosis of neoplastic B cells, has been shown to have complementary effects in phase 2 studies when combined with rituximab.

Study Details

The open-label trial was conducted in 1030 patients with advanced-stage follicular lymphoma with high tumor burden (grade 1 to 3a) who required systemic therapy. The median age of the patients was 59 years; 49% had Follicular Lymphoma International Prognostic Index scores of ≥3; 93% had stage III/IV disease; and 41% had bulky disease (>7 cm).

The patients were randomly assigned to one of two groups. One group received the novel combination of lenalidomide/rituximab. Lenalidomide 20 mg/day was given on days 2-22/28 in cycles 1 to 6-12; in patients who showed a response, it was continued at 10 mg/day for a total of 18 cycles. Rituximab 375 mg/m2 was given weekly in cycle 1, day 1 in cycles 2-6, and continued in patients who showed a response for 12 additional cycles.

The other group received the standard of care combination of rituximab plus chemotherapy (investigators choice) and included standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), rituximab plus bendamustine, or rituximab plus cyclophosphamide, vincristine, and prednisolone, followed by 12 cycles of rituximab as maintenance therapy.

At a median follow-up of 37.9 months, the trial did not achieve the coprimary endpoints of superiority of lenalidomide/rituximab over standard therapy in complete response at 120 weeks (48% vs 53%; P = .13) or progression-free survival at 3 years (77% vs 78%).

The 3-year overall survival rate was 94% in both arms.

However, there were significant differences in toxicity between the two treatment arms.

Compared to the rituximab/chemotherapy group (n = 517), patients in the lenalidomide/rituximab group (n = 513) had significantly lower rates of any grade of fatigue (23% vs 29%), nausea (20% vs 42%), peripheral neuropathy (11% vs 22%), vomiting (7% vs 19%), stomatitis (3% vs 7%), and alopecia (1% vs 9%) .

For some adverse events, rates were higher with lenalidomide/rituximab group; these events included cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), and treatment-associated tumor flare reaction (6% vs 0.2%).

Although there were no significant differences in rates of thromboembolic events between the groups, the rituximab/chemotherapy group had higher rates of grade 3/4 laboratory neutropenia (34% vs 50%) and febrile neutropenia (2% vs 6%). Treatment with lenalidomide/rituximab was associated with higher grade 3/4 cutaneous reactions (7% vs 1%).

Adverse events leading to treatment discontinuation were higher in the lenalidomide/rituximab group (11% vs 3%), although for grade 5 events, the rate was 1% in both groups.

Second primary malignancies were reported in 7% (n = 38) in the lenalidomide/rituximab group and 9% (n = 48) in the rituximab/chemotherapy group; in both groups, 5% of such malignancies were invasive.

There are a number of possible explanations for the higher rate of adverse events leading to treatment discontinuation in the lenalidomide/rituximab group, Morschhauser told Medscape.

"First is that the treatment duration of lenalidomide (about 18 months) was longer than that of chemotherapy (about 6 months)," he said.

"Second, all investigators are very familiar with rituximab plus chemo combinations and know how to manage chemotherapy-associated toxicities," he continued.

"Conversely, most investigators in RELEVANCE had little or no experience with lenalidomide/rituximab in follicular lymphoma and were likely to take a more cautious approach in managing toxicities associated with lenalidomide/rituximab, including discontinuation," Morschhauser said.

Finally, not all adverse events leading to discontinuation of lenalidomide/rituximab were related to the combination. Importantly, rates of completion of 30 months of treatment were similar for the two groups (69% in the lenalidomide/rituximab group, and 71% in the rituximab/chemotherapy group), he noted.

Seventy-six percent of patients in the lenalidomide/rituximab group completed all 18 cycles of lenalidomide.

Efforts are still underway to determine the best candidates for lenalidomide/rituximab, and there are signs that some of the prognostic factors may not fall in line with expectations, Morschhauser said.

"Subgroup analyses showed that conventional prognostic factors do not predict lenalidomide/rituximab benefit," he said. "More analyses based on biology are being conducted to better characterize the ideal lenalidomide/rituximab patient."

Approached for comments on the study, Anton Hagenbeek, MD, PhD, a professor of hematology at the University of Amsterdam, the Netherlands, said the findings are an encouraging beginning for a chemo-free approach for follicular lymphoma.

"I think it's an important finding that this is the first randomized study of a chemo-free regimen, and it was quite effective and at least as effective as rituximab and chemotherapy for follicular lymphoma," he told Medscape Medical News.

An important caveat, however, is the cost, he noted. "It is less toxic and effective, but lenalidomide is much more expensive, particularly if given for a long time," Hagenbeek said.

"So, personally, I don't think this is going to take over current first-line regimens, not only because of the cost but because the toxicities with RCHOP [chemotherapy] can be managed — we've had 20 years to [work with] them," he said.

"But I do see this as a good first step for the development of chemo-free regimens. There will be more to follow, including new agents combining different agents in the chemo-free arena," he predicted.

EHA President-Elect John Gribben, MD, of the Center for Hemato-Oncology, Barts Cancer Institute, London, United Kingdom, agreed that cost is an important caveat in the lenalidomine/rituximab regimen.

"The results of the RELEVANCE trial are controversial," he told Medscape Medical News. "I have heard my American colleagues discussing this in positive terms, but I consider the study negatively," he said.

"This is a much more expensive treatment with no benefit in terms of progression-free or overall survival, and whereas the term 'chemo-free' is attractive to some, I do not believe that this will be reimbursed widely in Europe, even if it does achieve license," he said.

The study was supported by Celgene. Dr Morschhauser is on the advisory board and/or has speaking relationships with Celgene, Roche, Janssen, Bristol-Myers Squibb, and Gilead. Dr Hagenbeek is an advisor for Takeda Oncology.

European Hematology Association (EHA) 2018 Congress. Abstract S154, presented June 16, 2018.

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