Progress Toward Reducing Failure in Follicular Lymphoma

Nathan Fowler, MD

Lack of improvement in failure-free survival (FFS) for patients with follicular lymphoma has fueled interest in new treatment strategies that might offer promise of better outcomes, lymphoma specialist Nathan Fowler, MD, said in a presentation at the 2015 Society of Hematologic Oncology (SOHO) annual meeting.

Over the past 25 years, new regimens for follicular lymphoma have led to better overall survival. However, even the most intensive regimens have failed to push FFS much beyond 5 years.

In the past decade or so, emerging information about the microenvironment of follicular lymphoma has provided a basis for exploring new approaches to increase FFS.

“We’ve learned a lot about the key role that the B-cell receptor plays,” said Fowler, an associate professor of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center. “We know a lot more about T-cell signaling and T-cell activation in the microenvironment, as well as certain other cells and the tumor vasculature.”

The BTK inhibitor ibrutinib offers one example of potential new approaches to treatment of follicular lymphoma. Having demonstrated efficacy in chronic lymphocytic leukemia and mantle cell lymphoma, ibrutinib was evaluated in a phase I study of follicular lymphoma.

At a daily dose of 2.5 mg/kg, 55% of patients had objective responses, half of which were complete responses. At double the dose, the overall response rate was the same, but a third of patients achieved complete responses. Median duration of response and progression-free survival (PFS) were 10.3 and 13.4 months, respectively, with 2.5 mg, and increased to 12.3 and 19.6 months with the higher dose.

A subsequent phase II study involving 40 patients produced an overall response rate of 28%. A waterfall plot, however, showed that about 70% of patients had some degree of tumor shrinkage associated with inhibition of the BTK pathway.

“I think that explains why despite an overall response rate of 28%, the progression-free survival was a year. A lot of patients who had stable disease maintained stable disease for quite some time with ibrutinib,” said Fowler.

A planned phase III study has an accrual goal of 400 patients with relapsed follicular or marginal zone lymphoma. All patients will receive bendamustine-rituximab or R-CHOP chemoimmunotherapy plus either ibrutinib or placebo. The trial has a primary endpoint of PFS.

Additionally, investigators recently completed a trial of frontline ibrutinib-rituximab combination therapy in follicular lymphoma. The trial had a primary outcome measure of objective response rate, and results could be reported at the American Society of Hematology annual meeting in December, according to Fowler.

A trial of the PI3 kinase inhibitor idelalisib offered another demonstration of how objective response rate does not necessarily tell the entire story about a drug’s activity. Patients with rituximab- and alkylator-refractory indolent non-Hodgkin lymphoma received idelalisib 150 mg twice daily until disease progression (N Engl J Med. 2014;370:1008-1018). The overall response rate was 57% (54% in patients with follicular lymphoma) but few patients failed to derive some degree of benefit in terms of tumor regression, associated with a median PFS of about a year.

Based on these data, the FDA granted idelalisib an accelerated approval in 2014 for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma who were previously treated with ≥2 systemic therapies.

Although not as toxic conventional therapy, many new drugs do have specific toxicities that can be severe in some instances, Fowler noted. For example, more than 40% of the patients in the idelalisib trial had diarrhea, which was grade 3/4 severity in almost 15% of cases. The diarrhea may persist for as long as a patient continues the drug.

Not to be overlooked among targeted therapies are newer agents that home in on the CD20 pathway targeted by rituximab, whose activity was demonstrated in a pivotal trial reported almost 20 years ago.

“This is still a very active pathway and there are good drugs still being approved that have additional activity targeting the CD20 pathway,” said Fowler.

Investigators recently completed a multicenter randomized trial to evaluate bendamustine alone or with the anti-CD20 antibody obinutuzumab (Gazyva) in patients with indolent lymphomas refractory to both rituximab and another CD20-targeting agent. As reported at the 2015 ASCO Annual Meeting in June, the addition of obinutuzumab to bendamustine was associated with a significant 45% reduction in the PFS risk, despite the fact that the dose of bendamustine was 25% lower than in the monotherapy arm.

Fowler was the principal investigator in a phase II study of a regimen that has gained widespread attention in the lymphoma community because of impressive response rates. The so-called R2 (lenalidomide-rituximab) regimen was evaluated in 110 patients with indolent lymphomas. In the subgroup of 50 patients with follicular lymphoma, the regimen resulted in an overall response rate of 98%, including complete responses in 87% and PET-negative disease in more than 90% (ASH Annual Meeting Abstracts. 2012;120[21]:901).

“We now have a median progression-free survival of almost 44 months, and 80% of our patients with follicular lymphoma remain in remission,” said Fowler.

Prolonged responses also were seen in patients with small lymphocytic lymphoma and marginal zone lymphoma, though not quite as good as those seen in patients with follicular lymphoma.

The results were subsequently validated in another phase II trial that enrolled only patients with follicular lymphoma.

The collective results led to a 1000¬-patient phase III trial of the R2 regimen. Patients were randomized to rituximab plus investigator’s choice of chemotherapy or to the R2 combination. Accrual was completed several months ago.

In an effort to improve on results obtained with the R2 regimen, Fowler and colleagues have launched a trial of lenalidomide plus obinutuzumab in patients with relapsed indolent NHL. Phase I has been completed and patient accrual has begun in phase II of the investigation.

Investigation of immune checkpoint inhibitors also has expanded to follicular lymphoma. In a phase II trial, the investigational anti¬—PD-1 drug pidilizumab was combined with rituximab in relapsed follicular lymphoma (Lancet Oncol. 2014;15:69-77). Objective responses were observed in 19 of 29 (66%) patients, including complete responses in 15 (52%) patients.