Although follicular lymphoma remains incurable, recently approved targeted and immunotherapeutic agents have extended remissions and overall survival durations for patients. As phase III trials of even more new treatment combinations approach completion, knowledge of the available treatment options can help physicians recommend the most appropriate treatment for their patients with newly diagnosed or relapsed or refractory follicular lymphoma.
For nearly 40 years, cytotoxic chemotherapy was the standard of care for follicular lymphoma, which is the second most common non-Hodgkin lymphoma and the most common indolent lymphoma. The standard of care began to change with the U.S. Food and Drug Administration (FDA)’s approval of the anti-CD20 antibody rituximab for relapsed/refractory follicular lymphoma in 1997 and for first-line treatment of follicular lymphoma in 2006. Since then, more novel agents have emerged to treat follicular lymphoma.
“We’ve seen a paradigm shift in the past 5 years, with most new treatment regimens incorporating novel targeted or immunotherapeutic agents,” said Nathan Fowler, M.D., an associate professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center.
The changing standard of care
The standard first-line therapies for follicular lymphoma are rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP); and rituximab and bendamustine. In most patients, these rituximab-containing regimens achieve remissions lasting 4–7 years. Rituximab is used alone as a first-line treatment for patients whose frailty or comorbidities preclude cytotoxic therapy. Single-agent rituximab also may be beneficial as maintenance therapy for patients who experience a partial remission with any first-line regimen.
Second-line treatments for follicular lymphoma include re-exposure to common first-line regimens, the radiopharmaceutical yttrium Y 90–ibritumomab tiuxetan, and the recently approved combination of bendamustine and obinutuzumab, a second-generation anti-CD20 antibody.
The choice of third-line treatment for relapsed/refractory follicular lymphoma depends largely on a patient’s age, how long the most recent remission lasted, and how aggressive the disease is. In 2014, monotherapy with the PI3K inhibitor idelalisib was approved for treating patients with follicular and small lymphocytic lymphomas who have received at least two previous lines of therapy. Dr. Fowler, who led phase I and II trials of idelalisib, said the drug is only one of several third-line options. “If the second line of therapy fails, we often encourage participation in a clinical trial of a novel agent or referral to our stem cell transplant center,” he said. Patients also may be eligible to participate in clinical trials of T cells or natural killer cells expressing chimeric antigen receptors (see Chimeric Antigen Receptor–Directed Natural Killer Cells for B Cell Malignancies, OncoLog, May/June 2017).
As a result of the shifting standard of care, outcomes have improved for patients with follicular lymphoma. Dr. Fowler said, “Several long-term follow-up studies of patients who have received current standard therapies have shown that, unlike patients 10–15 years ago, most patients today will not die of their disease.”
More changes to come
The standard of care for follicular lymphoma continues to evolve. Several multicenter phase III randomized controlled trials comparing new treatment regimens with standard therapies are ongoing or recently completed (see table, above), and Dr. Fowler expects some of these new regimens to be approved by the FDA within the next few years.
The combination of rituximab and the immune modulator lenalidomide, a regimen commonly known as R2, is in phase III trials for patients with previously untreated (No. 2011-0805) or relapsed/refractory (2015-0038) follicular lymphoma. Dr. Fowler said that earlier trials of this treatment combination also were performed at MD Anderson (see graphs, above). “We were the first center to do combination immunotherapy trials of a monoclonal antibody with an immune modulator in patients with untreated follicular lymphoma,” he said. Both phase III trials of R2 have completed enrollment, and Dr. Fowler expects to see preliminary results in the coming months.
A phase III trial of obinutuzumab and cytotoxic chemotherapy in patients with previously untreated follicular lymphoma also recently completed enrollment. Dr. Fowler—who was MD Anderson’s principal investigator of the phase III trial that led to the FDA’s approval of obinutuzumab and bendamustine as a second-line therapy—anticipates the combination’s approval as a first-line therapy.
Two ongoing phase III trials are evaluating the Bruton tyrosine kinase inhibitor ibrutinib (which is approved for the treatment of other indolent lymphomas) for patients with follicular lymphoma. In one trial (No. 20140088), ibrutinib is given with R-CHOP or with rituximab and bendamustine to patients with relapsed/refractory disease. This trial has completed enrollment. In the other trial, ibrutinib is given with rituximab to previously untreated follicular lymphoma patients in whom cytotoxic therapy is contraindicated. Dr. Fowler, the ibrutinib-rituximab trial’s national principal investigator, said the trial will soon begin enrolling patients at MD Anderson. Patients in the ibrutinib-rituximab trial must be at least 70 years old or at least 60 years old with one or more major comorbidities, and it is hoped that the noncytotoxic regimen will yield a better progression-free survival rate than monotherapy with rituximab.
Noncytotoxic regimens are of increasing interest in follicular lymphoma research. “In a disease where patients are surviving longer,” Dr. Fowler said, “we have to pay a lot more attention to the short- and long-term toxic effects of any given therapy because patients are going to have to live with this disease along with any side effects of the treatment.”
Therefore, Dr. Fowler said, “We’ve recently launched an initiative to open studies focusing on immunotherapy for follicular lymphoma.”
One current trial at MD Anderson (No. 2015-1063) is evaluating the PDL1 (programmed cell death protein 1 ligand) inhibitor durvalumab alone or combined with other follicular lymphoma treatments. Another trial (No. 2015-0361), led by Loretta Nastoupil, M.D., an assistant professor in the Department of Lymphoma and Myeloma, is testing the efficacy of R2 plus ibrutinib. And a third trial (No. 2013-0261) is assessing the safety and tolerability of obinutuzumab given with lenalidomide. These and other trials of immunotherapeutic and targeted agents for patients with follicular lymphoma will be discussed in detail in an upcoming issue of OncoLog.
“The field of follicular lymphoma treatment is changing, and outcomes are improving,” Dr. Fowler said. “And with the new tools we are discovering, I’m optimistic that the future outcomes of patients diagnosed with this chronic disease will continue to improve.”
For more information, contact Dr. Nathan Fowler at 713-794-5206 or firstname.lastname@example.org. For more information about ongoing clinical trials for patients with follicular lymphoma, visit www.clinicaltrials.org.
OncoLog, September 2017, Volume 62, Issue 9