NEW YORK (FRONTLINE MEDICAL NEWS) – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.

But when a patient with follicular lymphoma experiences early disease progression on bendamustine, what should the next treatment be? Autologous stem cell transplantation (ASCT)? Novel therapies? That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD , of the University of Iowa Hospitals & Clinics in Iowa City.

Dr. Casulo: ASCT

“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.

“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.

To lay out her argument for ASCT, Dr. Casulo pointed to four studies suggesting that about 20% of patients with follicular lymphoma will experience disease progression within 24 months of chemoimmunotherapy. Similar patterns of progression at 24 months were seen with R-CHOP in the SWOG S0016 trial , with both bendamustine-rituximab and R-CHOP in the StiL Study , with lenalidomide (Revlimid) and rituximab in a phase 3 clinical trial , and with one of three rituximab-based immunochemotherapy regimens in the PRIMA trial.

The results from these trials suggest that “there is an inherent biology to this population that relapses early, regardless of what induction strategy is used. However, what’s not known, until now, is whether early relapse implies poor survival in this disease,” she said.

To examine this question Dr. Casulo and her colleagues performed an analysis of time to progression among patients with newly-diagnosed follicular lymphoma treated with R-CHOP who were enrolled in the National LymphoCare Study (NLCS). “What we found was that there were very poor outcomes associated with early-relapsing follicular lymphoma,” she said.

Overall survival (OS) at 8 years was 50% for patients with disease progression within 24 months of therapy, compared with 90% for patients who did not have early progression, a finding that was validated in a cohort of patients from the University of Iowa and the Mayo Clinic in which 8-year OS for early progressors was 34%, compared with 90% for other patients. The results held up when the researchers controlled for Follicular Lymphoma International Prognostic Index scores and in patients treated with rituximab and the cyclophosphamide, vincristine, and prednisone regimen rather than CHOP, Dr. Casulo noted.

“So, given these findings, how does one navigate the treatment landscape for patients with early relapsing follicular lymphoma? The reality is that there is really no standard of care or best approach,” she said.

“Ultimately, the goal of therapy, at least in my opinion, should be overcoming the chemoresistance that’s inherent to this biology, and establishing durable disease control, and there are a couple of strategies that might be able to achieve that,” she added.

There have been only two clinical trials of ASCT in patients with relapsed follicular lymphoma.

In the CUP trial , initiated prior to the introduction of rituximab, 89 patients with relapsed follicular lymphoma were treated with three cycles of CHOP, and those with a response were then randomized to either purged or unpurged ASCT, or to three additional cycles of CHOP. Four-year OS in this study was 70% for patients who underwent ASCT vs. 50% for those who received six cycles of CHOP.

In the EBMT LYM1 trial , 280 rituximab-naive patients with relapsed follicular lymphoma after a partial or complete remission were randomized to rituximab-purged or unpurged ASCT, followed by randomization to observation or rituximab maintenance. In this trial, the 10-year OS with ASCT ranged from 68% to 73%.

A Spanish registry study presented in a poster session at the 14th International Conference on Malignant Lymphoma in Lugano, Italy, showed long-term efficacy of ASCT in relapsed follicular lymphoma, with plateaus in both PFS and OS about 9 years after transplant for both rituximab-exposed and rituximab-naive patients, “suggesting that perhaps a subset of patients with relapsed follicular lymphoma can be cured with this approach,” Dr. Casulo said.

Similarly, a trial from the German Low Grade Lymphoma Studies group, presented at the 2016 American Society of Hematology annual meeting, showed 5-year OS of 77% with ASCT vs. 46% for patients who did not receive a transplant.

Dr. Casulo and her colleagues collaborated with investigators at the Center for International Blood and Marrow Transplant Research and the NLCS to see whether ASCT can improve OS compared with no transplant in patients with early-relapsed follicular lymphoma. They found that patients who received ASCT within 1 year of therapy failure had a 5-year OS of 73%, compared with 60% for those who did not receive ASCT (P = .02).

She acknowledged that toxicities associated with ASCT are a concern, pointing to a 2007 study looking at long-term follow-up of myeloablative ASCT for follicular lymphoma at the time of second or subsequent remission. The investigators found that rates of myelodysplasia were as high as 20% at 10 years, especially among patients who had undergone total body irradiation, a practice that has since fallen out of favor.

A separate study led by Matt Kalaycio, MD, of the Cleveland Clinic, showed that more lines of prior therapy (4-6 vs. 1-3) and radiation were both risk factors for subsequent myelodysplastic syndrome and acute myeloid leukemia.

“I hope we have demonstrated that autologous transplant can have durable response in these patients, with possibly a cure in a subset; but, ultimately, I think strategies that combine novel agents and autologous transplant in a clinical trial are the way to go to improve outcomes,” she said.

Dr. Link: Novel agents

“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.

“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.

He cited data from the University of Iowa/Mayo Clinic series, validated in a cohort of patients from Lyon, France, showing that high-risk patients with early progression after immunochemotherapy had “especially poor outcomes.” In contrast, patients who were not early progressors fared quite well.

“It suggested that with agents that were available as of 2015, if you’re not an early progressor, your survival at least matches, or essentially matches with statistical power, that of the expected age- and gender-matched populations. So, novel agents are not required necessarily nor are clinical trials necessarily required for people who have good early outcomes,” Dr. Link said.

The best snapshot of current practice for high-risk patients comes from unpublished data from the NLCS showing that after a median follow-up of 8 years, 889 of 2,652 patients had received a second line of therapy, with the choice of agents or approaches generally similar between early progressors and others.

Early progressors were slightly less likely to receive rituximab monotherapy (30% vs. 36%) or an investigational agent (4.4% vs. 5.5%), whereas they were slightly more likely to receive an anthracycline (18% vs. 13%) or to undergo ASCT (3.5% vs. 1.1%).

In the treatment of patients with high-risk follicular lymphoma, a novel agent can be considered as one that was either not available or had not been used in follicular lymphoma when the previously mentioned survival data were generated, including immunomodulators such as thalidomide analogues, targeted kinase inhibitors, new anti-CD20 antibodies such as obinutuzumab (Gazyva), and immune checkpoint inhibitors.

For example, in Alliance 50803 , a phase 2 trial in patients with previously untreated stage II-IV follicular lymphoma, the combination of lenalidomide (Revlimid) and rituximab was associated with a 95% overall response rate (ORR), including 72% complete response, and 5-year PFS rate of 70%, comparable to trials with rituximab plus bendamustine, CHOP, or cyclophosphamide-vincristine-prednisone, Dr. Link said.

In the phase 2 GALEN study , the combination of lenalidomide and obinutuzumab was associated with an ORR of 74% among 86 patients with relapsed/refractory follicular lymphoma, with a 1-year PFS rate of 76%.

An analysis of responses by time to relapse in GALEN showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 International Working Group criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.

Idelalisib, an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), was granted accelerated approval in 2014 for treatment of patients with follicular lymphoma after two or more prior lines of therapy, but toxicities associated with this agent caused the drug maker Gilead to dial back its development of this agent.

“But idelalisib is not the only PI3 kinase inhibitor on the block,” Dr. Link said, noting that more than a dozen similar agents are currently in development.

In clinical trials, PI3 kinase inhibitors have been associated with ORRs of about 60% in patients who experience early disease progression on other therapies, “suggesting an uncoupling between the paradigm that says that early progressors are going to have a less effective outcome than late progressors, perhaps, with targeted therapies.

The best evidence for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) comes from the DAWN study , a phase 2 trial in patients with follicular lymphoma refractory to immunochemotherapy. The drug showed some biologic activity, but only a 21% ORR.

Dr. Link noted that the S1608 trial , currently recruiting patients, may give clinicians a better idea of which novel agent is most effective. The phase 2 trial is enrolling patients with early-progressing or refractory follicular lymphoma who will be randomized to receive obinutuzumab with either the investigational PI3 kinase inhibitor TGR-1202, lenalidomide, or CHOP chemotherapy.

“High-risk follicular lymphoma is a bad hombre,” Dr. Link said. “If we want to be any smarter as a society 10 years from now, we should incorporate clinical trials with novel therapies as standard operating practice into this setting of high-risk follicular lymphoma.”

Dr. Casulo reported serving on the speakers bureau for Gilead. Dr. Link reported serving as a consultant to AbbVie, Celgene, Genentech, and Gilead.


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