Data Emerges on Maintenance Therapies, Developing Treatments for Relapsed/Refractory FL

Jane N. Winter, MD

Survival for patients with grade 1 to 2 follicular lymphoma (FL) is now measured in decades to coincide with improvements in therapy. “This needs to inform and be in the back of our minds because treatment of FL for most patients is a marathon, not a sprint,” said Jane N. Winter, MD, at the NCCN 12th Annual Congress on Hematologic Malignancies in San Francisco, California.

Key issues in treatment include watchful waiting versus early therapy for low burden, asymptomatic disease; the best induction treatment, observation versus extended therapy versus maintenance; and the identification and treatment of high-risk patients,¹ Winter said.

Radiotherapy has been the recommended strategy for patients with early stage disease, based on achievement of very long remission and possibly cure in up to half of patients with this approach, said Winter, professor of medicine, Division of Hematology/Oncology, Northwestern University, Chicago. Unfortunately, fewer than one-third of patients receive radiotherapy for treatment of localized disease. Staging with positron emission tomography (PET) appears to improve outcome with radiotherapy.

For patients with PET-staged I FL, involved-site radiation therapy (ISRT) remains the recommended strategy. In contrast, “for the patients with [PET] stage II disease, the outcomes are not very good with continuing relapses,” she said. “We need to avoid radiation for patients with stage II disease. I treat them more as advanced-stage patients.”

Some indications for treating advanced (stage III-IV) FL include symptoms, threatened end-organ function, cytopenia secondary to lymphoma, bulky disease (≥7 cm), and steady disease progression. For patients without an indication for treatment, overall survival (OS) is equivalent between immediate treatment and delayed treatment (watchful waiting).

Forty percent of patients older than 70 years never require treatment, Winter said. If treatment with rituximab (Rituxan) is chosen, indefinite maintenance is not better than retreatment in asymptomatic patients with no improvement in quality of life with maintenance. “In general, I think there’s no improvement in quality of life when we choose to treat patients who are asymptomatic,” she said.

She continued with a discussion about upfront treatment for patients who do require treatment, first citing a long-term follow-up of the FOLL05 trial presented at the 2017 International Conference on Malignant Lymphoma (ICML).² This update confirmed the positive outcomes for patients with advanced stage FL, regardless which treatment was used (rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP], rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP], or rituximab plus fludarabine and mitoxantrone [R-FM]), with 83% OS at 8 years. Disease control was better with R-CHOP compared with R-CVP, but OS was not different between those 2 arms. “We really have not been able to identify 1 regimen that improves OS over another,” she said.

In an update of the StiL NHL 1-2003 study comparing upfront bendamustine-R with R-CHOP, the time to next treatment was delayed with bendamustine-R versus R-CHOP (median: not yet reached vs 56.0 months) after 117 months of follow up, but no difference in OS was found in the FL subgroup of patients despite improved disease control with bendamustine-R.³ The OS rate (70%) at 10 years with 6 cycles of bendamustine-R with no maintenance “is fairly remarkable,” she said.

In the GALLIUM study, investigator-assessed 3-year progression-free survival (PFS) was superior with obinutuzumab (Gazyva) maintenance therapy compared with rituximab maintenance after induction therapy with the same agent plus chemotherapy, but OS was again not different.⁴ The obinutuzumab arm experienced higher rates of cytopenia, infection, and infusion-related adverse events. The results suggest that maintenance may not improve meaningful outcomes following induction with standard therapy. “We’re learning that the deeper the remission with our induction treatment, the smaller effect that maintenance will have,” Winter said.

The Alliance/CALGB 50803 study of a non-cytotoxic regimen consisting of lenalidomide plus rituximab, presented at ICML 2017, demonstrated an overall response rate of 95% and a complete response (CR) rate of 95%.⁵ The 5-year PFS was “dramatic” at 70%, said Winter. According to Winter, a phase III study should determine whether a non-cytotoxic approach can replace the standard chemotherapy induction regimen.

Patients with FL who progress within 24 months of R-CHOP have a 5-year OS rate of only 50%. New strategies are needed for this subgroup with poor prognosis, Winter said. “The big challenge is how to identify these patients without who can’t wait for the relapses to occur,” she said. Several novel agents have been or are being investigated for the treatment of relapsed/refractory FL.

One such agent that recently received accelerated U.S. Food and Drug Administration approval is copanlisib (Aliqopa), a pan-class I PI3K inhibitor with activity against alpha and delta isoforms. The median PFS is 11.2 months with copanlisib.

FL is an immunoresponsive disease, “so it shouldn’t be a surprise to us that checkpoint inhibition is likely to play a role in the treatment of FL,” Winter said. As presented at ICML 2017, the combination of pembrolizumab (Keytruda) plus rituximab was associated with a CR of 50% in 20 evaluable patients with relapsed FL.⁶ Responses have been durable, especially among those with CR, according to Winter.

Combining therapies may represent the future in the treatment of advanced stage or relapsed FL, said Winter, “but we should do that scientifically to avoid unnecessary toxicities that combination therapy brings.”

References

1. Winter JN. Updates on the treatment of follicular lymphoma. Presented at the NCCN 12th Annual Congress on Hematologic Malignancies; October 6-7, 2017; San Francisco, CA.
2. Lumnari S, Tranatino A, Anastasia A, et al. Long term results of the FOLL05 randomized study comparing R-CVP with R-CHOP and R-FM as first line therapy in patients with advanced stage follicular lumphoma. a FIL study. Presented at the 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. http://onlinelibrary.wiley.com/doi/10.1002/hon.2437_14/full.
3. Rummel MJ, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study. J Clin Oncol 2017 (suppl 15, abstr 7501).
4. Hiddemann W, Barbui AM, Canales Albendea MA, et al. Immunochemotherapy with obinutuzumab or rituximab in previously untreated follicular lymphoma in the randomised phase III GALLIUM study: analysis by chemotherapy regimen. Hematol Oncol. 2017;35(S2):117—119. doi: 10.1002/hon.2437_106.
5. Martin P, Jung SH, Pitcher B, et al. A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol. 2017. doi: 10.1093/annonc/mdx496.
6. Nastoupil LJ, Westin J, Fowler N, at al. High response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: interim results of an on open-label, phase II study. Hematol Oncol. 2017;35(S2):120-121. doi:10.1002/hon.2437_108.