Careful Data Review Recommended for Upfront Treatment Selection in iNHL

Sonali M. Smith, MD

Sonali M. Smith, MD

Can the "Chemo-Free" R²Regimen Replace Chemotherapy?

To enhance outcomes for patients with indolent non-Hodgkin lymphoma (iNHL), an in-depth review of the available data is required. As a start, Sonali M. Smith, MD, University of Chicago Medicine, reviewed the clinical trial findings that are currently informing treatment selection in the frontline iNHL paradigm, at 24th Annual International Congress on Hematologic Malignancies.When therapy is indicated, the frontline armamentarium of iNHL includes chemotherapy, anti-CD20 monoclonal antibodies, and the immunomodulatory drug lenalidomide (Revlimid).

The phase III RELEVANCE trial²sought to determine whether the “chemotherapy-free” combination of rituximab (Rituxan) and lenalidomide (Revlimid; R²regimen) could replace the standard chemoimmunotherapy regimen of rituximab plus chemotherapy in the frontline setting for patients with follicular lymphoma (FL).

The RELEVANCE trial randomized 1030 patients to receive R²(n = 513) or rituximab/chemotherapy (n = 517), which consisted of R-CHOP (72%), rituximab/bendamustine (23%), and R-CVP (5%). The chemotherapy regimens were given at standard doses. In the R²arm, lenalidomide was administered at 20 mg/day on days 2 through 22 of a 28-day cycle until CR/CRu then at 10 mg/day. Rituximab was given at 375 mg/m²weekly in cycle 1 and then on day 1 of cycle 2 through 6. It was continued in responders every 8 weeks for 12 cycles.

Baseline characteristics were well-balanced across groups. The median age in both arms was 59 years and two-thirds of patients were ECOG performance status 0. Bulky disease (>7 cm) was found in 42% of those in the R²group and for 38% in the rituximab/chemotherapy group. FLIPI score was low (15%), intermediate (36% to 37%), and high (48% to 49%). B symptoms were presented for approximately one-quarter of patients.

The study results showed that the combination of rituximab and lenalidomide showed similar efficacy compared with rituximab plus chemotherapy, which failed to satisfy the primary study endpoints of improved progression-free survival (PFS) and complete response (CR) rates with the “chemo-free” regimen; however, the R²regimen had a more favorable safety profile, making it a potential first-line option.

After 120 weeks, the R²regimen showed a CR or unconfirmed CR rate of 48% compared with 53% for rituximab/chemotherapy (P= .13). The objective response rate (ORR) with the R²regimen was 84% compared with 89% for rituximab/chemotherapy. The 3-year duration of response was 77% with R²compared with 74% for rituximab/chemotherapy.

At a median follow-up of 37.9 months, PFS was similar in both arms. By independent review, 3-year PFS rate was 77% with R²compared with 78% for rituximab/chemotherapy (HR, 1.10; 95% CI, 0.85-1.43; P= .048). By investigator assessment, the 3-year PFS rate was 77% with R²and 78% with rituximab/chemotherapy (HR, 0.94; 95% CI, 0.73-1.22; P= 0.63).

The rate of grade 3/4 neutropenia was 32% for patients treated with R²compared with 50% for rituximab/chemotherapy. The grade 4 rates were 8% and 31%, respectively. Just 1% of patients in the R²arm had an absolute neutrophil count nadir of <100/&mu;L compared with 6% for rituximab/chemotherapy. Moreover, the time to grade 3/4 neutropenia was significantly longer with the chemotherapy-free regimen (3.7 vs 0.6 months).

All patients in each group experienced treatment-emergent adverse events (TEAEs). The rage of grade &ge;3 TEAEs was higher in the chemotherapy arm (approximately 60% vs 70%). Grade 3/4 infections were twice as likely in the chemotherapy arm (2% vs 4%) and more patients experienced febrile neutropenia in the chemotherapy group (2% vs 7%). Febrile neutropenia requiring hospitalization was more than double in the chemotherapy arm (2% vs 5%) and nearly 3-times as many patients received growth factor agents in the chemotherapy group compared with R²(23% vs 68%).

Can Obinutuzumab Replace Rituximab?

Another key question recent research in iNHL has addressed is whether or not a different anti-CD monoclonal antibody, obinutuzumab (Gazyva), can replace rituximab in the frontline setting.

In November 2017, the FDA approved obinutuzumab in combination with chemotherapy, followed by obinutuzumab alone, for the first-line treatment of patients with advanced follicular lymphoma. The approval was based on findings from the phase III GALLIUM study.³

The international phase III GALLIUM study included 1401 treatment-naive patients with indolent non-Hodgkin lymphoma, of whom 1202 had follicular lymphoma, to obinutuzumab plus chemotherapy, followed by obinutuzumab alone (n = 601), or rituximab plus chemotherapy, followed by rituximab alone (n = 601).

The obinutuzumab regimen extended PFS versus the rituximab regimen. The 3-year PFS rate at a median follow-up of 34.5 months (range, 0-54.5) was 80% versus 73.3% with obinutuzumab versus rituximab, respectively (HR, 0.66; 95% CI, 0.51-0.85;P= .001). The ORR was 88.5% versus 86.9%, respectively.

Should Patients Receive Maintenance Therapy?

Despite the PFS benefit, however, there was no difference in OS between the 2 arms and toxicity was worse with obinutuzumab. The rates of grade 3 to 5 (74.6% vs 67.8%) and serious (46.1% vs 39.9%) adverse events were higher with obinutuzumab versus rituximab.There is also no precise answer on whether or not to use maintenance therapy in patients with iNHL who respond to induction therapy. The phase III PRIMA trial⁴sought to answer this question by examining the impact of 2 years of maintenance rituximab in patients with high tumor burden FL who achieved a complete or partial response to a rituximab plus chemotherapy induction regimen.

Patients who responded to induction therapy were randomized to rituximab maintenance or observation. Nine-year follow-up data for the trial showed that maintenance rituximab significantly extended PFS at a median of 10.5 years compared with 4.1 years with observation (HR, 0.61; 95% CI, 0.52-0.73;P<.001); however, there was no OS benefit with rituximab, as the 10-year OS rate was approximately 80% in both of the trial arms.

Not All iNHLs Are the Same

Stressing that an individualized approach is necessary in frontline iNHL, Smith shared data showing how treatments have performed in patients with marginal zone lymphoma (MZL).

For example, long-term results from the phase II MALT 2008-01 trial showed that at 7 years&rsquo; follow-up, the OS rate was 96% with a frontline regimen of bendamustine plus rituximab in 57 patients with extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue.⁵

Another trial, the phase III IELSG-19 study, showed that at 5 years&rsquo; follow-up, frontline combination therapy with rituximab plus chlorambucil significantly improved event-free survival (EFS;P= .0009) and PFS (P= .0119) compared with either agent alone.⁶The 5-year PFS rate was 68% with the combination compared with 51% with chlorambucil monotherapy and 50% with rituximab monotherapy. However, there was no corresponding improvement in OS with the combination. The 5-years OS rates were approximately 90% in each of the 3 study arms.

Regarding upfront rituximab versus obinutuzumab in MZL, Smith shared a subset analysis from the GALLIUM trial of 99 patients with MZL treated with obinutuzumab and 96 patients with MZL treated with rituximab. The results showed that unlike in patients with FL, there was no difference in PFS (P= .49) favoring obinutuzumab. There was also no difference between the 2 arms in response rates, time to new antilymphoma treatment (P= .57), and OS (P= .78).

Key Takeaways

In her concluding remarks, Smith noted that because the clinical trial data do not yield definitive answers, and because not all iNHLs are the same, the approach to upfront treatment—both induction and maintenance&mdash;will vary from patient to patient. She stressed that it is essential to have a discussion with the patient regarding their personal preferences. Although not yet available, Smith said the future of treatment selection in this setting will be a personalized approach based on individual risk assessment and predictive markers.

References

1. Smith, SM. How to Choose the Best Up-Front Therapy in iNHL. Presented at: 24th Annual International Congress on Hematologic Malignancies&reg;; February 27 — March 1, 2020; Miami Beach, FL.
2. Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma.J Clin Oncol. 2018;36 (suppl; abstr 7500).
3. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma.N Engl J Med. 2017;377(14):1331-1344. doi: 10.1056/NEJMoa1614598
4. Bachy E, Seymour JF, Feugier P, et al. Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study.J Clin Oncol. 2019;37(31):2815-2824. doi: 10.1200/JCO.19.01073
5. Salar A, Domingo-Domenech E, Panizo C, et al. ong-term results of a phase 2 study of rituximab and bendamustine for mucosa-associated lymphoid tissue lymphoma.Blood. 2017;130(15):1772-1774. https://doi.org/10.1182/blood-2017-07-795302.
6. Zucca E, Conconi A, Martinelli G, et al. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy.J Clin Oncol. 2017;35(17):1905-1912. doi: 10.1200/JCO.2016.70.6994.