In the phase III JCOG1411/FLORA trial of patients with untreated advanced-stage, very low–tumor burden follicular lymphoma, rituximab induction delayed disease progression to high–tumor burden follicular lymphoma and delayed the initiation of cytotoxic chemotherapy, according to Japanese investigators who reported the findings at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.¹

“We recommend the early administration of rituximab as an initial treatment approach for such patients,” said Noriko Fukuhara, MD, PhD, of Tohoku University Graduate School of Medicine, Sendai, Japan.

“We hypothesized that early rituximab administration, without initial observation, would benefit patients with low–tumor burden follicular lymphoma.”

— Noriko Fukuhara, MD, PhD

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Watchful waiting is thought to be a reasonable initial approach for low–tumor burden follicular lymphoma. For about 10 years, rituximab monotherapy has been an initial treatment option for low–tumor burden follicular lymphoma. Dr. Fukuhara said she typically gives rituximab to patients with low–tumor burden follicular lymphoma after initially being observed but who do not meet the criteria for high tumor burden. The optimal timing for starting rituximab in this setting, however, is unclear, she said.

“We hypothesized that early rituximab administration, without initial observation, would benefit patients with low–tumor burden follicular lymphoma. Therefore, we conducted a randomized phase III study to confirm the superiority of early rituximab administration over watchful waiting in patients with untreated advanced-stage, low–tumor burden follicular lymphoma,” she said.

About FLORA

In this study, 292 patients from 54 centers with low–tumor burden follicular lymphoma by Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria were divided into two groups:

• Very low tumor burden: Largest mass < 5 cm, two or fewer nodal sites (each ≥ 3 cm), and no effusion
• Intermediate tumor burden: One or more of the following—largest mass ≥ 5 cm but < 7 cm, three nodal sites (each ≥ 3 cm), and no serious effusion.

Patients with previously untreated and advanced-stage, very low–tumor burden disease (grade 1–3A) were randomly assigned to the watchful waiting arm or rituximab induction arm. Patients in the rituximab arm were immediately started on rituximab (375 mg/m² on days 1, 8, 15, and 22). Rituximab monotherapy was administered to both arms when the tumor burden was repeatedly classified as intermediate. The primary endpoint was event-free survival, defined as follows: progression to high tumor burden, initiation of cytotoxic chemotherapy and/or radiotherapy, histologic transformation, or death.

Key Results

At the second interim analysis in December 2023, the primary endpoint had been met, and in June 2024, the data and safety monitoring committee recommended the early termination of the study. With a median follow-up of 2.5 years for all patients, the event-free survival was significantly better in the rituximab induction arm than in the watchful waiting arm (hazard ratio [HR] = 0.625; P = .0078; < .0123 adjusted significance).

Events in both arms were primarily developing high tumor burden and exposure to cytotoxic chemotherapy, with rituximab. Twice as many patients with histologic transformation were found on the control arm.

The primary (updated) analysis done in June 2024 was consistent with the previous findings (HR for event-free survival = 0.690; 95% confidence interval = 0.485–0.982). The 3-year overall survival rates were 97.5% with rituximab and 98.5% with watchful waiting, based on seven deaths in the rituximab arm (of 144 patients), mostly from solid tumors, and eight in the control arm (of 144 patients), mostly from lymphoma. Progression-free survival at 4 years did not significantly differ between the two arms.

As expected, adverse events were more common with rituximab. Grade 3 or 4 lymphocytopenia was reported in 11.4% of those given rituximab and 8.9% of those being monitored. 

DISCLOSURE: Dr. Fukuhara has received honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical Co., Genmab, Kyowa Kirin, Takeda, Eisai, Gilead Sciences, Eli Lilly, Janssen, Meiji Seika Pharma Co., Nippon Kayaku, Novartis, Ono, and Sorriso Pharmaceuticals; and has received research funding from AbbVie, Chugai Pharmaceutical Co., Chordia Therapeutics, Genmab, Kyowa Kirin, Loxo Oncology, Incyte, and Takeda.

REFERENCE

1. Fukuhara N, Maruyama D, Ishizawa K, et al: Randomized phase III study of watchful waiting vs. rituximab as first-line treatment in patients with advanced stage low tumor burden follicular lymphoma: JCOG1411/FLORA study. 2024 ASH Annual Meeting & Exposition. Abstract 338. Presented December 7, 2024.

EXPERT POINT OF VIEW 

Andrew D. Zelenetz, MD, PhD, Medical Director of Quality Informatics at Memorial Sloan Kettering Cancer Center, New York, expressed some concerns about the FLORA study in an interview with The ASCO Post. FLORA was a prospective randomized phase III study of initial active surveillance vs rituximab monotherapy in untreated advanced-stage, very low–tumor-burden follicular lymphoma. “The authors concluded that rituximab monotherapy should be administered immediately at the time of diagnosis. In contrast to the abstract authors, I view FLORA as a negative study,” he said.

Andrew D. Zelenetz, MD, PhD

Dr. Zelenetz continued: “While the study met its endpoint of event-free survival, there was no statistical difference between the arms for transformation-free, progression-free, or overall survival. Failure-free survival had an unusual definition in this study: development of high–tumor burden disease, need for cytotoxic or radiation treatment, histologic transformation, or death. This is a nonstandard definition, since it does not include all treatment.”

“Also, patients developing intermediate–tumor burden disease could receive multiple courses of rituximab monotherapy weekly times four,” Dr. Zelenetz added. “This is not the standard of care and makes for a unique definition used only in this trial.”

Furthermore, he noted, “the relative exposure to rituximab in each arm was not reported—and this information is key to understanding the findings. If the interval between courses of rituximab was short
(≤ 12 months), we know from prior studies that retreating with rituximab monotherapy gives a poor outcome. In fact, when treatment is necessary, it is generally a good idea to maximize progression-free survival, so the immunosuppressive effects of treatment completely resolve,” Dr. Zelenetz maintained. “Frequent retreatment with rituximab results in sustained B-cell aplasia, which increased the risk of hypogammaglobulinemia and infection.”

“Since the surveillance arm was not initially treated,” he continued, “it is not surprising that more of those patients had high–tumor burden disease on reassessment. However, the progression from low tumor burden to high tumor burden depends on the frequency of assessments (information that was not provided). With frequent assessments, you are likely not to miss the transition from low to intermediate tumor burden,” he noted.

Dr. Zelenetz offered these additional thoughts: “Nonetheless, since one arm starts by reducing the tumor burden with rituximab, if the interval of assessment is suitably long, then it is apparent, with this definition of event-free survival, the study biases toward the initial treatment arm. In fact, I feel the definition of failure-free survival was not independent of the therapy and therefore is flawed. By the definitions used, progression-free survival was less biased (since it was essentially rituximab resistance), and overall survival was unbiased—and neither of these endpoints showed benefit for immediate rituximab. Finally, histologic transformation (a key negative event in the natural history of follicular lymphoma) was also the same between the arms,” he said.

Recommendation of Deferring Therapy

Dr. Zelenetz shared these closing comments: “We learned from the COVID-19 pandemic that B-cell depletion can be a substantial risk and that avoiding immunosuppressive therapy is still a good idea. Since progression-free and overall survival are not impacted by immediate treatment with rituximab, which is immunosuppressive, I would recommend deferring therapy.” 

DISCLOSURE: Dr. Zelenetz reported financial relationships with BMS, Celgene, Juno Pharmaceuticals, Genentech/Roche, Gilead/Kite, BeiGene, Pharmacyclics, Janssen, Amgen, AstraZeneca, Novartis, MEI Pharma, Ipsen, and AbbVie.