Obinutuzumab improves PFS for follicular lymphoma across chemotherapy backbones

Patients with previously untreated follicular lymphoma demonstrated improved PFS with the addition of obinutuzumab to chemotherapy, regardless of the chemotherapy regimen, according to results of the GALLIUM trial.

However, safety differed among the chemotherapy regimens.

“Follicular lymphoma is the most common type of indolent B-cell non-Hodgkin lymphoma. In patients requiring therapy, the combination of rituximab [Rituxan; Genentech, Biogen] with chemotherapy followed by rituximab maintenance is standard treatment,” Wolfgang Hiddemann, MD, director of the department of hematology and oncology at University of Munich, and colleagues wrote. “The choice of chemotherapy backbone is usually determined by local policies or algorithms, the most commonly used being CHOP; cyclophosphamide, vincristine and prednisone (CVP); and bendamustine.”

In the open-label GALLIUM trial, researchers assessed 1,202 patients with previously untreated advanced follicular lymphoma randomly assigned 1:1 to 1,000 mg obinutuzumab (Gazyva, Genentech) plus chemotherapy or 375 mg/m² rituximab plus chemotherapy. Each center selected a chemotherapy regimen — CHOP, CVP or bendamustine — prior to the study.

Previous results from the study showed investigator-assessed PFS was superior with obinutuzumab plus chemotherapy compared with rituximab plus chemotherapy (HR = 0.66; 95% CI, 0.51-0.85).

In the current analysis, researchers used an updated dataset to evaluate the impact of the three different chemotherapy backbones on efficacy and safety.

Median follow-up was 41.1 months.

Results showed obinutuzumab plus chemotherapy prolonged PFS compared with rituximab plus chemotherapy (HR = 0.68; 95% CI, 0.42-1.47). These results appeared consistent across the bendamustine (HR = 0.63; 95% CI, 0.46-0.88), CHOP (HR = 0.72; 95% CI, 0.48-1.1) and CVP (HR = 0.79; 95% CI, 0.42-1.47) backbones.

Obinutuzumab plus CHOP or CVP led to higher rates of grade 3 to grade 5 adverse events than obinutuzumab plus bendamustine. CHOP was associated with the greatest frequency of grade 3 to grade 5 adverse events, driven by higher incidence of cytopenias.

However, patients treated with bendamustine plus obinutuzumab had higher rates of grade 3 to grade 5 infections and second neoplasms, which resulted in marked and prolonged reductions in T-cell counts. Also, more fatal events occurred among patients treated with bendamustine (4%) than with CHOP or CVP (2% each).

The higher proportion of fatal adverse events with bendamustine was “somewhat [surprising],” Jonathan W. Friedberg, MD, MMSc, director of Wilmot Cancer Institute at University of Rochester Medical Center, wrote in an accompanying editorial.

“Although a proportion of these events occurred during induction treatment, most of the increased deaths in patients treated with bendamustine were observed during the maintenance phase, and these occurred at an equivalent rate with obinutuzumab and with rituximab,” he wrote. “The vast majority of excess deaths not related to new anticancer treatment occurred in patients who had more than one comorbidity, were older than 80 years of age or had a poor performance status.”

Because the chemotherapy regimens were not randomized, the treatment groups were not balanced, which may have confounded the results, Friedberg added.

“There were higher percentages of elderly patients and patients with high comorbidity scores treated with bendamustine; conversely, a higher percentage of patients with bulky disease were treated with CHOP,” he wrote. “The majority of patients in GALLIUM were treated with bendamustine, with approximately one-third of patients receiving CHOP and 10% receiving CVP.”

The study authors acknowledged limitations of the study included it was not designed to detect significant differences between chemotherapy regimens, and that patients had imbalances in baseline characteristics and were not randomized to chemotherapy options.

“The nature of adverse events in patients with follicular lymphoma in GALLIUM in this analysis was consistent with the known safety profiles of the study treatments,” the researchers wrote. “Hence, although obinutuzumab can be considered as the new standard anti-CD20 antibody for first-line therapy of follicular lymphoma, the most appropriate chemotherapy partner should be selected with care, taking individual patient characteristics and risk profiles into consideration.” – by Cassie Homer

Disclosures: Hiddemann reports consultant/advisory roles with and honoraria or research funding from Celgene, Janssen and Roche. Please see the study for all other authors’ relevant financial disclosures. Friedberg reports consultant/advisory roles with Astellas Pharma and Bayer, institutional research funding from Seattle Genetics and travel accommodations/expenses from Roche.