A Review of the GALLIUM Study

Andrew Davies, MD:The GALLIUM study was a large, phase III study that was conducted by the UK NCRI [National Cancer Research Institute] Lymphoma Group, the German Low-Grade Lymphoma Study Group, and a number of other territories asking the question, is obinutuzumab a better anti-CD20 monoclonal antibody than rituximab in follicular lymphoma when given with chemotherapy? It had a very simple design. Investigators chose 1 of 3 different chemotherapies: bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], or CVP [cyclophosphamide, vincristine, prednisone]. The patients who required therapy were randomized to receive either rituximab or obinutuzumab. For the responding patients, they continued to receive maintenance obinutuzumab or rituximab for 2 years given every 8 weeks, according to the arm that they had been assigned to.

There were 1200 patients in the study. All these patients had a clear indication for frontline treatment of follicular lymphoma. Each center chose 1 regimen. They chose to treat all their patients with bendamustine or with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], for example. The majority of patients received bendamustine—about 60%, 70% of patients. There were many patients with high-risk features in the study design as a whole.

The primary end point was progression-free survival, and we see from the study that those patients who were treated with obinutuzumab had a prolonged progression-free survival. Indeed, the use of obinutuzumab over rituximab resulted in a 34% prolongation of progression-free survival compared with rituximab. There’s a massive improvement in progression-free survival, which actually equates to an extension of progression-free survival estimated to be on the order of 2 to 3 years. There was a significant improvement in time without disease for patients who received obinutuzumab rather than rituximab.

This size of effect has held up with prolonged follow-up of patients. We’ve now got over 5 years of follow-up, and we see that degree of improvement is continuing to be seen.

To date, we’ve seen no improvement in overall survival, but we have seen that there has been a prolongation in time to next anti-lymphoma therapy in patients who receive obinutuzumab rather than those patients who receive rituximab.

It’s really interesting. With some of the other end points in this study, we demonstrate that the degree of MRD [minimal residual disease] negativity that can be achieved is greater in those patients receiving obinutuzumab rather than rituximab. We see that the number of patients who achieve metabolic complete response, as defined by a PET [positron emission tomography] scan, is greater in those patients who receive obinutuzumab versus rituximab. That’s important. If you achieve a metabolic complete response, you’re likely to have a more durable response. We also know that the number of patients who have early progression of disease when treated with obinutuzumab is less than with rituximab. Really, obinutuzumab provides a superior choice for a number of reasons for patients in the frontline setting of follicular lymphoma.

There is a different safety profile in patients treated with obinutuzumab compared with patients treated with rituximab. First, we foresee that there are a greater number of adverse reactions with obinutuzumab rather than rituximab. But with good mitigation strategies in your chemotherapy-delivery suite, these are very easily managed. We’ve all become used to using obinutuzumab in other settings, such as CLL [chronic lymphocytic leukemia]. With good training, good mitigation strategies, the infusion-related reaction—the slightly increased incidence of that—is not really an everyday problem. We see that there’s a degree of increase in neutropenia in patients receiving obinutuzumab rather than rituximab. This is particularly in patients receiving CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]. The use of prophylactic growth factors can, again, mitigate against that. There is also a slightly increased risk of infection in patients receiving obinutuzumab rather than those patients receiving rituximab.

There is a group of patients with follicular lymphoma who unfortunately have high-risk disease. These are patients who progress within the first 24 months after chemoimmunotherapy. This group represents about 20% of patients treated with rituximab and chemotherapy. These patients have a poor outcome. Indeed, their overall survival from progression is somewhere in the order of just 36 months. It’s really important for us, as investigators, to try to work out ways that, first of all, we can reduce the number of patients who fall into this high-risk group. Also, we can find effective treatment strategies for these patients. We call this group of patients POD24, or progression of disease within 24 months. Interestingly, the results of the GALLIUM study demonstrated that by using obinutuzumab rather than rituximab, we can reduce the number of patients who have early disease progression compared with using just rituximab. Indeed, we can reduce the risk of early progression by some 40%. This is a good reason for choosing to use obinutuzumab over rituximab.

Transcript edited for clarity.

Case: A 72-Year-Old Man With Symptomatic Follicular Lymphoma

Initial Presentation

A 72-year-old man presented to his physician with fatigue, and an involuntary 9-lb weight loss over the last 3 months. He complained of intermittent night sweats and decrease activities of daily living

Clinical work-up

• PE: Splenomegaly, firm nontender, rubbery lymph nodes on palpation in left axillary and bilateral inguinal region
• CBC: WBC, 13.6 X 10⁴/L, platelets, 114 X 10⁹/L, Hb, 8.9 g/dL, LDH, 380 U/L
• Beta 2 microglobulin 3.4 µg/mL
• HIV, HBV-, HCV-negative
• Excisional biopsy showed grade 3 follicular lymphoma; CD10+, CD23+
• Bone marrow biopsy; 50% involved
• PET/CT showed widespread lymphadenopathy above and below the diaphragm: largest lymph node measuring 7.6 cm, spleen measuring at 12.3 cm
• Diagnosis: Grade 3A, Stage IVB follicular lymphoma
• FLIPI2 score: high-risk
• ECOG PS 1

Treatment

• Patient started on obinutuzumab + CVP q8W of 21-day cycles
• Post-therapy PET showed partial response
• Continued on obinutuzumab 1000 mg q8W for 12 doses as monotherapy, well-tolerated

Follow-up

• PET scan at 12 months was negative
  • Completed treatment; after 24 months of obinutuzumab maintenance remains in on-going remission