SUMMARY: The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years.
GAZYVA® (Obinutuzumab) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells (natural killer cells, macrophages and neutrophils), Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis are significantly enhanced but induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® which is a first-generation type I, chimeric, anti-CD20 targeted monoclonal antibody that kills lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.
GALLIUM is a randomized, Phase III trial, which included 1,202 patients with newly diagnosed Follicular Lymphoma, who had Grade I-IIIa tumors and had an ECOG PS of 2 or less. Patients were randomly assigned to receive either GAZYVA® plus chemotherapy, followed by GAZYVA® maintenance (N=601), or RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance (N=601). The chemotherapy regimens used were CHOP, CVP or Bendamustine, based on the discretion of the treating physician. Patients received either RITUXAN® 375mg/m2 IV on day 1 of each cycle or GAZYVA® 1000 mg IV on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (CHOP and CVP) or six 28-day cycles (Bendamustine). Patients who achieved a Complete Response (CR) or Partial Response (PR) at the end of induction therapy, received maintenance therapy with RITUXAN® or GAZYVA® every 2 months for 2 years or until disease progression. The median age was 59 years and 57.1% of patients received Bendamustine, 33.1% received CHOP, and 9.8% received CVP. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Response Rate, Overall Survival (OS), Disease Free Survival and safety. After a median follow up of 34.5 months, upon recommendations from the Independent Monitoring Committee, the study was unblinded after a preplanned interim efficacy analysis. The estimated 3-year rate of Progression Free Survival in the GAZYVA® group was 80% compared with 73.3% in the RITUXAN® group, with a 34% reduction in the risk of progression or death noted in the GAZYVA® group (HR=0.66; P=0.001).
The researchers conducted a preplanned analysis of the Phase III Gallium study and explored the role of Minimal Residual Disease (MRD) as a predictor of outcome after GAZYVA® or RITUXAN® based treatment, in these previously untreated patients with Follicular Lymphoma. MRD status was assessed at predefined time points (Mid-Induction-Day 85 for all treatment groups, End of Induction, and at 4-6 monthly intervals during maintenance and follow-up) and the study objectives were to evaluate the depth and kinetics of MRD response to first-line GAZYVA® plus chemotherapy or RITUXAN® plus chemotherapy, and explore the prognostic role of MRD-status prospectively, to evaluate the use of MRD as a dynamic parameter for treatment modification. Patients with evaluable biomarker data at diagnosis were included in the survival analysis.
MRD analysis was performed at the central reference laboratory and was assessed by nested and quantitative PCR for clonal immunoglobulin gene rearrangement and the t(14;18) translocation. MRD status was classified as positive if both quantitative PCR and nested PCR were positive and were detectable at or above 104 sensitivity. Both peripheral blood and bone marrow samples were collected and MRD status was evaluated at Mid-Induction, End of Induction, during maintenance treatment and follow up. MRD status at End of Induction was determined as positive if at least one sample (PB or BM) was positive. Assessments during maintenance were conducted every 4 months during the first year, every 6 months thereafter, and at the final termination/discontinuation visit. Assessments were conducted every 6 months during follow-up. Patients who progressed during induction were excluded from the corresponding MRD analysis. Of the 1064 patients enrolled for MRD evaluation, 249 patients (23%) had no clonal PCR marker detected or had samples that did not meet MRD evaluability criteria.
At a median follow up of 59 months, MRD positivity at the Mid-Induction or End of Induction was significantly associated with inferior Progression Free Survival compared with MRD negativity. (PFS for those with detectable MRD at the Middle of Induction-HR=3.03, P<0.0001) and at the End of Induction- HR= 2.25, P<0.0001).
MRD response was higher after GAZYVA® plus chemotherapy versus RITUXAN® plus chemotherapy at the Middle of Induction (94.2% vs 88.9%, P=0.013) and at the End of Induction (93.1% vs 86.7%, P=0.0077), respectively.
Late responders with detectable MRD at the Middle of Induction and undetectable MRD at the End of Induction had significantly poorer PFS versus early responders who had undetectable MRD at both the Middle of induction and the End of Induction (HR=3.11, P=0.00011).
MRD positivity at the Middle of Induction was observed in a smaller proportion of patients receiving Bendamustine than CHOP (4.8% versus 16.0%; P<0.0001).
GAZYVA® appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the GAZYVA® plus chemotherapy groups.
During maintenance, more patients treated with RITUXAN® had detectable MRD compared to GAZYVA®, and throughout maintenance treatment, MRD positivity was associated with clinical relapse.
The researchers concluded that based on this analysis, early and continuous MRD negativity after immunochemotherapy is the most important prognostic factor for long-term disease control and outcomes, following first line treatment in Follicular Lymphoma. Further, this analysis has also suggested that the higher MRD responses after GAZYVA®, compared to RITUXAN® based chemotherapy, confirm more effective tumor cell clearance with GAZYVA® based chemotherapy regimens.
Minimal Residual Disease Status Predicts Outcome in Patients with Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study. Pott C, Jurinovic V, Trotman J, et al. J Clin Oncol. 2024;42:550-561.
