Safety and Efficacy of Obinutuzumab Plus Fludarabine and Cyclophosphamide in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the GREEN Study

Introduction: Obinutuzumab (GA101; G) is a glycoengineered type II anti-CD20 antibody with significant activity in chronic lymphocytic leukemia (CLL). GREEN (NCT01905943) is a non-randomized, open-label, single-arm Phase 3b study investigating the safety and efficacy of G alone or in combination with chemotherapy in CLL patients (pts). Here, we report safety and efficacy results from 140 previously untreated, fit pts who received G plus fludarabine and cyclophosphamide (G-FC) in GREEN.

Methods: Pts were aged ≥18 years with documented CLL, an ECOG PS of 0-2, and adequate hematologic function. To receive G-FC, pts had to be fit, with a cumulative illness rating scale score ≤6 and a creatinine clearance of ≥70mL/min at screening. Dosing for G-FC pts was G 1000mg intravenous (IV) on Day (D) 1/D2 (as a split dose: either 25mg/975mg or 100mg/900mg Cycle [C] 1D1/D2), 8, and 15 of C1, and D1 of C2-6 (six 28-day cycles) and FC administered on D1-3 at standard doses, either IV or orally. Results are presented for the pre-specified subgroup of fit G-FC pts in the primary study analyses, with a data cut-off of Dec 29, 2016. The primary study outcome is safety.

Results: In 140 previously untreated fit pts who received G-FC (analysis set), median age was 57 years (range, 34-74), 26.4% had Binet stage A disease, 52.9% were Binet B and 20.7% Binet C. The analysis set was younger and had a more favorable Binet stage than the GREEN intent-to-treat population (972 pts; median age, 66 years (33-90); Binet A, 25.3%, Binet B, 41.2%; and Binet C, 32.9%). Of the 140 pts analyzed, IgVH was mutated in 26.4% and unmutated in 55.7%(missing in 17.9%); 40.7% were CD38+, and 75.7% had chromosomal abnormalities by fluorescence in situ hybridization (e.g. 13q deletion, 30.7%; 11q deletion, 21.4%; trisomy 12, 14.3%; 17p deletion, 2.9%). The AE profile of G-FC did not show any unexpected safety signals. Most of the 140 pts reported ≥1 adverse event (AE) of any grade (98.6%), the most frequent (affecting >20% pts) were neutropenia (75.7% plus febrile neutropenia in 7.1%), nausea (42.1%), pyrexia (37.1%), thrombocytopenia (35%), anemia (25.7%), vomiting (25.7%), and diarrhea (20.7%). Infections were reported by 56.4% of pts, most commonly bronchitis (8.6%), pneumonia (7.1%), nasopharyngitis (7.1%), and upper respiratory tract infection (6.4%). In total, 87.1% of pts experienced grade 3-5 AEs; the 2 most common were neutropenia (67.1%) and thrombocytopenia (17.1%; Table 1); 15.7% of pts had grade 3-5 infections (most commonly pneumonia [5.7%]). Serious AEs were experienced by 42.1% of pts, most commonly neutropenia (15.7%), febrile neutropenia (6.4%), pneumonia (5.7%), and pyrexia (5.7%). AEs and AE categories of special interest included infusion-related reactions (IRRs: any grade, 69.3%; grade ≥3, 19.3%), malignant and unspecified second neoplasms of any grade (4.3%), and tumor lysis syndrome (TLS; 2.1%; all grade 3 and all laboratory TLS) (Table 1). There were 4 deaths, 3 (2.1%) considered related to AEs (1 sepsis, 1 second malignancy [acute myeloid leukemia], and 1 pneumonia) and 1 due to progressive disease (PD). AEs caused discontinuation of G and chemotherapy in 10% of pts, and discontinuation of chemotherapy only in 1 pt. Two additional pts discontinued G, 1 due to investigator decision and 1 withdrew consent. The overall response rate (iwCLL 2008) was 90% (126/140): complete response (CR; including CRi) was 46.4%, partial response 43.6%, stable disease 0.7%, and PD 1.4% (7.9% of pts had missing response data). With a median follow-up time of 24.2 months, median PFS was not reached (Figure 1). In IgVH mutated and unmutated pts, PFS rates at 2 years were 0.96 and 0.88, respectively. Six pts received new anti-leukemia therapy (NALT); time to NALT was 1.2-37.8 months. Of the 96 pts with blood samples available for minimal residual disease (MRD) assessment by flow cytometry (response defined as <1x10^-4 malignant B cells) at the final response assessment, 93.8% were MRD-negative (64.3% as proportion of all 140 pts) and of 69 pts with a bone marrow sample, 72.5% were MRD-negative (Table 2).

Conclusions: G-FC had manageable toxicity in previously untreated fit pts with CLL. Both the CR rate and the high MRD negativity rates achieved are favorable and indicate that the combination of G with FC chemotherapy may be a suitable option for previously untreated fit pts with CLL

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