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Clinical Trial
. 2018 Aug;32(8):1778-1786.
doi: 10.1038/s41375-018-0146-5. Epub 2018 Apr 27.

Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study

Affiliations
Clinical Trial

Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study

Stephan Stilgenbauer et al. Leukemia. 2018 Aug.

Abstract

GREEN (NCT01905943) is a non-randomized, open-label phase IIIb study investigating obinutuzumab alone or plus chemotherapy in chronic lymphocytic leukemia (CLL). We report a preplanned subgroup analysis of 158 previously untreated CLL patients receiving obinutuzumab-bendamustine (G-B). Patients received six 28-day cycles (C) of G-B: obinutuzumab day (D)1/D2 of C1 (25 mg D1/975 mg D2), 1000 mg D8 and D15 of C1, and D1 of C2-6; and bendamustine 70/90 mg/m2 D1 and D2 of C1-6. The primary endpoint was safety/tolerability. Grade ≥3 adverse events (AEs) occurred in 82.3% of patients, including neutropenia (49.4%), thrombocytopenia (12.0%) and febrile neutropenia (10.8%). Serious AEs included neutropenia (12.7%), febrile neutropenia (9.5%) and pneumonia (7.6%). Rates of grade ≥3 infections and infusion-related reactions were 20.3% and 17.1%, respectively. Due to tumor lysis syndrome (TLS; 8.2%), including two associated fatalities (one in another study cohort), additional risk-minimization measures were implemented. Overall response rate was 81.0%. After 32.8 months' median observation time, 2-year progression-free survival was 81.8%. Minimal residual disease was undetectable in 59.5% (94/158) and 27.8% (44/158) of patients for blood and bone marrow, respectively. Frontline G-B appears to have manageable toxicity with clinical activity in CLL. Careful TLS risk assessment, pretreatment and monitoring is required.

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Conflict of interest statement

SS reports consulting fees, research funding, honoraria and membership of advisory committees from Roche. VL reports speaker’s bureau fees, consulting fees, research funding, honoraria and membership of advisory committees from Roche; speaker’s bureau fees, consulting fees, honoraria and membership of advisory committees from Janssen; speaker’s bureau fees, honoraria and membership of advisory committees from Gilead and GSK; membership of advisory committees for AbbVie; and speaker’s bureau fees from Mundipharma. RF reports speaker’s bureau fees, consulting fees, honoraria and membership of advisory committees from Roche, Janssen, Celgene, AbbVie, Amgen and Novartis. SB reports consulting fees from Roche and AbbVie; research funding from Roche, AbbVie and Celgene; and honoraria from Roche, AbbVie and Beckton Dickinson. WK reports honoraria and participation in advisory boards for Roche and Mundipharma. CR reports research funding and membership of advisory committees from Roche and Celgene. FB reports consulting fees and honoraria from Roche, Novartis, Janssen, AbbVie, Gilead and Mundipharma; and research funding from Roche and Janssen. OI, EM, ET and DW report research funding from Roche. EG, LL, T Moore, T Morris and SR report employment from Roche.

Figures

Fig. 1
Fig. 1
Progression-free survival in patients receiving G-B in cohort 1 of GREEN: a in the overall study population; b in fit vs unfit patients; c by genomic aberrations, according to the hierarchical model [29]; d by IGHV mutation status; and e by MRD status at final response assessment in blood (intent-to-treat population). *CIRS ≤6 and CrCl≥ 70 ml/min; CIRS >6 and/or CrCl <70 ml/min; these data should be interpreted with caution as the subgroups are based on a study outcome, not baseline characteristics. There was also a low number of events (n = 20) and small number of MRD-positive patients (n = 9). The MRD-evaluable subgroup comprised patients who did not progress or die and had an MRD result available at the final response assessment in either blood or bone marrow (n = 105). The time window for MRD assessment was 77 to 168 days after last treatment. The MRD-‘missing’ subgroup included 54 patients. In addition, 1 out of 105 patients had a result available only in bone marrow and therefore came out as ‘missing’ in the blood population (therefore the ‘missing’ group in e is n = 55 and not 54). Reasons for ‘missing’ included sample not taken (n = 20), shipment could not take place within 48 h (n = 18), measurement was outside the time window for the final response assessment (n = 9) or other reason (n = 7). Eleven patients with missing MRD status (in blood and bone marrow) progressed (n = 5) or died (n = 6) within the period since last treatment dose up to 168 days. CIRS Cumulative Illness Rating Scale, CrCl creatinine clearance, G-B obinutuzumab plus bendamustine, IGHV immunoglobulin heavy variable chain, MRD minimal residual disease, PFS progression-free survival

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