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Confirmed overall survival benefit of obinutuzumab in combination with chlorambucil in patients with previously untreated CLL and comorbidities

The final survival analysis from the CLL11 study confirms that obinutuzumab in combination with chlorambucil (G-Clb) provides clinically meaningful benefits in chronic lymphocytic leukemia (CLL) patients with comorbidities. Compared to rituximab + chlorambucil (R-Clb) and chlorambucil (Clb) alone, G-Clb was found to be associated with a statistically significant improvement in overall (OS) and progression-free survival (PFS). The treatment with G-Clb resulted in an absolute treatment-free duration of approximately 4 years, while maintaining an acceptable and manageable safety profile.

Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody that is able to attack CLL by binding and destroying malignant CLL cells. At EHA 2018, the final analysis of the CLL11 study was presented with approximately 2 years of additional follow-up compared with previous analyses. The primary endpoint was investigator-assessed PFS, while the secondary study objectives included OS, time to new treatment (TTNT) and safety.

In this study, patients were randomized (1:2:2) to receive 6 28-day cycles of Clb, R-Clb or G-Clb. Clb (0.5 mg/kg) was administered orally on day 1 and 15 of cycle 1–6. R was administered intravenously at a dose of 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycle 2–6. G (1,000 mg) was administered intravenously on day 1 (dose split over 2 days; 100 mg day 1, 900 mg day 2), day 8 and day 15 of cycle 1, and day 1 of cycle 2-6. Eligible patients had previously untreated CD20+ CLL, a total Cumulative Illness Rating Scale (CIRS) score of >6 and/or a creatinine clearance (CrCl) of <70 mL/min.

A total of 781 patients were enrolled and received treatment (median age: 73 years; CIRS score: 8; CrCl: 62 mL/min). No new safety signals were identified at this update. After a median observation time of 62.5 months, treatment with G-Clb (n=238) was associated with improved outcomes compared with Clb alone (n=118). The median PFS with G-Clb reached 31.1 months versus 11.1 months with Clb alone (HR: 0.21; 95% CI: 0.16-0.28; p<0.0001). This PFS benefit also translated into a significant OS benefit with G-Clb over Clb alone (median not reached versus 66.7 months; HR: 0.68; 95% CI: 0.49-0.94; p=0.0196). Also the TTNT was significantly improved when G was added to Clb: median 55.7 versus 15.1 months (HR: 0.25; 95% CI: 0.19-0.35; p<0.0001).

After a median observation time of 59.4 months, G-Clb (n=333) demonstrated a clinically meaningful improvement in outcomes compared with R-Clb (n=330); median: PFS: 28.9 versus 15.7 months (HR: 0.49; 95% CI: 0.41-0.58; p<0.0001) and TTNT: 56.4 versus 34.9 months (HR 0.58, 95% CI 0.46-0.73, p<0.0001). Notably, G-Clb also provided a clinically meaningful improvement in OS compared with R-Clb; median OS: not reached versus 73.1 months (HR: 0.76; 95% CI: 0.60-0.97; p=0.0245). Two- and five-year survival rates were 91% versus 84% and 66% versus 57% for G-Clb versus R-Clb, respectively. Overall, fewer patients died in the G-Clb arm (37%) than in the R-Clb arm (45%). During the survival follow-up period, the most common cause of death was disease progression (G-Clb: 10%; R-Clb: 15%).

These findings support the use of G-Clb as first-line treatment for CLL patients with comorbidities, and suggest G as the preferred anti-CD20 antibody in future combination regimens for CLL. 



Goede V, Fischer K, Dyer MJ, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Presented during EHA 2018; Abstract S151.

Spreker Valentin Goede


Valentin Goede, MD, PhD, University Hospital, Cologne, Germany


Zie: Keyslides


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