Obinutuzumab/Chlorambucil Solidified as Frontline CLL Option

Valentin Goede, MD

The combination of obinutuzumab (Gazyva, US; Gazyvaro, EU) and chlorambucil reduced the risk of death by 24% versus rituximab (Rituxan, US; MabThera, EU) plus chlorambucil in treatment-naïve patients with chronic lymphocytic leukemia (CLL) with comorbidities, according to long-term follow-up data from the phase III CLL11 study presented at the 2018 European Hematology Association (EHA) Congress.

In the final overall survival (OS) analysis, which occurred at a median follow-up of nearly 5 years (59.4 months), the median OS was not reached with the anti-CD20 monoclonal antibody obinutuzumab (Gazyva) plus chlorambucil compared with 73.1 months for the anti-CD20 monoclonal antibody rituximab plus chlorambucil (HR, 0.76; 95% CI, 0.60-0.97; P <.0245).

The obinutuzumab combination also reduced the risk of disease progression or death by 51% compared with the rituximab regimen. The median progression-free survival (PFS) was 28.9 versus 15.7 months, respectively (HR, 0.49; 95% CI, 0.41-0.58; P <.0001).

The time to next treatment (TTNT) was 56.4 months with obinutuzumab/chlorambucil compared with 34.9 months with rituximab/chlorambucil (HR, 0.58; 95% CI, 0.46-0.73; P <.0001). Additionally, the rate of minimal residual disease negativity was 24% versus 2%, respectively.

“Results from this final analysis of the CLL11 study support the use of obinutuzumab plus chlorambucil as front-line therapy in patients with CLL and comorbidities,” said lead study author Valentin Goede MD, Hematologist/Oncologist in the Department I of Internal Medicine at the University Hospital of Cologne in Cologne, Germany.

“These findings strongly suggest obinutuzumab be the preferred CD-20 antibody when combined with chlorambucil and also that obinutuzumab should be the preferred CD-20 antibody used in further combination regimens in CLL,” Goede continued.

The update presented at EHA also showed the benefit of obinutuzumab/chlorambucil over chlorambucil alone. At a median follow-up of 62.5 months, the median OS was not reached with the obinutuzumab combination versus 66.7 months with chlorambucil alone (HR, 0.68; 95% CI, 0.49-0.94; P = .0196). The median PFS was 31.1 versus 11.1 months (HR 0.21, 95% CI, 0.16-0.28, P <.0001), and the median TTNT was 55.7 versus 15.1 months (HR, 0.25; 95% CI, 0.19-0.35; P <.0001), respectively.

The CLL11 study, which was conducted by the German CLL Study Group, randomized 781 patients with previously untreated CLL and comorbidities in a 1:2:2 ratio to receive six 28-day cycles of chlorambucil (n = 118), rituximab plus chlorambucil (n = 330), or obinutuzumab plus chlorambucil (n = 333). Oral chlorambucil was given at 0.5 mg/kg on days 1 and 15 of cycles 1 through 6. Rituximab was administered intravenously (IV) at 375 mg/m² on day 1 of cycle 1 and at 500 mg/m² on day 1 of cycles 2 through 6. Patients on obinutuzumab received 1000 mg IV on day 1 (dose split over 2 days: 100 mg on day 1, 900 mg day 2), day 8, and day 15 of cycle 1, as well as on day 1 of cycles 2 through 6.

Patients had not received prior treatment for CD20-positive CLL and had a total Cumulative Illness Rating Scale (CIRS) score of >6 and/or a creatinine clearance (CrCl) of <70 mL/min. The median patient age was 73 years, the median CIRS score was 8, and the median CrCl was 62 mL/min. The final analysis was done after data cutoff in October 2017.

“The purpose of this study was to improve treatment of unfit elderly CLL patients by the use of immunochemotherapy and to compare the type 1 antibody rituximab with obinutuzumab head to head,” said Goede.

The updated safety analysis revealed no new safety signals. Overall, fewer deaths occurred with obinutuzumab/chlorambucil, where 37% of patients died during the survival follow-up compared to 45% of patients receiving rituximab/chlorambucil. The most commonly reported cause of death was disease progression in 10% of patients receiving obinutuzumab plus chlorambucil compared with 15% in the rituximab/chlorambucil arm.

Responding to a question regarding cost, Goede said “Of course the lower cost of rituximab, and especially rituximab biosimilars, comes into consideration, but the improved outcomes provided by obinutuzumab show that the second-generation antibody gets better results and should be considered over type 1 antibodies.”

Goede V, Fischer K, Dyer MJS, 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 at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S151.

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