Salvage Therapy with Obinutuzumab (GA101) Plus Chlorambucil (Clb) after Treatment Failure of Clb Alone in Patients with Chronic Lymphocytic Leukemia (CLL) and Comorbidities: Results of the CLL11 Study
Authors: Goede Valentin , Engelke Anja , Fischer Kirsten , Lopez Jimenez Javier , Kuzmin Alexej , Dyer Martin JS , Le Dû Katell , Liberati Anna Marina , Schlag Rudolf , Langerak Anton W , Ritgen Matthias , Stilgenbauer Stephan , Asikanius Elina , Humphrey Kathryn , Wenger Michael K , Fingerle-Rowson Günter , Hallek Michael 
Published: October 2019

Abstract
Introduction: Chemoimmunotherapy with the glycoengineered type II anti-CD20 antibody obinutuzumab plus the alkylating drug chlorambucil (G-Clb regimen) has been investigated in the CLL11 study and demonstrated clinical benefit in patients with previously untreated CLL and comorbidities. Whether G-Clb is also an active treatment in patients with refractory CLL after frontline therapy with Clb alone has been explored in the subpopulation of CLL11 subjects treated with such salvage therapy.
Methods: Thirty patients who received Clb alone as initial study treatment, but developed progressive CLL within up to 6 months after end of Clb treatment were offered G-Clb as optional salvage therapy. The dosing schedule for obinutuzumab was 100 mg intravenously on day 1, 900 mg on day 2, and 1000 mg on day 8 and 15 of cycle 1, and 1000 mg on day 1 of cycles 2-6. Clb was administered orally with 0.5 mg/kg body weight on day 1 and 15 of each 28-day cycle.
Results: The median age in the crossover patient population (n=30) was 72 years. The comorbidity burden was high as assessed at study entry (median cumulative illness rating scale total score 8), and renal function was reduced (median calculated creatinine clearance 67 mL/min). Deletions of 11q and 17p were present in 12% and 20% of the patients, respectively; and 64% had unmutated IGHV genes. When crossing over to G-Clb, the majority (93%) had not responded to the initial study treatment with Clb while two patients had responded transiently to Clb with a partial remission, but had relapsed early (median time from start of Clb to crossover: 9.7 months). After crossover, all but one patient completed the 6 cycles of salvage therapy with G-Clb; one subject discontinued after the first infusion of obinutuzumab due to an infusion-related reaction (IRR). Grade 3 or 4 IRRs occurred in 17% of the patients. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and infection were reported in 33%, 7%, 10%, and 13% of the patients, respectively. Response rates at the end of crossover treatment with G-Clb are given in the table. Negativity for minimal residual disease in bone marrow and/or peripheral blood after crossover treatment was achieved in 23% of the patients. The median progression-free survival from start of crossover treatment was 17.2 months (95% CI 14.2; 22.4 months) (median observation time: 23 months).
Conclusions: These results suggest that, besides its established role as frontline treatment of CLL, chemoimmunotherapy with G-Clb could be a safe and active treatment for patients with CLL refractory to prior chlorambucil chemotherapy.
Table: Clinical response to G-Clb after failure of Clb alone n (%) Responders 26 (87) Complete response 2 (7) Complete response incomplete 1 (3) Partial response 23 (77) Non-Responders 4 (13) Stable disease 2 (7) Progressive disease 1 (3) Not evaluable* 1 (3) * Due to early treatment discontinuation after IRR

Disclosures
Goede: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other. Off Label Use: Obinutuzumab (GA101, Gazyva); approved for 1st line treatment of CLL; paper includes results / discussion of drug use in 2nd line treatment of CLL. Engelke:Roche: Travel grants Other. Langerak:Roche: Research Funding. Ritgen:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding. Asikanius:Roche: Employment. Humphrey:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:Roche: Employment. Hallek:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.