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493 Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green StudyClinically Relevant Abstract

CLL: Therapy, excluding Transplantation:
Program: Oral and Poster Abstracts
Type: Oral
Session: 642. CLL: Therapy, excluding Transplantation: Upfront CLL Therapy Excluding Transplantation
Monday, December 7, 2015: 7:00 AM
Valencia A (W415A), Level 4 (Orange County Convention Center)

Stephan Stilgenbauer, MD PhD1, Osman Ilhan2*, Darius Woszczyk3*, Christoph Renner4*, Eva Mikuskova5*, Sebastian Böttcher, MD6*, Eugen Tausch, MD7*, Tom Moore8*, Nicola Tyson9*, Helena Adamis8*, Véronique Leblonde10*, Francesc Bosch11 and Robin Foà12*

1University of Ulm, Ulm, Germany
2Ankara University, Ankara, Turkey
3State Hospital, Opole, Poland
4OnkoZentrum Zurich, Zurich, Switzerland
5National Cancer Institute, Bratislava, Slovakia
6Campus Kiel, University Hospital of Schleswig-Holstein, Kiel, Germany
7Department of Internal Medicine III, Ulm University Medical Center, Ulm, Germany
8F. Hoffmann-La Roche Ltd, Basel, Switzerland
9Roche Products Ltd, Welwyn, United Kingdom
10UPMC GRC11-GRECHY AP-HP Hôpital Pitié Salpêtrière, Paris, France
11Hospital Vall d'Hebron, Barcelona, Spain
12Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza” University, Rome, Italy

Background

The glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101; GAZYVA/GAZYVARO; G) combined with chlorambucil (Clb) has superior efficacy to Clb monotherapy and to rituximab plus Clb with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL), as shown in the CLL11 study (Goede V, et al. NEJM 2014). GREEN is an ongoing, non-randomized, multi-cohort phase IIIb study (NCT01905943) investigating the safety (primary objective) and efficacy of G alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL and assessing various strategies (cohorts 1–3) for reducing the rate of infusion-related reactions (IRRs) during the first infusion of G (Bosch F, et al. Blood 2014). We report safety and efficacy data from a subgroup of previously untreated patients in cohort 1 who received G-bendamustine (G-B).

Methods

Subjects were aged ≥18 years with documented CLL (except one case of SLL), an ECOG performance status of 0–2, and adequate hematologic function. Non-fit patients were those with a CrCl of <70 mL/min, and/or a CIRS score of >6. Fit patients comprised all others.

Treatment was six 28-day cycles of G-B, where G was administered IV on D1/D2 of C1 (split dose: 25mg D1/975mg D2), and 1000mg on D8 and D15 of C1 and D1 C2–6. B was administered ≥30 minutes after G on D1 and D2 of each cycle at 90mg/m2 IV, or at 70mg/m2in non-fit patients at the investigator’s discretion.

Safety endpoints included incidence, type and severity of AEs. Efficacy endpoints included ORR (investigator-assessed) and minimal residual disease (MRD) measured 3 months post-treatment. ORR was strictly assessed per International Workshop Group criteria (iwCLL 2008). Patients with missing response assessment components had their responses downgraded mandatorily. MRD negativity was defined as <1x10-4malignant B cells in peripheral blood or bone marrow aspirate, measured in a central laboratory by 4-color flow cytometry. The population comprised all patients from cohort 1 of GREEN who received at least a partial dose of both G and B, and was based on a data cut-off of 26 March 2015.

Results

With a planned overall sample size of 950 patients in GREEN, the G-B subgroup in cohort 1 comprised 158 patients (157 CLL, 1 SLL; 74 fit, 84 non-fit). Median age was 67.6 years, 15.8% of patients had a CIRS score of >6, and 44.9% had a CrCl of <70 mL/min; 31.6% of patients had Binet stage A disease, 38% Binet B, and 30.4% Binet C. 7.0% of patients’ disease displayed 17p deletion, 16.5% 11q deletion, and 58.2% unmutated IGHV. 91.1% of patients receiving B and 93.0% of those receiving G took ≥90% of the recommended total dose.

The safety profile of G-B was as expected. 50% of patients developed grade 3–5 neutropenia and 12.7% developed a grade 3–5 infection. Other common grade 3–5 AEs included thrombocytopenia (12.7%) and tumor lysis syndrome (TLS; 10.1%). The most common serious AEs were neutropenia (10.8%), pyrexia (7.6%), febrile neutropenia (7.0%), and TLS (5.1%). There were nine deaths – one due to progression, and eight due to AEs (considered related to study drug by the investigator: 1 infection, 1 sudden death, 1 acute hepatic failure, and 1 febrile neutropenia combined with TLS; considered unrelated: 2 infections and 2 secondary neoplasms). IRRs occurred in 55.7% of patients (15.2% grade 3–5, none fatal). Overall, 26 patients (16.5%) prematurely discontinued treatment due to ≥1 adverse event.

The ORR was 78.5% (124/158). The rate of CR (including incomplete CR [CRi]) was 32.3% (51/158), PR 46.2% (73/158), SD 10.8% (17/158), and PD 0.6% (1/158); 10.1% (16/158) of patients had missing data. Response rates were similar in non-fit (34.5% CR/CRi, 41.7% PR, 10.7% SD, and 1.2% PD) and fit (29.7% CR/CRi, 51.4% PR, 10.8% SD, and 0% PD) patients.

In an intent-to-treat analysis including all missing (not taken or evaluable) MRD results, MRD negativity was 58.9% (93/158, including 56 missing) in blood and 27.8% (44/158, including 95 missing) in bone marrow. With a median observation time of 11.2 months, PFS data were immature and the median was not reached.

Conclusions

Treatment with G-B in previously-untreated CLL patients is generally well tolerated and the observed toxicities are manageable and not unexpected. G-B achieves a promising rate of CRs and a high rate of MRD-negative remissions, and may offer a new treatment option for fit and non-fit patients with CLL.

Disclosures: Stilgenbauer: AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffman La Roche: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding . Off Label Use: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL.. Renner: Roche: Membership on an entity’s Board of Directors or advisory committees ; Celgene: Membership on an entity’s Board of Directors or advisory committees . Böttcher: Roche: Consultancy , Honoraria , Research Funding ; AbbVie: Consultancy , Honoraria , Other: Travel, accommodation, expenses , Research Funding ; Celgene: Research Funding ; Beckton Dickinson: Honoraria . Tausch: Gilead: Other: Travel support . Moore: Roche: Employment . Tyson: Roche: Employment , Equity Ownership . Adamis: Roche: Employment . Leblonde: Roche: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau ; Janssen: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Gilead: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; GSK: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Mundipharma: Speakers Bureau . Bosch: Roche: Consultancy , Research Funding , Speakers Bureau . Foà: Roche: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau .

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