Randomized Trial in Unfit, Elderly Chronic Lymphocytic Leukemia (CLL) Patients with Comorbidities of Dose-Reduced Oral Fludarabine and Cyclophosphamide Plus Obinutuzumab (FC+G) Versus Chlorambucil Plus Obinutuzumab (Cbl+G) As Front-Line Therapy
Authors: Mulligan Stephen P. , Freeman Jane A. , Badoux Xavier , Eek Richard , Cull Gavin , Mackinlay Naomi J. , Murphy Nicholas E. , Carradice Duncan P. , Solterbeck Ann C. , Best Oliver Giles , Tam Constantine S. , Kuss Bryone J. 
Published: October 2019

Abstract
BACKGROUND
The prior Australasian Leukaemia and Lymphoma Group (ALLG) CLL5 Study showed dose-reduced oral fludarabine and cyclophosphamide plus rituximab (FCR3) was safe, tolerable and effective in fit elderly patients for front-line therapy for CLL. The German CLL11 Study showed chlorambucil plus obinutuzumab (Cbl+G) was superior to chlorambucil alone or with rituximab in unfit patients requiring initial therapy. We conducted a randomized study to assess the safety, tolerability, and efficacy of dose-reduced FC + obinutuzumab (G) (FC+G) versus Cbl+G in unfit (i.e. with comorbidity), elderly patients with CLL.
METHODS
Patients aged ≥65 years and considered "unfit" defined by co-morbidities using the Cumulative Illness Rating Scale [CIRS] ≥6 were eligible for the ALLG CLL7 study. Patients with any single organ system score ≥4 were excluded. Previously untreated patients with progressive CLL aged ≥65 and CIRS ≥6 were randomised to one of 2 therapy arms: (i) Chlorambucil 0.5mg/kg D1+15 p.o. + obinutuzumab ("G") (i.v. 1000mg/m2 cycle 1, Day 1, 8, 15, and 1000mg/m2 D1 cycles 2-6), or (ii) FC(rd)+G: F-24mg/m2 p.o. and C-150mg/m2 p.o. D1-3 + G (same schedule above) at 4 weekly intervals for planned 6 cycles. Early stopping for toxicity was mandated: treatment could be delayed for 2 weeks for grade 3+ toxicity, but if unresolved by 2 weeks, patients were taken off study. The primary end-point was grade 3+ non-hematological, and grade 4 hematological adverse events. Secondary objectives were overall response rate (ORR), complete remission (CR), partial remission (PR), progression-free survival (PFS) and overall survival (OS) and minimal residual disease (MRD) negativity. Final staging was performed between 2-3 months following final treatment cycle.
RESULTS
Patient characteristics Patient recruitment was terminated early due to poor recruitment. At the time of study closure, there were 32 patients, with 15 on Cbl+G and 17 on FC(rd)+G. The mean age was 74.2 years (range 66-85 years) with 23 females (71.9%) and 9 males (28.1%). The CIRS score was 6 in 4 patients (12.5%), 6-8 in 14 (43.8%), 8-10 in 11 (34.4%) and >10 in 3 (9.4%). Binet stage at registration was stage A 18.2%, B 27.3% and C 54.5%.
Tolerability Both therapies were tolerable with 15/17 (88.2%) completing all 6 cycles of FC(rd)+G and 12/15 (92.3%) completing six cycles of Cbl+G.
Toxicity Most toxicity was hematological and manageable. Grade 3/4 hematological toxicity was more common with FC(rd)+G than Cbl+G occurring in 60% with FC(rd)+G and 38.5% with Cbl+G (Table 1). There was one death due to progressive CLL on the FC(rd)+G arm.
Response rate A complete remission (CR), confirmed by bone marrow (BM) trephine, was achieved in 86.6% of patients on FC(rd)+G versus (vs) 53.9% on Cbl+G, partial response (PR/nPR) in 1 (6.7%) on FC(rd)+G, and 6 (46.2%) on Cbl+G, and either stable or progressive disease (SD or PD) on 1 on FC(rd)+G, and nil on Cbl+G. BM MRD-negativity rates were 3/17 (20.0%) FC(rd)+G vs 1/15 (7.7%) Cbl+G (Table 2).
CONCLUSION
This randomized trial of dose-reduced FC(rd)+G vs Cbl+G in elderly patients aged ≥65 and with co-morbidities (CIRS ≥6) was terminated early due to poor recruitment. Due to the dose-reduced FC, and early stopping rule, treatment was safe and tolerable and most patients completed all 6 cycles of planned therapy. Grade 3/4 toxicity was mainly hematological and manageable, with higher rates of neutropenia with the FC (60%) vs Cbl (35.7%) backbone. FC(rd)+G compared to Cbl+G resulted a higher CR rate of 86.6%% versus 53.9%, and higher MRD-negativity (20% vs 7.7%). Progression-free and overall survival are being evaluated.

Disclosures
Badoux: Roche: Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.