Treatment Patterns and Outcomes of Patients with CLL Treated with Chemoimmuno- and Novel Agent-Based Therapy: A Multicenter Study
Authors: Mato Anthony R , Sarraf Yazdy Maryam , Hill Brian T. , Shadman Mazyar , Tuncer Hande , Winter Allison M. , Kennard Kaitlin , Allan John N. , Ujjani Chaitra S. , Brander Danielle M. , Nabhan Chadi , Barr Paul , Brown Jennifer R. , Fox Christopher P. , Rhodes Joanna , Schuh Anna , Eyre Toby A. , Lamanna Nicole , Jain Nitin , Wierda William G. , Skarbnik Alan P , Roeker Lindsey E. , Bannerji Rajat , Evens Andrew M. , Lansigan Frederick , Samp Jennifer C. , Nielsen Jacqueline , Pauff James M. , Kipps Thomas J. , Schuster Stephen J. , Follows George A , Cheson Bruce , Eichhorst Barbara 
Published: October 2019

Abstract
BACKGROUND: Targeted B-cell receptor signaling pathway inhibitors have changed the treatment landscape of chronic lymphocytic leukemia (CLL); however, treatment decisions remain challenging due to emergence of therapeutic resistance and uncertainties regarding optimal sequencing of therapies. Clinical trials have focused on single treatment options and reported limited outcome data. With increasing options for CLL treatment, research on how to best sequence CLL treatments is needed to optimize patient outcomes.
METHODS: The CLL Collaborative Study of Real-World Evidence (CORE) study is a retrospective, multicenter, international, collaborative observational study of patients (pts) with CLL treated at either community or academic sites. For this analysis, pts were randomly selected and eligible for inclusion if they started 1st-line CLL therapy from January 1st, 2012 through present. Demographics, clinical characteristics, treatment patterns, and progression-free survival (PFS) were evaluated. The reason(s) for discontinuing 1st-line and initiating 2nd-line therapy were collected; multiple reasons could be selected. For this analysis, pts were grouped according to whether they received novel agent-based therapy (eg, ibrutinib, idelalisib, venetoclax) or chemotherapy/chemoimmunotherapy (CT/CIT) as 1st-line treatment.
RESULTS: Of 351 pts studied, 179 received CT/CIT and 172 received novel agents as 1st-line therapy. Patient data, stratified by 1st-line therapy (CT/CIT vs. novel agents), are shown in Table 1. Most pts were treated in community settings (81%). The median ages were 62 and 66 years for pts receiving CT/CIT and novel agents, respectively. Demographics were generally similar between CT/CIT and novel agent groups with one exception: 17p deletion/TP53 mutations were present in 20% who received novel agents, compared to only 4% who received CT/CIT (p <0.0001). The most common 1st-line CT/CIT treatments were bendamustine + rituximab (56%; 101/179), fludarabine + cyclophosphamide + rituximab (20%), chlorambucil + obinutuzumab (8%), and fludarabine + rituximab (5%). The most common novel-agent based therapies were ibrutinib (80%; 138/172), ibrutinib + rituximab (7%), and venetoclax-based treatments (7%). Median follow up was longer for pts who received CT/CIT compared to novel agents in the 1st-line (15.6 vs. 9.9 months). For pts with intact 17p and nonmutated TP53 (n=286), the 12-month PFS was 90% and 87% for pts who received CT/CIT and novel agents as 1st-line, respectively (unadjusted hazard ratio: 1.11 [95% CI 0.6-2.0]; p = 0.73). Among pts treated with 1st-line CT/CIT, 27% (n=49) received 2nd-line therapy after a median of 14.2 months; the majority initiated 2nd-line due to relapse/progression (84%; 41/49). Of pts treated with novel agents in the 1st-line, 31% (n=53) discontinued and 18% (n=31) initiated 2nd-line therapy; common reasons for discontinuing novel agents were disease progression/refractory to treatment (34%; 18/53), completed scheduled duration of treatment (30%; 16/53), and adverse events/intolerance (19%; 10/53). The most common reason for initiating 2nd-line therapy after 1st-line novel agent was relapse (48%; 15/31); median time to next treatment was 8.0 months. Regardless of 1st-line therapy, >80% of pts received a novel agent-based therapy as 2nd-line treatment.
CONCLUSIONS: In this study, pts with CLL treated since 2012 with CT/CIT or novel agent-based therapies (87% ibrutinib-based) in 1st-line had similar demographics; notably, more pts with 17p deletion/TP53 mutation were treated with novel agents. Although treatment failure was the primary reason for initiating 2nd-line therapy, many pts discontinued novel agents for other reasons, including adverse events and, unexpectedly, completion of therapy. With limited follow-up, in patients largely from community setting, PFS was similar between pts treated with CT/CIT and novel agents; more analyses are necessary to determine whether outcomes are impacted due to discontinuation of treat-to-progression novel agents for reasons other than progression. Overall, novel agents were the 2nd-line therapy of choice, irrespective of 1st-line therapy. These data constitute a first-look at CORE, a long-term study designed to determine how novel therapies and treatment sequencing impacts adverse events and outcomes in the treatment of CLL.

Disclosures
Mato: TG Therapeutics: Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Prime Oncology: Speakers Bureau; AstraZeneca: Consultancy; Acerta: Research Funding; Regeneron: Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Consultancy; Janssen: Consultancy, Honoraria. Sarraf Yazdy:Bayer: Speakers Bureau. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shadman:Abbvie: Consultancy; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding; AstraZeneca: Consultancy; Gilead: Research Funding; Mustang: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Celgene: Research Funding; Genentech: Consultancy, Research Funding; Acerta: Research Funding; Verastem: Consultancy. Kennard:AbbVie, Gilead, Verastem: Consultancy. Allan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees. Ujjani:AbbVie: Consultancy, Speakers Bureau. Brander:Novartis: Consultancy, Other: DSMB; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Nabhan:Cardinal Health: Employment, Equity Ownership. Barr:AbbVie, Gilead: Consultancy. Brown:Abbvie: Consultancy; Verastem: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Sun Pharmaceutical Industries: Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Celgene: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy; Roche/Genentech: Consultancy. Fox:Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Sunesis: Consultancy. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Eyre:AbbVie, Gilead, Janssen: Honoraria, Other: Travel support. Lamanna:AbbVie, Genentech, Gilead, Verastem, Bei-Gene, TG Therapeutics, Acerta: Research Funding; AbbVie, Celgene, Roche-Genentech, Janssen, Pharmacyclics, Gilead, Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Jain:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Cellectis: Research Funding; Servier: Research Funding; Pfizer: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Verastem: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Abbvie: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Skarbnik:Gilead Sciences: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bannerji:AbbVie, Inc.: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Samp:AbbVie: Employment, Equity Ownership. Nielsen:AbbVie, Inc: Employment, Equity Ownership. Pauff:AbbVie: Employment, Equity Ownership. Kipps:Celgene: Consultancy; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Genentech Inc: Consultancy, Research Funding. Schuster:Genentech: Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding. Follows:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding.