Characterization of Real World Survival Outcomes Among Older Adults with Chronic Lymphocytic Leukemia Receiving Second Line Treatment in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database
Authors: Mato Anthony R. , Jahnke Jordan , Li Pengxiang , Mehra Maneesha , Ladage Vrushabh P , Mahler Michelle , Fanning Molly , Doshi Jalpa A , Huntington Scott F 
Published: October 2019

Abstract
Introduction: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries with a median age of 72 years at diagnosis. Prior to the introduction of kinase inhibitor therapies, chemoimmunotherapy (CIT) combinations, monoclonal antibody monotherapies, and chemotherapy combinations were the predominant therapy regardless of line of CLL treatment. Given the increased frequency of high-risk features (del17p, del11q,) and prior exposure to CIT combinations, shortened disease-free periods and increased short-/long-term toxicities are frequently seen in relapsed CLL setting. However, data from recent randomized clinical trials of novel agents, such as ibrutinib in the relapsed setting, have shown significant improvements in overall survival (OS). While we await real-world data on how novel agents impact real-world CLL outcomes, little is known about the management and survival among CLL patients prior to their availability, particularly in the relapse setting. Our study uses comprehensive prescription and medical insurance claims linked with registry data to describe survival outcomes in older adults with CLL receiving second line treatment between 2007-2013--an era that predates the approvals of ibrutinib, idelalisib, venetoclax and obinutuzumab.
Methods: This retrospective cohort study used the 2007 to 2013 SEER-Medicare linked database. The sample included patients with first primary tumor site as CLL or SLL (ICD-O histology codes '9670' and '9823') diagnosed between 2007 and 2011. This date of first diagnosis of CLL or SLL defines the index date. Patients aged > 65 years with Medicare fee-for-service coverage in the 12 months pre-index and Medicare fee-for-service and prescription drug coverage in the 6-months post-index period or until death were included. Second line treatment date was defined as the date a treatment was received that was not part of the initial therapy or the date where initial therapy was restarted after a 180+ day gap in treatment. Our primary study outcome was overall survival (OS) from the date of initiation of second line treatment. The association of patient-level characteristics with OS was measured using cox regression analysis.
Results: Of the 1047 patients who received any CLL treatment, 387 (37%) patients met the definition for receiving a second line of therapy. The mean age of this second line cohort was 76 years (SD = 6) and 48.3% were male. Only 9 patients who left fee-for-service Medicare during the second line follow up period were excluded from analysis. Of our 387 patient cohort, 25.3% (n=98) received fludarabine as part of their initial treatment, with remaining 74.7% (n=289) receiving a non-fludarabine containing initial therapy. The median time from CLL diagnosis date to second treatment was 664 days (Q1-Q3 390-1159 days). Rituximab containing regimens were the most common second line treatment (n=276, 71.3% of patients), with 118 patients (30.5%) in our second line cohort receiving rituximab monotherapy. Another 35 (9%) patients received chlorambucil monotherapy and the remaining 76 (19.6%) patients received a non-rituximab mono- or combination chemotherapy as their second line treatment. The median follow-up time in the sample from second line treatment was 14.9 months. Median OS for the cohort from initiation of their second line of treatment was 34.3 months, with 72% OS at 1-year and 58% at 2-years (See Figure). Multivariate Cox regression modeling showed OS from second line of treatment was associated with year of CLL diagnosis (2011 vs. 2007, HR 2.2; p=0.02), higher age at time of treatment (70-74 vs 80+, HR 0.67; P=0.04), male gender (HR 1.5; P=0.01), Northeast census region (vs West, HR 1.7; P=0.01),and initial treatment that included fludarabine (HR 1.5; P=0.04).
Conclusions: In our real world analysis, over one-third of the newly diagnosed CLL patients who received treatment progressed to second line therapy. We found poor survival in these older adults following initiation of second line CLL therapy treated in the pre-kinase / BCL-2 inhibitor era with about half who died within two years of initiating second line therapy. While available clinical trials suggest novel CLL agents offer significant improvements in OS in relapsed CLL, future studies should examine real world CLL outcomes to correlate how results obtained in recent landmark clinical trials translate into clinical practice.

Disclosures
Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Mehra:Janssen: Employment, Equity Ownership. Mahler:Janssen Research & Development: Employment. Doshi:Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Other: Spouse owns stock in company, Research Funding; Alkermes: Membership on an entity's Board of Directors or advisory committees; Forest Labs: Membership on an entity's Board of Directors or advisory committees; National Pharmaceutical Council: Research Funding; PhRMA: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Merck & Co., Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Spouse owns stock; Sanofi: Research Funding; Humana: Research Funding. Huntington:Pharmacyclics: Honoraria; Celgene: Consultancy, Honoraria; Johnson & Johnson: Consultancy; Oncosec Medical: Equity Ownership; Exelixis: Equity Ownership; Geron: Equity Ownership.