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Optimal treatment of chronic lymphocytic leukemia (CLL) remains unclear. The Connect CLL Registry, a United States-based multicenter prospective observational cohort study, enrolled 1494 patients between 2010 and 2014 from predominantly community-based settings. Patients were grouped by line of therapy (LOT) at enrollment. With a median follow-up of 46.6 months (range, 0-63.0 months), median overall survival (OS) was not reached in LOT1, 63.0 months (95% confidence interval [CI], 46.0-63.0 months) in LOT2, and 38.0 months (95% CI, 33.0-47.0 months) in LOT≥3. Bendamustine and rituximab (BR; 33.5%); fludarabine, cyclophosphamide, and rituximab (FCR; 21.4%); and rituximab monotherapy (18.5%) were the most common regimens across LOTs. Median event-free survival (EFS) was similar in patients treated with BR (59.0 months) and FCR (55.0 months) in LOT1; median OS was not reached. In multivariable analysis, BR or FCR vs other treatments in LOT1 was associated with improved EFS (hazard ratio [HR], 0.60; P < .0001) and OS (0.67; P = .0162). Using the Kaplan-Meier product limit, ibrutinib vs other treatments improved OS in LOT2 (HR, 0.279; P = .009), LOT3 (0.441; P = .011), and LOT≥4 (0.578; P = .043). Prognostic modeling of death at 2 years postenrollment identified 3 risk groups: low (mortality rate, 6.2%), medium (14.5%), and high (27.4%). The most frequent adverse events across LOTs were pneumonia (11.6%) and febrile neutropenia (6.2%). These data suggest that advantages of LOT1 FCR over BR seen in clinical trials may not translate to community practice, whereas receiving novel LOT2 agents improved outcomes. This trial was registered at www.clinicaltrials.gov as NCT01081015., (© 2020 by The American Society of Hematology.)

Chemoimmunotherapy for chronic lymphocytic leukemia (CLL) promotes clonal evolution of aggressive clones, which in some patients may lead to early progression of disease (POD). We studied the prognostic value of early POD in a cohort of patients with CLL enrolled between 2010 and 2014 in the Connect CLL Registry. Overall, 829 eligible patients receiving first-line therapy were categorized into 3 groups: early POD (progression <2 years after treatment initiation), late POD (progression ≥2 years after treatment initiation), and no POD as of 1 May 2017. Baseline demographics, treatment characteristics, and overall survival (OS) were analyzed. Logistic regression models identified independent predictors of early POD; Cox regression models were used to evaluate the risk of early POD. With a median follow-up of 48.8 months, 209 (25.2%), 162 (19.5%), and 458 (55.3%) patients had early, late, and no POD, respectively. Patients with early POD were older and had inferior response to similar first-line treatment regimens vs late and no POD groups (overall response rate: 53% vs 80% vs 84%). Patients with early POD were more likely to have unfavorable-risk cytogenetics (del[11q]/del[17p]) than patients with no POD (34% vs 20%; P = .04). Early POD was associated with an inferior OS across all patients (hazard ratio, 3.6; 95% confidence interval, 2.6-5.1; P < .01) and in patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab ( P < .05). Early POD within 2 years of first-line therapy is a robust clinical prognostic factor for inferior OS in patients with CLL. The Connect CLL Registry was registered at www.clinicaltrials.gov as #NCT01081015., Competing Interests: Conflict-of interest disclosure: C.M.F. received research funding from Genentech and Gilead; received consulting and lecturing fees from Celgene Corporation, Genentech, Gilead, Janssen, Pharmacyclics, and Seattle Genetics; served on the advisory committee for Celgene Corporation; and received honoraria from Janssen. M.S.D. received research funding and served at the scientific advisory board for Genentech, Infinity, Pharmacyclics, and TG Therapeutics, and received consulting fees from AbbVie, Celgene Corporation, Gilead, Infinity, Janssen, Merck, and AstraZeneca. D.L.G. received consulting and lecturing fees from Celgene Corporation. N.E.K. received research funding from Gilead, Morphosys, Celgene Corporation, and Pharmacyclics. N.L. received research funding from AbbVie, Genentech, Gilead, Infinity, and Pronai; received consulting fees from AbbVie, Genentech, Gilead, Pharmacyclics, and Pronai; and served on the advisory committee for Celgene Corporation. A.M. received research funding from AbbVie, Gilead, Pronai, and TG Therapeutics; received consulting fees from AbbVie; and received lecturing fees from Celgene Corporation. C.N. is an employee of Cardinal Health. P.K., A.S.S., E.D.F., and K.S. are employees of Celgene Corporation and have equity ownership in Celgene Corporation. J.P.S. received consulting fees from Celgene Corporation, Genentech, Gilead, Pharmacyclics, and TG Therapeutics, and received lecturing fees from Gilead. C.R.F. received research funding from AbbVie, Acerta, Gilead, Millennium, Infinity, Janssen, Pharmacyclics, Spectrum, and TG Therapeutics, and received consulting fees from Bayer, Celgene Corporation, Genentech/Roche, Gilead, Millennium, Optum Rx, and Seattle Genetics. I.E.A. declares no competing financial interests.