Beyond Maximum Grade: a Novel, Longitudinal Toxicity Over Time (toxt) Adverse Event Analysis of Lenalidomide in Follicular Lymphoma in Calgb 50401 (alliance)
Year: 2017
Type: article
Abstract: Introduction: Chronically administered agents are increasingly used to treat indolent lymphomas. Tables of high grade (gr) adverse events (AEs) do not provide a time profile of AEs by severity and duration or describe longer lasting, low gr AEs pertinent to patients (pts) receiving continuous therapies for months to years. We developed a novel approach for AE analysis, the Toxicity over Time (ToxT, Thanarajasingam et al., Lancet Oncol 2016), a standardized package of graphical and analytical assessments that depicts AEs longitudinally. In Alliance A151617, we applied ToxT analyses to a phase II randomized multicenter trial to characterize time course and severity of AEs associated with lenalidomide (L) alone or with rituximab (LR) in pts with relapsed follicular lymphoma (FL). Methods: CALGB 50401 accrued 94 pts (L = 48, LR = 46). L was given in both study arms on days 1–21 of a 28-day cycle. ToxT plots depicting summary statistics or individual pt data over discrete time points were combined with longitudinal techniques (repeated measures modeling, time-to-event and area-under-curve [AUC] analyses) including assessment of chronic low gr events. Results: Standard CTCAE analysis identified neutropenia and fatigue as the most common gr 3+ adverse events on L and LR (16% v 20%, respectively, for neutropenia, and 9% v 13% for fatigue). With ToxT analyses, bar charts of incidence and gr per cycle (c) define the AE trajectory, showing a steady rise in neutropenia incidence and gr in both arms as treatment continued. Among pts on LR (Panel A), 4/43[9.3%] experienced gr1 neutropenia at c1 and 11/31[35.4%] experienced gr ≤ 3 at c9. In contrast, fatigue decreased in incidence and gr for pts in both arms over time (Panel B, 20/43[46.5%] gr1 ≤ 3 fatigue at c1 versus 11/31[35.5%] gr1 at c9 on LR). Stream plots depict decreasing mean gr of fatigue over time for both arms (mean across all gr including gr0 was 0.8 and 0.7 on L and LR, respectively, at c1 and drop to 0.4 and 0.4 by c9). Time-to-event bar charts indicate that for pts on LR, onset and worst gr fatigue (median: 8 and 8 days) occur early. In contrast, onset and worst gr of neutropenia occur late (median: 57 and 86 days). AUC analyses showed a similar burden of chronic low gr fatigue in both arms over time (AUC of 3.2 and 4.0 [p = 0.39] on L and LR, respectively). Keywords: follicular lymphoma (FL); lenalidomide; rituximab.
Source: Hematological Oncology
DOI: 10.1002/hon.2438_78
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2621451312