The following article features coverage from the American Society of Clinical Oncology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Conventional adverse-event analysis (ToxC) concentrates on the incidence of grade 3 and higher events without considering exactly when adverse events of any grade may possibly occur. To address the need for analyses that account for chronic low-grade events and the overall burden of adverse events, researchers have developed a new metric that measures and illustrates the exact degree of this burden over time. The findings were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, on Sunday, June 2.

“Fifty years ago we were using chemicals to treat our patients and our focus was on: ‘Are they surviving these very, very toxic treatments that we are giving them?’” said lead study author Gita Thanarajasingam, MD, an assistant professor of medicine at the Mayo Clinic in Rochester, Minnesota. “Now we have oral targeted agents, we have immune therapies, we have all sorts of different approaches that are chronically administered and have drastically different toxicity profiles than the usual cytotoxic chemos. Yet our approach to adverse event assessment has not changed in parallel.”

The researchers applied both the conventional ToxC analysis and  a longitudinal, “Toxicity over Time” analysis to a trial in which patients with high-risk follicular lymphoma were randomized (1:2:2) to receive 1 of these 3 treatments: 6 cycles of bendamustine-rituxumab then rituximab maintenance for 2 years; 6 cycles of bendamustine-rituxumab-bortezomib then rituximab maintenance for 2 years; or 6 cycles of bendamustine-rituxumab then rituximab maintenance for 2 years and lenalidomide for 1 year.

In their analysis, the researchers included 3 laboratory and 5 symptomatic adverse events that had the highest incidence during maintenance in the first group — the one that received 6 cycles of bendamustine-rituxumab then rituximab maintenance for 2 years, and in the third one — the one that received 6 cycles of bendamustine-rituxumab then rituximab maintenance for 2 years and lenalidomide for 1 year. The investigators also analyzed treatment-related adverse events of any grade by conventional adverse event analysis (ToxC) and Toxicity over Time (ToxT). ToxT analysis included repeated measures, time-to-event, and area-under-the-curve analyses to record trends over time. Finally, maximum grade over time analysis combined the 5 symptomatic adverse events.

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The researchers looked at 147 patients randomly selected to receive treatments — including 88 who received lenalidomide along with rituximab maintenance, and 59 who received rituximab maintenance but not lenalidomide.

ToxC analysis of laboratory adverse events revealed that neutropenia was significantly more common in patients who received lenalidomide (84.1%) than those who did not (42%, b n < .001). ToxT found that neutropenia did not increase over time. In terms of symptomatic adverse events, ToxC showed 3.4% grade 3 or higher gastrointestinal adverse events. But the researchers also found that gastrointestinal adverse events of any grade were more common in the patients who received lenalidomide (59%) than those who did not (23%, P < .001).  ToxT area-under-the-curve analysis showed there was a higher burden of gastrointestinal adverse events over time among patients who received lenalidomide (unadjusted area under the curve: 2.6) than those who did not (unadjusted area under the curve: 0.9).

Time-to-event analysis showed that gastrointestinal adverse events occurred sooner among patients who received lenalidomide than those who did not; namely, 10% of those who received lenalidomide experienced a grade 2 or higher GI event by day 50, compared with 0% of those who did not receive lenalidomide (P =.03). This trend, however, improved over time across all groups of patients. Knowing that GI symptoms improve over time can be reassuring to patients, Dr Thanarajasingam said.

ToxT maximum grade over time analysis showed that grade 2 or higher adverse events were more likely to occur earlier among patients who received lenalidomide (63% by day 50) than those who did not (31% by day 50, P <.001). The analyses also demonstrated that overall adverse event burden over time was higher among patients who received lenalidomide (area under the curve 18.2) than those who did not (11.8, P <.001).

The findings showed that “longitudinal toxicity analysis was feasible across different datasets,” Dr Thanarajasingam said.

“The goal here is to use this information to directly guide [adverse event] interventions and symptom control measures and try to make cancer therapy more tolerable to our patients,” Dr Thanarajasingam noted.

Read more of Cancer Therapy Advisor‘s coverage of ASCO’s annual meeting by visiting the conference page.

Reference

Thanarajasingam G, Dueck AC, Novotny PJ, et al. Longitudinal toxicity analysis with novel summary metrics of lenalidomide maintenance in follicular lymphoma in ECOG-ACRIN 2408. Presented at 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 6511.