‘Unequivocal’ data emerges from trial of CLL therapy guided by measurable residual disease
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SAN DIEGO — A combination of targeted therapies used for a response-directed duration significantly improved outcomes compared with chemoimmunotherapy for fit patients with untreated chronic lymphocytic leukemia, according to study results.
Ibrutinib (Imbruvica; Janssen, Pharmacyclics) plus venetoclax (Venclexta; AbbVie, Genentech) reduced risk for death by 69%, findings presented at ASH Annual Meeting and Exposition showed.
“The survival curves are very impressive — in fact, I don’t think they could’ve been much better given we conducted this trial during a pandemic,” researcher Peter Hillmen, MB, ChB, PhD, professor of experimental hematology at University of Leeds School of Medicine and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust, told Healio.
The results highlight how directing therapy duration according to patients’ measurable residual disease response can maximize outcomes, Hillmen added.
“This was based on a lot of work over the past 20 years. The depth of remission is critical and, from the modeling, we knew we had to get to the really low levels we can’t measure,” he said.
Background
Ibrutinib — an oral Bruton tyrosine kinase inhibitor — and venetoclax, a BCL-2 inhibitor, are approved in the United States for treatment of CLL.
In one component of the randomized phase 3 FLAIR study, researchers compared the ibrutinib-venetoclax combination with the FCR regimen — fludarabine, cyclophosphamide and rituximab — for patients with treatment-naive CLL who required therapy by conventional criteria.
The analysis included 523 patients aged 75 years or younger treated at 96 centers in the United Kingdom from July 2017 through March 2021.
Exclusion criteria included history of Richter’s transformation, greater than 20% TP53 deletion, and symptomatic cardiac failure or angina.
Methods
Patients assigned FCR received a conventional schedule for six cycles.
Patients assigned the combination received ibrutinib dosed at 420 mg/daily for 2 months. Venetoclax then was added with weekly escalation (20 mg daily to 400 mg daily) over 5 weeks, with combination therapy continuing for between and 2 to 6 years.
“Conventionally these drugs are either given as monotherapy until disease progression or, in the case of venetoclax, given in combination usually with an antibody for an arbitrary fixed duration of treatment,” Hillmen said. “In this trial we modified the duration of therapy by the response of patients.”
Traditional measurable residual disease testing can reliably measure complete response to 1 in 100,000 cells, Hillmen said. However, some patients treated to that level still relapse.
Through modeling, researchers identified a level at which patients could be potentially cured. To reach that level, treatment in the ibrutinib-venetoclax group continued for twice as long as it took patients to reach traditional measurable residual disease-negative status.
PFS served as the primary endpoint. Secondary endpoints included OS, response — including measurable residual disease — safety and toxicity.
Results
Median follow-up for PFS was 43.7 months.
Patients assigned ibrutinib-venetoclax exhibited an 87% reduced risk for progression or death (HR = 0.13; 95% CI, 0.07-0.24). A higher percentage of patients treated with the combination remained progression free at 3 years (97.2% vs. 76.8%).
Median follow-up for OS was 43 months.
Results showed a 69% reduction in risk for death among patients assigned ibrutinib-venetoclax (HR = 0.31; 95% CI, 0.15-0.67). At 3 years, 98% of those assigned the combination and 93% of those assigned the FCR regimen remained alive.
More than half (58%) of patients assigned the combination had stopped therapy due to undetectable measurable residual disease.
After 5 years of combination therapy, the majority of patients had undetectable measurable residual disease in the bone marrow (65.9%) and peripheral blood (92.7%).
The combination also improved outcomes across subgroups, with those who had IGHV-unmutated disease deriving considerable benefit (HR for PFS = 0.07; 95% CI, 0.02-0.19).
Safety analyses showed comparable risks for infections in the ibrutinib-venetoclax and FCR groups (22.2% vs. 18.8%). A higher percentage of patients assigned ibrutinib-venetoclax developed cardiac disorders (10.7% vs. 0.4%).
The rate of secondary malignancies was twice as high in the FCR group (incidence per 100 person-years, 5.4% vs. 2.6%), with the most striking difference being for myelodysplastic syndrome/acute myeloid leukemia (n = 8 vs. n = 1).
Perspective
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Mikkael A. Sekeres, MD
This is an exciting abstract on so many levels. We now have unequivocal randomized phase 3 data showing that ibrutinib and venetoclax improves overall survival compared with the old standard bearer of cytotoxic chemotherapy in CLL. We also have very clear guidance on how to use measurable residual disease in CLL to adjust the length of time that patients receive venetoclax and ibrutinib.
We have great new approaches that target specific abnormalities, but we have to keep giving them. Now we have some guidance for when to stop giving them. This has tremendous ramifications. A patient no longer has to sign on the dotted line to continue treatment ad infinitum. There’s now light at the end of the tunnel.
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Hillmen P, et al. Abstract 631. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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