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Minimal residual disease status correlates with PFS in CLL
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Quantifying minimal residual disease improved PFS predictions in patients with chronic lymphocytic leukemia who achieved a partial or complete response, according to the results of a systematic review of randomized phase 3 trials.
Persisting splenomegaly did not impact outcomes of patients with minimal residual disease (MRD)–negative partial response, although residual lymphadenopathy did, results also showed.
New therapeutic options and combination treatments have produced long-lasting responses and prolonged OS and PFS in patients with CLL.
“Given the availability of many new, highly efficacious compounds for the treatment of CLL, an enhanced assessment of the efficacy of these agents and their combinations before completion of follow-up is highly desirable,” Barbara Eichhorst, MD, PhD, of the Center of Integrated Oncology at University of Cologne in Germany, and colleagues wrote. “Quality of response as a potential efficacy endpoint in clinical trials, therefore, has attracted interest.”
The 2008 International Workshop on CLL recommended MRD assessment in clinical trials, and the FDA and European Medicines Agency are currently considering MRD as a putative endpoint for clinical trials.
The degree to which MRD and clinical response can predict PFS remains debated. European Medicines Agency guidelines require a complete response for MRD negativity; however, further study of the significance of MRD in patients who achieve partial response has been recommended.
Eichhorst and colleagues analyzed the results of two trials conducted by the German CLL Study group to determine the prognostic value of MRD in patients who achieved complete or partial response, as well as in patients with a partial response who presented with residual splenomegaly, lymphadenopathy or bone marrow involvement.
The study included data from 312 patients enrolled in the CLL10 trial and 242 patients enrolled in the CLL8 trial. The researchers analyzed MRD in peripheral blood at a threshold of 10-4, along with clinical response.
The median observation times was 45.3 months (range, 5.5-96.1) from randomization and 36.4 months (range, 2.6-82.7) from the end of treatment.
Median PFS from end of treatment was 61 months for patients with MRD–negative complete response, 54 months for patients with MRD–negative partial response, 35 months for patients with MRD–positive complete response and 21 months for patients with MRD–positive partial response.
The researchers did not observe a significant PFS difference between patients with MRD–negative complete response and MRD–negative partial response.
However, patients with MRD–negative partial response experienced significantly longer PFS than those with MRD–positive complete response (P = .048), and patients with MRD–positive complete response experienced longer PFS than those with MRD–positive partial response (P = .002).
Median OS has not been reached in patients with MRD–negative complete response, MRD–positive complete response or MRD–negative partial response. OS was comparable among patients with MRD–negative complete response compared with MRD–positive complete response (HR = 0.92; 95% CI, 0.37-2.26) and MRD–negative partial response (HR = 0.85; 95% CI, 0.45-1.61).
Patients with MRD–negative partial response had significantly shorter median OS (72 months) than patients with MRD–negative complete response (HR = 2.38; 95% CI, 1.44-3.94) and MRD–positive complete response (HR = 2.56; 95% CI, 1.09-6).
The researchers assessed the impact of bone marrow MRD in 351 patients with paired test results. Patients with negative test results in bone domains (40.7%) had a longer PFS than patients with negative MRD by peripheral blood but positive by bone marrow.
Patients who tested positive for MRD by peripheral blood and bone marrow had the shortest PFS.
Among all patients with MRD–negative partial response (n = 161), 48.4% had residual splenomegaly, 15.5% had residual lymphadenopathy, 11.2% had residual morphologic bone marrow involvement, and 24.8% had a combination of these.
Patients with residual lymphadenopathy had a significantly shorter PFS than those with MRD–negative complete response (30.9 months vs. 61 months; HR = 2.6; 95% CI, 1.53-4.4).
Contrastingly, patients with MRD–negative partial response and residual splenomegaly — as well as those with residual bone marrow involvement or more than one involved site — had no significant PFS difference. Further, patients with MRD–negative partial response and residual splenomegaly showed a PFS benefit compared with patients with MRD–positive complete response (63 months vs. 61 months; HR = 0.4; 95% CI, 0.22-0.71).
The researchers acknowledged study limitations, including their incomplete access to MRD samples.
“The determination of MRD in all patients with a clinical response will allow an early and accurate comparison of treatment efficacy in future randomized trials that are designed to achieve high-quality responses,” Eichhorst and colleagues wrote.
The findings of this meta-analysis should help to solidify the role of MRD in formulating treatment goals and predicting outcomes for patients with CLL, according to William G. Wierda, MD, PhD, professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, who wrote an accompanying editorial.
“MRD status is not yet a standard of care for patients with CLL,” Wierda wrote. “Data such as that reported by Kovacs and colleagues confirm correlation of MRD–free status at end of treatment with time-to-event endpoints (PFS and OS), which requires years of follow-up. MRD status as a surrogate endpoint may allow for earlier determination of more effective therapy and, in work by the German CLL Study Group, was used to model the PFS HRs in randomized trials. ... MRD status is an important and meaningful clinical endpoint that will likely guide future clinical trials and development for patients with CLL.” – by Cameron Kelsall
Disclosure: Eichhorst reports research funding and travel expenses from, as well as consultant and speakers bureau roles with, AbbVie, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Janssen Pharmaceuticals, Mundipharma and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures. Wierda reports research funding from and/or consultant roles with AbbVie, Acerta Pharma, Celgene, Emergent BioSolutions, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics and Sanofi.
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