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MRD negativity predicts long-term survival in CLL
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Minimal residual disease negativity is an independent predictor of long-term PFS and OS in patients with chronic lymphocytic leukemia, according to a retrospective analysis.
In addition, minimal residual disease (MRD) conferred the greatest prognostic benefit when achieved in the upfront setting.
MRD can be reliably detected following complete remission from CLL, and most trials have shown a consistent correlation between posttreatment MRD level and therapeutic outcome.
“However, the independent prognostic relevance and long-term benefit of MRD negativity in other therapeutic settings, such as with chemotherapy-free treatments, remain unclear,” Peter Hillmen, MD, PhD, professor of experimental hematology at Leeds Institute of Cancer and honorary hematology at Leeds Teaching Hospitals NHS Trust, and colleagues wrote. “Moreover, a direct comparison of the clinical impact of MRD negativity between frontline and relapsed/refractory settings has not hitherto been undertaken.”
The researchers analyzed all patients with CLL who completed treatment from 1996 to 2007, achieved at least partial response, and underwent a bone marrow MRD assessment within 6 months of treatment completion to assess the long-term prognostic value of MRD status across various therapeutic settings and treatment modalities.
Of the 133 patients analyzed, 67 received combination chemotherapy or chemoimmunotherapy, 31 received single-agent chemotherapy, seven underwent autologous stem cell transplantation, and 28 were treated with chemotherapy-free regimens.
In addition, 55 patients were MRD negative posttreatment — defined as less than one CLL cell detectable per 10,000 leukocytes (< 0.01%). This included 46 patients with complete responses and nine with partial responses.
Median follow-up was 10.1 years (range, 7.8-18.6).
Researchers compared outcomes of patients who were MRD negative with the outcomes of patients with MRD levels of 0.01% to 1%, and patients with levels greater than 1%. Results showed patients who were MRD negative demonstrated superior median PFS (7.6 years vs. 3.3 vs. 2) and OS (10.6 years vs. 5.3 vs. 3.6).
“Patients with MRD–negative partial response appeared to have outcomes intermediate between patients with MRD–negative complete response and those with MRD–positive complete/partial response,” the researchers wrote.
A greater proportion of patients who attained MRD negativity upfront achieved 10-year PFS (65% vs. 10%) and 10-year OS (70% vs. 30%) compared with MRD–positive patients.
Survival outcomes were not as high among patients who achieved MRD negativity in the relapsed or refractory setting in terms of 10-year PFS (30% vs. 0%) and 10-year OS (47% vs. 11%).
“The prognostic significance of MRD with novel treatments will need to be prospectively validated,” the researchers wrote. “In the future, chemotherapy-free combinations may potentially allow MRD eradication with minimal toxicity, making MRD negativity a feasible therapeutic goal.” – by Kristie L. Kahl
Disclosures: The researchers report no relevant financial disclosures.
Perspective
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Brian T. Hill
Despite the influx of novel targeted agents for chronic lymphocytic leukemia, conventional chemoimmunotherapy remains commonly used in the frontline setting for most patients, a proportion of whom may experience long-term remissions that may be durable beyond 10 years.
In the study by Kwok and colleagues, the researchers evaluated the impact of minimal residual disease (MRD) on treatment outcomes using data from a long-term historical cohort of patients treated in the U.K. The assay used for MRD detection from bone marrow aspirates was capable of detecting one cell in 10,000 (0.01%).
The researchers report that patients who had no MRD detectable at the conclusion of frontline treatment had a 65% PFS rate at 10 years, relative to 10% for those with detectable MRD. This also translated into a significant OS benefit. It should be noted that only responding patients were included in the analysis, and treatment did not uniformly incorporate an anti-CD20 monoclonal antibody.
What are the implications of this study? Due to very long follow-up, the current report strengthens the mounting evidence that a subset of patients treated with conventional therapy can enjoy very long-term remissions without progression, possibly being cured of CLL. This appears to be true for patients with CLL characterized by mutated immunoglobulin heavy chain variable gene who achieve MRD negativity with intensive treatment such as FCR (fludarabine, cyclophosphamide and rituximab [Ritxuan; Genentech, Biogen). However, due to the concerns of late toxicities of such therapy, particularly secondary myelodysplasia, there is significant interest in limiting excessive exposure to these potentially genotoxic agents.
As methods to detect MRD have increased in sensitivity relative to the technique used in this study, several questions remain. In particular, is MRD negativity a surrogate for favorable disease biology, or should it be a goal of therapy with conventional as well as targeted therapy in the future? Answering these questions will require analysis of further prospective study with the goal of individualizing treatment regimens so as to achieve optimal disease control while avoiding excess toxicity.
Reference:
Thompson PA, et al. Blood 2016; doi: 10.1182/blood-2015-09-667675.
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