clonoSEQ MRD testing and fixed-duration therapy in CLL: a potential clinical pathway
Based on available evidence, this clinical strategy reflects a potential approach for integrating blood-based clonoSEQ MRD testing into the management of patients with CLL.
Use of clonoSEQ MRD testing for prognostic evaluation by correlating MRD results to PFS.
337 newly diagnosed CLL patients assessed for MRD by clonoSEQ after three months of therapy.
Ability to predict clinical outcomes
clonoSEQ predicts outcomes three months after the completion of therapy
clonoSEQ predicts progression-free survival
The CLL14 study assessed the combination of obinutuzumab plus venetoclax versus obinutuzumab plus chlorambucil in previously untreated CLL patients with coexisting conditions. MRD was assessed in peripheral blood samples from 337 patients three months after completion of therapy using an MRD threshold of 10-5. U-MRD by clonoSEQ significantly predicted progression-free survival (PFS; P = 3.075 x 10-19; Figure 1) with a 6.64-fold higher event risk in MRD-positive patients compared to U-MRD patients (95% CI: 3.65-12.1).
Figure 1: Kaplan-Meier survival curves for PFS given clonoSEQ MRD detection at a threshold of 10-5 three months after completion of therapy
Lower levels of MRD are correlated with better outcomes
When assessing the correlation between clinical outcomes and continuous clonoSEQ MRD measurements (vs. a pre-defined sensitivity threshold), a patient’s risk of an event was shown to increase by 2.15-fold for every 10-fold increase in MRD (95% CI: 1.86-2.48).
Patients with U-MRD or very low levels of MRD detected by clonoSEQ have the best outcomes. Patients with clonoSEQ MRD < 10-6 or between 10-6 and 10-5 have longer PFS, followed by patients with MRD between 10-5 and 10-4 and patients with MRD ≥ 10-4 (P = 4.902 x 10-31).
These data demonstrate that patients with MRD < 10-5 have better outcomes than patients with MRD ≥ 10-5, and that increasing MRD levels above 10-5 are associated with an increased risk of disease progression within the follow-up time of this study.
Figure 2: Kaplan-Meier Survival Curve for PFS using clonoSEQ at four MRD levels in CLL: <10-6, 10-6 – 10-5, 10-5 – 10-4, ≥10-4
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Real-world case studies inform care
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Clinical studies show advantages to using clonoSEQ in CLL:
clonoSEQ predicts outcomes in both bone marrow and peripheral blood samples
Concordance between blood and bone marrow
In bone marrow samples, clonoSEQ is predictive of PFS
Thompson et al. assessed 62 previously untreated CLL patients who received therapy with fludarabine, cyclophosphamide, and rituximab (FCR). These patients were initially determined to be U-MRD by 4-color flow cytometry at an MRD threshold of 10-4. From these patients, 57 bone marrow (BM) samples were evaluated at the end of treatment by clonoSEQ. Patients who achieved the lowest levels of MRD in the bone marrow (10-5 – 10-6) or who had a U-MRD status (<10-6) experienced the best outcomes. Patients who had a U-MRD status at a threshold of < 10-5 had superior PFS compared to patients with MRD ≥ 10-5 (P = 0.01; Figure 3).
Figure 3: Patients who had a U-MRD status at a threshold of <10-5 had longer PFS compared to MRD-positive patients (≥10-5)
clonoSEQ predicts outcomes using either blood or bone marrow
An expanded analysis of the Thompson et al. data set supported the clinical validation of clonoSEQ. This data shows a significant association between PFS and continuous clonoSEQ MRD measurement (vs. at a pre-specified sensitivity threshold) in both blood and bone marrow, after end of treatment (P= 9.6 x 10-4 for blood; P= 2.13 x 10-4 for bone marrow). Additionally, patients who were MRD-negative at a threshold of 10-6 had longer progression-free survival compared to patients with MRD >10-6 (p = .02 for blood and p = 8.17E-05 for bone marrow).
Figure 4A and B: Patients with U-MRD (<10-6) had longer PFS compared to patients with detectable MRD whether assessed in blood or bone marrow
Clinical Practice Guidelines recommend MRD testing in CLL
NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for CLL recommend MRD testing at a sensitivity of at least 10-4. Next-generation sequencing (NGS) is listed as one of the recommended methods for MRD assessment.
NCCN makes no warranties of any kind whatsoever regarding its content, use, or application and disclaims any responsibility for how its content is applied or used, in any way.
This page is intended for a US-based audience.
clonoSEQ® is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect minimal residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). Additionally, clonoSEQ is available for use in other lymphoid cancers and specimen types as a CLIA validated laboratory developed test (LDT). IGHV testing is available as a CLIA-validated LDT and has not been cleared or approved by the FDA. For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit clonoSEQ.com/technical-summary.
Adaptive Biotechnologies does not recommend or endorse any particular course of treatment.
- clonoSEQ®. [technical summary]. Seattle, WA: Adaptive Biotechnologies; 2020. https://clonoseq.com/technical-summary.
- Thompson P, et al. Blood. 2019;134(22):1951-1959.
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia V.4.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed July 23, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.