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Assistant Professor of Medicine
Division of Hematologic Malignancies & Cellular Therapy
Department of Medicine
Attending Physician, Hematologic Malignancies
Duke University Health System
Durham, North Carolina
Danielle M. Brander, MD, has disclosed that she has received consulting fees from AbbVie, ArQule, AstraZeneca, Genentech, Pfizer, Pharmacyclics, Teva, TG Therapeutics, and Verastem and funds for research support paid to her institution from AbbVie; ArQule; Ascentage; AstraZeneca; BeiGene; DTRM; Genentech; Juno Therapeutics, a Bristol-Myers Squibb company; MEI Pharma; Pharmacyclics; TG Therapeutics; Tolero; and Verastem.
As more patients begin to receive highly efficacious targeted agents and novel combination therapies for the treatment of chronic lymphocytic leukemia (CLL), having the right metrics to assess disease and to guide decisions regarding the duration of therapy is essential. How do we achieve deeper minimal residual disease (MRD) negativity? Why does that matter? And when should MRD negativity be used in clinical practice? Here, I review clinical trial data probing the role of MRD evaluation during CLL management.
Improving MRD Negativity Rates
The phase III CLL14 trial compared venetoclax vs chlorambucil, each combined with obinutuzumab, in patients with previously untreated CLL and coexisting medical conditions. At the end of therapy, a greater proportion of venetoclax-treated patients had achieved MRD negativity by bone marrow assessment: 57% vs 17% with the chlorambucil-based combination. This MRD negativity predicted a more favorable 24‑month PFS in both arms compared with those testing MRD positive. This suggests that reaching MRD negativity may be an important benchmark for patients. Of note, at initial reporting in this trial, 6 of 14 venetoclax-treated patients experiencing progressive disease harbored high-risk prognostic markers, namely, a TP53 deletion or mutation (or both). Especially in this subset of patients, evaluating MRD may be critical when considering treatment trajectory, and the cessation of fixed-duration venetoclax at 12 months may not be ideal.
Recently, to increase the depth of response in patients with CLL, various trials have been evaluating the combination of BTK inhibitors and venetoclax. Achieving MRD negativity with BTK inhibitor monotherapy is fairly rare, but venetoclax is effective at eradicating disease in the bone marrow compartment. One phase II study by Jain and colleagues is examining treatment-naive high-risk CLL using combined ibrutinib and venetoclax to increase the depth of response. In this trial, serial examination of MRD status via bone marrow biopsy showed that the proportion of patients reaching MRD negativity increased after each successive 3-month interval, including through a second year of treatment. Again, this reinforces the potential use of extending venetoclax therapy past 12 months when appropriate. Because cytopenias accompany the use of this regimen, close monitoring would be required throughout administration. Another potential advantage to this combination is that initial treatment with a BTK inhibitor reduces the tumor burden before venetoclax initiation, reducing the risk of tumor lysis syndrome.
Harnessing MRD Evaluation by Blood
Results from the phase II CAPTIVATE trial, also pairing frontline ibrutinib with venetoclax, were similar to the MD Anderson Cancer Center data in that the prevalence of MRD negativity increased over the course of treatment. Another key point to be made is how concordant the MRD results were between peripheral blood and bone marrow assessments. CAPTIVATE and other key studies of novel agents have highlighted this phenomenon wherein, as time goes on, the peripheral blood begins to match blood in the marrow. This is encouraging, as the incorporation of peripheral blood MRD testing in clinical practice would be preferred to repeated bone marrow biopsies.
Truncating Salvage Therapy for CLL
A correlation between deeper remission and extended PFS has also been observed in the setting of relapsed/refractory CLL, including among patients enrolled in the phase III MURANO trial comparing venetoclax and bendamustine, each in combination with rituximab.
Efficacious fixed-duration treatment strategies afford the patient a reduction in toxicity and financial burden. With that in mind, the phase II CLARITY trial formulated treatment-stopping rules based on MRD status to determine if combination ibrutinib plus venetoclax should be discontinued at 12 months or if continued ibrutinib monotherapy would be required for relapsed/refractory CLL. After 12 months of combination treatment, 58% of patients achieved undetectable MRD (< 0.01% CLL cells by flow cytometry) in peripheral blood, and 40% achieved that in bone marrow. Furthermore, the rate at which depletion occurred during the first 2 months of therapy correlated with response rate. These results hint that there are patients for which an MRD-guided cessation of salvage therapy may be reasonable.
The potency of combination therapy with BTK inhibitors and venetoclax is clear. Many patients with CLL achieve MRD negativity, both in the peripheral blood and bone marrow. At present, using MRD evaluation to direct CLL treatment decisions is not standard of care because we do not yet know whether reaching MRD negativity reliably translates to long-term or even permanent disease eradication. We need more time and follow-up data from these and other ongoing studies to clarify this relationship.
Do you anticipate discussing the potential implications of MRD status with your patients who have CLL? Share your experience by answering the poll question or leaving a comment. I also invite you to hear extended remarks on CLL management in this on-demand Webcast, on which I am joined by my colleagues Drs. Jeff Sharman and Nicole Lamanna.
Click here to use CCO’s “Interactive Decision Support Tool: Expert Guidance for the Treatment of CLL” to receive management recommendations from a panel of 5 experts for a wide variety of patient presentations. (Update Coming Soon!)