Minimal residual disease or MRD offers a highly independent prognostic factor for leukemia patients and assessment with clonoSEQ, developed by Adaptive Biotechnologies, improves outcomes both for patients and the healthcare system, as patients with undetectable MRD may be able to discontinue active treatment.
That is the conclusion based on new real-world data presented during the 62ndAmerican Society of Hematology (ASH) Annual Meeting and Exposition, hosted virtually from 5-8 December 2020, highlighting the clinical utility of the next-generation sequencing (NGS) clonoSEQ® Assay to assess minimal residual disease (MRD) in patients with multiple myeloma.
Minimal residual disease
Minimal residual disease refers to the small number of cancer cells that can remain in a patient’s body after treatment, which often cause no signs or symptoms but eventually can lead to the recurrence of the disease. These residual cells can be present at very low levels and require highly sensitive tests to identify them.
Measurement of minimal residual disease (MRD) has been recognized as an established and sensitive prognostic tool to assess the depth of response during and after treatment of chronic lymphocytic leukemia (CLL) and to understand disease dynamics after treatment.
Adaptive Biotechnologies’ clonoSEQ, which is the only test cleared by the U.S. Food and Drug Administration (FDA) for MRD assessment in lymphoid malignancies, is highly accurate, sensitive, and standardized compared to other technologies.
The assay leverages Adaptive’s proprietary immune medicine platform to identify and quantify specific DNA sequences found in malignant cells, allowing clinicians to assess and monitor MRD during and after treatment. The assay provides a standardized, accurate, and sensitive measurement of MRD that allows physicians to predict patient outcomes, assess response to therapy over time, monitor patients during remission, and predict potential relapse.
In addition to chronic lymphocytic leukemia (CLL) data presented during ASH also demonstrates the impact of the clonoSEQ Assay in acute lymphoblastic leukemia (ALL), and mantle cell lymphoma (MCL).
“The data presented at ASH this year reflect the growing evidence supporting clonoSEQ’s ability to provide a meaningful benefit for patients with [hematological malignancies] in a variety of clinical settings,” said Lance Baldo, M.D., Chief Medical Officer of Adaptive Biotechnologies.
Real-world evidence generated by clinicians at the University of California San Francisco (UCSF) and in Madrid demonstrated that MRD-based decision-making with the clonoSEQ Assay improved outcomes for multiple myeloma patients.
The result from one study (Abstract #2273) will be presented in a poster presentation. The retrospective review evaluated 373 multiple myeloma patients from three health centers who had at least one MRD assessment. Of the 373 patients, physicians made a clinical decision to change treatment for 58 patients based on their MRD status. Results showed that these 58 patients had a significantly improved progression-free survival (PFS) versus patients who did not change treatment (n=312) (median PFS 97 vs. 75 months, p=0.006).
“We are encouraged by these real-world data and the impact MRD testing can have on the way we manage patients who have had great but not perfect responses to therapy and the way we can make earlier decisions,” said Jeffrey Wolf, MD, Clinical Professor, Department of Medicine, UCSF; and Director, Myeloma Program, UCSF Helen Diller Family Comprehensive Cancer Center.
“These results support the integration of MRD assessment as a standard of care in the management of multiple myeloma patients. MRD assessment allows physicians and patients alike to have more confidence in their treatment decisions,” Wolf added.
Myeloma patient advocates agree that there are meaningful, practical real-world benefits for patients who undergo MRD testing.
“The ability to accurately monitor disease burden in multiple myeloma is critical when making decisions that impact each patient’s care,” noted Daniel Auclair, Ph.D., Chief Scientific Officer of the Multiple Myeloma Research Foundation.
“We are encouraged by the data emerging in MRD assessment, which we believe will help myeloma patients and their doctors better manage their disease,” Auclair said.
MRD-informed treatment changes
Patients may also benefit from potential MRD-informed treatment changes which may reduce the cost of their care. Additionally, researchers from the Winship Cancer Institute of Emory University present results (Abstract #3426) from a study that evaluated a framework that allowed patients with sustained MRD negativity (defined as MRD <10-5 across two assessments at least 12-months apart) to discontinue indefinite maintenance therapy. The results showed that, based on savings of maintenance therapy costs or no longer requiring active treatment for relapsed and/or refractory (R/R) disease,
MRD testing with clonoSEQ provided estimated lifetime savings of U.S. $916,000 per patient annually for the institution. The data also showed that MRD testing with clonoSEQ resulted in improved health outcomes in comparison to no testing (0.009 QALYs), primarily due to the avoidance of treatment-related adverse events.
Residual Disease Using Peripheral Blood in ALL
Scientists at Stanford University, Stanford, CA and Kaiser Permanente, Santa Clara, CA conducted a prospective, multi-institutional observational study of NGS-based MRD of the peripheral blood among adult ALL patients undergoing cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor (CAR) T-cells) in order to determine the correlation between peripheral blood and bone marrow MRD and to explore the clinical utility of monitoring MRD in peripheral blood.
- The prospective study (Abstract 975) investigated the prognostic and predictive utility of peripheral blood-based MRD assessment in 62 ALL patients who received cellular therapy.
- The study demonstrated a strong correlation between MRD assessed from peripheral blood and bone marrow using clonoSEQ, and concluded that less-invasive clonoSEQ MRD monitoring in peripheral blood represents an alternative to serial bone marrow examinations in patients undergoing curative-intent cellular therapies.
Insights from the Randomized, Phase III CLL14 Trial
Understanding a patient’s response both during and after the treatment of chronic lymphocytic leukemia (CLL) and correctly analyze disease dynamics after treatment requires retracing the kinetics of patients is at risk of relapsing despite initial MRD response. In a phase III study researchers from the University of Cologne, Department of Internal Medicine and Center of Integrated Oncology in Aachen, Bonn, Cologne, Duesseldorf, Cologne, Cologne, Germany, and industry partners, including Adaptive Biotechnologies, Gentech/Roche and AbbVie, evaluated MRD as a secondary endpoint in 432 CLL patients with previously untreated CLL and co-existing conditions who were randomized to receive chlorambucil or venetoclax in combination with obinutuzumab. MRD was assessed every 3-6 months in PB. The subset of data presented at ASH analyzes MRD and clonal growth patterns in both cohorts of patients to better understand disease dynamics during and after treatment.
- The results showed that clonal growth, a measure for how quickly cancer cells grow, was significantly lower after treatment with venetoclax plus obinutuzumab than after treatment with chlorambucil and obinutuzumab, indicating more effective MRD eradication and clonal growth modulation with venetoclax plus obinutuzumab. Additionally, 40% of patients in the venetoclax arm had undetectable MRD levels of <10-6 compared to just 7% of patients in the chlorambucil arm.
- This analysis of the trial data demonstrates that understanding patient-specific cancer growth rates in addition to MRD status may be helpful in informing treatment duration.
Frontline Sequential Immunochemotherapy + Lenalidomide for Mantle Cell Lymphoma
Researchers at the Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, the University of Miami Sylvester Sylvester Comprehensive Cancer Center, Miami, FL, and industry partners, including Adaptive Biotechnologies and AstraZeneca conducted a phase II study (Abstract 119) of sequential immunochemotherapy incorporating lenalidomide enriching for patients with high-risk disease features (defined as blastoid/pleomorphic histology and/or Ki67 >=30%).
- The study evaluated frontline sequential immunochemotherapy plus lenalidomide for the treatment of patients diagnosed with MCL.
- During the study, MRD testing with clonoSEQ was performed on peripheral blood after each phase of treatment and at six months post end of treatment.
- There was a high rate of MRD negativity after induction chemoimmunotherapy (Len-R-CHOP + R-HiDAC) at thresholds of 10-5 (97%) and 10-6 (80%), with the deepest responses (10-6) shown to be predictive of remission duration. Several patients converted from MRD-negative to MRD-positive at six months post-treatment and eventually relapsed, suggesting that a more prolonged period of maintenance may be beneficial.
“It is increasingly clear that MRD testing with clonoSEQ, utilizing our immune medicine platform, is playing an important role in treatment decision-making which can have a dramatic impact not only on patients but could also enable cost savings for the healthcare system overall,” Adaptive Biotechnologies’ Baldo concluded.
 Martinez Lopez, Fernández RA, Wong SW, Rios R, Shah N, Cedena Romero MT, Ruiz-Heredia Y., et al. Making Clinical Decisions to Change Therapy Using Measurable Residual Disease Improves the Outcome in Multiple Myeloma – (Abstract #2273).
 Carlson JJ, Zimmermann M, Demaree A, Hewitt T, Eckert B, Nooka A. Cost-Effectiveness of Implementing clonoSEQ NGS-MRD Testing Using the Emory MRD Decision Protocol in Multiple Myeloma” (Abstract 3426).
 Muffly L, Sundaram V, Chen C, Yurkiewicz I, Kuo E, Burnash S, Spiegel JY, Chyan K, et al. Monitoring Measurable Residual Disease Using Peripheral Blood in Acute Lymphoblastic Leukemia: Results of a Prospective, Observational Study (Abstract 975)
 Al-Sawaf O, Zhang C, Robrecht S, Wilson C, Tandon M, Ching T, Fink AM, Ritgen M, et al. Clonal Dynamics after Venetoclax-Obinutuzumab Therapy: Novel Insights from the Randomized, Phase 3 CLL14 Trial (Abstract 127)
 Epstein-Peterson ZD, Batlevi CL, Caron P, Dogan A, Drullinsky P, Gerecitano J, Hamilton A, et al. Frontline Sequential Immunochemotherapy Plus Lenalidomide for Mantle Cell Lymphoma Incorporating MRD Evaluation: Phase II, Investigator-Initiated, Single-Center Study (Abstract 119)
The clonoSEQ® Watch Registry – NCT04545333
Study to Assess for Measurable Residual Disease (MRD) in Multiple Myeloma Patients – NCT04108624
DNA Sequencing-Based Monitoring of Minimal Residual Disease to Predict Clinical Relapse in Aggressive B-cell Non-Hodgkin Lymphomas – NCT02633111