The next-generation sequencing assay clonoSEQ has gained FDA approval as a test for minimal residual disease in patients with acute lymphoblastic leukemia or multiple myeloma.
The next-generation sequencing (NGS) assay clonoSEQ has gained FDA approval as a test for minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma.
The assay from Adaptive Biotechnologies is an in vitro diagnostic that identifies and quantifies gene sequences in DNA extracted from the bone marrow of patients with ALL or multiple myeloma using multiplex polymerase chain reaction and NGS. The assay detects as few as 1 tumor cell within more than 1 million healthy (<10-6) cells.
“At the FDA, we’re continuing to maximize opportunities for innovation that can improve patient outcomes,” FDA commissioner Scott Gottlieb, MD, said in a press release. “Today’s approval is an important step forward for patients suffering from ALL and multiple myeloma. Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care.”
To evaluate the clinical validity of clonoSEQ, the FDA reviewed data from a retrospective analysis of samples collected from a clinical trial involving 273 patients with ALL and 2 trials involving 323 and 706 patients with multiple myeloma.
Investigators in the trials used the assay to assess MRD at various disease burden thresholds and determined that MRD status correlated with event-free survival (EFS). EFS was longer and EFS rates were higher for patients assessed as MRD-negative. Findings were similar for progression-free survival (PFS) and disease-free survival among patients with multiple myeloma.
Data from a study of 56 children with B-cell ALL enrolled in the COG ASCT0431 trial showed that MRD assessment by clonoSEQ better predicted survival and relapse compared with multichannel flow cytometry prior to hematopoietic cell transplantation (P<.0001). Among MRD-negative patients, no patient identified by clonoSEQ relapsed compared with 16% for those detected by flow cytometry (P= .02). Two-year OS also favored NGS, 96% vs 77% (P= .003).1
Results from the Intergroupe Francophone du Myéloma (IFM) 2009 trial published in theNew England Journal of Medicinein 2017 showed that clonoSEQ was more accurate than conventional muliparametric flow cytometry, which can detect 1 myeloma cell among 10,000 healthy cells (10-4). Flow cytometry identified 233 patients as MRD-negative, but assessment by clonoSEQ showed that 113 (48%) of those patients were MRD-positive.2
Findings from IFM 2009 recently published inBlooddemonstrated the importance of MRD in patients with multiple myeloma. Investigators assessed the prognostic value of MRD for PFS and overall survival (OS) in 127 patients who achieved MRD negativity at least once while being treated with the lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone regimen (RVD).2,3
MRD negativity was defined as the absence of tumor plasma cell within <10-6bone marrow cells. Investigators used clonoSEQ to detect the presence of disease before and after maintenance therapy.
MRD-negative patients had extended PFS both before (P<.001) and after completion (P<.001) of maintenance therapy. Patients who had sustained MRD negativity or who became MRD-negative at the end of maintenance had superior PFS (P<.001) and OS (P= .004). OS was 94% among MRD-negative patients compared with 79% for MRD-positive patients 4 years after the start of maintenance therapy (HR, 0.24; 95% CI, 0.11-0.54;P= .001).
“The IFM 2009 analysis underscores the need for a deeply sensitive, highly accurate and reliable NGS MRD test that can detect and monitor disease burden throughout the treatment continuum,” Charles Sang, senior vice president of diagnostics with Adaptive Biotechnologies, said in a press release. “This study adds to the growing body of evidence that MRD is a critical endpoint that should routinely be incorporated into clinical trials and clinical practice to ensure the best patient outcomes.”
The FDA reviewed clonoSEQ through the de novo premarket review pathway for new types of novel, low-to-moderate-risk devices. The agency also established “special controls” clarifying expectations regarding the efficacy, accuracy, and reliability of tests using MRD to assess changes in disease burden during and after treatment. Along with general controls, these special controls are designed to provide a reasonable promise of efficacy and safety.
This approval also creates a new regulatory classification that allows devices of the same type and the same intended use to go through the FDA’s 510(k) process. These devices can gain approval by demonstrating “substantial equivalence” to clonoSEQ.