On September 28, 2018, the U.S. Food and Drug Administration (FDA) approved – a test for detecting acute lymphoblastic leukemia (ALL) or multiple myeloma (MM) patients – the ClonoSEQ assay (manufactured by Adaptive Biotechnologies), a test to detect minimal residual disease (MRD) in the bone marrow. (produced by Adaptive Biotechnologies).
This is a new assay based on second-generation sequencing (also known as next generation sequencing (NGS)) and is the first second-generation sequencing assay approved for the detection of minimal residual disease.
What is microscopic residual disease-positive acute lymphoblastic leukemia or multiple myeloma?
Acute lymphoblastic leukemia is a common malignant hematologic disease with diverse and clinically heterogeneous biology, characterized by abnormal proliferation and aggregation of immature lymphocytes in bone marrow and lymphoid tissue.
Acute lymphoblastic leukemia accounts for 15% of all leukemias, approximately 30% to 40% of acute leukemias, and approximately 20% of adult leukemias. Although most acute lymphoblastic leukemias are sensitive to chemotherapy, they often relapse after treatment remission.
Multiple myeloma originates from terminally differentiated B lymphocytes (plasma cells) after the germinal center and manifests as monoclonal plasma cells that proliferate in the bone marrow and synthesize and secrete monoclonal immunoglobulins, leading to hypercalcemia, renal impairment, anemia, bone disease, and organ damage such as amyloidosis. Among hematologic tumors, multiple myeloma has the second highest incidence after lymphoma. As with acute lymphoblastic leukemia, relapse is a major challenge in multiple myeloma.
Minor residual disease is a measure of tumor load in the body and refers to the number of cancer cells that remain in the body during or after treatment. In both acute lymphoblastic leukemia and multiple myeloma, the presence of residual cancer cells after treatment is often indicative of a low level of remission as well as a short duration of remission and vulnerability to relapse.
What is ClonoSEQ analysis?
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ClonoSEQ analysis is an in vitro diagnosis that uses multiplex PCR (polymerase chain reaction) and second-generation sequencing to identify and quantify certain gene sequences in DNA extracted from a patient’s bone marrow.
The primary principle of second-generation sequencing for detection of microscopic residual disease is based on specific rearrangements of the lymphocyte genome. Second-generation sequencing technology can monitor for microscopic residual disease by identifying specific genomic rearrangements in acute lymphoblastic leukemia cells.
The previous detection modalities for microscopic residual disease – flow cytometry technology and polymerase chain reaction – are more sensitive than ClonoSEQ analysis, which is able to detect microscopic residual disease at less than The ClonoSEQ assay is more sensitive than the previous methods – flow cytometry and polymerase chain reaction – and is able to detect microscopic residual disease at a level of less than 1 part per million cells, compared to the previous methods, which were typically able to measure microscopic residual disease at 1/10000 or 1/100000 of the residual cell volume, with less time and effort.
Evidence of efficacy: significantly better survival in MRD-negative patients
The approval of the ClonoSEQ analysis was based primarily on the results of 3 clinical trials involving 273 patients with acute lymphoblastic leukemia, 323 patients with multiple myeloma (study still ongoing), and 706 patients with multiple myeloma.
For patients with acute lymphoblastic leukemia, microresidue levels were found to be associated with event-free survival (EFS) in patients when assessed using ClonoSEQ analysis. Event-free survival refers to the duration of time after treatment that the patient is free of events such as complications or progression-free recurrence of cancer. In the study, patients who were negative for microscopic residual disease on ClonoSEQ analysis had higher event-free survival, and conversely, patients who were positive for microscopic residual disease and had higher values had worse event-free survival.
In patients with multiple myeloma, microscopic residual disease levels were found to correlate with progression-free survival (PFS) when assessed using ClonoSEQ analysis. Progression-free survival refers to the amount of time a patient lives with a stable, controlled cancer during and after treatment, before the cancer progresses. In the study, patients with minimal residual disease on ClonoSEQ analysis had higher progression-free survival, and conversely, patients with positive minimal residual disease and higher values had worse progression-free survival.
New review pathway ensures accurate and reliable ClonoSEQ analysis
Along with advances in sequencing technology, the FDA has provided more assistance with applications and approvals for second-generation sequencing tests, while also applying new regulatory approaches to ensure that these rapidly evolving second-generation sequencing tests are accurate and reliable.
ClonoSEQ analysis was approved through the de novo premarket review pathway, a regulatory pathway for novel low to moderate risk medical devices. With the approval of the ClonoSEQ assay, a new regulatory classification was created, meaning that the same type of follow-on assay with the same intended use can be marketed through the FDA 510(k) process, demonstrating the same efficacy as the previously approved assay. With the facilitation of the approval system, it is believed that more and more second-generation sequencing tests will play a more important role in the treatment of leukemia.