FDA Clears First MRD Assay for Chronic Lymphocytic Leukemia


The FDA has cleared the clonoSEQ® assay to identify and monitor minimal residual disease in blood or bone marrow from patients with chronic lymphocytic leukemia.

The FDA has cleared the clonoSEQ® assay to identify and monitor minimal residual disease (MRD) in blood or bone marrow from patients with chronic lymphocytic leukemia (CLL), according to an announcement from Adaptive Biotechnologies Corporation.1

This assay is the first and only in vitro diagnostic to receive FDA clearance for the monitoring of MRD in this disease. The clonoSEQ® assay was previously granted de novo designation for use in the detection and monitoring of MRD in bone marrow from patients with multiple myeloma and those with B-cell acute lymphoblastic leukemia (ALL).

“FDA clearance of clonoSEQ®, which can detect 1 single cancer cell among a million healthy cells, is an important milestone for the CLL community,” Brian Coffman, MDCM, FCFP, DABFM, MS, Ed, chief medical officer and executive vice president of the CLL Society, Inc, stated in a press release. “Looking with greater accuracy for persistent cancer cells can show how well treatment is working and may help inform important decisions such as changing or stopping therapy. In my own CLL journey, knowing my clonoSEQ® MRD status has impacted the way my expert team of doctors and I manage my disease.”

The decision that led to the clearance of the assay was based on clinical validation data collected from 2 important clinical trials: the phase 3 CLL14 (NCT02242942) and a phase 2 trial (NCT00759798).

An analysis of data collected from 337 patients on the CLL14 trial indicated that patients with MRD negativity at 3 months following treatment experienced about a seven-fold reduction in the risk of disease progression versus those who did not achieve undetectable levels. For the analysis, undetectable MRD had been defined as a level of 1 cancer cell among 100,000 healthy cells (10-5). Additional assessment suggested that at 30 months following treatment, evaluable patients with MRD negativity had only a 5% probability of disease progression versus 36% in those with detectable disease.

Additionally, data from the other phase 2 study indicated that the results of the clonoSEQ® assay were significantly predictive of outcomes when used on blood and bone marrow samples, irrespective of the threshold at which MRD had been evaluated.

In the phase 3 CLL trial, patients with CLL and comorbidities were given 12 cycles of either venetoclax (Venclexta) in combination with obinutuzumab (Gazyva) or chlorambucil plus obinutuzumab. Findings from the primary analysis revealed that fixed-duration venetoclax/obinutuzumab resulted in a significant progression-free survival (PFS) benefit versus chlorambucil/obinutuzumab.2

Updated data presented during the 2020 ASCO Virtual Scientific Program showed that at a median follow-up of 39.6 months, PFS continued to favor venetoclax/obinutuzumab over chlorambucil/obinutuzumab (HR, 0.31; 95% CI, 0.22-0.44; P <.001); notably, the benefit was observed across all clinical and biological risk subgroups.3 The estimated 3-year PFS rate of 81.9% with venetoclax/obinutuzumab versus 49.5% with chlorambucil/obinutuzumab.

Moreover, at 3 months posttreatment, a higher rate of undetectable MRD in peripheral blood by allele-specific oligonucleotide polymerase chain reaction was reported with the venetoclax combination versus chlorambucil/obinutuzumab, at 75.5% (n = 163/216) versus 35.2%, respectively (P <.001). Furthermore, 11 patients on the investigational arm had low MRD, defined as 10-4 or greater and less than 10-2; 9 patients had high MRD, which was defined as 10-2 or greater at this time.

At 18 months post treatment completion, 47.2% of those on the venetoclax arm had undetectable MRD, while 13% had low MRD, and 7.9% had high MRD versus 7.4%, 17.1%, and 26.9%, respectively, of those on the comparator arm.

Importantly, patients who had undetectable MRD at the end of their treatment were found to have a longer PFS than those with low or high MRD (HR, 0.10; 95% CI, 0.06-0.15; P <.001).

In the second study, investigators set out to assess the depth of remission following first-line treatment with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) in patients with CLL. To do this, they used the clonoSEQ® assay to evaluate MRD in a total of 62 patients; all patients had undetectable MRD in the bone marrow, defined as 10-4, via multicolor flow cytometry at the end of their treatment with FCR.

Fifty-seven bone marrow samples were collected, along with 29 peripheral blood mononuclear cell samples, and 32 plasma samples. Of the 62 patients, only 27.4% had undetectable MRD via next-generation sequencing.4 The rate of undetectable MRD was lowest in bone marrow (25%) compared with peripheral blood (55%) or plasma (75%).

Moreover, patients with undetectable MRD at the end of their treatment had superior PFS compared with those who had MRD positivity, irrespective of the kind of sample that was tested (bone marrow: median not reached [NR] vs 67 months, P = .02; peripheral blood: median NR vs 74 months, P = .02).

The availability of the clonoSEQ® assay for use in blood will make it easier to test for MRD in patients with CLL, according to Adaptive Biotechnologies; however, because of the COVID-19 crisis, patients might be hesitant to go to the hospital or clinic for a blood draw.

To address this concern, the company has launched a service that provides minimal-content blood collection at approximately 2000 LabCorp Patient Service Centers throughout the United States. Patients will also have the option of having a blood draw done by a qualified professional in the comfort of their own homes through the company’s collaboration with Phlebotek Solutions.

“The FDA clearance of clonoSEQ® in CLL represents a significant advancement for patients with CLL,” Lance Baldo, chief medical officer of Adaptive Biotechnologies, added in the release. “We believe the first-time clearance of clonoSEQ® in blood will be advantageous for both providers and patients. Given the risks that COVID-19 poses for [patients with] cancer, we are proud to be collaborating with 2 best-in-class service providers to offer patients flexible and safe options for blood sample collection outside of a hospital or clinic.”


  1. Adaptive Biotechnologies receives expanded FDA clearance for the clonoSEQ assay to assess minimal residual disease (MRD) in patients with chronic lymphocytic leukemia. News release. Adaptive Biotechnologies Corporation. August 6, 2020. Accessed August 6, 2020. https://bit.ly/2XzyAFE.
  2. Fischer A, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281
  3. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized phase III CLL14 trial. J Clin Oncol. 2020;38(suppl 15):8027. doi:10.1200/JCO.2020.38.15_suppl.8027
  4. Thompson PA, Srivastava J, Peterson C, et al. Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL and chemoimmunotherapy. Blood. 2019;134(suppl 22):1951-1959. doi:10.1182/blood.2019001077
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