How can clonoSEQ be used to inform patient management decisions?

Learn how clonoSEQ MRD results may inform clinician decision-making. Explore the Real-world Experience Hub, a new repository of clinician and patient perspectives on the practical value of MRD, published real-world evidence and data illustrating how clonoSEQ is really being used.

Real-World Experience Hub

A sensitive, accurate and standardized method for MRD detection and monitoring

The clonoSEQ^® Assay is a robust, highly-validated tool for identifying and monitoring measurable residual disease (MRD) in lymphoid malignancies.^[1] Across a variety of large, multi-center clinical trials, clonoSEQ has generated a wealth of peer-reviewed clinical evidence in disease states including multiple myeloma (MM), B-cell acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).^[2-3]

Review specific data for:

MULTIPLE MYELOMA ACUTE LYMPHOBLASTIC LEUKEMIA CHRONIC LYMPHOCYTIC LEUKEMIA

Multiple Myeloma

Data Spotlight

COLLABORATORS

Maria-Victoria Mateos, University of Salamanca, Salamanca, Spain

PATIENTS

569 relapsed and refractory patients assessed for MRD by clonoSEQ at the time of suspected complete response (CR)

STUDY OBJECTIVE

Evaluate use of clonoSEQ MRD testing for prognostic evaluation by correlating MRD results to PFS.^[4]

PROGNOSTIC VALUE

The clonoSEQ Assay can predict progression-free survival in myeloma patients

MRD negativity* (as measured by clonoSEQ at 10-5 threshold) was associated with longer PFS than MRD positivity, regardless of the treatment received

In the ALCYONE (NCT02195479) study of 706 patients with newly diagnosed, transplant-ineligible multiple myeloma, patients received bortezomib, melphalan, and prednisone (VMP) with or without daratumumab (D-VMP). Patients were assessed by clonoSEQ (at a sensitivity level of 10^-5) at study screening, and time of CR/sCR, as well as at 12, 18, 24, and 30 months in patients who had achieved a CR/sCR following initiation of induction. After 18 months of follow-up, the proportion of MRD-negative patients in the experimental treatment arm was more than three times higher than in the control group (22.3% versus 6.2%, P<0.001; Figure 1). Additionally, regardless of treatment arm, MRD-negative patients had longer PFS than MRD-positive patients (Figure 2).^[5] The MRD negativity rate data from this study has been incorporated in an FDA-approved product label for the treatment of newly-diagnosed, transplant-ineligible multiple myeloma patients.^[6]

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Figure 1: Comparison of clonoSEQ MRD negativity rate in the control arm (VMP) versus the experimental arm (D-VMP)

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Figure 2: Correlation of clonoSEQ MRD status and PFS

clonoSEQ MRD-negative patients have longer progression-free survival

The POLLUX study assessed 569 relapsed and refractory multiple myeloma patients to determine if the addition of daratumumab to lenalidomide and dexamethasone (Rd) resulted in prolonged progression-free survival. MRD was assessed at three MRD thresholds (10^-4 to 10^-6) by clonoSEQ at the time of suspected complete response (CR). At three evaluated thresholds, MRD negativity by clonoSEQ was associated with longer PFS relative to MRD positivity (Figure 3, 10^-6 threshold shown). Additionally, the rate of MRD negativity at all evaluated thresholds (10^-4, 10^-5, 10^-6) was significantly higher in the experimental treatment arm than in the control arm (by 3-5x). Specifically, at an MRD threshold of 10^-5, the rate of MRD negativity was 22.4% in the experimental group (DRd) versus 4.6% in the control group (Rd; P<0.001).^[7]

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Figure 3: Correlation of clonoSEQ MRD status and PFS

4. Kumar S, et al. Lancet Oncol. 2016;17(8):e328-e346.
5. Mateos M, et al. N Engl J Med. 2018;378:518-528.
6. DARZALEX^® Prescribing Information. Horsham, PA: Janssen Biotech, Inc; 2018.
7. Dimopoulos M, et al. N Engl J Med. 2016;375:1319-31.
* Per multiple myeloma clinical practice guidelines, in the setting of CR, MRD negativity is defined as the absence of detectable cancer cells using a validated method with a minimum sensitivity of 10^-5 nucleated cells or higher.^[6] MRD status should be evaluated in the context of clinicopathological features and is not a determination of the absence of disease.

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Peer-reviewed publications show advantages to using clonoSEQ in Multiple Myeloma:

MRD assessment by clonoSEQ predicts time to tumor progression (TTP) and overall survival (OS).[8]

PROGNOSTIC VALUE

The clonoSEQ Assay has prognostic value in Multiple Myeloma

MRD by NGS predicts time to tumor progression and overall survival

A study of 133 patients on GEM clinical trials (GEM00, GEM05, and GEM2010) found that MRD assessment by NGS was prognostic for time to progression (TTP; Figure 4) and overall survival (OS; Figure 5).^[8]

Patients in a CR and MRD negative had longer TTP than patients in a CR who were MRD positive.^[8]
clonoSEQ MRD identified trackable sequences in 121/133 patients (91%).^[8]
There were 82 concordant MRD results between NGS and flow cytometry. There were 17 discordant MRD cases: 12 were NGS MRD-positive and flow MRD-negative; 5 were NGS MRD-negative and flow MRD-positive.

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Figure 4 (left): MRD-negativity by NGS was associated with significantly longer TTP
Figure 5 (right): MRD-negativity by NGS was associated with significantly longer OS

8. Martinez-Lopez J, et al. Blood. 2014;123(20):3073-3079.*
* Study author’s research was funded, in part, via product grants from Adaptive.

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MRD negativity when assessed pre- and post-maintenance at deeper sensitivity correlated with improved outcomes.

SENSITIVITY MATTERS

MRD negativity when assessed pre- and post-maintenance at deeper sensitivity correlated with improved outcomes

Better outcomes for patients who achieve lower levels of disease burden (deeper response) pre-maintenance

When assessing MRD by clonoSEQ, pre-maintenance, patients (N=246) were stratified by level of MRD detected (≥10^-4, 10^-4 – 10^-5, 10^-5 – 10^-6, <10^-6). Patients with the deepest level of MRD negativity (<10^-6), had superior PFS compared to clonoSEQ MRD-positive patients with disease >10^-6 (P<0.0001, Figure 6).^[9]

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Figure 6: Correlation of pre-maintenance MRD, assessed by flow cytometry and clonoSEQ, to PFS

Better outcomes for patients who achieve lower levels of disease burden (deeper response) post-maintenance

When assessing MRD by clonoSEQ post-maintenance, patients (N=178) were stratified by level of MRD (≥10^-4, 10^-4 – 10^-5, 10^-5 – 10^-6, <10^-6). Patients with the deepest level of MRD negativity (<10^-6) had superior PFS compared to clonoSEQ MRD-positive patients with disease >10^-6 (P<0.0001, Figure 7).^[9]

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Figure 7: Correlation of post-maintenance MRD, assessed by flow cytometry and clonoSEQ, to PFS

9. Avet Loiseau H, et al. ASH 2015: Abstract 191.*
* Herve Avet-Loiseau acts in a consulting capacity with Adaptive.

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clonoSEQ MRD testing identified additional MRD-positive patients who were MRD-negative by flow cytometry in this study.

ADDITIONAL PATIENTS CAPTURED WITH CLONOSEQ MRD DETECTION

clonoSEQ MRD testing identified additional MRD-positive patients who were MRD-negative by flow cytometry in this study

Additional 84 MRD-positive patients captured pre-maintenance

In a study evaluating MRD in 475 patients, 322 patients had no detectable disease by flow cytometry, of which 163 patients were assessed by clonoSEQ. Of the clonoSEQ-assessed patients, 84 were identified as MRD-positive. These 84 patients had worse PFS compared to patients who had no detectable MRD by flow and were NGS MRD-negative (P=0.0002, Figure 8).^[9]

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Figure 8: Pre-maintenance assessment of MRD by NGS in patients who were MRD-negative by flow cytometry

Additional 42 MRD-positive patients captured post-maintenance

Post-maintenance, 232 patients had no detectable MRD by flow cytometry, of which 111 were then assessed by clonoSEQ. Of these 111 patients, 42 were identified as MRD-positive by clonoSEQ. These patients had worse PFS compared to patients who were MRD-negative by flow and clonoSEQ (P=0.0006, Figure 9).^[9]

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Figure 9: Post-maintenance assessment of MRD by NGS in patients who were MRD-negative by flow cytometry

9. Avet Loiseau H, et al. ASH 2015: Abstract 191.*
* Herve Avet-Loiseau acts in a consulting capacity with Adaptive.

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International Clinical Practice Guidelines recommend MRD testing in Myeloma

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) recommend MRD testing as a Category 2A recommendation for multiple myeloma patients after each treatment stage (e.g., induction, high-dose therapy/ASCT, consolidation, maintenance) at times of suspected complete response. Next-generation sequencing (NGS) is specifically included in these guidelines among the recommended tools for MRD assessment.^[10] International response criteria, including IMWG and ESMO, also specifically include MRD negativity by NGS as a measure of disease response in myeloma.^[4,11]

Download Myeloma Clinical Data

Download our Multiple Myeloma clinical data summary to explore and share the data.

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Review NCCN Guidelines®

Access the NCCN Guidelines.

GUIDELINES

Acute Lymphoblastic Leukemia

Data Spotlight

PATIENT POPULATION:

579 pediatric patients were assessed for MRD at baseline and end of induction (Day 29)

STUDY OBJECTIVE:

Evaluate non-inferiority of clonoSEQ to flow cytometry using an MRD threshold of 10^-4 and understand if increased sensitivity of clonoSEQ identifies additional patients with residual disease compared to flow cytometry. Assessment of MRD at end of induction showed that sequencing-based MRD detection identified an additional 55 patients who were MRD-positive by the clonoSEQ Assay and MRD-negative by flow cytometry (p=0.036).^[3]

ADDITIONAL PATIENTS CAPTURED WITH CLONOSEQ MRD DETECTION

The sensitivity and specificity of clonoSEQ MRD enables robust detection of disease

Additional 55 MRD-positive patients captured

A study evaluated MRD in the bone marrow of 579 pediatric ALL patients. Next-generation sequencing MRD detection identified an additional 55 patients who were MRD-positive by the clonoSEQ Assay and MRD negative* by flow cytometry at an MRD threshold of 10^-4. 17 patients were identified as MRD-positive by flow cytometry and MRD-negative by clonoSEQ at a sensitivity of 10^-4 (Table 1)^[3]. When assessing MRD at a threshold of 10^-5, clonoSEQ identified an additional 87 patients with disease who were MRD-negative by flow cytometry.^[3]

clonoSEQ MRD demonstrates ability to predict event-free survival (EFS) in pediatric ALL

This study demonstrated that 55 patients who had no detectable MRD by flow cytometry and who were MRD-positive by NGS had a worse EFS than those who were MRD-negative by NGS and had no detectable MRD by flow cytometry (threshold of 10^-4). Using an MRD cutoff level of 10^-4, flow cytometry identified 17 patients as MRD-positive that NGS identified as MRD-negative. When those 17 patients were assessed at an MRD cutoff level of 10^-5, NGS identified residual disease in 11 of these patients. Additionally, NGS MRD (threshold of 10^-4) was able to predict EFS in the standard risk subgroup. Patients who were NGS MRD-negative had longer EFS compared to the NGS MRD-positive patients (P=0.0226).^[3]

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Table 1: Comparison between the clonoSEQ Assay and flow cytometry (both assessed at 1/10,000)^[3]

3. Wood B, et al. Blood. 2018;131(12):1350-1359.
* Per ALL clinical practice guidelines, MRD negativity is defined as the absence of detectable cancer cells using a method with a minimum sensitivity of 10^-4 nucleated cells or higher.^[1] MRD status should be evaluated in the context of clinical clinopathological features and is not a determination of the absence of disease.

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Peer-reviewed publications show advantages to using clonoSEQ in ALL:

In one study, clonoSEQ was shown to be superior to flow cytometry in predicting post treatment relapse and survival.[13]

PREDICTIVE POWER OF CLONOSEQ MRD

clonoSEQ MRD assessment pre-transplant may predict relapse and overall survival

In this analysis of pre-transplant bone marrow samples from 41 pediatric patients with ALL, it was found that clonoSEQ MRD detection predicted relapse and overall survival post-allogeneic transplant significantly better than 6-color flow cytometry (Table 2).^[13]

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Table 2

13. Pulsipher M, et al. Blood. 2015;125(22):3501-8.*
*Study author’s research was supported, in part, by product grants from Adaptive.

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clonoSEQ may be used to predict relapse and disease free survival in the post-transplant setting.[13]

PROGNOSTIC VALUE

clonoSEQ MRD assessment has demonstrated prognostic value post-transplant in the pediatric and adult ALL settings

Analysis of bone marrow samples from 53 pediatric patients analyzed post-allogeneic transplant showed that clonoSEQ may be used to predict relapse. In the case of discordant MRD determinations, there were 11 patients identified as clonoSEQ MRD-positive and flow cytometry MRD-negative and 3 patients identified as clonoSEQ MRD-negative and flow cytometry MRD-positive.^[13]

Strong predictive power

One month after transplant, flow cytometry was unable to distinguish between patients who ultimately relapsed and those who did not (p=0.91; Figure 3). NGS MRD showed an estimated relapse probability of 67% in MRD-positive patients vs. 25% in MRD-negative patients (p=0.01).^[13]

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Figure 3: flow cytometry (MFC) vs. next-generation sequencing (NGS) MRD +30 days post-transplant

Long range predictive power

Better predictive power of post-transplant NGS MRD detection vs. flow cytometry continued at day 100 and 8 months post-transplant.^[13]

13. Pulsipher M, et al. Blood. 2015;125(22):3501-8.*
* Study author’s research was supported, in part, by product grants from Adaptive.

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clonoSEQ is concordant with traditional methods for MRD detection and offers increased sensitivity.[12]

CONCORDANCE

The clonoSEQ Assay is highly concordant with traditional MRD detection methods in ALL

In a study of more than 100 pediatric ALL patients, the clonoSEQ Assay showed quantitative concordance with both flow cytometry and allelespecific oligonucleotide PCR (ASO-PCR; Figure 2).^[12]

Increased sensitivity

The clonoSEQ Assay was able to detect additional patients with disease present below the detection limits of flow cytometry (N=10) and ASO-PCR (N=3), respectively (Figure 2, red boxes).^[12] ASO-PCR identified one patient with residual disease that was MRD-negative by clonoSEQ.^[12]

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Figure 2: Comparison between sequencing and flow cytometry and ASO-PCR. The number of concordant measurements are shown in the lower left and upper right. The number of discordant measurements are shown in the upper left and lower right. Boxed numbers highlight increased sensitivity provided by NGS MRD detection over other methods.

12. Faham M, et al. Blood. 2012;120(26):5173-5180.*
* Study author was an employee of Adaptive at time of publishing.

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Clinical Practice Guidelines recommend MRD testing in ALL:

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) for ALL recommend MRD testing at a sensitivity of 10^-4 or better because of its clinical utility.^[14,15] Next-generation sequencing (NGS) is listed as one of the recommended methods for MRD assessment in these Guidelines.^[16]

Download ALL Clinical Data

Download our Acute Lymphoblastic Leukemia clinical data summary to explore and share the data.

VIEW PDF

Review NCCN Guidelines®

Access the NCCN Guidelines.

GUIDELINES

Chronic Lymphocytic Leukemia

Data Spotlight

STUDY OBJECTIVE

Evaluate use of clonoSEQ MRD testing for prognostic evaluation by correlating MRD results to PFS.^[1]

PATIENTS

337 newly diagnosed CLL patients assessed for MRD by clonoSEQ after three months of therapy.

ABILITY TO PREDICT CLINICAL OUTCOMES

clonoSEQ predicts outcomes three months after the completion of therapy

clonoSEQ predicts progression free survival

The CLL14 study assessed the combination of obinatuzumab plus venetoclax versus obinatuzumab plus chlorambucil in previously untreated CLL patients with coexisting conditions. MRD was assessed in peripheral blood samples from 337 patients three months after completion of therapy using an MRD threshold of 10^-5. U-MRD by clonoSEQ significantly predicted progression-free survival (PFS; P = 3.075 x 10^-19; Figure 1) with a 6.64-fold higher event risk in MRD-positive patients compared to U-MRD patients (95% CI: 3.65-12.1).^[1]

/wp-content/uploads/CLL_data_figure1@2x_BoxFree_NEW3.jpg

Figure 1: Kaplan-Meier survival curves for PFS given clonoSEQ MRD detection at a threshold of 10^-5 three months after completion of therapy

Lower levels of MRD are correlated with better outcomes

When assessing the correlation between clinical outcomes and continuous clonoSEQ MRD measurements (vs. a pre-definied sensitivity threshold), a patient’s risk of an event was shown to increase by 2.15-fold for every 10-fold increase in MRD (95% CI: 1.86-2.48).

Patients with U-MRD or very low levels of MRD detected by clonoSEQ have the best outcomes. Patients with clonoSEQ MRD < 10^-6 or between 10^-6 and 10^-5 have the longest PFS, followed by patients with MRD between 10^-5 and 10^-4 and patients with MRD ≥ 10^-4 (P = 4.902 x 10^-31).
These data demonstrate that patients with MRD < 10^-5 have better outcomes than patients with MRD ≥ 10^-5, and that increasing MRD levels above 10^-5 are associated with an increased risk of disease progression within the follow-up time of this study.^[1]

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Figure 2: Kaplan-Meier Survival Curve for PFS using clonoSEQ at four MRD levels in CLL: <10^-6, 10^-6 – 10^-5, 10^-5 – 10^-4, ≥10^-4

1. clonoSEQ^®. [technical summary]. Seattle, WA: Adaptive Biotechnologies; 2020. https://clonoseq.com/technical-summary.

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Clinical studies show advantages to using clonoSEQ in CLL:

clonoSEQ predicts outcomes in both bone marrow and peripheral blood samples.

CONCORDANCE BETWEEN BLOOD AND BONE MARROW

clonoSEQ predicts outcomes in both bone marrow and peripheral blood samples

In bone marrow samples, clonoSEQ is predictive of PFS

Thompson et al assessed 62 previously untreated CLL patients who received therapy with fludarabine, cyclophosphomide, and rituximab (FCR). These patients were initially determined to be U-MRD by 4-color flow cytometry at an MRD threshold of 10^-4. From these patients, 57 bone marrow (BM) samples were evaluated at the end of treatment by clonoSEQ. Patients who achieved the lowest levels of MRD in the bone marrow (10^-5 – 10^-6) or who had a U-MRD status (<10^-6) experienced the best outcomes. Patients who had a U-MRD status at a threshold of < 10^-5 had superior PFS compared to patients with MRD ≥ 10^-5 (P = 0.01; Figure 3).^[17]

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Figure 3: Patients who had a U-MRD status at a threshold of <10^-5
had longer PFS compared to MRD-positive patients (≥10^-5)

clonoSEQ predicts outcomes in both blood and bone marrow

An expanded analysis of the Thompson et al data set supported the clinical validation of clonoSEQ. This data shows a significant association between PFS and continuous clonoSEQ MRD measurement (vs. at a pre-specified sensitivity threshold) in both blood and bone marrow, after end of treatment (P= 9.6x 10^-4 for blood; P= 2.13 x 10^-4 for bone marrow). Additionally, patients who had U-MRD status at a threshold < 10^-6 had superior PFS compared to patients with MRD ≥ 10^-6 (P = 7.74 x 10^-2 for blood, Figure 4A; and P = 8.10 x 10^-2 for bone marrow, Figure 4B).^[1]

/wp-content/uploads/CLL_data_figure4@2x_BoxFree_NEW4.jpg

Figure 4A and B: Patients with U-MRD (<10^-6) had longer PFS compared to patients with detectable MRD whether assessed in blood or bone marrow

1. clonoSEQ^®. [technical summary]. Seattle, WA: Adaptive Biotechnologies; 2020. https://clonoseq.com/technical-summary.
17. Thompson P, et al. Blood. 201928;134(22):1951-1959.

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Clinical Practice Guidelines recommend MRD testing in CLL:

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) for CLL recommend MRD testing at a sensitivity of at least 10^-4. Next-generation sequencing (NGS) is listed as one of the recommended methods for MRD assessment.^[18]

This page is intended for use by healthcare professionals of the United States.

clonoSEQ^® is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect measurable residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available for use in other lymphoid cancers as a CLIA-validated laboratory developed test (LDT) service. For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit clonoSEQ.com/technical-summary.

Download CLL Clinical Data

Download our Chronic Lymphocytic Leukemia clinical data summary to explore and share the data.

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Review NCCN Guidelines®

Access the NCCN Guidelines.

GUIDELINES

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Citations

clonoSEQ^®. [technical summary]. Seattle, WA: Adaptive Biotechnologies; 2020. https://clonoseq.com/technical-summary.
Perrot A, et al. Blood. 2018;132(23):2456-2464.
Wood B, et al. Blood. 2018;131(12):1350-1359.
Kumar S, et al. Lancet Oncol. 2016;17(8):e328-e346.
Mateos M, et al. N Engl J Med. 2018;378(6):518-528.
DARZALEX^® Prescribing Information. Horsham, PA: Janssen Biotech, Inc; 2018.
Dimopoulos M, et al. N Engl J Med. 2016;375(14):1319-31.
Martinez-Lopez J, et al. Blood. 2014;123(20):3073-3079.
Avet Loiseau H, et al. ASH 2015: Abstract 191.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Multiple Myeloma V.3.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed March 11th, 2020. To view the most recent and complete version of the guideline, go to NCCN.org.
Moreau P, et al. Ann Oncol. 2017;00:1-11.
Faham M, et al. Blood. 2012;120(26):5173-5180. (study author was an employee of Adaptive at time of publishing)
Pulsipher M, et al. Blood. 2015;125(22):3501-8.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Pediatric Acute Lymphoblastic Leukemia V.2.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed March 11th, 2020. To view the most recent and complete version of the guideline, go to NCCN.org.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Acute Lymphoblastic Leukemia V.1.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed March 11th, 2020. To view the most recent and complete version of the guideline, go to NCCN.org.
Hoelzer D, et al. Ann Oncol. 2016;27 (suppl_5): v69-v82.
Thompson P, et al. Blood. 201928;134(22):1951-1959.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia V.4.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed [February 19, 2020]. To view the most recent and complete version of the guideline, go online to NCCN.org.