Pediatric ALL Data
clonoSEQ MRD testing in pediatric ALL: a potential clinical pathway
Based on available evidence, this clinical strategy reflects a potential approach for integrating clonoSEQ MRD testing into the management of patients with pediatric ALL.
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).
579 pediatric patients were assessed for MRD at baseline and end of induction (Day 29).
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). When assessing MRD at a threshold of 10-5, clonoSEQ identified an additional 87 patients with disease who were MRD-negative by flow cytometry.
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).
Table 1: Comparison between clonoSEQ and flow cytometry (both assessed at 1/10,000)[1,2]
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
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).
clonoSEQ may be used to predict relapse and disease-free survival in the post-transplant setting
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.
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 1). NGS MRD showed an estimated relapse probability of 67% in MRD-positive patients vs. 25% in MRD-negative patients (p=0.01).
Figure 1: 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.
clonoSEQ is concordant with traditional methods for MRD detection and offers increased sensitivity
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 allele-specific oligonucleotide PCR (ASO-PCR; Figure 2).
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). ASO-PCR identified one patient with residual disease that was MRD-negative by clonoSEQ.
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.
Clinical Practice Guidelines recommend MRD testing in Pediatric ALL:
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pediatric ALL recommend MRD testing at a sensitivity of 10-4 or better because of its clinical utility.
NCCN makes no warranties of any kind whatsoever regarding its content, use, or application and disclaims any responsibility for how its content is applied or used, in any way.
This page is intended for a US-based audience.
clonoSEQ® is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect minimal 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 and specimen types as a CLIA-validated laboratory developed test (LDT). For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit clonoSEQ.com/technical-summary.
- Wood B, et al. Blood. 2018;131(12):1350-1359.
- Kirsch I, et al. SIOP. 2016. Abstract O-031.
- Pulsipher M, et al. Blood. 2015;125(22):3501-3508.*
- Faham M, et al. Blood. 2012;120(26):5173-5180.†
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pediatric Acute Lymphoblastic Leukemia V.3.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed July 23, 2021. To view the most recent and complete version of the guideline, go to NCCN.org.
*Study author’s research was funded, in part, via product grants from Adaptive.
†Study author was an employee of Adaptive at time of publishing.