Abstract:Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of and genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR… Show more
“…Advantages/disadvantages of HTS screening and MRD monitoring have been discussed previously, particularly in tandem with flow cytometry MRD monitoring . HTS MRD monitoring may lead to assessment at different time points post treatment as well as potentially in blood samples . In the imminent future, it is likely that HTS will be the technique of choice for both screening and follow‐up MRD, but at a minimum, HTS needs to be adopted by MRD laboratories for screening in cases where traditional methods have failed.…”
Section: Discussionmentioning
confidence: 99%
“…The “gold standard” molecular MRD assessment is based on the allele‐specific amplification of immunoglobulin and T‐cell receptor gene (IG/TCR) rearrangements followed by real‐time quantitative PCR (RT‐qPCR) performed on bone marrow (BM). Recent studies have shown the applicability and potential benefits of a high‐throughput sequencing (HTS) approach to MRD measurement . We aimed to utilize a targeted HTS strategy on diagnostic/relapse BM to identify novel clonal rearrangements in patients proving difficult to analyze using conventional screening.…”
Section: Introductionmentioning
confidence: 99%
“…Recent studies have shown the applicability and potential benefits of a high-throughput sequencing (HTS) approach to MRD measurement. 6,7 We aimed to utilize a targeted HTS strategy on diagnostic/relapse BM to identify novel clonal rearrangements in patients proving difficult to analyze using conventional screening. We present detailed results on an illustrative cohort of six patients, demonstrating the feasibility of HTS to provide timely markers to use in subsequent RT-qPCR in cases where conventional molecular screening failed.…”
The molecular detection of minimal residual disease (MRD) is standard of care in acute lymphoblastic leukemia to personalize the stratification of patients to appropriate intensity chemotherapy regimens. High‐throughput sequencing (HTS) techniques are driving changes to MRD methodologies. Our study demonstrates HTS can identify suitable diagnostic markers, even in cases where traditional screening has been unsuccessful. Markers identified by HTS were used to track MRD using standard real‐time quantitative PCR. We show, with six patient examples, clinical benefits of utilizing HTS to screen diagnostic samples and its necessity when traditional screening techniques fail. This is practical evidence that current MRD diagnostic marker screening should be replaced by an HTS approach.
“…Advantages/disadvantages of HTS screening and MRD monitoring have been discussed previously, particularly in tandem with flow cytometry MRD monitoring . HTS MRD monitoring may lead to assessment at different time points post treatment as well as potentially in blood samples . In the imminent future, it is likely that HTS will be the technique of choice for both screening and follow‐up MRD, but at a minimum, HTS needs to be adopted by MRD laboratories for screening in cases where traditional methods have failed.…”
Section: Discussionmentioning
confidence: 99%
“…The “gold standard” molecular MRD assessment is based on the allele‐specific amplification of immunoglobulin and T‐cell receptor gene (IG/TCR) rearrangements followed by real‐time quantitative PCR (RT‐qPCR) performed on bone marrow (BM). Recent studies have shown the applicability and potential benefits of a high‐throughput sequencing (HTS) approach to MRD measurement . We aimed to utilize a targeted HTS strategy on diagnostic/relapse BM to identify novel clonal rearrangements in patients proving difficult to analyze using conventional screening.…”
Section: Introductionmentioning
confidence: 99%
“…Recent studies have shown the applicability and potential benefits of a high-throughput sequencing (HTS) approach to MRD measurement. 6,7 We aimed to utilize a targeted HTS strategy on diagnostic/relapse BM to identify novel clonal rearrangements in patients proving difficult to analyze using conventional screening. We present detailed results on an illustrative cohort of six patients, demonstrating the feasibility of HTS to provide timely markers to use in subsequent RT-qPCR in cases where conventional molecular screening failed.…”
The molecular detection of minimal residual disease (MRD) is standard of care in acute lymphoblastic leukemia to personalize the stratification of patients to appropriate intensity chemotherapy regimens. High‐throughput sequencing (HTS) techniques are driving changes to MRD methodologies. Our study demonstrates HTS can identify suitable diagnostic markers, even in cases where traditional screening has been unsuccessful. Markers identified by HTS were used to track MRD using standard real‐time quantitative PCR. We show, with six patient examples, clinical benefits of utilizing HTS to screen diagnostic samples and its necessity when traditional screening techniques fail. This is practical evidence that current MRD diagnostic marker screening should be replaced by an HTS approach.
“…A correct interpretation requires substantial expertise and familiarity on the part of the interpreting pathologist and it is limited by the potential for false‐positive or false‐negative results especially with post‐induction bone marrow with normal blasts (so called “hematogones”) or too few blasts, respectively. Standard (eg, steroids) and new monoclonal antibody (CD19, 20, 22)‐based treatments can also influence the detectability of residual blasts as it can cause marker shifts . Another major limitation is the lack of standardization of MFC across US, especially in adult ALL although some evidence exists in the pediatric realm, whereas in Europe extensive efforts have made significant progress, again in the pediatric population .…”
Section: Mrd Testingmentioning
confidence: 99%
“…This technique relies on the high‐level multiplex PCR capability of NGS to allow the design of balanced primers that simultaneously amplify all possible combinations of the IGH/TR rearrangements . NGS has been compared to MFC as well as RT‐qPCR with NGS showing better sensitivities and discordant results favoring NGS. However, just like MFC, it is limited by the requirement of pretreatment diagnostic samples to obtain an index sequence for IGH/TR MRD detection.…”
Adult acute lymphoblastic leukemia management has traditionally relied upon pretreatment conventional risk factors for treatment decisions. Despite using intensive multiagent chemotherapy followed by a prolonged maintenance or allogeneic stem cell transplantation, these patients remain at a high risk of relapse. Improved techniques for detection of measurable residual disease (MRD) have tremendously changed the posttreatment disease burden assessment and evolved as a powerful predictor of relapse and survival superseding historical prognostic factors. Moreover, MRD measurement has become an integral part of risk stratification, prognosis assessment, intensification or de‐escalation of treatment, monitoring of disease burden, and an endpoint in clinical trials. With existing approaches like allogeneic hematopoietic stem cell transplantation and emergence of novel agents (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor [CAR] T cells) that are highly effective in eradicating residual disease, understanding the role of MRD in treatment decisions is getting more and more important and complex. This review will highlight the advances that have been achieved in MRD monitoring over the years and the practical applications in different time points of treatment to provide a framework for rational management decisions by practicing hematologists and oncologists.
The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data. We report that B/T MPAL commonly presents with lymphadenopathy in adolescence and young adulthood. While the tumors have diverse cytogenetic and genomic perturbations, recurrent acquired aberrations include mutations in the putative transcriptional regulator PHF6 and the JAK-STAT and Ras signaling pathways. Alterations were also identified in genes encoding hematopoietic transcription factors, cell cycle regulators/tumor suppressors, and chromatin modifying enzymes. The genomic landscape of B/T MPAL strongly resembles that of T-ALL subgroups associated with early developmental arrest, while genetic alterations that are common in B-ALL were rarely seen. Two-thirds of the patients responded to ALL-based chemotherapy with or without stem cell transplantation. Our observations lay the groundwork for further study of the unique biology and clinical trajectory of B/T MPAL.
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