scholarly journals High-throughput sequencing in acute lymphoblastic leukemia: Follow-up of minimal residual disease and emergence of new clones

2017 ◽  
Vol 53 ◽  
pp. 1-7 ◽  
Author(s):  
Mikaël Salson ◽  
Mathieu Giraud ◽  
Aurélie Caillault ◽  
Nathalie Grardel ◽  
Nicolas Duployez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

scholarly journals Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies

Blood ◽  
2015 ◽  
Vol 125 (26) ◽  
pp. 3996-4009 ◽  
Author(s):  
Jacques J. M. van Dongen ◽  
Vincent H. J. van der Velden ◽  
Monika Brüggemann ◽  
Alberto Orfao
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Pcr Analysis ◽  
Advantages And Disadvantages ◽  
Minimal Residual

Abstract Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia (ALL) and in many adult ALL patients. MRD diagnostics has proven to be the strongest prognostic factor, allowing for risk group assignment into different treatment arms, ranging from significant treatment reduction to mild or strong intensification. Also in relapsed ALL patients and patients undergoing stem cell transplantation, MRD diagnostics is guiding treatment decisions. This is also why the efficacy of innovative drugs, such as antibodies and small molecules, are currently being evaluated with MRD diagnostics within clinical trials. In fact, MRD measurements might well be used as a surrogate end point, thereby significantly shortening the follow-up. The MRD techniques need to be sensitive (≤10−4), broadly applicable, accurate, reliable, fast, and affordable. Thus far, flow cytometry and polymerase chain reaction (PCR) analysis of rearranged immunoglobulin and T-cell receptor genes (allele-specific oligonucleotide [ASO]-PCR) are claimed to meet these criteria, but classical flow cytometry does not reach a solid 10−4, whereas classical ASO-PCR is time-consuming and labor intensive. Therefore, 2 high-throughput technologies are being explored, ie, high-throughput sequencing and next-generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Each of them has specific advantages and disadvantages.

scholarly journals Detection of Minimal Residual Disease in B Lymphoblastic Leukemia by High-Throughput Sequencing of IGH

2014 ◽  
Vol 20 (17) ◽  
pp. 4540-4548 ◽  
Author(s):  
David Wu ◽  
Ryan O. Emerson ◽  
Anna Sherwood ◽  
Mignon L. Loh ◽  
Anne Angiolillo ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

High-Throughput Sequencing to Detect Minimal Residual Disease in Acute T Lymphoblastic Leukemia

2013 ◽  
Vol 13 ◽  
pp. S369 ◽  
Author(s):  
Anna Sherwood ◽  
David Wu ◽  
Jonathan R. Fromm ◽  
Stuart S. Winter ◽  
Kimberly P. Dunsmore ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

scholarly journals Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia

Blood ◽  
2012 ◽  
Vol 120 (26) ◽  
pp. 5173-5180 ◽  
Author(s):  
Malek Faham ◽  
Jianbiao Zheng ◽  
Martin Moorhead ◽  
Victoria E. H. Carlton ◽  
Patricia Stow ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
High Throughput Sequencing ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Receptor Gene ◽  
Multiparameter Flow Cytometry ◽  
Minimal Residual

Abstract The persistence of minimal residual disease (MRD) during therapy is the strongest adverse prognostic factor in acute lymphoblastic leukemia (ALL). We developed a high-throughput sequencing method that universally amplifies antigen-receptor gene segments and identifies all clonal gene rearrangements (ie, leukemia-specific sequences) at diagnosis, allowing monitoring of disease progression and clonal evolution during therapy. In the present study, the assay specifically detected 1 leukemic cell among greater than 1 million leukocytes in spike-in experiments. We compared this method with the gold-standard MRD assays multiparameter flow cytometry and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) using diagnostic and follow-up samples from 106 patients with ALL. Sequencing detected MRD in all 28 samples shown to be positive by flow cytometry and in 35 of the 36 shown to be positive by ASO-PCR and revealed MRD in 10 and 3 additional samples that were negative by flow cytometry and ASO-PCR, respectively. We conclude that this new method allows monitoring of treatment response in ALL and other lymphoid malignancies with great sensitivity and precision. The www.clinicaltrials.gov identifier number for the Total XV study is NCT00137111.

scholarly journals Minimal Residual Disease Sensitivity in Patients with Pre-B Cell Acute Lymphoblastic Leukemia Using Gemstone Analysis Method

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5348-5348
Author(s):  
Muaz Alrazzak ◽  
Beth Hill ◽  
Elizabeth A. Griffiths ◽  
Eunice S. Wang ◽  
Meir Wetzler ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Retrospective Review ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Analysis Method ◽  
Chi Square ◽  
Minimal Residual

Abstract The clinical management of patients with acute lymphoblastic leukemia (ALL) relies on accurate prediction of relapse hazard to determine the intensity of therapy and to avoid over- or under- treatment. Minimal residual disease (MRD) is a very effective method for predicting response to treatment and potential relapse in patients with ALL. The most validated method used to assess MRD in ALL is flow cytometric (FCM) analysis of leukemia-associated immunophenotypes which can detect up to 1 leukemic cell per 10,000 normal cells (0.01%). There is no standard method for detecting MRD by FCM in ALL patients. Our institutional approach has been to evaluate 20,000- 50,000 events using a specific immunophenotypic panel and to analyze the data using WinList software with a concurrent comparison with the diagnostic immunophenotype. GemStone™ is a new data analysis program that uses a Probability State Modeling (PSM) approach to analyze FCM data. The incorporated TriCOM technology numerically correlates all the immunophenotype combinations which can be used to detect MRD and other rare populations. In this study, we compared the GemStone and WinList analysis methods on the same patient data files. We identified 33 patients suitable for comparison by performing a retrospective review of the medical records from 2004-2010 in our pre-B cell ALL database. Patients were newly diagnosed, untreated, age ≥17 years and had FCM data available at diagnosis, week 4 (range 3-8) and week 16 (range 12-20) post therapy. We analyzed the FCM files to detect MRD using both GemStone and WinList methods separately, we subsequently reviewed the clinical course of the patients and identified those who sustained complete remission or relapsed. The clinical and FCM results were statistically correlated in Chi Square 2x2 table to identify the predictive value of each analysis method. WinList: we used CD10, CD19, CD34 and CD38 as a backbone marker set and tracked the same abnormal immunophenotype upon diagnosis in the subsequent follow up samples. GemStone: We used the same marker set and incorporate the TriCOM technology identify the MRD numerically. Figure 1 compares the outcome between GemStone and WinList methods at 16 weeks follow up. Table 1 reviews Chi Square with both method of analysis which gives comparable results. In summary, our retrospective review showed that GemStone method in detecting the MRD had comparable clinical and statistical significance to the WinList method. However, we found that the limited number of events collected (20,000) reduced our ability to completely automate the analysis process in GemStone due to intensity differences in the data. We are now conducting a prospective analysis by GemStone on ALL patients with higher number of collected events (5 x 10⁵- 2x 10⁶) Further, in our review, the MRD at 4 months post diagnosis (average 12-20 weeks) was more clinically significant than the one at 4 weeks follow up (range 3-8 weeks). Figure 1: A. Correlation between the clinical and FCM result using WinList method at 16 weeks follow up B. Correlation between the clinical and FCM result using GemStone method at 16 weeks follow up Figure 1:. A. Correlation between the clinical and FCM result using WinList method at 16 weeks follow up B. Correlation between the clinical and FCM result using GemStone method at 16 weeks follow up Abstract 5348 Table 1: comparison between WinList and GemStone method. Sensitivity Specificity PPV NPV P value Statistically significant WinList at 4 week F/U 33% 58% 23% 70% 0.49 no GemStone at 4 week F/U 44% 79% 44% 79% 0.17 no WinList at 16 week F/U 78% 58% 41% 88% 0.0323 yes GemStone at 16 week F/U 89% 67% 50% 94% 0.0022 yes Disclosures Hill: Verity Software house: Employment. Griffiths:Astex Pharmaceuticals: Research Funding; Celgene, Incyte and Alexion: Honoraria.

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