Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant

Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression

David A. Jacobsohn, Michael R. Loken, Mingwei Fei, Alexia Adams, Lisa Eidenschink Brodersen, Brent R. Logan, Kwang Woo Ahn, Bronwen E. Shaw, Morris Kletzel, Marie Olszewski, Sana Khan, Soheil Meshinchi, Amy Keating, Andrew Harris, Pierre Teira, Reggie E Duerst, Steven P. Margossian, Paul L. Martin, Aleksandra Petrovic, Christopher C. Dvorak & 29 others Eneida R. Nemecek, Michael W. Boyer, Allen R. Chen, Jeffrey H. Davis, Shalini Shenoy, Sureyya Savasan, Michelle P. Hudspeth, Roberta H. Adams, Victor A. Lewis, Albert Kheradpour, Kimberly A. Kasow, Alfred P. Gillio, Ann E. Haight, Monica Bhatia, Barbara J. Bambach, Hilary L. Haines, Troy C. Quigg, Robert J. Greiner, Julie An M. Talano, David C. Delgado, Alexandra Cheerva, Madhu Gowda, Sanjay Ahuja, Mehmet Ozkaynak, David Mitchell, Kirk R. Schultz, Terry J. Fry, David M. Loeb, Michael A. Pulsipher

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a “difference from normal” flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P <.001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

Original languageEnglish (US)
Pages (from-to)2040-2046
Number of pages7
JournalBiology of Blood and Marrow Transplantation
Volume24
Issue number10
DOIs
StatePublished - Oct 1 2018

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Wilms' Tumor Genes
Chimerism
Wilms Tumor
Hematopoietic Stem Cells
Acute Myeloid Leukemia
Flow Cytometry
Hematopoietic Stem Cell Transplantation
Pediatrics
Transplants
Gene Expression
Phenotype
Recurrence
Multicenter Studies
Disease-Free Survival
Tissue Donors
Prospective Studies

Keywords

  • Cytogenetics and molecular genetics
  • Laboratory hematology
  • Measurable residual disease
  • Stem cell transplantation

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Jacobsohn, David A. ; Loken, Michael R. ; Fei, Mingwei ; Adams, Alexia ; Brodersen, Lisa Eidenschink ; Logan, Brent R. ; Ahn, Kwang Woo ; Shaw, Bronwen E. ; Kletzel, Morris ; Olszewski, Marie ; Khan, Sana ; Meshinchi, Soheil ; Keating, Amy ; Harris, Andrew ; Teira, Pierre ; Duerst, Reggie E ; Margossian, Steven P. ; Martin, Paul L. ; Petrovic, Aleksandra ; Dvorak, Christopher C. ; Nemecek, Eneida R. ; Boyer, Michael W. ; Chen, Allen R. ; Davis, Jeffrey H. ; Shenoy, Shalini ; Savasan, Sureyya ; Hudspeth, Michelle P. ; Adams, Roberta H. ; Lewis, Victor A. ; Kheradpour, Albert ; Kasow, Kimberly A. ; Gillio, Alfred P. ; Haight, Ann E. ; Bhatia, Monica ; Bambach, Barbara J. ; Haines, Hilary L. ; Quigg, Troy C. ; Greiner, Robert J. ; Talano, Julie An M. ; Delgado, David C. ; Cheerva, Alexandra ; Gowda, Madhu ; Ahuja, Sanjay ; Ozkaynak, Mehmet ; Mitchell, David ; Schultz, Kirk R. ; Fry, Terry J. ; Loeb, David M. ; Pulsipher, Michael A. / Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant : Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression. In: Biology of Blood and Marrow Transplantation. 2018 ; Vol. 24, No. 10. pp. 2040-2046.
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abstract = "We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a “difference from normal” flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23{\%} of patients screened for HSCT had detectable residual disease by ΔN (.04{\%} to 53{\%}). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04{\%} to 14{\%}) by ΔN. The disease-free survival of this group was 10{\%} (0 to 35{\%}) compared with 55{\%} (46{\%} to 64{\%}, P <.001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.",
keywords = "Cytogenetics and molecular genetics, Laboratory hematology, Measurable residual disease, Stem cell transplantation",
author = "Jacobsohn, {David A.} and Loken, {Michael R.} and Mingwei Fei and Alexia Adams and Brodersen, {Lisa Eidenschink} and Logan, {Brent R.} and Ahn, {Kwang Woo} and Shaw, {Bronwen E.} and Morris Kletzel and Marie Olszewski and Sana Khan and Soheil Meshinchi and Amy Keating and Andrew Harris and Pierre Teira and Duerst, {Reggie E} and Margossian, {Steven P.} and Martin, {Paul L.} and Aleksandra Petrovic and Dvorak, {Christopher C.} and Nemecek, {Eneida R.} and Boyer, {Michael W.} and Chen, {Allen R.} and Davis, {Jeffrey H.} and Shalini Shenoy and Sureyya Savasan and Hudspeth, {Michelle P.} and Adams, {Roberta H.} and Lewis, {Victor A.} and Albert Kheradpour and Kasow, {Kimberly A.} and Gillio, {Alfred P.} and Haight, {Ann E.} and Monica Bhatia and Bambach, {Barbara J.} and Haines, {Hilary L.} and Quigg, {Troy C.} and Greiner, {Robert J.} and Talano, {Julie An M.} and Delgado, {David C.} and Alexandra Cheerva and Madhu Gowda and Sanjay Ahuja and Mehmet Ozkaynak and David Mitchell and Schultz, {Kirk R.} and Fry, {Terry J.} and Loeb, {David M.} and Pulsipher, {Michael A.}",
year = "2018",
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language = "English (US)",
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pages = "2040--2046",
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Jacobsohn, DA, Loken, MR, Fei, M, Adams, A, Brodersen, LE, Logan, BR, Ahn, KW, Shaw, BE, Kletzel, M, Olszewski, M, Khan, S, Meshinchi, S, Keating, A, Harris, A, Teira, P, Duerst, RE, Margossian, SP, Martin, PL, Petrovic, A, Dvorak, CC, Nemecek, ER, Boyer, MW, Chen, AR, Davis, JH, Shenoy, S, Savasan, S, Hudspeth, MP, Adams, RH, Lewis, VA, Kheradpour, A, Kasow, KA, Gillio, AP, Haight, AE, Bhatia, M, Bambach, BJ, Haines, HL, Quigg, TC, Greiner, RJ, Talano, JAM, Delgado, DC, Cheerva, A, Gowda, M, Ahuja, S, Ozkaynak, M, Mitchell, D, Schultz, KR, Fry, TJ, Loeb, DM & Pulsipher, MA 2018, 'Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression', Biology of Blood and Marrow Transplantation, vol. 24, no. 10, pp. 2040-2046. https://doi.org/10.1016/j.bbmt.2018.06.010

Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant : Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression. / Jacobsohn, David A.; Loken, Michael R.; Fei, Mingwei; Adams, Alexia; Brodersen, Lisa Eidenschink; Logan, Brent R.; Ahn, Kwang Woo; Shaw, Bronwen E.; Kletzel, Morris; Olszewski, Marie; Khan, Sana; Meshinchi, Soheil; Keating, Amy; Harris, Andrew; Teira, Pierre; Duerst, Reggie E; Margossian, Steven P.; Martin, Paul L.; Petrovic, Aleksandra; Dvorak, Christopher C.; Nemecek, Eneida R.; Boyer, Michael W.; Chen, Allen R.; Davis, Jeffrey H.; Shenoy, Shalini; Savasan, Sureyya; Hudspeth, Michelle P.; Adams, Roberta H.; Lewis, Victor A.; Kheradpour, Albert; Kasow, Kimberly A.; Gillio, Alfred P.; Haight, Ann E.; Bhatia, Monica; Bambach, Barbara J.; Haines, Hilary L.; Quigg, Troy C.; Greiner, Robert J.; Talano, Julie An M.; Delgado, David C.; Cheerva, Alexandra; Gowda, Madhu; Ahuja, Sanjay; Ozkaynak, Mehmet; Mitchell, David; Schultz, Kirk R.; Fry, Terry J.; Loeb, David M.; Pulsipher, Michael A.

In: Biology of Blood and Marrow Transplantation, Vol. 24, No. 10, 01.10.2018, p. 2040-2046.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant

T2 - Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression

AU - Jacobsohn, David A.

AU - Loken, Michael R.

AU - Fei, Mingwei

AU - Adams, Alexia

AU - Brodersen, Lisa Eidenschink

AU - Logan, Brent R.

AU - Ahn, Kwang Woo

AU - Shaw, Bronwen E.

AU - Kletzel, Morris

AU - Olszewski, Marie

AU - Khan, Sana

AU - Meshinchi, Soheil

AU - Keating, Amy

AU - Harris, Andrew

AU - Teira, Pierre

AU - Duerst, Reggie E

AU - Margossian, Steven P.

AU - Martin, Paul L.

AU - Petrovic, Aleksandra

AU - Dvorak, Christopher C.

AU - Nemecek, Eneida R.

AU - Boyer, Michael W.

AU - Chen, Allen R.

AU - Davis, Jeffrey H.

AU - Shenoy, Shalini

AU - Savasan, Sureyya

AU - Hudspeth, Michelle P.

AU - Adams, Roberta H.

AU - Lewis, Victor A.

AU - Kheradpour, Albert

AU - Kasow, Kimberly A.

AU - Gillio, Alfred P.

AU - Haight, Ann E.

AU - Bhatia, Monica

AU - Bambach, Barbara J.

AU - Haines, Hilary L.

AU - Quigg, Troy C.

AU - Greiner, Robert J.

AU - Talano, Julie An M.

AU - Delgado, David C.

AU - Cheerva, Alexandra

AU - Gowda, Madhu

AU - Ahuja, Sanjay

AU - Ozkaynak, Mehmet

AU - Mitchell, David

AU - Schultz, Kirk R.

AU - Fry, Terry J.

AU - Loeb, David M.

AU - Pulsipher, Michael A.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a “difference from normal” flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P <.001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

AB - We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a “difference from normal” flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P <.001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

KW - Cytogenetics and molecular genetics

KW - Laboratory hematology

KW - Measurable residual disease

KW - Stem cell transplantation

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U2 - 10.1016/j.bbmt.2018.06.010

DO - 10.1016/j.bbmt.2018.06.010

M3 - Article

VL - 24

SP - 2040

EP - 2046

JO - Biology of Blood and Marrow Transplantation

JF - Biology of Blood and Marrow Transplantation

SN - 1083-8791

IS - 10

ER -