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 language | English (US) |
---|---|
Pages (from-to) | 2040-2046 |
Number of pages | 7 |
Journal | Biology of Blood and Marrow Transplantation |
Volume | 24 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2018 |
Keywords
- Cytogenetics and molecular genetics
- Laboratory hematology
- Measurable residual disease
- Stem cell transplantation
ASJC Scopus subject areas
- Hematology
- Transplantation
Access to Document
Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.
Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
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, 10.2018, p. 2040-2046.Research output: Contribution to journal › Article › peer-review
}
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.
N1 - Funding Information: The authors thank the patients, study personnel, and care providers who participated in this study., Financial disclosure: This work was supported by the St. Baldrick's Foundation and the Otsuka Pharmaceutical Group. The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; a grant/cooperative agreement (4U10HL069294) from NHLBI and National Cancer Institute; a contract (HHSH250201200016C) with Health Resources and Services Administration; 2 grants (N00014-17-1-2388 and N0014-17-1-2850) from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; *Amgen, Inc.; *Amneal Biosciences; *Angiocrine Bioscience, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Juno Therapeutics; Karyopharm Therapeutics, Inc.; Kite Pharma, Inc.; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Mediware; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; *Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Otsuka Pharmaceutical Co, Ltd. ? Japan; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; and University of Minnesota. Asterisk denotes corporate members. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration, or any other agency of the US Government., Conflict of interest statement: M.R.L. is an employee and owner of Hematologics, Inc. L.E.B. is an employee of Hematologics, Inc. B.R.L. is a grant recipient from the St. Baldrick's Foundation., Authorship statement: D.A.J., M.R.L., B.R.L., K.W.A., M.K., A.Keating., A.C., M.B., K.S., T.F., D.L., and M.A.P. designed the research study. D.A.J., A.Keating., A.H., P.T., R.D., S.M., P.L.M., A.P., C.C.D., E.N., M.B., A.C., J.D., S. Shenoy, S. Savasan, M.H., R.A., V.L., A.Kheradbpour., K.A.K., A.G., A.E.H., M.B., B.B., H.H., T.Q., R.G., J.T., D.D., A.C., M.G., S.A., M.O., D.M., K.S., and M.A.P. performed the research study and recruited study subjects. M.R.L., L.E.B., M.K., M.O., S.K., and S.M. performed study experiments. D.A.J. and A.A. supervised the study. A.A. managed study data collection. M.F., A.A., B.R.L., and K.W.A. retrieved study data. M.F., B.R.L., K.W.A., and B.E.S. performed data analysis. M.F. generated the manuscript figure. D.A.J., M.R.L., M.F., B.R.L., K.W.A., B.E.S., and M.A.P. interpreted study data. DAJ, MRL, MF, AA, KWA, MAP wrote the manuscript. All authors reviewed the manuscript. Funding Information: Financial disclosure: This work was supported by the St. Baldrick's Foundation and the Otsuka Pharmaceutical Group. The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; a grant/cooperative agreement (4U10HL069294) from NHLBI and National Cancer Institute; a contract (HHSH250201200016C) with Health Resources and Services Administration; 2 grants (N00014-17-1-2388 and N0014-17-1-2850) from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; *Amgen, Inc.; *Amneal Biosciences; *Angiocrine Bioscience, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Juno Therapeutics; Karyopharm Therapeutics, Inc.; Kite Pharma, Inc.; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Mediware; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; *Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; and University of Minnesota. Asterisk denotes corporate members. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration, or any other agency of the US Government.
PY - 2018/10
Y1 - 2018/10
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
UR - http://www.scopus.com/inward/record.url?scp=85050818070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050818070&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2018.06.010
DO - 10.1016/j.bbmt.2018.06.010
M3 - Article
C2 - 29933069
AN - SCOPUS:85050818070
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 -