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Title: Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing

Abstract

Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samplesmore » and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. In conclusion, these initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.« less

Authors:
 [1];  [2];  [2];  [2];  [3]; ORCiD logo [4];  [5]
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  1. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  3. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine; Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States); VA Northern California Health Care System, Mather, CA (United States)
  4. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine; Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
  5. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine; VA Northern California Health Care System, Mather, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1513119
Report Number(s):
LLNL-JRNL-769867
Journal ID: ISSN 0893-228X; 961209
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Research in Toxicology
Additional Journal Information:
Journal Volume: 31; Journal Issue: 10; Journal ID: ISSN 0893-228X
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Scharadin, Tiffany M., Malfatti, Michael A., Haack, Kurt, Turteltaub, Kenneth W., Pan, Chong-xian, Henderson, Paul T., and Jonas, Brian A. Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing. United States: N. p., 2018. Web. doi:10.1021/acs.chemrestox.8b00107.
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Scharadin, Tiffany M., Malfatti, Michael A., Haack, Kurt, Turteltaub, Kenneth W., Pan, Chong-xian, Henderson, Paul T., & Jonas, Brian A. Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing. United States. doi:10.1021/acs.chemrestox.8b00107.
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Scharadin, Tiffany M., Malfatti, Michael A., Haack, Kurt, Turteltaub, Kenneth W., Pan, Chong-xian, Henderson, Paul T., and Jonas, Brian A. Tue . "Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing". United States. doi:10.1021/acs.chemrestox.8b00107. https://www.osti.gov/servlets/purl/1513119.
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@article{osti_1513119,
title = {Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing},
author = {Scharadin, Tiffany M. and Malfatti, Michael A. and Haack, Kurt and Turteltaub, Kenneth W. and Pan, Chong-xian and Henderson, Paul T. and Jonas, Brian A.},
abstractNote = {Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samples and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. In conclusion, these initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.},
doi = {10.1021/acs.chemrestox.8b00107},
journal = {Chemical Research in Toxicology},
number = 10,
volume = 31,
place = {United States},
year = {2018},
month = {8}
}
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Journal Article:
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DOI:  10.1021/acs.chemrestox.8b00107
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Figures / Tables:

Table 1 Table 1: Cell line IC50 values with 72 h continuous treatment (μM)
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Works referencing / citing this record:

Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science
journal, May 2019

  • Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A.
  • Toxics, Vol. 7, Issue 2
  • DOI: 10.3390/toxics7020027

Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science
journal, May 2019

  • Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A.
  • Toxics, Vol. 7, Issue 2
  • DOI: 10.3390/toxics7020027
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    Table 1 (p. 27)table
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    Figure 2 (p. 31)figure
    Figure 3 (p. 32)figure
    Figure 4 (p. 33)figure
    Figure 5 (p. 33)figure
    Figure S1 (p. 37)figure
    Figure S2 (p. 38)figure
    Figure S3 (p. 38)figure
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