BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

Ilaria S. Pagani, Phuong Dang, Ivar O. Kommers, Jarrad M. Goyne, Mario Nicola, Verity A. Saunders, Jodi Braley, Deborah L. White, David T. Yeung, Susan Branford, Timothy P. Hughes, David M. Ross

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, BCR-ABL1 mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of BCR-ABL1 mRNA are proportional to the depletion of leukemic cells.
Original languageEnglish
Pages (from-to)2026-2032
JournalHaematologica
Volume103
Issue number12
DOIs
Publication statusPublished - 2018

Cite this

Pagani, Ilaria S. ; Dang, Phuong ; Kommers, Ivar O. ; Goyne, Jarrad M. ; Nicola, Mario ; Saunders, Verity A. ; Braley, Jodi ; White, Deborah L. ; Yeung, David T. ; Branford, Susan ; Hughes, Timothy P. ; Ross, David M. / BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia. In: Haematologica. 2018 ; Vol. 103, No. 12. pp. 2026-2032.
@article{deeeae65aaf142e9ab29cd97134b106b,
title = "BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia",
abstract = "Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, BCR-ABL1 mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48{\%} of samples with undetectable BCR-ABL1 mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of BCR-ABL1 mRNA are proportional to the depletion of leukemic cells.",
author = "Pagani, {Ilaria S.} and Phuong Dang and Kommers, {Ivar O.} and Goyne, {Jarrad M.} and Mario Nicola and Saunders, {Verity A.} and Jodi Braley and White, {Deborah L.} and Yeung, {David T.} and Susan Branford and Hughes, {Timothy P.} and Ross, {David M.}",
year = "2018",
doi = "10.3324/haematol.2018.189787",
language = "English",
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pages = "2026--2032",
journal = "Haematologica",
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Pagani, IS, Dang, P, Kommers, IO, Goyne, JM, Nicola, M, Saunders, VA, Braley, J, White, DL, Yeung, DT, Branford, S, Hughes, TP & Ross, DM 2018, 'BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia' Haematologica, vol. 103, no. 12, pp. 2026-2032. https://doi.org/10.3324/haematol.2018.189787

BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia. / Pagani, Ilaria S.; Dang, Phuong; Kommers, Ivar O.; Goyne, Jarrad M.; Nicola, Mario; Saunders, Verity A.; Braley, Jodi; White, Deborah L.; Yeung, David T.; Branford, Susan; Hughes, Timothy P.; Ross, David M.

In: Haematologica, Vol. 103, No. 12, 2018, p. 2026-2032.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

AU - Pagani, Ilaria S.

AU - Dang, Phuong

AU - Kommers, Ivar O.

AU - Goyne, Jarrad M.

AU - Nicola, Mario

AU - Saunders, Verity A.

AU - Braley, Jodi

AU - White, Deborah L.

AU - Yeung, David T.

AU - Branford, Susan

AU - Hughes, Timothy P.

AU - Ross, David M.

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N2 - Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, BCR-ABL1 mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of BCR-ABL1 mRNA are proportional to the depletion of leukemic cells.

AB - Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, BCR-ABL1 mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of BCR-ABL1 mRNA are proportional to the depletion of leukemic cells.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/29976745

U2 - 10.3324/haematol.2018.189787

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