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Randomized Controlled Trial
. 2010 Nov 11;116(19):3758-65.
doi: 10.1182/blood-2010-03-273979. Epub 2010 Aug 2.

Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS)

Timothy P Hughes  1 , Andreas Hochhaus, Susan Branford, Martin C Müller, Jaspal S Kaeda, Letizia Foroni, Brian J Druker, François Guilhot, Richard A Larson, Stephen G O'Brien, Marc S Rudoltz, Manisha Mone, Elisabeth Wehrle, Vijay Modur, John M Goldman, Jerald P Radich; IRIS investigators
Affiliations
Randomized Controlled Trial

Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS)

Timothy P Hughes et al. Blood. .

Abstract

This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients enrolled in the International Randomized Study of Interferon and STI571 (IRIS). Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time. Analyses of event-free survival (EFS) and time to progression to accelerated phase/blast crisis (AP/BC) at 7 years were based on molecular responses using the international scale (IS) at 6-, 12-, and 18-month landmarks. Patients with BCR-ABL transcripts > 10% at 6 months and > 1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response [MMR: BCR-ABL (IS) ≤ 0.1%] by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years. The probability of loss of complete cytogenetic response by 7 years was only 3% for patients in MMR at 18 months versus 26% for patients with complete cytogenetic response but not MMR (P < .001). This study shows a strong association between the degree to which BCR-ABL transcript numbers are reduced by therapy and long-term clinical outcome, supporting the use of time-dependent molecular measures to determine optimal response to therapy. This study is registered at www.clinicaltrials.gov as NCT00006343.

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Figures

Figure 1
Figure 1
Median BCR-ABL (IS) transcript levels in substudy and nonsubstudy patients over 84 months. Lines along x-axis connect medians over time; vertical bars represent 25th and 75th percentiles; vertical lines represent range.
Figure 2
Figure 2
EFS at 6 (A), 12 (B), and 18-month (C) landmarks by molecular response. These figures use the original EFS definition, without loss of CCyR counting as an event.
Figure 3
Figure 3
Time to loss of CCyR at 18-month landmarks by molecular response.
Figure 4
Figure 4
Time to AP/BC according to 6 (A), 12 (B), and 18-month (C) landmarks by molecular response.
See this image and copyright information in PMC

Comment in

  • CML: how low can you go?
    Schiffer CA. Schiffer CA. Blood. 2010 Nov 11;116(19):3686-7. doi: 10.1182/blood-2010-08-302323. Blood. 2010. PMID: 21071610 No abstract available.

References

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    1. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–2417. - PubMed
    1. Hochhaus A, O'Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23(6):1054–1061. - PubMed
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    1. Hughes T, Branford S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev. 2006;20(1):29–41. - PubMed

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