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Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients
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Abstract
Abstract Purpose: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation. Patients and Methods: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML. Results: A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1–64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%–59%] at 6 months, and 50% (95% CI, 43%–57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360–0.858), respectively. Conclusions: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML. See related commentary by Yan et al., p. 6561
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The depth of remission at the time of stopping TKI, particularly if evaluated by ddPCR, can predict TFR success.
“Other groups have shown that the depth of remission at the time of stopping TKI, particularly if the evaluation was by the more sensitive ddPCR, can also predict success [105, 106]”
From 2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia (2025) · cites this paper as [105]
Standardized clinical assessment of mRNA expression in CML can be performed with droplet digital PCR and the Cepheid GeneXpert qPCR cartridge system.
“The technical platforms allowing a standardized clinical assessment of mRNA expression levels for CML samples include droplet digital PCR (ddPCR; ref. 46) and the Cepheid GeneXpert qPCR cartridge system (47).”
From Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias (2021) · cites this paper as [46]
BCR-ABL1/ABL1 mRNA ratios on the international scale predict success of treatment-free remission attempts in de novo chronic phase CML.
“As an example, BCR-ABL1/ABL1 mRNA ratios on the international scale were shown to predict the success of treatment-free remission attempts for patients with de novo chronic phase CML (46).”
From Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias (2021) · cites this paper as [46]
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“…that the depth of remission at the time of stopping TKI, particularly if the evaluation was by the more sensitive ddPCR, can also predict success [105, 106] The mechanisms which prevent recurrence are poorly understood: current studies focus on possible immune-mediated control of residual…”
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Metadata
- Authors
- Nicolini, F. E., Dulucq, S., Boureau, L., Cony-Makhoul, P., Charbonnier, A., Escoffre-Barbe, M., Rigal-Huguet, F., Coiteux, V., Varet, B., Dubruille, V., Lenain, P., Rousselot, P., Rea, D., Guerci-Bresler, A., Legros, L., Liu, J., Gardembas, M., Ianotto, J.-C., Turlure, P., Johnson-Ansah, H., Martiniuc, J., Jardel, H., Joly, B., Zunic, P., Henni, T., Villemagne, B., Berger, M. G., Cayssials, E., Guilhot, F., Larosa, F., Guilhot, J., Etienne, G., & Mahon, F.-X.
- Affiliations
- Inserm (FR)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- 3Groupe Fi-LMC, Bergonié Institut, Bordeaux, France.
- Institut Bergonié (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Hôpital Necker-Enfants Malades (FR)
- Hôpital André Mignot (FR)
- Centre Hospitalier de Valence (FR)
- Centre Hospitalier Universitaire d'Angers (FR)
- Centre Hospitalier Universitaire de Limoges (FR)
- Centre Hospitalier de Saint-Brieuc (FR)
- Centre hospitalier Bretagne Atlantique (FR)
- Centre Hospitalier Sud Francilien (FR)
- Centre Hospitalier Universitaire de La Réunion (RE)
- 27Department of Internal Medicine and Onco-hematology, La Roche sur Yon, France.
- Centre Hospitalier Universitaire de Besançon (FR)
- Corresponding author
- Mahon, François-Xavier
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2019-11-15
- Volume
- 25
- Issue
- 22
- Pages
- 6606-6613
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2960549986
- Cited by
- 111
- References
- 18
- Citations by year
- 2026: 3 · 2025: 16 · 2024: 11 · 2023: 15 · 2022: 17 · 2021: 22 · 2020: 23 · 2019: 4
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- French Ministery of Health (CHUBX 2010/25)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- chronic myeloid leukemia, imatinib discontinuation, molecular recurrence, treatment-free remission, BCR-ABL1, residual disease, droplet digital PCR, predictive factors, chronic phase CML, MR4.5
- MeSH terms
- Imatinib Mesylate, Adult, Aged, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Prognosis, Prospective Studies, Remission Induction, Leukemia, Myeloid, Chronic-Phase, Gene Expression Regulation, Leukemic, Survival Analysis, Fusion Proteins, bcr-abl, Treatment Outcome, Neoplasm, Residual, Protein Kinase Inhibitors
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