Increased Tumour Burden over a 36 Month Period in Chronic Myeloid Leukemia Patients Following Imatinib Discontinuation: Role of Digital PCR
Notice bibliographique
Résumé
Introduction. Discontinuation (D/C) of Imatinib or other TKIs in Chronic Myeloid Leukemia (CML) represents an important issue in the management of this disease. It is generally accepted that relapse develops (and treatment must be resumed) when patients (pts) lose Major Molecular Remission (MMR), i.e. when the amount of the BCR-ABL1 transcript, measured in peripheral blood by RT-PCR, exceeds 0.1 %. The Imatinib Suspension And Validation (ISAV) study, which started in 2011, enrolled pts with CML treated with Imatinib who showed no evidence of BCR-ABL1 transcript for at least 18 months before enrollment. Methods. A digital PCR (dPCR) for BCR-ABL1 was performed at the time of Imatinib D/C while a second dPCR was performed when non relapsed patients exited the study, 36 months later. dPCR experiments were performed by the QX200 system (BioRad) in the same lab and using the same methodology. The BCR-ABL1 fusion and ABL1 transcripts were quantified using DigiDrop P210 MasterMix and DigiDrop P210 Positive Control (Bioclarma), according to manufacturer's protocol. The target concentration in each sample was expressed as percentage of BCR-ABL1/ABL1. Results. A total of 107 pts were enrolled in the ISAV study. Relapses occurred in 54 pts (52%); among the 53 non relapsed pts, 41 (77%) presented at least one positive RT-PCR result following Imatinib D/C, and only 12 (23%) maintained PCR negativity throughout the duration of the study. Among the non-relapsed pts dPCR performed at treatment D/C showed positivity in 20.6% of cases (95% confidence interval [C.I.] 9-36%), while 91.1% of pts (95%, C.I. 80-97%) evaluated 36 months later showed a positive dPCR value, although no patient resumed treatment. The evaluation of non relapsed pts by dPCR showed that mean values at D/C were 0.00143% +/- 0.0006 (SE); when tested at study exit, the same pts showed average dPCR values of 0.0115 % +/- 0.002. This difference is statistically highly significant and corresponds to a change of approximately 1 log in the residual tumor burden: from 2x107 to 2x108 cells. There was no correlation between the results of RT-PCR performed during the study and the dPCR status at study exit: pts who tested negative by RT-PCR during the study were uniformly negative in dPCR at D/C but tested positive at study exit in 83.3% of cases; pts who showed at least on positive RT-PCR during the study showed positivity by dPCR in 25% at D/C and in 89.3% at study exit. Finally, half of the pts who tested negative by dPCR at study exit showed dPCR positivity when tested at the time of Imatinib D/C. Conclusions. These results show that during a three year period, the D/C of Imatinib led to the increase of approximately 1 log in the tumour burden of non-relapsed pts, although none of them lost MMR and resumed treatment. These data strongly indicate the need for a long-term monitoring of pts who D/C Imatinib; they also suggest that the functional status of residual CML cells rather than their number could represent the critical factor to predict the tumour load present after 3 years of Imatinib D/C. Disclosures Le Coutre: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Elena:Novartis: Consultancy; Pfizer: Consultancy. Assouline:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Stagno:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding. Fava:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».