Reevaluating the Role of Cytogenetic Testing in Patients with Suspected Myelodysplastic Syndrome in the Era of Next Generation Sequencing
Notice bibliographique
Résumé
Background: In patients with suspected myelodysplastic syndrome (MDS), ancillary tests including cytogenetics (CG) and molecular diagnostics often support the diagnosis and add prognostic value guiding treatment decisions. Frequently, high-cost new technologies such as next generation sequencing (NGS) are added to the existing test menu without consideration for redundancy or added value. In our institution most patients with suspected MDS or cytopenias of undetermined origin will have conventional CG and NGS routinely ordered in addition to bone marrow (BM) morphology and flow cytometry (FCM). In a previous retrospective study, we evaluated combined NGS and CG in 120 patients and we found that our NGS panel had enhanced diagnostic and prognostic advantages over standard karyotyping. Based on these results, we undertook a quality improvement (QI) project to streamline molecular diagnostic testing, reduce test redundancy, turnaround time and cost. Methods: Between February and June 2019 we prospectively evaluated an "NGS first approach" to investigate patients with suspected MDS or cytopenias of undetermined origin. We assessed BM morphology, FCM, NGS testing (Oncomine Myeloid Research Assay, Thermo-Fisher) and CG for all patients. To assess whether BM aspirates can be used to triage appropriate use of NGS and CG, expert morphologists assigned BM samples to either the NGS/CG group or NGS only group, based exclusively on the presence of morphological abnormalities suggesting the possibility of an MDS. Results: We included 50 patients with suspected MDS or cytopenias of undetermined origin. Of these, 33 (66%) were triaged into the NGS/CG group and the remaining 17 (34%) into the NGS only group. In the NGS/CG group NGS testing revealed DNA mutations in 27 (81.8%) patients, whereas CG showed an abnormal karyotype in 12 (36.4%). Among the 21 patients with normal karyotype, NGS revealed mutations in 17 (81%). Two patients (6%) were identified as MDS by morphological examination and had an abnormal karyotype but negative NGS. Of those assigned to the NGS/CG group, 27 (81.8%) were morphologically diagnosed as either MDS (54.5%), acute myeloid leukemia (AML) (15.2%), MDS/myeloproliferative neoplasms (MPN) (6.1%), or therapy related myeloid neoplasms (t-MNs) - MDS/AML (6.1%). Among the patients assigned to the NGS only group, NGS testing showed no abnormalities in 16 (94.1%) patients. One patient was found to carry a BRAF mutation and subsequently diagnosed with hairy cell leukemia. CG testing showed a normal karyotype in 16 (94.1%) patients. One patient was found to carry an inv(2)(p11.2q13) and was diagnosed as clonal B cell lymphocytosis. Conclusion: We proposed and validated a testing algorithm based on an "NGS first approach" with CG restricted to patients with morphological changes suggestive of MDS, in order to reduce the number of samples karyotyped. Overall, in patients with a morphological diagnosis of MDS, NGS defined genetic abnormalities in more patients (84.2%) compared to CG (47.4%) alone. Additional cytogenetic testing only detected chromosomal abnormalities in less than 10% of MDS cases. Most importantly, nearly no mutations or CG abnormalities were detected in patients without dysplastic features. Based on these results we estimated that we could reduce karyotyping by 10% to 20% for patients presenting with probable MDS or cytopenias of undetermined origin using an "NGS first approach". Further studies are warranted to validate and provide cost saving estimates of this approach. Disclosures Hsia: Amgen: Honoraria; Jansen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.
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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 | 0,006 | 0,011 |
| 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 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».