UM171 Cord Blood Transplantation for TP53 Mutated and EVI1 Rearranged Myelodysplasia/Acute Myeloid Leukemia
Notice bibliographique
Résumé
Background: UM171 is a molecular glue (Fares et al, Science 2014) developed by our group which expands balanced-hematopoietic stem cells (B-HSCs) while enhancing their lymphoid differentiation potential (Dumont-Lagace et al, TCT, 2021) and generating cells in the graft with direct activity against acute myeloid leukemia (AML) blasts through a novel mechanism of action that involves degradation of CoREST1 (Chagraoui et al, Cell Stem Cell, 2012) and nuclear cMYC (Chagraoui et al, Blood 2024). Cord blood transplantation (CBT) has several advantages including lower risk of relapse in high risk hematologic diseases (Milano et al, NEJM 2016, Horgan et al, Blood Adv 2023). However CBT is hampered by high non relapse mortality (NRM) due to low cell dose and selection of poorly HLA matched cords. From 2016 to 2018, 22 patients with hematologic malignancies who lacked a donor were transplanted on a phase I-II clinical trial with a single UM171-expanded CB (Cohen S et al, Lancet Haematol 2019). The goal was to accelerate engraftment while selecting smaller, better HLA matched CBs to decrease NRM. Results demonstrated prompt neutrophil engraftment and lower NRM compared to controls (Cohen S et al, Blood Adv., 2023). Between 2019 and 2022, 30 additional patients with high and very high-risk myelodysplasia/acute leukemia underwent a single UM171 CBT on a phase II trial. Amongst these 52 patients on these 2 trials, there were patients with very high-risk myelodysplasia (MDS) or AML, defined as TP53 mutation/deletion or EVI1 rearrangement. Expected long term outcomes after a conventional allogeneic stem cell transplant for these diseases are dismal to the point that some transplant centers now exclude these patients from transplantation. The aim of this current analysis is to examine the outcome of patients with poor outcome TP53 or EVI1 anomalies who were transplanted with a single UM171 CBT during the course of these 2 clinical trials. Methods: Data for this analysis were drawn from both trials listed above. Eligibility criteria for this analysis included patients with MDS or AML with TP53 mutation/deletion or EVI1 rearrangement who were transplanted with a single UM171 CB. Examined clinical outcomes included NRM, relapse, progression-free survival (PFS) and overall survival (OS) at 2- and 3-years post-transplant. PFS and OS were estimated by Kaplan-Meir method; relapse and NRM were calculated using cumulative incidence estimates. Results: A total of 10 patients met inclusion criteria, 1 from the initial phase I-II trial and 9 from the phase II trial. Three patients had EVI1 rearrangements and 7 patients had TP53 mutation/deletion. One patient had MDS and 9 had AML. Patient characteristics included 9 men and 1 woman with a median age and weight of 50 years and 83kg, respectively. Median HCT-CI was 1(0-4). One patient (10%) had previously failed an allogeneic transplant. Conditioning regimen was myeloablative or reduced intensity. Median follow-up is 35 months. Three patients died from NRM (NRM was 11% for the entire group of 52 patients from both clinical trials). Cumulative incidence of relapse was 10% at 2 years and 22% at 3 years. OS and PFS at 2 years were both 60% (95%CI 36-99%) and at 3 years 48% (95%CI 25-94%). Conclusion: We previously showed that UM171 expanded CBT permits the use of CB with a low NRM of 11% and that these grafts are highly effective in high/very high-risk malignancies. Subset analyses presented herein suggest that this technology has the potential to overcome the negative prognosis associated with TP53/EVI1 MDS/AML with OS and relapse at 24 months of 60% and 10%, respectively. These results compare quite favorably to previous publications with OS usually being reported at ≈20% at 2 years. The main limitation of our study is the low number of patients, and thus more patients are needed to confirm these results.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».