Real World Experience of FLT3-Inhibitor Post-Transplant Maintenance with Sorafenib Demonstrating Superior Overall- and Relapse Free Survival Following Allogeneic Hematopoietic Stem Cell Transplantation in FLT3-ITD Mutated Acute Myeloid Leukemia
Notice bibliographique
Résumé
Introduction Acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD) is known to have a significantly high risk of relapse even with allogeneic stem cell transplantation (HCT), for which post-transplant maintenance therapy with FLT3 inhibitors (FLT3i) has been applied. Although there is a randomized trial comparing Sorafenib maintenance vs no treatment, real world experience is still limited. Despite the increased use of FTL3i maintenance in clinical practice, the optimal dose and duration of post-transplant Sorafenib maintenance remains uncertain. Accordingly, we performed a retrospective chart review to analyze the survival benefit with Sorafenib maintenance, dose tolerability and the impact of FLT3-ITD allele frequency (AF) at initial diagnosis of AML on treatment outcomes in the context of post-HCT Sorafenib maintenance. Patients and method We conducted a retrospective study including 69 patients who received an allogeneic HCT from 2019 to 2023 for AML with FLT3-ITD, of which 24 patients received Sorafenib as post-HCT maintenance therapy. Primary endpoint was relapse-free survival (RFS). The use of Sorafenib maintenance treatment was treated as a time-dependent covariate and Mantel-Byar test (MBT) was conducted to compare outcomes between Sorafenib maintenance group vs others, which will avoid immortal bias. FLT3-ITD allele frequency (AF) was assessed by molecular PCR test, and the cutoff was determined using a binary recursive partitioning method with AF of 54.6% as a cutoff. Results Out of 69 patients, 61 (88%) were in CR1 vs 8 (12%) in CR2 prior to HCT. Sorafenib was started in 24 patients (35%) at a median of 95 days post-HCT with a dose of 200mg every other day (n=2), 200mg once daily (n=17) or 200mg twice daily (n=5). The most common maintenance dose was 200mg once daily (n=9), followed by 200mg twice daily (n=6), 200mg every other day (n=5), and 400mg twice daily (n=1). The median Sorafenib maintenance duration was 15 months (1-53 months) at the last follow-up. There were no relapses in the patients who completed 2 years of Sorafenib maintenance. Sorafenib was discontinued in 6 patients, due to relapse (n=2), death of unrelated cause (n=1), GVHD (n=1), pneumonitis (n=1) and recurrent hypoglycemia (n=1). Adverse events requiring Sorafenib dose reduction included, GI intolerance (n=7), skin rash (n=7), thrombocytopenia (n=4), transaminitis (n=3), neuropathy (n=3), GVHD (n=2) and pneumonitis (n=2). The median follow-up duration for all the patients was 27 months (5-51) following HCT, or 13 months (1.3-48) following Sorafenib maintenance. Using Kaplan-Meier test, the 2-year RFS in patients on Sorafenib maintenance was 84.5% vs 40.5% for no Sorafenib (p=0.00049). The 2-year OS was 88.2% vs 53.9% (p=0.0043), respectively. The CIR was 9.8% vs 39.9% (p=0.00634), while the NRM was 5.6% vs 19.7% (p =0.122), respectively. In the MBT, Sorafenib maintenance was found to reduce the mortality risk by 62.5% (HR 0.375 (0.109-1.29], p=0.120) and reduced the relapse/mortality risk by 71.2% (HR 0.288 [0.084-0.984], p=0.047). With respect to FLT3-ITD AF, the group with higher AF showed extremely higher HR for RFS compared to those with lower FLT-ITD (HR 29.37 [3.007-286.8], p=0.0036). When evaluating RFS and OS with combined risk incorporating the use of Sorafenib and FLT3-ITD AF, we have 4 subgroups (figure 1). In patients with a lower AF, the RFS was 87.7% vs 56.8% in the Sorafenib (n=20), vs no Sorafenib group (n=31), respectively. In patients with a higher AF, the RFS was 66.7% vs 0.0% in the Sorafenib (n=3), vs no Sorafenib group (n=8; p=0.0009), respectively. In a multivariate analysis, we confirmed the 2-year RFS for patients who had a high FLT3-ITD and received Sorafenib maintenance was statistically significant when compared to no Sorafenib maintenance. Conclusion Sorafenib maintenance post-transplant in FLT3-ITD mutated AML patients significantly improves the OS and RFS. Sorafenib maintenance is tolerable with 200mg twice daily or lower in most patients. Reduced doses of Sorafenib improve tolerability, with no significant impact on increased risk of relapse. Higher AF group of FLT3-ITD at initial diagnosis defined by ≥54.6% using PCR, was associated with significantly increased risk of relapse even after HCT. Sorafenib maintenance seems to provide survival benefit in terms of RFS, particularly in the patients with higher AF FLT3-ITD.
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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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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 | 0,000 |
| 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 ».