Long-Term Outcomes of Patients with Acute Myeloid Leukemia Treated with Salvage High-Dose Etoposide and Cyclophosphamide
Notice bibliographique
Résumé
Abstract Background Salvage chemotherapy using high-dose etoposide and cyclophosphamide (VP-Cy) was developed for acute leukemia and myeloid malignancies resistant to cytarabine-based induction regimens. The Leukemia/Bone Marrow Transplant (L/BMT) program of British Columbia has a 25-year experience using VP-Cy for patients with relapsed and refractory (R/R) acute myeloid leukemia (AML). We report on a retrospective analysis to evaluate the efficacy and early toxicity of this regimen. Methods The L/BMT database was searched to identify R/R AML patients treated with VP-Cy. Patients were treated with etoposide 2.4 g/m2 given as continuous infusion over 34 hours on days 1-2 followed by cyclophosphamide 2 g/m2/day on days 3-5. The primary aims of this analysis were to determine response rate, long-term survival outcomes, and early toxicity. Secondary aims were to determine the impact of initial induction chemotherapy, using either standard-dose cytarabine and daunorubicin (7+3) or high-dose cytarabine and daunorubicin (HiDAC-D), on response rate to salvage as well as to assess the impact of cytogenetics and FLT3-ITD mutations on outcome. Survival curves were calculated using the Kaplan-Meier method, and comparisons between curves were made using the log-rank test. Chi-squared test was used to compare differences in categorical variables. Results 169 patients diagnosed with R/R AML treated with VP-Cy from 1991-2015 were identified. Baseline characteristics are shown in Table 1. CR rate was 45% and 5-year OS was 20% (95% CI 14-26%) for the entire cohort. Rate of CR (p=0.98) and median OS (p=0.8) were not different between cohorts receiving standard-dose cytarabine vs. high-dose cytarabine during initial induction. 74% (56/76) of responding patients received allogeneic hematopoietic stem cell transplant. 42% (32/76) of patients relapsed after initially responding to VP-Cy and the median CR duration was 221 days (range: 36 to 2561 days). In responding patients (n=76), 5-year relapse-free survival (RFS) and OS were 33% (95% CI 24-46%) and 35% (95% CI 25-47%) respectively. Initial disease status did not significantly influence response rate [52% (refractory day 14) vs. 42% (refractory day 28) vs. 47% (relapsed), p=0.46] although median OS was longer in patients with refractory disease [422 days (refractory day 14) vs. 281 days (refractory day 28) vs. 122 days (relapsed), p=0.03)]. Patients with FLT3-ITD mutation (30/78) had lower CR rate (23% vs. 53%; p=0.01) and worse OS (median OS 135 days vs. 357 days; p<0.0001) compared to those without. Patients with adverse risk cytogenetics (34/169) had a trend towards lower CR rate (38% vs. 50%; p=0.2) and a significantly worse OS (median OS 155 days vs. 304 days; p<0.0001) compared to patients with favourable/intermediate cytogenetics. Rate of early death (<60 days) was 12% (20/171) and causes included: bacterial infection (n=4), fungal infection (n=3), intracranial hemorrhage (n=1), and progressive AML (n=9). Conclusion VP-Cy is an effective salvage regimen with response rates, long-term survival and rates of early death comparable to reported outcomes using cytarabine-based salvage regimens. Initial dose of cytarabine given during induction did not influence response rate or survival. The probability of long-term survival for the entire cohort was low (20%) and outcomes were significantly worse in patients with FLT3-ITD mutation and adverse risk cytogenetics, emphasizing the need for investigation of novel treatments in these groups. Figure (a) Overall Survival. (b) Relapse-Free Survival in Patients Achieving CR Status After VP-Cy. Figure. (a) Overall Survival. (b) Relapse-Free Survival in Patients Achieving CR Status After VP-Cy. Figure Baseline Characteristics of Cohort. Figure. Baseline Characteristics of Cohort. Table 1 Table 1. Disclosures Song: Celgene: Honoraria, Research Funding; Janssen: Honoraria; Otsuka: Honoraria. Toze:Roche Canada: Research Funding. Gerrie:Roche Canada: Research Funding.
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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 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| 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 ».