Raffoux Emmanuel, Cras Audrey, Recher Christian, Boëlle Pierre-Yves, de Labarthe Adrienne, Turlure Pascal, Marolleau Jean-Pierre, Reman Oumedaly, Gardin Claude, Victor Maud, Maury Sébastien, Rousselot Philippe, Malfuson Jean-Valère, Maarek Odile, Daniel Marie-Thérèse, Fenaux Pierre, Degos Laurent, Chomienne Christine, Chevret Sylvie, Dombret Hervé
Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), and Université Denis Diderot - Paris 7, EA 3518, Institut Universitaire d'Hématologie (IUH), Paris.
UMR-S-940, Université Denis Diderot-Paris 7, IUH, Paris.
Oncotarget. 2010 May;1(1):34-42. doi: 10.18632/oncotarget.106.
In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.
在这项2期研究中，我们评估了5-氮杂胞苷（AZA）、丙戊酸（VPA）和全反式维甲酸（ATRA）联合用药对高危急性髓系白血病（AML）或骨髓增生异常综合征（MDS）患者的疗效。治疗包括六个周期的AZA和VPA，持续7天，随后是21天的ATRA。共纳入65例患者（中位年龄72岁；55例AML，包括13例复发/难治性患者，10例MDS；30例核型不良）。最佳反应包括14例完全缓解（CR）和3例部分缓解（PR）（26%），75%的缓解者和36%的未缓解者实现了红系反应。中位总生存期（OS）为12.4个月。未治疗患者的OS比复发/难治性患者更长。在完成6个计划周期的患者中，OS似乎不取决于是否达到CR/PR，这表明治疗期间病情稳定将是这种治疗方法生存的一个替代指标。治疗期间，早期血小板反应以及FZD9、ALOX12、HPN和CALCA基因的去甲基化与临床反应相关。最后，没有证据表明治疗期间ATRA诱导的分化得以恢复。表观遗传调控值得与高危AML患者的传统治疗进行前瞻性比较，至少在那些之前未接受治疗且原始细胞计数低的患者中如此。
