Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.
Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.
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TP53突变(TP53mut)与急性髓系白血病(AML)预后不良有关。使用去甲基化药物的万乃馨是目前老年患者的标准，然而最近的报告表明，TP53mut对万乃馨具有抵抗力。我们调查了使用地西他滨和万乃馨(DEC10-VEN，NCT03404193)治疗TP53mut AML患者的结果。初诊AML患者给予地西他滨20 mg/m2，每4~6周1次，连服10天，诱导后5天开始用地西他滨。万乃馨剂量为400 mg/d。用NGS方法在骨髓标本中检测到TP53突变，敏感性为5%。根据ELN 2017指南对结果进行分析。118例患者中，53%(n=63)为继发性AML，33%(n=39)为复杂核型AML，30%(n=35)为TP53mut AML。Tp53变异等位基因频率中位数为32%(四分位数范围16%−65%)，23%(n=8)患者只有一个突变，43%(n=15)有多个突变，34%(n=12)有突变+缺失。与TP53WT AML相比，TP53mut的预后明显更差，总有效率为66%比(p=.002)，CR/CRI为57%比77%(p=.029)，60天死亡率为26%比4%(p<；.001)。TP53mut与TP53WT患者的总生存期分别为5.2个月和19.4个月(风险比为4.67，95%CI为2.44-8.93，p<；0.0001)，无复发生存期分别为3.4个月和18.9个月(HR为4.80，95%CI为1.97-11.69，p<；0.0001)。在TP53突变的AML中，使用DEC10-VEN的结果与单独使用10天地西他滨的历史结果相似。TP53突变的AML患者接受DEC10-VEN治疗的有效率较低，生存期较短。
TP53 mutation (TP53mut) confers adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients, however recent reports suggest that TP53mut confers resistance to venetoclax. We investigated outcomes of patients with TP53mut AML treated with 10-day decitabine and venetoclax (DEC10-VEN, NCT03404193). Patients with newly diagnosed AML received decitabine 20mg/m2 for 10-days every 4–6 weeks for induction, followed by decitabine 5-days after response. Venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using NGS with sensitivity of 5%. Outcomes were analyzed per ELN 2017 guidelines. Among 118 patients (median age: 72 years, range 49–89), 53% (n=63) had secondary AML, 33% (n=39) had AML with complex karyotype and 30% (n=35) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range 16%−65%), 23% (n=8) patients had only a single TP53 mutation, 43% (n=15) had multiple mutations, and 34% (n=12) had mutation+deletion. Outcomes were significantly worse in TP53mut compared to TP53WT AML with overall response rate of 66% vs 89% (p=.002), CR/CRi of 57% vs 77% (p=.029) and 60-day mortality of 26% vs 4% (p<.001), respectively. Patients with TP53mut vs TP53WT had shorter overall survival at 5.2 vs. 19.4 months (hazard ratio [HR] 4.67, 95%CI 2.44–8.93, p<.0001), and shorter relapse-free survival at 3.4 vs 18.9 months (HR 4.80, 95%CI 1.97–11.69, p<.0001), respectively. Outcomes with DEC10-VEN in TP53mut AML were comparable to historical results with 10-day decitabine alone. Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.
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影响因子：
82.9
作者：
Bernard E;Nannya Y;Hasserjian RP;Devlin SM;Tuechler H;Medina-Martinez JS;Yoshizato T;Shiozawa Y;Saiki R;Malcovati L;Levine MF;Arango JE;Zhou Y;Solé F;Cargo CA;Haase D;Creignou M;Germing U;Zhang Y;Gundem G;Sarian A;van de Loosdrecht AA;Jädersten M;Tobiasson M;Kosmider O;Follo MY;Thol F;Pinheiro RF;Santini V;Kotsianidis I;Boultwood J;Santos FPS;Schanz J;Kasahara S;Ishikawa T;Tsurumi H;Takaori-Kondo A;Kiguchi T;Polprasert C;Bennett JM;Klimek VM;Savona MR;Belickova M;Ganster C;Palomo L;Sanz G;Ades L;Della Porta MG;Elias HK;Smith AG;Werner Y;Patel M;Viale A;Vanness K;Neuberg DS;Stevenson KE;Menghrajani K;Bolton KL;Fenaux P;Pellagatti A;Platzbecker U;Heuser M;Valent P;Chiba S;Miyazaki Y;Finelli C;Voso MT;Shih LY;Fontenay M;Jansen JH;Cervera J;Atsuta Y;Gattermann N;Ebert BL;Bejar R;Greenberg PL;Cazzola M;Hellström-Lindberg E;Ogawa S;Papaemmanuil E
通讯作者：
Papaemmanuil E
DOI：
10.1016/s2352-3026(20)30210-6
发表时间：
2020-10
期刊：
The Lancet. Haematology
影响因子：
--
作者：
DiNardo CD;Maiti A;Rausch CR;Pemmaraju N;Naqvi K;Daver NG;Kadia TM;Borthakur G;Ohanian M;Alvarado Y;Issa GC;Montalban-Bravo G;Short NJ;Yilmaz M;Bose P;Jabbour EJ;Takahashi K;Burger JA;Garcia-Manero G;Jain N;Kornblau SM;Thompson PA;Estrov Z;Masarova L;Sasaki K;Verstovsek S;Ferrajoli A;Weirda WG;Wang SA;Konoplev S;Chen Z;Pierce SA;Ning J;Qiao W;Ravandi F;Andreeff M;Welch JS;Kantarjian HM;Konopleva MY
通讯作者：
Konopleva MY
影响因子：
28.2
作者：
Nechiporuk, Tamilla;Kurtz, Stephen E.;Tyner, Jeffrey W.
通讯作者：
Tyner, Jeffrey W.
影响因子：
51.1
作者：
DiNardo, Courtney L.;Pratz, Keith W.;Pollyea, Daniel A.
通讯作者：
Pollyea, Daniel A.
DOI：
10.1056/nejmoa1605949
发表时间：
2016-11-24
期刊：
The New England journal of medicine
影响因子：
--
作者：
Welch JS;Petti AA;Miller CA;Fronick CC;O'Laughlin M;Fulton RS;Wilson RK;Baty JD;Duncavage EJ;Tandon B;Lee YS;Wartman LD;Uy GL;Ghobadi A;Tomasson MH;Pusic I;Romee R;Fehniger TA;Stockerl-Goldstein KE;Vij R;Oh ST;Abboud CN;Cashen AF;Schroeder MA;Jacoby MA;Heath SE;Luber K;Janke MR;Hantel A;Khan N;Sukhanova MJ;Knoebel RW;Stock W;Graubert TA;Walter MJ;Westervelt P;Link DC;DiPersio JF;Ley TJ
通讯作者：
Ley TJ