背景:B细胞前体急性淋巴细胞白血病(BCPALL)是一种遗传异质性肿瘤,具有>20种生物学亚型。每个亚型都显示出决定复发风险和患者生存的特定遗传性状。
目的:建立参加PETHEMALAL19试验(NCT04179929)的成年BCPALL患者的遗传亚型(原发改变),并将其与可测量的残留病(MRD)水平和生存率相关联。
方法:在LAL19试验(NCT04179929)中,Ph阴性患者(18-65岁)在第35天MRD≥0.01%或高风险遗传学接受alloHSCT和MRD<0.01%标准风险遗传学患者接受维持化疗。遗传分析是集中的:FISH和NGSDNA面板(萨拉曼卡医院),RNAseq小组(医院12号),FISH小组(医院LaFe),和SNP阵列(JosepCarreras研究所/ICO-医院德国人TriasiPujol)。MRD测定由细胞计量服务中的下一代流式细胞仪集中完成,NUCLEUS,萨拉曼卡大学。
结果:在54%(82/152)的患者中发现了遗传亚型。复发最多的亚型是KMT2Ar(11%),Ph样(主要是CRLF2::IGH,11%),低亚二倍体(7%),PAX5P80R(7%),高超二倍体(6%),和t(1;19)/TCF3::PBX1(6%)。此外,t(12;21)/ETV6::RUNX1,ZNF384r,iAMP21亚型(各1.5%)和MEF2Dr,MYCr,发现IDH1R132亚型(各<1%)。关于次要改动,NRAS(15%),TP53(13%),PAX5(13%),KRAS(10%)突变是最常见的。12例患者难治(主要是低亚二倍体,Ph-like,MYCr,和B-其他/未分类的患者)。在遗传亚型之间的第35天的MRD水平观察到统计学上的显着差异。Ph-like,低亚二倍体,KMT2Ar显示较低的MRD频率<0.01%(17%,33%,57%,分别)比PAX5P80R患者(100%),t(1;19)/TCF3::PBX1(83%),和高超二倍体(75%)(P=0.006)。尽管随访时间较短(11个月),对治疗的反应差异反映在患者的生存率上。在低反应亚型之间观察到生存的显着差异(Ph样,KMT2Ar,和低亚二倍体)和反应良好的亚型(PAX5P80R,t(1;19)/TCF3::PBX1和高超二倍体)。
结论:了解每个ALL的遗传亚型对于更好地预测复发风险和为每个患者提供最佳(个性化)治疗至关重要。
BACKGROUND: B-cell precursor acute lymphoblastic leukemia (BCP ALL) is a genetically heterogeneous neoplasm with >20 biologic subtypes. Each subtype shows specific genetic traits that determine relapse risk and patients\' survival.
OBJECTIVE: To establish the genetic subtype (primary alteration) of adult BCP ALL patients enrolled in the PETHEMA LAL19
trial (NCT04179929) and to correlate them with measurable residual disease (MRD) level and survival.
METHODS: In the LAL19
trial (NCT04179929), Ph-negative patients (18-65 y) with MRD≥0.01% at day+35 or high-risk genetics receive alloHSCT and MRD<0.01% patients with standard-risk genetics receive maintenance chemotherapy. The genetic analyses are centralized: FISH and NGS DNA panel (Hospital de Salamanca), RNAseq panel (Hospital 12 de Octubre), FISH panel (Hospital La Fe), and SNP array (Josep Carreras Institute/ICO-Hospital Germans Trias i Pujol). MRD determinations are centrally done by next-generation flow cytometry in the Cytometry Service, NUCLEUS, University of Salamanca.
RESULTS: The genetic subtype was identified in 54% (82/152) of patients. The most recurrent subtypes were KMT2Ar (11%), Ph-like (mostly CRLF2::IGH, 11%), low-hypodiploid (7%), PAX5 P80R (7%), high-hyperdiploid (6%), and t(1;19)/TCF3::PBX1 (6%). In addition, t(12;21)/ETV6::RUNX1, ZNF384r, and iAMP21 subtypes (1.5% each) and MEF2Dr, MYCr, IDH1 R132 subtypes (<1% each) were found. Regarding secondary alterations, NRAS (15%), TP53 (13%), PAX5 (13%), and KRAS (10%) mutations were the most frequently observed. Twelve patients were refractory (mainly low-hypodiploid, Ph-like, MYCr, and B-other/unclassified patients). Statistically significant differences were observed for day+35 MRD levels between genetic subtypes. Ph-like, low-hypodiploid, and KMT2Ar showed lower frequencies of MRD<0.01% (17%, 33%, and 57%, respectively) than patients with PAX5P80R (100%), t(1;19)/TCF3::PBX1 (83%), and high-hyperdiploid (75%) (P=0.006). Despite the short median follow-up (11 months), differences in response to treatment were reflected in patients\' survival. Significant differences in survival were observed between poor-response subtypes (Ph-like, KMT2Ar, and low-hypodiploid) and good-response subtypes (PAX5 P80R, t(1;19)/TCF3::PBX1, and high-hyperdiploid).
CONCLUSIONS: Knowing the genetic subtype of each ALL is crucial to better predict relapse risk and offer the best (personalized) treatment for each patient.