Kapp-Schwoerer Silke, Weber Daniela, Corbacioglu Andrea, Gaidzik Verena I, Paschka Peter, Krönke Jan, Theis Frauke, Rücker Frank G, Teleanu Maria-Veronica, Panina Ekaterina, Jahn Nikolaus, Herzig Julia, Kubanek Lena, Schrade Anika, Göhring Gudrun, Fiedler Walter, Kindler Thomas, Schroeder Thomas, Mayer Karin T, Lübbert Michael, Wattad Mohammed, Götze Katharina S, Horst Heinz A, Koller Elisabeth, Wulf Gerald, Schleicher Jan, Bentz Martin, Krauter Jürgen, Bullinger Lars, Krzykalla Julia, Benner Axel, Schlenk Richard F, Thol Felicitas, Heuser Michael, Ganser Arnold, Döhner Hartmut, Döhner Konstanze
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Department of Human Genetics, Hannover Medical School, Hannover, Germany.
Blood. 2020 Dec 24;136(26):3041-3050. doi: 10.1182/blood.2020005998.
Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.
监测可测量残留病（MRD）可为核磷蛋白1突变（NPM1mut）急性髓系白血病（AML）患者提供预后信息，并且是评估临床试验中治疗效果的有力工具。我们通过定量逆转录聚合酶链反应测定NPM1mut转录水平（TLs），并评估NPM1mut MRD的预后影响以及吉妥珠单抗奥唑米星（GO）对参加随机3期AMLSG 09-09试验的NPM1mut AML患者NPM1mut TLs和累积复发率（CIR）的影响。共分析了469例患者的3733份骨髓（BM）样本和3793份外周血（PB）样本。在2个治疗周期后及治疗结束（EOT）时，NPM1mut TL log10降低≥3以及BM和PB中MRD转阴与较低的CIR率显著相关。在多变量分析中，MRD阳性始终被证明是BM和PB中的不良预后因素。关于治疗效果，在所有治疗周期中，GO组的NPM1mut TLs中位数显著更低，导致在EOT时达到MRD阴性的患者比例显著更高（56%对41%；P = 0.01）。在MRD阳性患者中，添加GO后2个治疗周期NPM1mut TLs的更好降低导致CIR率显著更低（4年CIR，29.3%对45.7%，P = 0.009）。总之，在NPM1mut AML的强化化疗中添加GO导致所有治疗周期中NPM1mut TLs显著更好地降低，从而导致复发率显著更低。
