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Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors
American Journal of Hematology ( IF 10.1 ) Pub Date : 2022-01-03 , DOI: 10.1002/ajh.26447
Yazan Numan 1 , Zaid Abdel Rahman 2, 3, 4 , Justin Grenet 5 , Stephanie Boisclair 6 , Jan Philipp Bewersdorf 7 , Cailin Collins 8 , Dylan Barth 9 , Martina Fraga 10 , Dale L Bixby 11 , Amer M Zeidan 12 , Musa Yilmaz 13 , Pankil Desai 5 , Gabriel Mannis 8 , Yehuda E Deutsch 6 , Yasmin Abaza 1 , Shira Dinner 1 , Olga Frankfurt 1 , Mark Litzow 2, 3, 4 , Aref Al-Kali 2, 3, 4 , James M Foran 2, 3, 4 , Lisa Z Sproat 2, 3, 4 , Borko Jovanovic 14 , Naval Daver 13 , Alexander E Perl 15 , Jessica K Altman 1
Affiliation  

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

中文翻译:

Gilteritinib 在先前用 FLT3 抑制剂治疗的复发/难治性 FLT3 突变急性髓细胞白血病中的临床活性

Gilteritinib 被批准用于治疗具有 FLT3 突变 ( FLT3 mut+ ) 的复发/难治性 (R/R) 急性髓性白血病 (AML )。然而,gilteritinib 3 期 ADMIRAL 研究 (Perl 等 NEJM 2019) 是在广泛采用 midostaurin 作为标准强化诱导和巩固或移植后 FLT3 抑制剂维持的组成部分之前进行的。我们使用来自 11 个美国中心的数据进行了回顾性分析,其中我们确定了 113 名单独接受 gilteritinib 或作为治疗 R/R FLT3 mut+ AML 的联合疗法的患者。复合完全缓解 (CR) 率 (CRc,定义为 CR + CR i  + CR 伴血小板恢复不完全 [CRp]) 为 48.7% ( n = 55)。在仅接受过 7+3 和 midostaurin 合并或未合并巩固治疗的患者中,gilteritinib 治疗后的 CRc 率为 58%,中位生存期为 7.8 个月。获得 CR,尤其是 cMRD(临床最小或可测量残留病)阴性反应的患者的存活时间最长;在干细胞移植时进行审查后,这仍然很重要。与未表达这些突变的白血病患者相比,丝裂原活化蛋白激酶通路激活突变已知导致 gilteritinib 耐药(NRAS、KRAS 和 PTPN11)具有较低的 CRc(35% 对 60.5%)和较低的中位总生存期。 4.9 个月与 7.8 个月)(HR 2.4;95% CI 1. 5.4)p值 <.01。
更新日期:2022-02-10
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