Chen Yi-Bin, Li Shuli, Lane Andrew A, Connolly Christine, Del Rio Candice, Valles Betsy, Curtis Morgan, Ballen Karen, Cutler Corey, Dey Bimalangshu R, El-Jawahri Areej, Fathi Amir T, Ho Vincent T, Joyce Amy, McAfee Steven, Rudek Michelle, Rajkhowa Trivikram, Verselis Sigitas, Antin Joseph H, Spitzer Thomas R, Levis Mark, Soiffer Robert
Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Biol Blood Marrow Transplant. 2014 Dec;20(12):2042-8. doi: 10.1016/j.bbmt.2014.09.007. Epub 2014 Sep 17.
The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is associated with a high relapse rate for patients with acute myeloid leukemia (AML) even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor, which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.govNCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3 + 3 cohort design was used to define the maximum tolerated dose (MTD), with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT and continued for 12 28-day cycles. Twenty-two patients were enrolled (status at HSCT: first complete remission [CR1], n = 16; second complete remission [CR2], n = 3; refractory, n = 3). The MTD was established at 400 mg twice daily with 1 dose-limiting toxicity (DLT) observed (pericardial effusion). Two patients died of transplantation-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped because of attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1 to 35.0). There was 1 case of grade II acute graft-versus-host disease (GVHD) after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% confidence interval [CI], 21% to 56%). For all patients, 1-year progression-free survival (PFS) was 85% (90% CI, 66% to 94%) and 1-year overall survival (OS) was 95% (90% CI, 79% to 99%) after HSCT. For patients in CR1/CR2 before HSCT (n = 19), 1-year PFS was 95% (90% CI, 76% to 99%) and 1-year OS was 100%, with only 1 patient who relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse.
FMS样酪氨酸激酶3内部串联重复（FLT3-ITD）突变与急性髓系白血病（AML）患者的高复发率相关，即便在异基因造血干细胞移植（HSCT）后亦是如此。索拉非尼是一种酪氨酸激酶抑制剂，可抑制FLT3酪氨酸激酶，在FLT3-ITD AML中已显示出令人鼓舞的活性。我们开展了一项针对FLT3-ITD AML患者HSCT后使用索拉非尼维持治疗的I期试验（ClinicalTrials.govNCT01398501）。患者接受了多种预处理方案和移植物来源。采用剂量递增的3+3队列设计来确定最大耐受剂量（MTD），另有10名患者在MTD剂量下接受治疗。索拉非尼在HSCT后第45天至120天之间开始使用，并持续12个28天周期。共纳入22例患者（HSCT时的状态：首次完全缓解[CR1]，n = 16；第二次完全缓解[CR2]，n = 3；难治性，n = 3）。MTD确定为每日两次400 mg，观察到1例剂量限制性毒性（DLT）（心包积液）。2例患者死于移植相关原因，均与索拉非尼无关。2例患者在复发后停用索拉非尼，5例在DLT期后因可归因的毒性而停药。存活患者HSCT后的中位随访时间为16.7个月（范围8.1至35.0个月）。开始使用索拉非尼后有1例II级急性移植物抗宿主病（GVHD），慢性GVHD的12个月累积发生率为38%（90%置信区间[CI]，21%至56%）。对于所有患者，HSCT后1年无进展生存期（PFS）为85%（90%CI，6%至94%），1年总生存期（OS）为95%（90%CI，79%至99%）。对于HSCT前处于CR1/CR2的患者（n = 19），1年PFS为95%（90%CI，76%至99%），1年OS为100%，仅有1例患者复发。对于FLT3-ITD AML患者，HSCT后使用索拉非尼是安全的，值得进一步研究以预防复发。
