cancer | sorafenib combined with intensive chemotherapy can prolong the overall survival of newly diagnosed patients with acute myeloid leukemia with flt3-九游会ag

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acute myeloid leukemia (aml) is a malignant tumor that originates from hematopoietic stem cells. patients with flt3 mutations had shorter response times and worse prognosis than wild-type flt3. recently, a study was published in cancer to investigate whether sorafenib combined with intensive induction chemotherapy can improve the prognosis of flt3 gene internal tandem repeat (flt3-itd) mutant aml patients.

research background
ratify studies have shown that the addition of the flt3 inhibitor midostaurin to chemotherapy can prolong the event-free survival (efs) and overall survival (os) of newly diagnosed flt3 mutant aml patients.
sorafenib is an effective multi-kinase inhibitor that blocks multiple pathways involved in the development and progression of aml, including ras / raf, c-kit, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. and flt3.

the soraml study is a randomized, double-blind, placebo-controlled phase 2 trial evaluating the efficacy of sorafenib in combination with standard chemotherapy in newly diagnosed patients with ≤60 years of age with or without flt3-itd mutations. tolerance.

despite a significant prolongation of median efs and recurrence-free survival in the sorafenib group, patients receiving sorafenib did not benefit from os. the aml patients without flt3-itd mutations were included in the soraml study, while the ratify study included only fll3-itd mutation-positive aml patients, which may explain the difference between the two studies.

for newly diagnosed patients with flm3-itd mutation-positive aml, the efficacy of sorafenib for survival remains unclear. the aim of this study was to determine the potential benefit of adding sorafenib to intensive chemotherapy in young patients with newly diagnosed flt3-itd mutation-positive aml.

research method

the enrolled patients were newly diagnosed flt3-itd mutation-positive aml patients aged 18 to 60 or 65 years with good organ function (ejection fraction ≥ 45% or 50%; creatinine ≤ 1.5, 2 or 3 mg/dl; total bilirubin ≤ 1.5, 2 or 2.5 mg / dl; alanine aminotransferase level ≤ 2.5 or 3 times the upper limit of the normal range), ecog score ≥ 2. patients with acute promyelocytic leukemia were excluded from the study. patients were divided into two groups, receiving sorafenib combined with intensive chemotherapy and intensive chemotherapy.

400 mg of sorafenib was orally administered twice daily on days 1-7 or days 1-14 of the induction treatment and continued to be 400 mg twice daily during the consolidation treatment after remission. after the consolidation treatment was completed, sorafenib 400 mg was maintained twice a day for 1 year.

42 patients were identified in each cohort by propensity score matching. this minimizes differences in the previous medical history of cytotoxic or radiotherapy and platelet counts at the time of diagnosis, making it statistically insignificant.

research result

from february 2001 to december 2017, a total of 183 patients with a new diagnosis of flt3-itd mutation-positive aml were enrolled. of these, 79 (43%) received sorafenib intensive chemotherapy and 104 (57%) received intensive chemotherapy.

the overall median follow-up time for the matched cohort was 53.5 months (range: 0.1-122.3 months). in the matched sorafenib group and intensive chemotherapy group, 22 (52%) and 19 (45%) patients received combination therapy with idarubicin cytarabine purine analog (p =0.513), 28 (67%) and 23 (55%) patients underwent subsequent allogeneic hematopoietic stem cell transplantation (asct) (p = 0.264). in the matched cohort, the objective response rate (orr) was 98% in the sorafenib group and 83% in the intensive chemotherapy group (p=0.057). median efs was 35 months and 8 months in the sorafenib group and intensive chemotherapy group (p=0.019) (figure 1), with median os of 42 months and 13 months, respectively (p=0.026). figure 2).

figure 1 kaplan-meier curve comparison matching queue efs

figure 2 kaplan-meier curve comparison matching queue os

at the time of asct, the median efs of the sorafenib group and the intensive chemotherapy group were 31 months and 8 months, respectively (p=0.031) (fig. 3), and the median os was not reached and 10 months, respectively. p = 0.001) (fig. 4).

图3 kaplan-meier曲线比较匹配队列中干细胞移植（sct）时的efs

figure 4 kaplan-meier curve compares os in stem cell transplantation (sct) in matching cohort

sorafenib treatment was a favorable prognostic factor by a multivariate cox proportional hazard model (p=0.009; hr=0.558; 95% ci=0.360-0.865).
in conclusion
sorafenib combined with intensive chemotherapy can improve survival in patients with flt3-itd mutation-positive aml, regardless of whether the patient is undergoing allogeneic hematopoietic stem cell transplantation.

医脉通 compiled from: koji sasaki, hagop m. kantarjian, et al. sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, flt3-internal tandem duplication mutation–positive acute myeloid leukemia. cancer. doi:10.1002/cncr. 32387