Activity of Rapamycin in Patients with Relapsed, Refractory or Poor-Risk Acute Myeloid Leukemia.
Authors: Recher Christian , Beyne-Rauzy Odile , Demur Cecile , Huguet Françoise , Laurent Guy , Chicane Gaëtan , Santos Cedric Dos , Mansat-Demas Veronique , Payrastre Bernard 
Published: October 2019

Abstract
We have recently demonstrated that the mammalian Target of Rapamycin (mTOR) pathway is constitutively activated in most AML cases and that rapamycin (RAPA) selectively inhibits the clonogenic properties of AML progenitors while sparing their normal counterparts (ASH 2003, #331). We report here the results of a pilot study evaluating the activity of RAPA in relapsed, refractory or poor-risk AML patients.
Twelve patients have been enrolled from October 2003 to March 2004. Patients’ characteristics were: median age, 72 years (range, 55-77); refractory AML (n=4), first relapse (n=5, 4 after autologous stem cell transplantation), secondary AML (n=3), median WBC (23.8 x 109/L, range, 1.8–103), cytogenetic (intermediate, n=11; unfavorable, n=1), performans status (PS>2; n=5). Patients received RAPA (6 mg at day 1 then 2 mg per day) for 28 days on an outpatient basis. The primary study objective was to determine the overall response rate after 28 days of treatment. RAPA was well tolerated. Whole blood sirolimus concentrations were measured at day 7 and day 21. The range of sirolimus concentrations was highly variable according to patients (trace amounts to 31.4 μg/L). At day 28, hematologic response (HR), defined as a greater than 50% reduction in the absolute number of blood blasts or at least a 50% reduction in the percentage of marrow blasts, occurred in 4 pts, while 7 patients progressed and one had stable disease. The median duration of response was 38 days (range, 35–120). The median duration of treatment was 50 days (range, 21–240) and 90 days (range, 55–240) for all patients and responders, respectively. Two responding patients are alive at 8 and 10 months, respectively. The anti-leukemic activity of RAPA was accompanied by a restoration of normal neutrophils counts and a loss of transfusion requirement in these two responders. No correlations between clinical data, in vitro sensitivity to RAPA assessed by clonogenic assays and HR were found. In a responding patient, the phosphorylation of mTOR targets (p70S6K and 4E-BP1) in blood blasts was inhibited upon RAPA treatment, demonstrating that RAPA targets mTOR in vivo. As an example, a previously autografted 55 years patient with second relapse, displayed a very good response to RAPA. At d28, he had less than 5% of blasts in the marrow (vs 35% before RAPA) and restored normal absolute neutrophils counts. Moreover, cytogenetic response was documented by the disappearance of a pretreatment chromosomal abnormality (del 5q). However, CR was not truly obtained because of persistent mild thrombopenia. The duration of response in this heavily pre-treated patient was 3 months with RAPA alone. He then relapsed and is still alive (10 months +).
This study demonstrate that inhibition of mTOR can induce significant responses in high-risk AML patients and warrant further studies assessing the role of RAPA or analogues in combination with chemotherapy in this disease.