Priming of Mir-181a in Acute Myeloid Leukemia (AML) to Increase Chemosensitivity: A Phase I Trial of Lenalidomide (LEN) Followed by Idarubicin and Cytarabine.

Abstract 2619 Expression of miR-181a confers better prognosis in cytogenetically normal (CN) AML (Schwind et al, JCO 2010). Laboratory studies by our group have demonstrated that miR-181a is upregulated by C/EBPα-p30. CN AML patients (pts) harboring CEBPA mutations, the majority of which block C/EBPAα-p42 expression but allow C/EBPα-p30 expression, have elevated miR-181a and more favorable clinical outcome (Marcucci et al, JCO 2008). We hypothesized that pharmacologic potentiation of C/EBPa-p30 expression, and in turn miR-181a upregulation, would increase chemosensitivity and improve clinical outcomes in AML. Based on prior in vitro and in vivo studies, LEN was selected as a candidate agent to achieve these pharmacodynamic (PD) endpoints. Pharmacokinetic (PK) and PD studies from our prior single-agent, high-dose LEN trial demonstrated upregulation of miR-181a in leukemic blasts at tolerable doses; preclinical studies showed that this effect is dose dependent. Given these results and previously demonstrated LEN clinical activity in AML (Blum et al, JCO 2010; Fehniger et al, Blood 2011; Ades et al, ASH 2010; Lancet et al, ASH 2011), a phase I trial was conducted of LEN as miR “priming” with intensive chemotherapy in two parallel cohorts of AML: Prior Therapy (PT) Cohort for relapsed/refractory pts 60 years. In both groups, LEN was given for 14 days(d) starting at 25mg/d; cytarabine and idarubicin (starting dose 12/mg/m2 × 3d) began on d5. PT Cohort received cytarabine at a starting dose of 1.5 g/m2/d over 24 hours for 4d; U Cohort received 100mg/m2 for 7d in standard fashion. 31 pts enrolled, 17 with relapsed/refractory AML and 14 with previously untreated AML. PT Cohort pts had median age 53 years (range, 22–64) and median presenting WBC count of 4.2 × 109 (range, 0.9–22.7 × 109). U Cohort pts had median age 69 years (range, 48–77), median presenting WBC count of 3.1 × 109 (range, 0.5–31.9 × 109), and median marrow blasts of 36%. None of the U Cohort pts had favorable risk disease by ELN classification, 6 had adverse risk. Note that one patient 60 years) in the U Cohort. One pt in U Cohort was not evaluable for response as the pt discontinued treatment before chemotherapy was given. Preliminary PK parameters and LEN exposure (Figure 1) are consistent with what we reported previously. Observed PK of idarubicin was similar to expected and did not suggest an interaction with LEN. There was no apparent difference in PK of LEN in those who experienced skin rash (or other toxicities/clinical outcomes) compared with those that did not. Preliminary PD testing of LEN-induced modulation of miR-181a expression was consistent with the hypothesis of the trial. Results in a small subset of pts (N=6) tested to date showed a trend for greater post-LEN increase in miR-181a(pretreatment vs. d5 before chemotherapy began) in pts who achieved CR compared with those who did not (Figure 2). In conclusion, LEN priming with chemotherapy is reasonably well tolerated and active in AML. We are planning a randomized phase II study in previously untreated patients to test the hypotheses and compare efficacy of LEN priming vs. post-chemotherapy LEN. For the current trial, an amendment to shorten the course of LEN in order to facilitate dose escalation above 25mg is planned. Updated correlative results for all enrollees will be presented. Supported by NCI U01 CA 76576-05, NIH/NCI K23CA120708, Leukemia and Lymphoma Society SCOR 7004-11, and SPORE P50-CA140158. Disclosures: Off Label Use: Lenalidomide in AML.