Low-Dose Lenalidomide Plus Low Dose Cytarabine Induce Complete Remission That Can Be Predicted By Genetic Profiling In Very Elderly Acute Myeloid Leukemia Patients
Authors: Visani Giuseppe , Di Raimondo Francesco , Ferrara Felicetto , Loscocco Federica , Piccaluga Pier Paolo , Fuligni Fabio , Gazzola Anna , Rossi Maura , Laginestra Antonella , Caraci Maria Rita , Riccardi Cira , Visani Axel , Barulli Sara , Guiducci Barbara , Ricciardi Teresa , Sparaventi Giovanni , Rocchi Marco , Isidori Alessandro 
Published: October 2019

Abstract
Outcome for older patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. In this phase II study we tested, for the first time, the efficacy of a novel combination therapy with low-dose lenalidomide plus low-dose cytarabine. Further, based on the hypothesis that genetic features might influence treatment response, we aimed at identifying a possible biomarker by studying the global gene expression profiles (GEP).
We designed a prospective phase II study to assess the efficacy of the concomitant administration of low-dose lenalidomide and low-dose cytarabine in patients with acute myeloid leukemia (AML) aged more than 70 years.
Forty-five patients (median age 76 years, range: 70-85) ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10 mg/day orally, days 1-21) plus low-dose cytarabine (10mg/m2 twice daily, subcutaneously, days 1-15) every six weeks, up to 6 cycles.
Median white blood cell count at diagnosis was 3.2x109/l (range: 0,4-46,8x109/l), whereas median hemoglobin was 8,9 g/dl and median platelet count was 31x109/l. Twenty-three out of 45 patients had an intermediate karyotype (18/23 normal), 18/45 an unfavorable karyotype and 4/45 were not evaluable. Nineteen patients had a de novo AML, whereas 26 patients had a secondary AML (18 after MDS, 3 after a CMPD, 2 after myelofibrosis, 3 after chemo-radiotherapy for a breast cancer). To identify possible biomarkers associated to sensitivity/resistance, global gene and miRNA expression profiling (Affymetrix Transciptome 2.0) was performed on purified AML cells.
Induction-period mortality was 17%, with 8 deaths occurring during cycle 1. Thirty-seven patients completed at least one cycle of therapy and are evaluable for response. Overall CR rate was 43% among evaluable patients. Nine out of 16 responding patients are still in CR after a median follow-up of 12 months (range: 2-39). Statistical analysis showed that responding patients had a longer median overall survival than non-responders (428 vs. 74 days, P = .000).
Conversely, by studying the global miRNA and gene expression profile we identified a molecular signature, including 114 genes and 18 miRNA associated with the clinical response (CR vs. no CR). Of note, the involved genes belonged to relevant functional categories such as angiogenesis, cell cycle regulation and immune response. Of note, based on the expression of 5 genes, we developed an algorithm to predict treatment response that was successfully validated by showing an 87% overall accuracy.
In conclusion, low-dose lenalidomide plus low-dose cytarabine has high clinical activity, predictable by GEP, in elderly AML patients with poor prognosis.
The study was registered at EMA (EUDRA-CT 2008-006790-33).

Acknowledgments
Celgene is acknowledged for providing Lenalidomide for the patients. The study was supported in part by AIL Pesaro Onlus.

Disclosures:
No relevant conflicts of interest to declare.