Safety and Efficacy of a Combination of 5-Azacitidine Followed by Lenalidomide in High-Risk MDS or AML Patients with Del(5q) Cytogenetic Abnormalities – Results of the “AZALE” Trial,
Authors: Platzbecker Uwe , Ganster Christina , Neesen Jürgen , Kuendgen Andrea , Götze Katharina , Bug Gesine , Shirneshan Katayoon , Braulke Friederike , Röllig Christoph , Naumann Ralph , Büssemaker Eckhard , Giagounidis Aristoteles , Hofmann Wolf-Karsten , Germing Ulrich , Haase Detlef , Ehninger Gerhard 
Published: October 2019

Abstract
Abstract 3799
Lenalidomide (LEN) has shown single agent activity in patients (pts) with low-risk MDS and a del(5q) cytogenetic abnormality although mutations of p53 have been recently associated with treatment failure. Further, the DNA methyltransferase inhibitor 5-azacytidine (AZA) is able to achieve responses in up to 50% of high-risk MDS (IPSS INT-2 or HIGH) and AML pts with a low rate of extramedullary toxicity compared to conventional induction chemotherapy (IC). Nevertheless, del(5q) abnormalities especially when part of a complex aberrant karyotype are associated with lower response rates compared to other cytogenetic aberrations. Therefore, studies combining both compounds are of interest in this population.
We report results of a phase I clinical trial within the German MDS study group (GMDS-SG) evaluating the maximum tolerated dose (MTD) of LEN in combination with AZA in pts with either high-risk MDS, refractory/relapsed AML or de novo AML not eligible for conventional IC with del(5q) cytogenetic abnormalities. Given the mechanism of action of both drugs a sequential approach was chosen. To determine the MTD, a standard “3+3” design was used. In fact, induction therapy consisted of AZA (75mg/m2 days 1–5) followed by increasing doses (10, 15, 20 and 25mg) of LEN (starting with 10mg p.o., days 6–19). In pts achieving a complete remission (CR) this was followed by a combined maintenance therapy every 8 weeks until disease progression.
Of 20 pts enrolled, median age was 69 years (range, 45 to 79 years), interval from MDS or AML diagnosis was 8 months (range, 1 to 100 months). IPSS categories were INT-2 (n = 5) or HIGH (n = 9) whereas 6 pts were included with advanced AML. Prior therapies included IC only (n=1), allogeneic HSCT (n=3), AZA (n=6), LEN (n=2) and/or low-dose cytarabine (n=2) while 10 pts had received supportive care only prior to study entry. It is of note, that the majority of pts (n=15, 75%) had a complex aberrant karyotype including a del(5q) abnormality. Further, p53 mutations could be detected in 7 (47%) out of 15 pts analyzed so far.
A median of 2 induction cycles were administered within the 4 dose cohorts. The MTD of LEN was determined to be 20mg. DLTs were either infectious complications (n=2), thrombosis (n=1) or incomplete hematologic recovery (n=1). In fact, therapy-induced grade 3–4 neutropenia or thrombocytopenia occurred in 12 (60%) pts, respectively. Out of the 19 pts evaluable for response 6 pts (32%) achieved a hematologic (CR: n=2, CRi: n=2, PR: n=1, HI: n=1) and 7 pts (36%) a cytogenetic (CR: n=3, PR: n=4) response while 13 pts (68%) had stable disease. Interestingly, 5 out of 7 pts with p53 mutations responded to combination therapy.
The combination of AZA and LEN is feasible and seems to be effective even in a very high risk patient group with advanced MDS or AML and a del(5q).

Disclosures:
Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hofmann:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.