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2871 Association of Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in High-Risk Myelodysplastic Syndromes. Final Results of a Randomized Phase II Multicenter Study

Myelodysplastic Syndromes – Clinical Studies
Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical Studies: Poster II
Sunday, December 6, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Carlo Finelli, MD1*, Cristina Clissa, M.D.2*, Matilde Follo, PhD3*, Marta Stanzani, M.D.1*, Sarah Parisi, M.D.1*, Sara Mongiorgi, PhD3*, Paolo Avanzini, MD4*, Costanza Bosi, M.D.5*, Barbara Castagnari, M.D.6*, Anna Candoni, MD7*, Monica Crugnola, MD8*, Maria Benedetta Giannini, M.D.9*, Marco Gobbi, MD10*, Giovanna Leonardi11*, Gian Matteo Rigolin12*, Domenico Russo13, Patrizia Tosi14*, Giuseppe Visani, M.D.15*, Lucio Cocco, M.D., PhD3* and Michele Cavo16*

1Hematology, S.Orsola-Malpighi University Hospital, Bologna, Italy
2Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
3Biomedical Sciences-Human Anatomy, University of Bologna, Bologna, Italy
4Hematology, S.Maria Nuova Hospital, Reggio Emilia, Italy
5Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy
6Hematology, S. Maria delle Croci Hospital, Ravenna, Italy
7Hematology, Santa Maria della Misericordia University Hospital, Udine, Italy
8Clinical and Experimental Medicine, University of Parma, Parma, Italy
9Oncology, I.R.S.T., Meldola (FC), Italy
10Chair of Hematology, Department of Internal Medicine (DiMI), IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy
11Hematology, University of Modena, MODENA, Italy
12Hematology Section, Azienda Ospedaliero-Universitaria S. Anna, University of Ferrara, Ferrara, Italy
13Chair of Hematology, University of Brescia, Brescia, Italy
14Oncology and Hematology, Infermi Hospital, Rimini, Italy
15Hematology, S.Salvatore Hospital, Pesaro, Italy
16Institute of Hematology, Bologna, Italy

Introduction. Azacitidine (AZA) is able to induce hematologic responses in 50-60 % of patients (pts) with Myelodysplastic Syndromes (MDS) and moreover to prolong survival in higher risk MDS pts. Recently, several studies have evaluated the efficacy and safety of combining, in high-risk MDS pts, AZA with Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), in both cases showing promising results, although in a limited number of pts. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts  (IPSS score risk: High or INT-2). Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow  Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006).

Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment  was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned.

Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: RCMD: 2 pts; RCMD-RS: 1 pt ; RAEB-1: 11 pts; RAEB-2: 30 pts; IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled  because of  severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts; IPSS cytogenetic risk was: Good: 17 pts; Intermediate: 11 pts; Poor: 14 pts; N.D.: 2 pts. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2.  At the time of this analysis, enrolment of  the planned 44 pts was completed. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining  10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8 (1-28) cycles; in ARM 1: 9 (1-22) cycles, in ARM 2: 8 (1-28) cycles, respectively. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was:  CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of  2 (1-8) cycles. Responder pts were: 13/17 (ORR: 76.5 %) in ARM 1 (3 CR; 1 PR; 1 mCR; 4 HI, 4 mCR+HI), and 13/17 (ORR: 76.5 %) in ARM 2 (5 CR; 2 mCR; 4 HI; 2 mCR+HI), respectively. Overall, the median duration of response was 8.5 (2-23) months: 6 (2-19) months in ARM 1; 16 (2-23) months in ARM 2. A grade > 2 non hematologic toxicity  was observed in 24/44 (54.5 %) pts (ARM 1: 66.7%; ARM 2: 43.5%). 27/44 pts (61.4 %) (ARM 1: 61.9%; ARM 2: 60.9%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 22 pts (50%) died (ARM 1: 47.6%; ARM 2: 52.2%).  14 pts (31.8%) (ARM 1: 23.8%; ARM 2: 39.1%) showed progression to AML.  Overall, median survival was 13 (1-28) months; ARM 1: 13 (1-25) months; ARM 2: 14 (2-28) months.

Conclusions. Our results confirm the efficacy of both AZA + LEN treatment regimens in high-risk MDS pts. Moreover, at a molecular level, a significant increase of phosphoinositide-specific phospholipase C (PI-PLC) beta1 and/or PI-PLCgamma1 expression was associated with a favourable clinical response to treatment. Responder cases also showed an increase of Beta-globin expression, hinting at a specific contribution  of LEN on erythroid activation

Disclosures: Finelli: Janssen: Other: Speaker ; Novartis: Other: Speaker ; Celgene: Other: Speaker , Research Funding . Visani: Celgene: Research Funding . Cavo: Janssen-Cilag, Celgene, Amgen, BMS: Honoraria .

*signifies non-member of ASH