Azacitidine in Myelodysplastic Syndromes: Multicenter Retrospective Study of 34 Long-Responder Patients
Authors: Finelli Carlo , Clissa Cristina , Voso Maria Teresa , Spiriti Maria Antonietta Aloe , Breccia Massimo , Gaidano Gianluca , Crugnola Monica , Giannini Maria Benedetta , Bosi Costanza , Naso Virginia , Follo Matilde Y , Mongiorgi Sara , Martinelli Giovanni , Cocco Lucio , Baccarani Michele 
Published: October 2019

Abstract
Abstract 4951

Introduction.
Azacitidine (AZA) has proven effective in myelodysplastic syndromes (MDS). The duration of haematological response is limited (median 13. 6 months) (Fenaux, 2009), although some patients (pts) show a prolonged response. The French Group (Itzykson 2011) identified some clinical and haematologic parameters (poor ECOG performance status, IPSS intermediate and poor risk cytogenetics, circulating blasts, high transfusion need) independently associated with a a poorer outcome, and these 4 criteria were integrated in a 3-group prognostic score, validated in other cohorts (van der Helm 2011; Breccia 2012). Moreover, a complex karyotype was also predictive of a shorter duration of response. However long term survival was also observed in some of the pts with poor risk features (Itzykson 2012).

Methods.
These data prompted us to retrospectively analyse our MDS pts treated with AZA who showed a favourable long-lasting response to AZA (i. e: duration of response ≥ 20 months), in order to enucleate the clinical and haematologic features of long-responder pts. The type of response was defined according to IWG criteria (Cheson 2006): Complete Remission (CR); Partial Remission (PR) and Hematologic Improvement (HI). The response duration was measured from the date of achievement of a first response (HI, PR or CR), (also in pts who subsequently achieved a higher response category) until the date of disease progression or death. Overall Survival (OS) was measured from the start of AZA treatment. Moreover, as some of us (Follo, 2009) demonstrated that phosphoinositide-phospholipase C (PI-PLC) beta1 may represent a target for AZA, in a subgroup of pts we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration.

Results.
Thirty-four pts (M/F: 20/14), from eight Institutions, with a median age of 72 (range 52–84) yrs, showed a response duration ≥ 20 months. At AZA onset, WHO diagnosis was: refractory anemia (RA): 1 pt; refractory cytopenia with multilineage dysplasia (RCMD): 1 pt; RCMD with ringed sideroblasts (RCMD-RS): 1 pt; refractory anemia with excess blasts (RAEB)-1: 8 pts; RAEB-2: 15 pts; cronic myelomonocytic leukemia(CMML): 4 pts; AML with 20–30% blasts: 3 pts, MDS with fibrosis (MDS-F): 1 pt. Four pts had therapy-related MDS. IPSS risk was: low: 3 pts; intermediate-1: 6 pts; intermediate-2: 20 pts, high: 5 pts. IPSS cytogenetic risk was: low: 21 pts (61. 8%); intermediate: 8 pts (23. 5%); high: 5 pts (14. 7%) (3 with complex karyotypes and 2 with isolated -7 or 7q-). ECOG-PS was poor (≥ 2) in 2 pts (5. 8%) and < 2 in the other 32 pts. Transfusion need was high (≥ 4 RBC units/8 weeks) in 17 pts (50%), and low or absent in the remaining 17 pts. Three pts (8. 8%) presented circulating blasts. Following Itzykson's AZA prognostic scoring system, the risk was low in 12 pts (35. 3%), intermediate in 21 pts (61. 8%), and high in 1 pt (2. 9%), respectively. Time from diagnosis to AZA onset was < 6 months in 21 pts, and > 6 months in 13 pts. The pts received a median of 22 cycles of AZA (range: 8–52). The median number of cyles to any first response was 4 (range: 2–10). Twenty pts (58. 8%) showed an at least two-fold increase of platelets after the first cycle of AZA. The best response achieved was: CR in 23 pts (67. 7%), PR in 2 pts (5. 8%), and HI in 9 pts (26. 5%). Cytogenetic remission was achieved in 7 pts (20. 6%). The median duration of response was 24. 5 (range: 23–88) months. A significant toxicity (grade > 2) was observed in 5 (14. 7%) pts. Twenty-two pts (64. 8%) are still maintaining hematologic response, 6 pts (17. 6%) are still alive but discontinued treatment because of disease progression, and 6 pts died, for AML (2 pts), infection (1 pt), haemorrhage (1 pt), myocardial infarction (1 pt), cachexy (1 pt), respectively. Median OS from the start of AZA was 35. 5 (range: 22–120) months. In a subgroup of pts, we observed an increase in PI-PLCbeta1 expression, that was maintained along with the hematologic response. Moreover, PI-PLCbeta1 early increase (during the cycles 1 to 3) was significantly associated with a higher duration of response.

Conclusions.
Although our data confirm the finding of other Authors, as the majority of long-responder patients showed pre-treatment favourable prognostic factors, a long-lasting hematologic response can be achieved even in a significant fraction of pts presenting one or more poor risk features (IPSS intermediate or high risk cytogenetics, high transfusion need).

Disclosures:
Finelli: Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Speakers Bureau.