Early Increase of Phospholipase Cbeta1 (PI-PLCbeta1) Gene Expression Predicts Azacitidine Responsiveness in MDS Patients
Authors: Follo Matilde Y , Finelli Carlo , Clissa Cristina , Mongiorgi Sara , Filì Carla , Bosi Costanza , Quaranta Marilisa , Paolini Stefania , Billi Anna Maria , Gobbi Marco , Baccarani Michele , Russo Domenico , Martinelli Giovanni , Manzoli Lucia , Cocco Lucio 
Published: October 2019

Abstract 1289

Introduction.

Azacitidine (AZA) is a DNA methyltransferase inhibitor currently approved for the treatment of high-risk MDS patients, which has been demonstrated to be feasible and effective also in low-risk MDS (Fenaux P et al, Lancet Oncol 2009; Musto P et al, Cancer 2010). However, at least 4 or 6 cycles of therapy are required for assessing the hematologic response, and predictive markers of responsiveness are still lacking. PI-PLCbeta1 plays a role in the MDS progression to AML and is a specific target for AZA therapy (Follo MY et al, PNAS 2009). Indeed, PI-PLCbeta1 has been demonstrated to be a dynamic marker for responsiveness to demethylating therapy, in that PI-PLCbeta1 mRNA increase or decrease could be associated with favourable response or failure, respectively. Stemming from these data, in this study we further investigated the role of PI-PLCbeta1 in MDS patients during AZA therapy.

Methods.

The study included 60 patients, 22 low-risk MDS (WHO: RA, RARS, RCMD, RAEB-1, and IPSS risk Low or Int-1), and 38 high-risk MDS (WHO: RCMD, RAEB-1, RAEB-2, and IPSS risk Int-1 or High). All the patients received a minimum of 6 cycles, in the absence of disease progression or unacceptable toxicity. Hematologic response was defined according to the revised IWG criteria (Cheson et al, Blood 2006). Positive clinical responses were defined as: Complete Remission (CR), Partial Remission (PR) or Hematologic Improvement (HI). At a molecular level, for each patient we quantified the amount of PI-PLCbeta1 mRNA at baseline and before each cycle of AZA therapy. PI-PLCbeta1 ratio was calculated as the mean expression of PI-PLCbeta1 at cycles 1 to 3, as compared with the baseline level within the same subject. In case the mean value of PI-PLCbeta1 gene expression during the cycles 1 to 3 was above the baseline level, we defined it as a “PI-PLCbeta1 early increase”. On the contrary, a “stable PI-PLCbeta1” expression was observed when subjects did not show any increase during the first three cycles of therapy, as compared with baseline.

Results.

Patients' median age was 69 years (range 37–85) and the median follow-up was 23 months (range 1–103). The median number of AZA cycles was 11 (range 3–59) for high-risk MDS, and 8 (range 1–8) for low-risk MDS. Positive clinical responses were observed in 37/60 (62%) of the MDS patients (7 CR, 1 PR, 29 HI). In particular, 13/22 (59%) of our low-risk MDS and 24/38 (63%) of our high-risk MDS patients showed a positive clinical response to AZA, with 4 CR, 1 PR, and 19 HI in high-risk MDS, and 3 CR and 10 HI in low-risk MDS. Overall survival (OS), Progression-Free Survival (PFS), and Overall Response Rate (ORR) were analyzed using a Kaplan-Meier method, considering p-values<0.05 as statistically significant. No differences in OS nor in PFS were noted between patients with early increased or stable PI-PLCbeta1 (OS: 36 vs. 30 months, p=0.45; PFS: 28 vs. 24 months, p=0.06). However, PI-PLCbeta1 early increase was significantly associated with ORR (increase: 25/38 (65%) vs. stable: 4/22 (18%); p<0.05). The predictive value of PI-PLCbeta1 was also analyzed: PI-PLCbeta1 early increase was significantly associated with duration of AZA response (increase vs. stable: 26 vs. 12 months; p<0.05), showing that an early increase of PI-PLCbeta1 was associated not only with a positive clinical response, but also with a higher probability of a longer response.

Conclusions.

Taken together, our data confirm the role of PI-PLCbeta1 as a dynamic marker of response to AZA and show that the detection of an increase in PI-PLCbeta1 gene expression within the first three cycles of AZA therapy is associated with a better clinical outcome and a longer hematological response. Further analyses are needed to confirm in a larger group of patients the predictive role of PI-PLCbeta1 mRNA detection during AZA therapy.

Disclosures:

No relevant conflicts of interest to declare.