Prospective Phase II Study on 5-Days Azacitidine for Treatment of Symptomatic and/or Erythropoietin Unresponsive Patients with Low/INT-1–Risk Myelodysplastic Syndromes

Abstract

Purpose: This phase II prospective study aimed to evaluate the efficacy and safety of 5-days azacytidine (5d-AZA) in patients with low-risk myelodysplastic syndromes (MDS). Second, single-nucleotide polymorphism (SNP) genetic profile and phosphoinositide-phospholipase C (PI-PLC) b1 levels were studied to evaluate possible biologic markers able to predict the hematologic response.Experimental Design: The study tested a lower intensity schedule of azacytidine. The treatment plan consisted of 75 mg/sqm/d subcutaneous administered for 5 days every 28 days, for a total of 8 cycles.Results: Thirty-two patients were enrolled in the study. The overall response rate was 47% (15 of 32) on intention-to-treat and 58% (15 of 26) for patients completing the treatment program. In this latter group, 5 (19%) achieved complete remission (CR) and 10 (38%) had hematologic improvement, according to the International Working Group (IWG) criteria. Three patients have maintained their hematologic improvement after 37, 34, and 33 months without other treatments. Moreover, 21 and 2 of 26 cases completing 8 cycles were transfusion-dependent for red blood cells and platelets at baseline, respectively. Of these, 7 (33%) and 2 (100%) became transfusion-independent at the end of the treatment program, respectively. Grade 3-4 neutropenia occurred in 28% of patients and 4 patients died early due to infections or hemorrhage. SNP results were not significantly correlated to the clinical outcome, whereas PI-PLCb1 level anticipated either positive or negative clinical responses.Conclusions: 5d-AZA is safe and effective in a proportion of patients with low-risk MDS. PI-PLCb1 gene expression is a reliable and dynamic marker of response that can be useful to optimize azacytidine therapy.

An increased expression of PI-PLCβ1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes

“…PI-PLCb1 is involved in hematopoietic differentiation and in MDS pathogenesis, as the presence of a PI-PLCb1 monoallelic deletion has been associated with a higher probability of AML evolution [39]. Moreover, not only is PI-PLCb1 a specific target for azacitidine therapy in high-and low-risk MDS [42], but also, the quantification of PI-PLCb1 during the whole treatment can correlate with, and somehow anticipate, the response to demethylating treatments, either positively or negatively [45].…”

“…Interestingly, this hypermethylated status can be reversed during the therapy with azacitidine, alone or in combination with histone deacetylase inhibitors [41][42][43][44][45]. Moreover, recent findings demonstrated that the amount of PI-PLCb1 mRNA can also act as a dynamic marker of the response to demethylating therapy in high-risk and low-risk MDS [45]. In particular, PI-PLCb1 can be a positive or negative indicator of the azacitidine response, in that a PIPLCb1 increase anticipates a clinical improvement, but a PIPLCb1 decrease is associated with a worsening of the clinical picture of the MDS patients [45].…”

“…So far, a PI-PLCb1 correlation with an azacitidine response was mostly assessed following several cycles of therapy [42][43][44][45], which is why in this study we investigated the predictive role of PI-PLCb1. In particular, we first quantified PI-PLCb1 promoter methylation and gene expression at baseline and during the first 3 cycles of azacitidine, and then we compared the mean value of PI-PLCb1 during these cycles with the clinical outcome of patients at the 6th cycle of azacitidine therapy.…”

A randomized phase II trial of azacitidine +/- epoetin- in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents

“…durations ranging from 511 to 10 months 20 were reported (Online Supplementary Table S4). Overall survival at 3 years in the present trial was 72.1% and 66.8% in the AZA arm and in the AZA plus EPO arm, respectively.…”

Eritropoietina Sérica como Marcador Prognóstico em Síndrome Mielodisplásica

“…Neste momento sabemos que os doentes com SMD com valores mais elevados de eritropoietina apresentam uma pior resposta à administração de eritropoietina, mesmo com doses mais elevadas. [16][17][18][19] Além da importância da eritropoietina sérica como um indicador de resposta à terapêutica com eritropoietina, 6,8,9 em 2002, o valor prognóstico da eritropoietina, foi descrito, numa série de 68 doentes em que se incluíam doentes com anemia refractária (AR), ARSA e AREB. 20 A nossa amostra alarga estas conclusões a todos os subtipos de SMD, numa amostra maior de doentes estudados, identificando um papel prognóstico para a eritropoietina.…”