P116 Azacitidine for the treatment of lower risk myelodysplastic syndromes: final results from an Italian named patient program

Musto, Pellegrino; Maurillo, Luca; Spagnoli, Alessandra; D’Arco, Alfonso Maria; Pollio, Berardino; Candoni, Anna; Spiriti, Antonietta Aloe; Lunghi, Monia; Filì, Carla; Orciuolo, Enrico; Venditti, Adriano; Morabito, F.; Mazza, P; Pastore, Domenico

doi:10.1016/s0145-2126(09)70197-3

Cited by 26 publications

(47 citation statements)

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“…In patients with low-risk MDS, azacytidine has been reported to induce transfusion independence and/or hematologic responses in 40% to 70% of cases (25)(26)(27). This high variability probably reflects the fact that the low-risk MDS patients' population is clinically and biologically heterogeneous (35)(36)(37) and explains why the effects of azacytidine in this setting of patients are less known and why dose and duration of treatment and profile of patients with low-risk MDS who can benefit of azacytidine are still undetermined.…”

Section: Discussionmentioning

confidence: 99%

“…In another independent study, including 23 to 65 patients with lowrisk MDS across 3 azacytidine alternate dosing cohorts, the ORR ranged between 44% and 56% and the rate of erythrocyte transfusion independence was 46% to 60% (26). More recently, a multicenter retrospective analysis conducted on 74 patients with MDS with International Prognostic Scoring System (IPSS) risk low or Int-1 treated with azacytidine at a dose of 75 mg/sqm for 7 to 10 days for a median of 7 cycles, reported 50% to 77% of responses, with a median duration of 6 months (27).…”

Section: Introductionmentioning

confidence: 99%

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

Filì

Malagola

Follo

et al. 2013

Clinical Cancer Research

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Filì

Malagola

Follo

et al. 2013

Clinical Cancer Research

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“…However, azacitidine is also effective in MDS patients at lower risk of AML evolution. 14,15 That is why in this study we focused on low-risk MDS subjects (IPSS low-or intermediate-1). We analyzed 30 low-risk MDS patients (26 under therapy with azacitidine and 4 treated with best supportive care only) at baseline and before the start of each cycle of azacitidine (that is, every 4 weeks, for a minimum of 8 cycles), in order to monitor the changes of PI-PLCbeta1 signaling during the therapy.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 In addition, azacitidine might potentially be a feasible and effective treatment also for lower-risk MDS subjects, including elderly and transfusion-dependent patients, who are refractory to or unsuited for treatment with growth factors and for whom limited treatment options are available. 14,15 The molecular mechanisms underlying the effect of the epigenetic therapy are not completely understood, although it is well known that most of all cancer-related signaling pathways may be affected by hypermethylation 16,17 and DNA methyltransferase inhibitors, such as azacitidine, which can induce the expression of methylated silenced gene products. 18 In the last few years, several studies demonstrated that nuclear inositide signaling pathways can be implicated in the MDS progression to AML.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment

et al. 2011

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Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation.Leukemia (2012) 26, 943 --950;

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“…This pattern of response fits with the objectives of treatment needed for lower risk MDS patients who carry other poor prognostic factors, or with resistance to ESAs. Use of AZA in these patients 5,6 resulted in hematologic responses (especially erythroid responses) in 30-40% of cases, but data on survival were limited. We previously reported that the outcome of patients with higher-risk MDS is very poor after AZA failure.…”

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confidence: 99%

Outcome of patients with low-risk myelodysplasia after azacitidine treatment failure

et al. 2012

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P116 Azacitidine for the treatment of lower risk myelodysplastic syndromes: final results from an Italian named patient program

Cited by 26 publications

References 0 publications

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

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

Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment

Outcome of patients with low-risk myelodysplasia after azacitidine treatment failure

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