Background: Azacitidine (AZA) has proven effective (response rate: 60–80%) in myelodysplastic syndromes (MDS). The currently approved AZA regimen is 75 mg/sqm/die subcutaneously (SC) or intravenously (IV) for 7 days every 28 days (Silverman, 2002; Fenaux, 2009). Introduction: Recently 3 different AZA dosing regimens, which avoid week-end dosing, have shown to induce therapeutic responses consistent with the currently approved schedule (Lyons, 2009). In particular, one of them, i.e. the AZA 5–2-5 regimen (50 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m2/d for 5 days) allows the administration of a nearly equivalent monthly total dose of AZA. Moreover, some data suggest the possibility that prolonged exposure to lower doses of AZA may increase the response rate (Gore, 2006). However, the communitybased study of Lyons mainly involved lower-risk MDS patients (pts). Purpose: These data prompted us to investigate the therapeutic effect of the more convenient AZA 5–2-5 regimen in higher-risk MDS pts (i.e.: IPSS risk: high or intermediate-2). Material and Methods: From December 2007, in our Institution, 18 IPSS high-or-intermediate-2 risk MDS pts. (12 males), with a median age of 69 (37–81) yrs, were treated with the AZA 5–2-5 regimen. Moreover, as our group (Follo, 2009) previously demonstrated that the inositide signalling pathways, in particular phosphoinositidephospholipase C (PI-PLC) beta1, may represent a target for AZA, we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration in this group of pts, and in a control group of high-risk pts previously treated with the conventional AZA regimen. Results: The pts received a median number of 7.5 (1–15) AZA cycles. Among the 14 evaluable pts (i.e.: ≥6 cycles), 12 (85.7%) showed a favourable response, following IWG criteria (Cheson, 2006): 5 Complete Remission (CR), and 7 Hematologic Improvement (HI). First response occurred after a median of 3 (3–7) cycles. The remaining 2 pts maintained a stable disease (SD). 4 pts showed evolution into Acute Myeloid Leukemia (AML) (3 died), and 2 pts died for other causes (infection, heart failure). PI-PLCbeta1 methylation and gene expression appeared to be related to the therapeutic response, but not to the dose schedule. Conclusions: Our data seem to confirm, in a population of highrisk MDS, the effectiveness, in terms of hematologic and molecular response, of the more convenient AZA 5–2-5 regimen. Our results need to be supported by larger studies.
Prolonged low-dose azacitidine schedule in high-risk MDS patients: Hematologic and molecular response
FINELLI, CARLO;FOLLO, MATILDE YUNG;PAOLINI, STEFANIA;PAPAYANNIDIS, CRISTINA;MONGIORGI, SARA;S. Parisi;MANZOLI, LUCIA;MARTINELLI, GIOVANNI;COCCO, LUCIO ILDEBRANDO;BACCARANI, MICHELE
2011
Abstract
Background: Azacitidine (AZA) has proven effective (response rate: 60–80%) in myelodysplastic syndromes (MDS). The currently approved AZA regimen is 75 mg/sqm/die subcutaneously (SC) or intravenously (IV) for 7 days every 28 days (Silverman, 2002; Fenaux, 2009). Introduction: Recently 3 different AZA dosing regimens, which avoid week-end dosing, have shown to induce therapeutic responses consistent with the currently approved schedule (Lyons, 2009). In particular, one of them, i.e. the AZA 5–2-5 regimen (50 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m2/d for 5 days) allows the administration of a nearly equivalent monthly total dose of AZA. Moreover, some data suggest the possibility that prolonged exposure to lower doses of AZA may increase the response rate (Gore, 2006). However, the communitybased study of Lyons mainly involved lower-risk MDS patients (pts). Purpose: These data prompted us to investigate the therapeutic effect of the more convenient AZA 5–2-5 regimen in higher-risk MDS pts (i.e.: IPSS risk: high or intermediate-2). Material and Methods: From December 2007, in our Institution, 18 IPSS high-or-intermediate-2 risk MDS pts. (12 males), with a median age of 69 (37–81) yrs, were treated with the AZA 5–2-5 regimen. Moreover, as our group (Follo, 2009) previously demonstrated that the inositide signalling pathways, in particular phosphoinositidephospholipase C (PI-PLC) beta1, may represent a target for AZA, we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration in this group of pts, and in a control group of high-risk pts previously treated with the conventional AZA regimen. Results: The pts received a median number of 7.5 (1–15) AZA cycles. Among the 14 evaluable pts (i.e.: ≥6 cycles), 12 (85.7%) showed a favourable response, following IWG criteria (Cheson, 2006): 5 Complete Remission (CR), and 7 Hematologic Improvement (HI). First response occurred after a median of 3 (3–7) cycles. The remaining 2 pts maintained a stable disease (SD). 4 pts showed evolution into Acute Myeloid Leukemia (AML) (3 died), and 2 pts died for other causes (infection, heart failure). PI-PLCbeta1 methylation and gene expression appeared to be related to the therapeutic response, but not to the dose schedule. Conclusions: Our data seem to confirm, in a population of highrisk MDS, the effectiveness, in terms of hematologic and molecular response, of the more convenient AZA 5–2-5 regimen. Our results need to be supported by larger studies.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
