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. These data prompted us to retrospectively analyse our MDS pts treated with AZA, in order to enucleate longresponder pts (duration of response ≥20 months). METHODS. From September 2004, in our Institution, 52 MDS pts (40 males), median age: 70 (37-85) yrs, were treated with AZA, following 4 different treatment regimens: 9 pts received the AZA 7 regimen (AZA 7: 75 mg/sqm/die SC for 7 days/28 days); 6 pts received the combination of AZA 7 with valproic acid and all-trans-retinoic acid ; while 25 and 12 pts respectively received the alternative regimens AZA 5-2-5 and AZA 5 (Lyons, JCO 2009). 37 pts (71%) showed a IPSS high-risk MDS, while 15 pts (29%) with IPSS low-risk MDS received AZA because of refractoriness or ineligibility to erythropoietin, or secondary MDS. Moreover, as our group (Follo, 2009) demonstrated that phosphoinositide-phospholipase C (PIPLC) beta1 may represent a target for AZA, we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration. RESULTS. 9 pts (17.3%) showed a prolonged hematologic response (≥ 20 months). Pre-treatment clinical and haematologic features of long-responders: sex (M/F): 4/5; median age: 69 (52- 84); WHO: RCMD-RS: 1 pt; RAEB-1: 1 pt; RAEB-2: 7 pts; IPSS risk: low: 1 pt; int-1: 2 pts; int-2: 5 pts; high: 1 pt; IPSS cytogenetic risk: low: 7 pts; interm: 1 pt; high: 1 pt; ECOG: 0-1: 8 pts, ≥ 2: 1 pt; transfusion need (N° U)/8 weeks: < 4 : 4 pts; ≥ 4 : 5 pts; time from diagnosis (months): < 6 : 6 pts; ≥ 6 : 3 pts. Therapeutic regimen: AZA 7: 3 pts; AZA 5: 3 pts; AZA 5-2-5: 3 pts. Therapeutic response: median number of cycles: 19 (8-59); median time to 1st response: 3 (2-6) months; type of response: Complete Remission (CR): 3 pts; Hematologic Improvement (HI): 6 pts; cytogenetic remission: 1 pt; median duration of response: 30 (24-66) months; doubling of platelet count after 1st cycle: 4 pts; toxicity (grade > 2): 3 pts; 4 pts are still maintaining hematologic response, 3 pts are still alive but discontinued treatment because of disease progression, and 2 pts died (1 for AML and 1 for cachexy). Median survival (from the start of AZA): 38 (25-103) months. All the pts showed an increase in PI-PLCbeta1 expression, that was maintained along with the hematologic response. 15 pts (28.8%) showed a short-lived reponse (< 20 months), 5 pts (9.6%) show a shorter response but are still on treatment, 2 pts underwent allogeneic transplantation after 5 and 10 months. 7 pts (13.4%) are not evaluable for response (< 6 cycles), and 14 pts (26.9%) did not respond to AZA. Conclusions. Our data show that a limited but significant fraction of MDS pts show a long-lasting hematologic and molecular response to AZA.
AZACITIDINE IN MYELODYSPLASTIC SYNDROMES: RETROSPECTIVE EVALUATION OF LONG-RESPONDER PATIENTS
FINELLI, CARLO;FOLLO, MATILDE YUNG;PAOLINI, STEFANIA;PAPAYANNIDIS, CRISTINA;MONGIORGI, SARA;Parisi S;MANZOLI, LUCIA;MARTINELLI, GIOVANNI;COCCO, LUCIO ILDEBRANDO;BACCARANI, MICHELE
2012
Abstract
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. These data prompted us to retrospectively analyse our MDS pts treated with AZA, in order to enucleate longresponder pts (duration of response ≥20 months). METHODS. From September 2004, in our Institution, 52 MDS pts (40 males), median age: 70 (37-85) yrs, were treated with AZA, following 4 different treatment regimens: 9 pts received the AZA 7 regimen (AZA 7: 75 mg/sqm/die SC for 7 days/28 days); 6 pts received the combination of AZA 7 with valproic acid and all-trans-retinoic acid ; while 25 and 12 pts respectively received the alternative regimens AZA 5-2-5 and AZA 5 (Lyons, JCO 2009). 37 pts (71%) showed a IPSS high-risk MDS, while 15 pts (29%) with IPSS low-risk MDS received AZA because of refractoriness or ineligibility to erythropoietin, or secondary MDS. Moreover, as our group (Follo, 2009) demonstrated that phosphoinositide-phospholipase C (PIPLC) beta1 may represent a target for AZA, we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration. RESULTS. 9 pts (17.3%) showed a prolonged hematologic response (≥ 20 months). Pre-treatment clinical and haematologic features of long-responders: sex (M/F): 4/5; median age: 69 (52- 84); WHO: RCMD-RS: 1 pt; RAEB-1: 1 pt; RAEB-2: 7 pts; IPSS risk: low: 1 pt; int-1: 2 pts; int-2: 5 pts; high: 1 pt; IPSS cytogenetic risk: low: 7 pts; interm: 1 pt; high: 1 pt; ECOG: 0-1: 8 pts, ≥ 2: 1 pt; transfusion need (N° U)/8 weeks: < 4 : 4 pts; ≥ 4 : 5 pts; time from diagnosis (months): < 6 : 6 pts; ≥ 6 : 3 pts. Therapeutic regimen: AZA 7: 3 pts; AZA 5: 3 pts; AZA 5-2-5: 3 pts. Therapeutic response: median number of cycles: 19 (8-59); median time to 1st response: 3 (2-6) months; type of response: Complete Remission (CR): 3 pts; Hematologic Improvement (HI): 6 pts; cytogenetic remission: 1 pt; median duration of response: 30 (24-66) months; doubling of platelet count after 1st cycle: 4 pts; toxicity (grade > 2): 3 pts; 4 pts are still maintaining hematologic response, 3 pts are still alive but discontinued treatment because of disease progression, and 2 pts died (1 for AML and 1 for cachexy). Median survival (from the start of AZA): 38 (25-103) months. All the pts showed an increase in PI-PLCbeta1 expression, that was maintained along with the hematologic response. 15 pts (28.8%) showed a short-lived reponse (< 20 months), 5 pts (9.6%) show a shorter response but are still on treatment, 2 pts underwent allogeneic transplantation after 5 and 10 months. 7 pts (13.4%) are not evaluable for response (< 6 cycles), and 14 pts (26.9%) did not respond to AZA. Conclusions. Our data show that a limited but significant fraction of MDS pts show a long-lasting hematologic and molecular response to AZA.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
