title: Combined differentiating therapy for myelodysplastic syndromes: a phase II study.
abstract: An in vitro synergism between different inducers of AML cell differentiation has been previously observed. Therefore, we treated 53 myelodysplastic (MDS) patients with a low dose combination of cis-retinoic acid (cRA, 20-40 mg/day) and 1,25 alpha (OH)2 cholecalciferol [(OH)2D3, 1-1.5 micrograms/day] +/- intermittent 6-thioguanine (30 mg/m2/day). The latter was reserved for patients with bone marrow (BM) blast excess (> or = 5%). The treatment was well tolerated, without major toxicity. Among 25 patients with BM blasts less than 5%, we observed one complete, eight partial and four minor responses (response rate 52%) with a median response duration of 8 months (2 +/- 24). Median survival, which did not correlate with response, is projected at 76 months. Thirty-one patients with BM blast excess (> or = 5%), including three of the previous group who progressed to refractory anemia with excess of blasts (RAEB), were treated with the three-drug protocol. One complete, 12 partial and six minor responses were obtained (response rate 61%) with a median response duration of 6 months (2-29+). A significant difference in survival (P < 0.005) was observed between the 19 responders (median 25 months) and the 12 non-responders (median 9 months). A reduction in the transfusion need was observed in 41% of the transfusion-dependent patients with blast excess and in 53% of those without blast excess. Therefore, combined differentiating therapy seems more effective than previously reported single agent treatments and should be considered for a larger randomized study to assess its actual impact on survival of MDS patients.
authors.affiliation: Dipartimento di Medicina ed Oncologia Sperimentale, Ospedale Molinette, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ferrero
authors.forename: B
authors.initials: B
authors.lastname: Bruno
authors.forename: P
authors.initials: P
authors.lastname: Pregno
authors.forename: S
authors.initials: S
authors.lastname: Stefani
authors.forename: E
authors.initials: E
authors.lastname: Larizza
authors.forename: G
authors.initials: G
authors.lastname: Ciravegna
authors.forename: A
authors.initials: A
authors.lastname: Luraschi
authors.forename: G
authors.initials: G
authors.lastname: Vietti-Ramus
authors.forename: P
authors.initials: P
authors.lastname: Schinco
authors.forename: M
authors.initials: M
authors.lastname: Bazzan
authors.forename: E
authors.initials: E
authors.lastname: Gallo
authors.forename: A
authors.initials: A
authors.lastname: Pileri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001752:Blast Crisis; D001803:Blood Transfusion; D016026:Bone Marrow Transplantation; D002762:Cholecalciferol / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy*; D012074:Remission Induction; D016019:Survival Analysis; D013866:Thioguanine / Q000008:administration & dosage; D014212:Tretinoin / Q000008:administration & dosage
chemical_list: D002762:Cholecalciferol; D014212:Tretinoin; D013866:Thioguanine