Oral 9-cis retinoic acid (Alitretinoin) in the treatment of myelodysplastic syndromes: results from a pilot study

A multicenter phase II study was initiated to investigate the efficacy, tox icity and tolerability of an oral regimen of 9-cis retinoic acid (9CRA) as a differentiation-inducing agent stimulating both retinoic acid receptor (R AR) and retinoic X receptor (RXR). Thirty patients with myelodysplastic syn dromes (MDS) were enrolled into the study. The MDS subtypes were distribute d as follows: 14 refractory anaemia (RA), four refractory anaemia with ring ed sideroblasts (RARS), and 12 refractory anaemia with excess blasts (RAEB) . The age ranged from 40 to 81 years (median 70). None of these had previou sly received treatment for MDS other than supportive therapy. 9CRA (Alitret inoin capsules, kindly provided by Allergan-Ligand Retinoid Therapeutics) w as given daily at 60 mg/m(2) p.o. for 1 week, followed by an intra-patient escalation to 100 mg/m(2) during the second week, up to a maximum of 140 mg /m(2). The planned treatment duration was 48 weeks. Twenty-five were availa ble for assessment. One patient (4%) with RA achieved complete hematologica l remission. Four (16%), two with RA, two with RAEB, had minor responses re sulting in decreased transfusion requirements or increased neutrophils. Thu s, the overall response rate was 20% in evaluable patients with MDS and 17% in the study group on an intention-to-treat basis. The most frequent side- effects Included headache (77%), dry skin (57%), arthralgias (30%), and ras h (23%). In conclusion, although modest responses were noted in this study, the treatment tolerability was suboptimal. It is conceivable that a lower dosage schedule may be efficacious and better tolerated so enabling prolong ed exposure which may be required to induce a differentiation effect.