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

Abstract

A multicenter phase II study was initiated to investigate the efficacy, toxicity and tolerability of an oral regimen of 9-cis retinoic acid (9CRA) as a differentiation-inducing agent stimulating both retinoic acid receptor (RAR) and retinoic X receptor (RXR). Thirty patients with myelodysplastic syndromes (MDS) were enrolled into the study. The MDS subtypes were distributed as follows: 14 refractory anaemia (RA), four refractory anaemia with ringed sideroblasts (RARS), and 12 refractory anaemia with excess blasts (RAEB). The age ranged from 40 to 81 years (median 70). None of these had previously received treatment for MDS other than supportive therapy. 9CRA (Alitretinoin capsules, kindly provided by Allergan-Ligand Retinoid Therapeutics) was 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 available for assessment. One patient (4%) with RA achieved complete hematological remission. Four (16%), two with RA, two with RAEB, had minor responses resulting in decreased transfusion requirements or increased neutrophils. Thus, 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 rash (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 prolonged exposure which may be required to induce a differentiation effect. Leukemia (2000) 14, 1583-1588.

Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays

“…However, in human clinical trials, 9-cis RA has been found to have significant toxicity (34). Therefore, receptor-selective retinoids that have reduced toxicity are now being developed as potential chemopreventive agents.…”

Epigenome-Based Drug Repositioning in Acute Myeloid Leukemia

“…alitretinoin, panobinostat, and progesterone. Both alitretinoin, a geometric isomer of tretinoin currently used in the treatment of Acute Promyelocytic Leukemia (a subclass of AML) [34] , and panobinostat, a histone deacetylase inhibitor commonly used in multiple myeloma [35] , have been investigated for use in AML [36][37][38][39] . Lastly, while progesterone itself has not, to our knowledge, been suggested for AML treatment, a synthetic progestin, medroxyprogesterone acetate, has recently been suggested as a possible drug repositioning candidate for AML [40] .…”

Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all-trans retinoic acid

“…51 9-cis retinoic acid, a ligand for both the RAR and RXR receptors, has shown activity in MDS. 22 ATRA has proven effective in other diseases, notably in acute promyelocytic leukemia, inducing differentiation and remissions which are karyotypically normal. 52 Clinical trials investigating the effects of PB on patients with acute myeloid leukemia and myelodysplasia have yielded promising changes in hematopoietic parameters including increased platelets and neutrophils, as well as decreased blasts.…”

“…16 We have recently shown that the biological activities of PB are closer to that of BA than PA. 53 Early studies of 13-cis retinoic acid, 9-cis retinoic acid, and all-trans retinoic acid (ATRA) have suggested limited clinical activity of these agents in MDS. [17][18][19][20][21][22] The present studies were undertaken to investigate whether the addition of retinoic acid could improve the pharmacodynamic profile of PB on the ML-1 myeloid leukemia cell model. Our studies show that ATRA acts synergistically with PB to induce differentiation and cell cycle arrest.…”