2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirem ents for blood transfusions. For patients with no HbF elevation after HU tr eatment, augmentation of HbF levels by 5-aza-2'-deoxycytidine (5-aza-CdR, d ecitabine) could serve as an alternate mode of treatment. Eight adult patie nts participated in a dose-escalating phase VII study with 5-aza-CdR at dos es ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, gamma-globin synthesis ratio, complete blood count, and che mistry were measured. The average gamma-globin synthesis relative to non-or -globin synthesis prior to therapy was 3.19% +/- 1.43% and increased to 13. 66% +/- 4.35% after treatment. HbF increased from 3.55% +/- 2.47% to 13.45% +/- 3.69%. F cells increased from 21% +/- 14.8% to 55% +/- 13.5% and HbF/F cell increased from 17% to 24%, In the HU nonresponders HbF levels increas ed from 2.28% +/- 1.61% to 2.6% +/- 2.15% on HU, whereas on 5-aza-CdR HbF i ncreased to 12.70% +/- 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerate d the drug. Maximum HbF was attained within 4 weeks of treatment and persis ted for 2 weeks be fore falling below 90% of the maximum. Therefore 5-aza-C dR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels wi th additional treatment cycles without toxicity is currently being performe d. (Blood. 2000; 96:2379-2384) (C) 2000 by The American Society of Hematolo gy.