1. ¹Inserm CIC 9504, Centre d'Investigations Cliniques, Hôpital Saint Louis, AP-HP, 1 Avenue Claude Vellefaux, Paris 75475, France
2. ²Inserm U717, Hôpital Saint Louis, Paris, France
3. ³Inserm U717, Département de Biostatistique et Infomatique Médicale, Hôpital Saint Louis, AP-HP, Paris, France
4. ⁴Service de Pharmacie Pharmacologie Toxicologie, Hôtel Dieu de Paris, AP-HP, Paris, France
5. ⁵Département d'Hématologie et d'Oncologie Médicale, Hôtel Dieu, AP-HP, Paris, France
6. ⁶Service d'Hématologie Clinique, Hôpital Saint Louis, AP-HP, Paris France

Correspondence: Dr V Lévy, E-mail: vincent.levy@sls.aphp.fr

Received 17 May 2006; Revised 14 June 2006; Accepted 14 June 2006; Published online 18 July 2006.

Abstract

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m^-2 day^-1 was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m^-2 day^-1. Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m^-2 day^-1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m^-2, and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m^-2 day^-1. The mean half-life of ssHHT was 11.013.4 h, the volume of distribution at steady state was 21.4 l kg^-1 and the plasma clearance was 11.610.4 l h^-1. Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m^-2 day^-1.