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Combined Treatment With Arsenic Trioxide and All-Trans-Retinoic Acid in Patients With Relapsed Acute Promyelocytic Leukemia

Emmanuel Raffoux, Philippe Rousselot, Joël Poupon, Marie-Thérèse Daniel, Bruno Cassinat, Richard Delarue, Anne-Laure Taksin, Delphine Réa, Agnès Buzyn, Annick Tibi, Geneviève Lebbé, Patricia Cimerman, Christine Chomienne, Jean-Paul Fermand, Hugues de Thé, Laurent Degos, Olivier Hermine, Hervé Dombret

From the Department and Institut of Hematology, Hôpital Saint-Louis; Department of Biochemistry-Toxicology, Hôpital Fernand Widal; Department of Hematology, Hôpital Necker; Etablissement Pharmaceutique des Hôpitaux de Paris; and Délégation à la Recherche Clinique, Paris, France.

Address reprint requests to Hervé Dombret, Hôpital Saint-Louis, Service Clinique des Maladies du Sang, 1 avenue Claude Vellefaux, 75010 Paris, France; email: herve.dombret{at}sls.ap-hop-paris.fr.

Purpose: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO.

Patients and Methods: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response.

Results: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity.

Conclusion: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.

Supported by grant no. P970708 and AOM 97088 from Le Programme Hospitalier de Recherche Clinique, Ministère de l’Emploi et de la Solidarité, France.

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