Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study.

E. Wattel (1) , E. Solary (1) , B. Hecquet (2) , D. Caillot (1) , N. Ifrah (3) , A. Brion (4) , N. Milpied (5) , M. Janvier (6) , A. Guerci (7) , H. Rochant (8) , C. Cordonnier (8) , F. Dreyfus (9) , A. Veil (10) , L. Hoang-Ngoc (10) , Am Stoppa (11) , N. Gratecos (12) , A. Sadoun (13) , H. Tilly (14) , P. Brice (15) , B. Lioure (16) , B. Desablens (17) , B. Pignon (18) , Jp Abgrall (19) , M. Leporrier (20) , P. Fenaux (1)

1 SERVICE DES MALADIES DU SANG - Groupe français des myéloplastes and groupe ouest est des leucemies aigües myéloïde
2 Centre Oscar Lambert
3 Service d'Hématologie Clinique (CHU de Dijon)
4 Service hématologie angers
5 Service d'Hématologie [CHRU Besançon]
6 service hématologie Nantes
7 CRLCC René Huguenin - CRLCC René Huguenin
8 Service d'Hématologie [CHRU Nancy]
9 Service hématologie Créteil
10 Hôpital Cochin [AP-HP]
11 Hôpital Necker - Enfants Malades [AP-HP]
12 IPC - Institut Paoli-Calmettes
13 Service hématologie Nice
14 Service hématologie Poitiers
15 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
16 AP-HP - Hopital Saint-Louis [AP-HP]
17 service hématologie Strasbourg
18 Laboratoire d'Hématologie [CHU Amiens]
19 URCA - Université de Reims Champagne-Ardenne
20 CHU-Brest-Hemato - CHRU Brest - Service d'Hématologie

We designed a randomized trial of IC with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged < or = 65 years with high risk MDS. Patients were randomized to receive Mitoxantrone 12 mg/m2/d d2-5 + AraC 1 g/m2/12 h d1-5, with (Q+) or without (Q-) quinine (30 mg/kg/day). 131 patients were included. PGP expression analysis was successfully made in 91 patients and 42 patients (46%) had positive PGP expression. In PGP positive cases, 13 of the 25 (52%) patients who received quinine achieved CR, as compared to 3 of the 17 (18%) patients treated with chemotherapy alone (p = 0.02). In PGP negative cases, the CR rate was 35% and 49%, respectively in patients who received quinine or chemotherapy alone (difference not significant). In the 42 PGP positive patients, median Kaplan-Meier (KM) survival was 13 months in patients allocated to the quinine group, and 8 months in patients treated with chemotherapy alone (p = 0.01). In PGP negative patients, median KM survival was 14 months in patients allocated to the quinine group, and 14 months in patients treated with chemotherapy alone. Side effects of quinine mainly included vertigo and tinnitus that generally disappeared with dose reduction. Mucositis was significantly more frequently observed in the quinine group. No life threatening cardiac toxicity was observed. In conclusion, results of this randomized study show that quinine increases the CR rate and survival in PGP positive MDS cases treated with IC. The fact that quinine had no effect on the response rate and survival of PGP negative MDS suggests a specific effect on PGP mediated drug resistance rather than, for instance, a simple effect on the metabolism of Mitoxantrone and/or AraC.

Mots clés: Adult; Aged; Anemia; Refractory; with Excess of Blasts/physiopathology; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use; Chromosome Aberrations; Comparative Study; Cytarabine/administration & dosage; Disease Progression; Female; Genes; MDR; Humans; Karyotyping; Leukemia; Myelocytic; Acute/physiopathology; Male; Middle Aged; Mitoxantrone/administration & dosage; Myelodysplastic Syndromes/*drug therapy/*genetics/mortality; P-Glycoprotein/*genetics; Phenotype; Quinine/*therapeutic use; Remission Induction; Research Support; Non-U.S. Gov't; Survival Analysis

Domaines: Virologie

E. Wattel, E. Solary, B. Hecquet, D. Caillot, N. Ifrah, et al.. Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study.. 2006. ⟨hal-00115657⟩