title: Quinine improves results of intensive chemotherapy (IC) in myelodysplastic syndromes (MDS) expressing P-glycoprotein (PGP). Updated results of a randomized study. Groupe Français des Myélodysplasies (GFM) and Groupe GOELAMS.
abstract: 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.
authors.affiliation: Service des Maladies du Sang, CHU, Lille, France.
authors.forename: E
authors.initials: E
authors.lastname: Wattel
authors.forename: E
authors.initials: E
authors.lastname: Solary
authors.forename: B
authors.initials: B
authors.lastname: Hecquet
authors.forename: D
authors.initials: D
authors.lastname: Caillot
authors.forename: N
authors.initials: N
authors.lastname: Ifrah
authors.forename: A
authors.initials: A
authors.lastname: Brion
authors.forename: N
authors.initials: N
authors.lastname: Milpied
authors.forename: M
authors.initials: M
authors.lastname: Janvier
authors.forename: A
authors.initials: A
authors.lastname: Guerci
authors.forename: H
authors.initials: H
authors.lastname: Rochant
authors.forename: C
authors.initials: C
authors.lastname: Cordonnier
authors.forename: F
authors.initials: F
authors.lastname: Dreyfus
authors.forename: A
authors.initials: A
authors.lastname: Veil
authors.forename: L
authors.initials: L
authors.lastname: Hoang-Ngoc
authors.forename: A M
authors.initials: AM
authors.lastname: Stoppa
authors.forename: N
authors.initials: N
authors.lastname: Gratecos
authors.forename: A
authors.initials: A
authors.lastname: Sadoun
authors.forename: H
authors.initials: H
authors.lastname: Tilly
authors.forename: P
authors.initials: P
authors.lastname: Brice
authors.forename: B
authors.initials: B
authors.lastname: Lioure
authors.forename: B
authors.initials: B
authors.lastname: Desablens
authors.forename: B
authors.initials: B
authors.lastname: Pignon
authors.forename: J P
authors.initials: JP
authors.lastname: Abgrall
authors.forename: M
authors.initials: M
authors.lastname: Leporrier
authors.forename: P
authors.initials: P
authors.lastname: Fenaux
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000754:Anemia, Refractory, with Excess of Blasts / Q000503:physiopathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002869:Chromosome Aberrations; D003561:Cytarabine / Q000008:administration & dosage; D018450:Disease Progression; D005260:Female; D019450:Genes, MDR; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D010641:Phenotype; D011803:Quinine / Q000627:therapeutic use*; D012074:Remission Induction; D016019:Survival Analysis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003561:Cytarabine; D011803:Quinine; D008942:Mitoxantrone