TY - JOUR
T1 - Quinine improves results of intensive chemotherapy (1C) in myelodysplastic syndromes (MDS) expressing P-glycoprotein (PGP)
T2 - Updated results of a randomized study
AU - Wattel, E.
AU - Solary, E.
AU - Hecquet, B.
AU - Caillot, D.
AU - Ifrah, N.
AU - Brion, A.
AU - Milpied, N.
AU - Janvier, M.
AU - Guerci, A.
AU - Rochant, H.
AU - Cordonnier, C.
AU - Dreyfus, F.
AU - Veil, A.
AU - Hoang-Ngoc, L.
AU - Stoppa, A. M.
AU - Gratecos, N.
AU - Sadoun, A.
AU - Tilly, H.
AU - Brice, P.
AU - Lioure, B.
AU - Desablens, B.
AU - Pignon, B.
AU - Abgrall, J. P.
AU - Leporrier, M.
AU - Dupriez, B.
AU - Guyotat, D.
AU - Lepelley, P.
AU - Fenaux, P.
PY - 1999/1/1
Y1 - 1999/1/1
N2 - We designed a randomized trial of 1C with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged ≤ 65 years with high risk MDS. Patients were randomized to receive Mitoxantrone 12mg/m2/d d2-5 + AraC Ig/m2/12h d1-5, with (Q+) or without (Q-) quinine (30mg/kg/day). 131 patients were included. PGP expression analysis was successfully made in 91 patients and 42 patients (46%) had positive POP 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.
AB - We designed a randomized trial of 1C with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged ≤ 65 years with high risk MDS. Patients were randomized to receive Mitoxantrone 12mg/m2/d d2-5 + AraC Ig/m2/12h d1-5, with (Q+) or without (Q-) quinine (30mg/kg/day). 131 patients were included. PGP expression analysis was successfully made in 91 patients and 42 patients (46%) had positive POP 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.
KW - Drug resistance
KW - Intensive chemotherapy
KW - Mdr
KW - Myelodysplastic syndromes
KW - Quinine
UR - http://www.scopus.com/inward/record.url?scp=0032619948&partnerID=8YFLogxK
U2 - 10.1007/978-1-4615-4811-9_5
DO - 10.1007/978-1-4615-4811-9_5
M3 - Article
C2 - 10500778
AN - SCOPUS:0032619948
SN - 0065-2598
VL - 457
SP - 35
EP - 46
JO - Advances in Experimental Medicine and Biology
JF - Advances in Experimental Medicine and Biology
ER -