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Combination of quinine as a potential reversing agent with mitoxantrone and
cytarabine for the treatment of acute leukemias: a randomized multicenter
study
E Solary, B Witz, D Caillot, P Moreau, B Desablens, JY Cahn, A Sadoun, B Pignon, C Berthou, F Maloisel, D Guyotat, P Casassus, N Ifrah, Y Lamy, B Audhuy, P Colombat and JL Harousseau
Clinical Hematology Unit, Centre Hospitalier Universitaire (CHU) Le Bocage,
Dijon, France.
A phase III prospective randomized multicenter study was performed to
determine whether quinine could improve the response rate of poor-risk
acute leukemias (ALs) to standard chemotherapy including a multidrug
resistance (MDR)-related cytotoxic agent. The rationale of the study was
based on the negative prognostic value of MDR phenotype in ALs and the
ability of quinine to reverse this phenotype both in vitro and ex vivo.
Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with
relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia
(AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia
(ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic
syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were
randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5)
and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination
with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion
beginning 24 hours before MXN infusion). Side effects of quinine were
observed in 56 of 161 quinine-treated patients and disappeared in all but
four cases after one or two 20% dose decreases. Sera from quinine-treated
patients showed increased MXN uptake in an MDR-positive cell line compared
with matched sera obtained before quinine infusion. Quinine induced a
significant increase in the incidence of nausea, vomiting, mucositis, and
cardiac toxicity. A complete response (CR) was observed in 85 of 161
patients (52.8%) from the quinine-treated group versus 70 of 154 patients
(45.5%) in the control group (P = .19). The most important differences
between quinine and control group CR rates were observed in patients with
refractory AMLs and blastic transformation of MDS and MPS. The CR rate was
higher in P-glycoprotein-positive cases, although the difference was not
significant. Failure of the regimen due to blastic persistence or blast
number increase was higher in the control group (61 of 154 patients) than
in the quinine group (45 of 161, P = .04). Early death was observed in
eight cases (four in each arm) and death in aplasia in 27 cases (20 in
quinine group v seven in control group, P = .01). The significant increase
of toxicity in the quinine arm could have masked the clinical benefit of
MDR reversion in poor- risk ALs.
Volume 88,
Issue 4,
pp. 1198-1205,
08/15/1996
Copyright © 1996 by The American Society of Hematology
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