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Quinine given as an MDR reversing agent in the treatment of adult acute myeloid leukemia Results of the randomized GOELAM 2 trial



Quinine given as an MDR reversing agent in the treatment of adult acute myeloid leukemia Results of the randomized GOELAM 2 trial



Blood 96(11 Part 1): 504a-505a



In our previous GOELAM trial, after a 1st course or intensive consolidation chemotherapy (ICC), a 2nd course of chemotherapy was less myelotoxic than autologous BMT but yielded comparable DFS and survival rates (Blood 1997; 90: 2978-86). Encouraging results obtained with quinine as an MDR reversing agent in secondary or advanced acute leukemias (Blood 1996; 88: 1198-205), led us to test the impact of quinine in the treatment of de novo AML. From February 95 to February 99, 429 patients (15-60 years) with de novo AML (M3 excluded) were recruited by 17 centers. Patients were randomly assigned to receive or not quinine throughout their whole treatment (induction and 2 courses of ICC). Induction consisted of Idarubicin (IDR: 8 mg/m2/D D1-D5) plus Ara-C (200 mg/m2/D D1-D7). If D20 bone marrow contained >20% blasts, a second course was administered with Ara-C 3g/m2 q12 H D1-D4 plus mitoxantrone (MTZ: 12mg/m2/D D5-D6). Allogeneic BMT was proposed to patients in complete remission (CR) with an HLA identical donor up to the age of 45. All other patients in CR received 2 courses of ICC: course 1 identical to the 2nd induction course, course 2 with m-AMSA 150 mg/m2/D D1-D5 plus VP 16 100 mg/m2/D D1-D5. Quinine was given at a dose of 30 mg/kg/D CI starting 12 hours before the 1st dose of IDR, MTZ or m-AMSA and ending 12 hours after the last dose. A significant MDR reversing activity was detected in serum from most patients receiving quinine. The 2 groups (quinine = 214 patients, control = 215 patients) were well balanced regarding sex, age, FAB, blood cell counts, cytogenetics and MDR expression (gene, protein and/or function). The CR rate was 81% with no significant difference between the 2 groups (quinine 80.5%, vs 81.5% p=0.95). The incidences of toxic deaths, failures or CR after 2 courses were identical as well. Overall 3-year survival was 44% and 3-year EFS was 36% without significant differences between the 2 groups. On an intent-to-treat basis, allogeneic BMT was superior to ICC (3-year DFS 63% vs 39%, p=0.001, 3 year survival 65% vs 49%, p = 0.14). For CR patients not eligible for BMT, the outcome was not influenced by quinine (3-year DFS 38% vs 39%, p=0.72, 3-year survival 50% vs 48%, p=0.58). In the subgroup of MDR positive patients, quinine did not significantly improve the outcome. We conclude that quinine does not significantly impact the results of treatment in adult patients with de novo AML.

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