Search

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.

From 11/01 until 04/05, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were included in prospective phase III AML 2001 trial. After achieving CR, research to identify an HLA-identical sibling was performed for all patients as they received low dose consolidation (Daunorubicin (D): 60 mg/m2 × 2d OR Idarubicin (I): 12 mg/m2 × 2d plus SC ARAC 100 mg/m2 ×7d). 33 % patients had a donor then could proceed to a T-replete alloSCT: either conventional if age ≤ 50 (bone marrow graft; conditioning regimen: TBI (12 Gy 6 fractions over 3d) - cyclophosphamide (60 mg/kg × 2d); GvHD prophylaxis: ciclosporin-methotrexate d1+3+6) = arm M; or NST if age 51–60 (peripheral blood; Busulfan (oral Bu 4–8 mg/kg over 2d) - Fludarabin (30 mg/m2 × 4d) – Thymoglobulin® (2,5 mg/kg × 2d); ciclosporin alone), AFTER intensive consolidation (D: 60 mg/m2 × 2d OR I: 12 mg/m2 × 2d plus ARAC 3 g/m2 × 8 doses over 4d) = arm m. A small group of patients with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction = 3% CR1 patients) didn’t receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered at relapse = arm C. Patients without donor proceed to intensive consolidation then 1 or 2 autoSCT (1st after HDM 200 mg/m2 according to randomization, then Bu 16 mg/kg over 4d + HDM 140 mg/m2 for all patients) = arms A + B; they were combined for analysis as no difference was observed for DFS and OS. Actual results concern 532 patients with 15 months follow-up (A + B = 367; M = 111; m = 54). Median age was different between 3 groups (A + B = 46; M = 40; m = 54) as no difference was observed regarding leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: A + B = 15%; M = 11%; m = 11%), intermediate (A + B = 72%; M = 78%; m = 67%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; A + B = 13%; M = 11%; m = 22%). Conventional alloSCT results in better 2y DFS than autoSCT arms (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06) as toxic death rate is higher (36% all deaths in arm M vs 14 % in arms A + B). No significant difference was observed between conventional alloSCT and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50: 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). After NST, toxicity accounts for 25% deaths, as relapse rate is 40% at 2y with no late relapse thereafter (vs 48 % at 2y and 61 % at 4y in arms A + B). In conclusion: 1) conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1 despite higher toxicity; 2) NST after intensive consolidation seems promising: for older patients as toxicity is lower than conventional alloSCT, as few late relapse are observed in comparison with chemotherapy or autoSCT approaches; 3) NST may extend use of alternative sources of allogeneic hematopoietic stem cells to propose alloSCT approach for the majority of patients ≤ 60 with AML in CR1. Data with more than 2 years follow-up will be presented.

From 11/01 until 04/05, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were included in prospective phase III AML 2001 trial. After achieving CR, research to identify an HLA-identical sibling was performed for all patients as they received low dose consolidation (Daunorubicin (D): 60 mg/m2× 2d OR Idarubicin (I): 12 mg/m2× 2d plus SC ARAC 100 mg/m2×7d). 33 % patients had a donor then could proceed to a T-replete alloSCT: either conventional if age ≤ 50 (bone marrow graft; conditioning regimen: TBI (12 Gy 6 fractions over 3d) - cyclophosphamide (60 mg/kg × 2d); GvHD prophylaxis: ciclosporin-methotrexate d1+3+6) = arm M; or NST if age 51–60 (peripheral blood; Busulfan (oral Bu 4–8 mg/kg over 2d) - Fludarabin (30 mg/m2× 4d) – Thymoglobulin® (2,5 mg/kg × 2d); ciclosporin alone), AFTER intensive consolidation (D: 60 mg/m2× 2d OR I: 12 mg/m2× 2d plus ARAC 3 g/m2× 8 doses over 4d) = arm m. A small group of patients with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction = 3% CR1 patients) didn't receive 1stline alloSCT but intensive consolidation then a 2ndHD ARAC course; alloSCT was therefore considered at relapse = arm C.