A Randomised Phase II Study of Pegylated Liposomal Doxorubicine in Elderly Patients with Acute Lymphoblastic Leukemia (ALL): The GRAALL-SA1 Study.

The GRAALL-SA1 study aimed to randomly compare the efficacy and toxicity of liposomal pegylated doxorubicin (Peg-Dox) vs continuous infusion doxorubicin (CI-Dox) in elderly patients with Philadelphia chromosome-negative ALL. Induction chemotherapy, supported by G-CSF, comprised either CI-Dox 12 mg/m²/d and CI-VCR 0.4 mg/d on d1-4 or Peg-Dox 40 mg/m² IV and standard VCR 2 on d1, in combination with dexamethasone. A second cycle, reinforced by cyclophosphamide 1 g/m², was started at d28. Consolidation included two additional cycles using reduced doses of CI-Dox (12mg/m2/d d1-3) or Peg- Dox (30 mg/m² d1) with VCR in both treatment arms (5 minutes infusion on d1,8,15) alternating with two cyclophosphamide (650 mg/m² d1) /thioguanine (60 mg/m² d2- d15) /cytarabine (75 mg/m²/d4-7 and d11-14) cycles. Maintenance included 6-MP and methotrexate for 2 years. CNS prophylaxis was based on 6 triple ITs and cranial irradiation. From March 2002 to October 2006, 60 patients aged 55 years or more from 26 centers were enrolled in this multicenter study. The median age was 66 years (range 55–80), 17% had initial WBC ³ 30 x10⁹/l, 2 patients had CNS leukemia and 6.6% had mediastinal involvement. Immunophenotyping showed 85% B-lineage ALL, 12% T-ALL, and 3% aberrant expression of myeloid antigens. Patient characteristics were comparable in the two randomization groups except for a small unbalance with more T-ALL and more steroids resistant leukemia in the Peg-Dox group (6/29 vs 1/31, P = .05 and 5/29 vs 1/31, P = .1, respectively). Tolerance was improved in the Peg-Dox arm with less Grade 3–4 infectious events during induction (27% vs 48%; P = .04), less Gram negative bacteriemia during induction (1 vs 9, P = .02) and consolidation courses (2 vs 7, P = .07) and less cardiac toxicities (1/29 vs 6 /31, P = .12). Duration of neutropenia was reduced from 7 days in the CI-Dox arm to 6 days in the Peg-Dox arm (P= .06). RBC units transfused were reduced from 7.2 to 4.5 during induction (P= .02) and from 2.9 to 1.1 during consolidation course (P= .003). Days with platelets < 50.10⁹/L were reduced from 13.4 to 6.4 (P=0.03). After the 2 induction cycles, CR rate was 82%, with 10% failures and 8% induction deaths. With a median follow-up of 40 months, median OS for the entire population was 10 months and 19% of the patients were alive in CR at 3 years (95% CI, 9–30). Despite the better tolerance, there was a trend for a worse 2-year OS in the Peg-Dox arm (11 vs 27% ; P=0.07), due to higher induction failure (17 vs 3%) as well as relapse incidence rates (62 vs 39%). Younger age, B-lineage, and steroid sensitivity were the three factors identified for a higher CR rate in multivariate analysis. The decreased toxicity of Peg-Dox over CI-Dox was thus offset by a decreased efficacy. Further studies should evaluated higher doses of pegylated versus conventional formulations of anthracycline in patients with ALL.