Outcome by Treatment Including An Intensified Consolidation Program with Dose-Escalated Doxorubicin for Newly Diagnosed Acute Lymphoblastic Leukemia (ALL): A Study by the Japan Adult Leukemia Study Group (JALSG ALL97 study).

We designed a multicenter study (JALSG ALL 97) including an intensified consolidation program with dose-escalated doxorubicin (DOX) in order to improve outcome in adults with acute lymphoblastic leukemia (ALL) in pre-imatinib era. We reported here the efficacy and prognostic factors of mainly Philadelphia chromosome (Ph)-negative patients.

From May 1997 to December 2001, patients (age ranges 15 - 64 years) with previously untreated ALL (excluding mature B-cell ALL) were consecutively registered in this study. We modified the standard induction program with five drugs; vincristine (VCR), daunorubicin, cyclophosphamide, prednisolone (PSL) and L-asparaginase and the maintenance program with daily 6-mercaptopurine, weekly methotrexate (MTX) and monthly pulses of VCR and PSL used in CALGB 8811 study. Consolidation therapy included eight courses featuring dose-intensified DOX and intermediate-dose MTX. The total dose of DOX in consolidation phase was 330 mg/m². For patients with Ph or t(4;11), allogeneic stem cell transplantation (HSCT) was recommended during their first complete remission (CR), if donors were available; whereas for patients without Ph or t(4;11) there was no criteria for choosing HSCT. The 5-year overall survival (OS), the 5-year disease-free survival (DFS), and the prognostic factors were evaluated.

There were 404 eligible patients (median age, 38 years), of whom 256 were Ph-negative and 116 were Ph-positive. Of the eligible patients, 298 patients (74%) achieved CR. With a median follow-up time of 5.8 years, the estimated 5-year OS rate was 32% (95%CI: 27.1-36.9), and the 5-year DFS was 33% (95%CI: 26.8 - 38.2). The CR rates in Ph-negative and Ph-positive patients were 81% (n=208) and 56% (n=65), respectively. The 5-year OS in Ph-negative and Ph-positive patients were 39% and 15%, respectively. In Ph-negative patients, multivariate Cox analysis showed that older age, PS and WBC count were the independent prognostic factors for OS. The 5-year OS rates for patients younger than 35 years and a WBC count less than 30 × 10⁹/L (risk group 1), for patients younger than 35 years and a WBC count above 30 × 10⁹/L (risk group 2), for patients older than 35 years and a WBC count less than 30 × 10⁹/L (risk group 3), and for patients older than 35 years and a WBC count above 30 × 10⁹/L (risk group 4), were 51%, 29%, 33%, and 27%, respectively (P=0.0005). Of the 208 Ph-negative patients who achieved CR, 60 patients (29%) were underwent allogeneic-HSCT during their first CR (37 from a related donor and 23 from an unrelated donor), resulting that 8 (13%) died in remission, 16 (27%) relapsed, and 36 (60%) remained in continuous CR. The 5-year OS rate for the 60 patients was 63 %. Among them, the 5-year OS rates for the 31 patients of the risk group 1 (standard risk group) and for other 29 patients (high risk group) were 73% and 54%, respectively. Among 148 patients who did not receive allogeneic-HSCT during first CR, six (4 %) died in remission, 105 (71%) relapsed, and 37 (25%) remained in continuous CR. The 5-year OS rates for the 148 patients, for patients with standard risk, and for patients with high risk were 37%, 44% and 33%, respectively.

Result of this study was in the range of those reported by most large cooperative groups, but showed little improvement of adult Ph-negative ALL therapy. The prognostic factors for long term outcome of Ph-negative patients were similar to those in previous reported. This study also suggested that allogeneic-HSCT for Ph-negative patients in first CR might have contributed to the improvement of the outcome.

No relevant conflicts of interest to declare.