Outcome of Dana-Farber Cancer Institute (DFCI) Consortium Protocol 95–01 for Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL).

DFCI Consortium Protocol 95–01 was designed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy. Patients were considered high risk (HR) if they met any of the following criteria: 1) white blood cell count (WBC) ≥ 50,000/microliter, 2) age between < 1.00 years or ≥ 10.00 years, 3) presence of leukemia blasts at diagnosis in a cytocentrifuged cerebrospinal fluid specimen, 4) presence of a mediastinal mass, 5) T-cell immunophenotype, or 6) presence of the Philadelphia chromosome. All other patients were considered standard risk (SR). The protocol included three randomizations designed to evaluate whether acute and late toxicities could be reduced, including comparisons of 1) Erwinia and E.coli asparaginase given weekly for 20 weeks during post-remission consolidation (SR and HR patients), 2) intrathecal chemotherapy given with or without 18 Gy cranial radiation as central nervous system (CNS)-directed treatment (SR patients only), and 3) doxorubicin given with or without dexrazoxane, a potential cardioprotectant agent, during remission induction and post-remission consolidation (HR patients only). Between 1996 and 2000, 491 eligible patients (ages 0-18 years) were enrolled, 272 of whom were classified as SR and 219 HR. With 4.6 years median follow-up, the estimated 5-year event-free survival (EFS) was 81 ± 2% for all patients. The 5-year EFS according to risk group was 86 ± 2% for SR and 76 ± 3% for HR patients (p<0.01). Erwinia asparaginase was associated with a decreased incidence of asparaginase-related toxicities compared with E.coli asparaginase (10 % versus 24%, p<0.01), but also significantly more relapses (19% versus 8%, p<0.01), including relapses involving the CNS (6% versus 1%, p<0.01). The 5-year EFS for the 139 patients randomized to Erwinia asparaginase was 78 ± 4% compared with 89 ± 3% for the 148 patients randomized to E.coli asparaginase (p<0.01). The 5-year EFS for SR patients randomized to CNS treatment without radiation (IT-only) was 82 ± 5% compared with 87 ± 4% for those randomized to receive cranial radiation (p=0.35). There were four relapses involving the CNS in the 83 SR patients randomized to IT-only (4.8%) and none in the 80 irradiated patients (0%) (p=0.12). However, three of the four CNS relapses in IT-only SR patients occurred in those who had also been randomized to Erwinia asparaginase. CNS relapses (isolated or combined with other sites) occurred in 1.9% of randomized IT-only SR patients who received E.coli asparaginase. Dexrazoxane did not significantly impact the EFS of HR patients, with a 5-year EFS of 75 ± 5% for the 105 patients randomized to doxorubicin with dexrazoxane compared with 77 ± 4% for the 101 patients randomized to receive doxorubicin alone (p=0.85). We conclude that 1) Erwinia asparaginase is less toxic but also less efficacious than E.coli asparaginase when dosed once weekly during post-remission consolidation, 2) Intensive intrathecal chemotherapy without cranial radiation provides adequate CNS prophylaxis in SR patients in the setting of effective systemic chemotherapy, and 3) Dexrazoxane does not appear to interfere with the anti-leukemic effect of Doxorubicin.