High Dose Intensive Chemotherapy, as Is Standard in Childhood Leukemia, Is Feasible and Efficacious in Adult Patients with Acute Lymphoblastic Leukemia (ALL) up to the Age of 40: Results From the Dutch-Belgian HOVON-70 Study.

Abstract 323

Event-free survival (EFS) at 5 years in pediatric ALL is > 80% with dose intensive multi-agent chemotherapy. In contrast, adult ALL still has an unsatisfactory outcome, which may partly be due to less cumulative dosing of chemotherapeutic agents and less strict adherence to timing of successive cycles of chemotherapy. Given the earlier reported feasibility of pediatric schedules in adolescent patients, the HOVON group performed a prospective multicenter phase II trial to evaluate the feasibility and efficacy of an intensified treatment regimen in adult patients with newly diagnosed ALL aged 18–40 years. The treatment regimen was based on the French FRALLE-2000 protocol, including dose intensification for steroids, vincristine, L-asparaginase, and high dose methotrexate (MTX).

Fifty-four patients, median age 26 years (range 17–39) were enrolled in 15 centres in the Netherlands and Belgium between December 2005 and August 2007. After a prednisolon prephase and a multidrug remission-induction (prednisolon, daunorubicin, vincristine, cyclophosphamide and L-asparaginase), patients received consolidation containing 5000 mg/m² MTX twice, two intensifications with intensified L-asparaginase, interspersed by an interphase with again two times high dose MTX, and maintenance chemotherapy (oral MTX and 6-mercaptopurine (6-MP) with reinduction with vincristine and prednisolon) for two years. CNS prophylaxis with MTX was delivered intrathecally 18 times. Standard risk patients with an HLA-identical sibling stem cell donor proceeded to allogeneic stem cell transplantation (alloSCT) after the first intensification, high risk patients received alloSCT from either sibling or unrelated donors. Adherence to the treatment schedule was urged by defining a strict timetable. Feasibility was defined by completion of chemotherapeutic and alloSCT protocol treatment within this a pre-defined timeframe.

Thirty-five patients (65%) had B-cell phenotype ALL, 17 (31%) had T-cell phenotype and 2 (4%) had biphenotypic leukemia. Moreover, 23 patients (43%) had high risk disease, of whom 9 patients with BCR-ABL positive ALL. In total 33 patients fully completed treatment as scheduled, including 18 alloSCT recipients. Complete remission (CR) was achieved in 91% (95% CI: 80–97). After a median follow-up of 26 months (range 15–36 months), 2-year event-free-survival (EFS) is 68% (95% CI: 53–78), 2-year disease free survival (DFS) 74% (95% CI: 59–84) and the 2-year overall survival (OS) 70% (95% CI: 55–81). Fifteen patients (28%) died, including 8 due to relapsed/refractory ALL, 3 due to infection, 3 due to toxicity and 1 due to graft versus host disease. CTC grade 4-5 toxicities (mainly liver/kidney function abnormalities and peripheral neuropathy) were observed in 15% during induction and 13% during consolidation. Severe infections (CTC grade 3-4) primarily occurred during induction (41%) and consolidation (39%). Failures were due to not reaching CR in 5 patients, early relapse in 2, severe extramedullary drug toxicity in 3, excessive delay in 7 and other reasons not otherwise specified (but most likely due to toxicity) in 4 patients.

In conclusion, these data show that a dose-intensified chemotherapeutic regimen based on a pediatric schedule is safe and feasible in most adult ALL patients up to the age of 40, although a delay of subsequent cycles was frequently observed. Early efficacy data suggest a high CR rate and favourable DFS and OS. Based on this experience, a randomised phase III trial has recently been initiated.

This trial was supported by the Dutch Cancer Foundation (CKTO 2005-08), EudraCT number 2005-000919-96