Table I.

Evolution of Therapy for Acute Lymphoblastic Leukemia

Treatment Modality	Decade					Historic Treatment Modalities Used in Contemporary Therapy
	1960	1970	1980	1990	Post-2000
Chemotherapy Agents	Antimetabolites (methotrexate, mercaptopurine), asparaginase, corticosteroids and vinca alkaloids used in combination Early use of cyclophosphamide	Widespread use of induction/consolidation/maintenance strategy Increased use of anthracyclines for high risk patients	Asparaginase intensification within DFCI consortium Epipodophyllotoxins abandoned for most children with ALL No widely used new agents.	Introduction of imatinib for small subset of patients with Philadelphia positive ALL Nelarabine introduced for T-cell ALL Dexamethasone more widely used in induction therapy	Additional refinement of risk based therapy No new agents added to initial therapeutic modalities	Prednisone Vincristine Daunomycin/Doxorubicin Cyclophosphamide L-Asparaginase Methotrexate Mercaptopurine
Dose-Intensity/Duration	Modest dose intensity Long maintenance therapy(3 to 5 years)	Intensity of drugs increased based on early BFM trials showing benefit of delayed intensification for all subsets of ALL patients	Further intensification for high risk children. Use of “double DI” Duration of therapy constant	Focus on stratification and application of intensified regimens to more limited subsets	Intensity of therapy remains constant Duration continues to be constant	Induction Consolidation Delayed intensification Maintenance 2 years for girls 2.5 years for boys
Radiation Therapy	Early use of cranial and craniospinal irradiation	Trials of extended field irradiation. Reduced use of spinal irradiation	Randomized trials show efficacy of CNS chemoprophylaxis. Reduced use of radiation therapy for SR children who are CNS negative	Further reduction in use of preventive irradiation. High risk patients no longer routinely irradiated. Dose remains constant at 18 Gy for prophylaxis; reduced doses investigated for T-cell ALL and CNS relapse	Further reduction in indications for radiation therapy.	Cranial irradiation limited to CNS disease refractory to systemic and intrathecal chemotherapy

ALL – acute lymphoblastic leukemia; BFM – Berlin-Frankfurt-Münster; CNS – central nervous system; DFCI – Dana Farber Cancer Institute; DI – delayed intensification