Table 1.

Factors Motivating Treatment Evolution and Progress in Childhood Acute Lymphoblastic Leukemia

Decade	Treatment Progress During Decade	Factors Motivating Change
1960s	Use of single-agent chemotherapy (methotrexate, mercaptopurine, vincristine, asparaginase, cyclophosphamide, daunorubicin, and cytarabine) Introduction of combination chemotherapy treatment protocols Standardization of therapy phases (remission induction, consolidation, CNS therapy, maintenance)	Demonstration of antileukemic activity among agents interfering with cellular metabolism Recognition that single-agent therapy produced transient responses Emulation of combination therapy approach successful in resistant tuberculosis and preclinical mouse models Appreciation of need for CNS-directed therapy with early use of cranial and craniospinal irradiation
1970s	Integration of anthracyclines in therapy protocols for high-risk ALL Demonstration of improved outcomes with use of therapy intensification and delayed intensification Reduction in use of spinal irradiation for CNS	Recognition of diverse ALL pathobiology and outcomes Appreciation of clinical factors that influence treatment outcomes (age at diagnosis, initial leukocyte count, response to treatment) Identification of pathobiologic differences in ALL that influence outcome (immunophenotype, cytogenetics, chromosomal translocations, chromosomal ploidy) Demonstration of comparable outcomes using craniospinal irradiation and cranial irradiation plus intrathecal chemotherapy
1980s	Integration of asparaginase intensification in therapy protocols for high-risk ALL	Appreciation of delayed neurocognitive and neuroendocrine toxicities after cranial irradiation
	Restriction of epipodophyllotoxin use for most children with ALL	Recognition of treatment-related acute myeloid leukemia associated with epipodophyllotoxins
	Reduction in use of cranial irradiation therapy for CNS-negative ALL	Demonstration that intensified (triple) intrathecal chemotherapy could sustain CNS remissions without the use of cranial irradiation in patients with standard-risk ALL
1990s	Introduction of imatinib for Philadelphia chromosome–positive ALL Integration of dexamethasone in induction therapy protocols Reduction in dose and use of preventive cranial irradiation Recognition of role of host pharmacogenomics in chemotherapy-related toxicity and ALL response Implementation of risk-stratified treatment protocols on the basis of ALL pathobiology	Identification of novel antileukemia drug targets on the basis of molecular and cellular changes stimulating leukemia development (eg, BCR-ABL) Recognition of radiation-related subsequent neoplasms Recognition of dose-related risk of anthracycline cardiotoxicity Recognition of dose-related risk of cyclophosphamide gonadal toxicity Demonstration of superiority of dexamethasone compared with prednisone in preventing CNS relapse
2000s	Personalization of therapy related to early treatment response (minimal residual disease) Elimination of use of cranial irradiation for most children with ALL Investigation (ongoing) of molecular targets for drug development	Demonstration of prognostic significance of minimal residual disease Recognition of role of pharmacogenomics in treatment response and acute/delayed toxicities Identification of novel leukemia subtypes on the basis of alterations in cellular signaling

Abbreviation: ALL, acute lymphoblastic leukemia.