Advances in Acute Lymphoblastic Leukemia

Abstract

DATA SOURCES: Current literature

DATA SYNTHESIS: Acute lymphoblastic leukemia (ALL) is a stem cell disorder characterized by an overproduction of lymphoblasts in the bone marrow that eventually spill into circulation, producing lymphocytosis. As with the other acute leukemias, the most common symptoms experienced by patients include fatigue, bleeding, and recurrent infections resulting from the suppression of normal hematopoiesis in the bone marrow by the accumulating blasts. ALL primarily affects children and exhibits the best response to standard chemotherapy as compared to acute myeloblastic leukemias (AML). Further, remission rates are highest among ALL patients, many of whom are experiencing sustained remissions suggesting cure. In light of early treatment successes, researchers began to investigate modifications of standard treatment regimens to accommodate variability in weight, age, and response to therapy among children with ALL. Individualized treatment plans were implemented where some patients received a reduced intensity course of therapy to minimize drug toxicity while others received drug intensification to maximize response. More recently, research efforts have been directed at the elucidation of leukemogenic mechanisms implicated in ALL to identify specific protein mutants that can be used to design drugs tailored to interfere with the activity of these mutant protein targets. Identification of chimeric proteins produced from chromosomal translocations and gene expression profiles from microarray analyses are the primary techniques used to identify the potential therapeutic targets.

CONCLUSION: Several reliable prognostic indicators have been identified and are being used to improve therapeutic planning and outcome prediction in ALL patients. Individualized treatment regimens have been developed based on the specific characteristics of each patient to minimize treatment related adverse events and maximize response. Through the use of cytogenetic, molecular, and microarray testing, ALL classification schemes have improved and potential therapeutic targets have been identified. It is anticipated that the next major advance in the treatment of ALL will involve the use of designer therapies developed to specifically interfere with particular molecular abnormalities producing the leukemogenic aberration to the normal signal transduction pathways.

ABBREVIATIONS: 6MP = 6-mercaptopurine; ABL = ableson oncogene found in a strain of mouse leukemia virus; ALL = acute lymphoblastic (lymphocytic) leukemia; BCR = breakpoint cluster region; CBF = core-binding factor; CCG = Children's Cancer Group; CDK = cyclin-dependent kinases; EFS = event free survival; FAB = French-American-British; HAT = histone acetyltransferase; HDAC = histone deacetylase; MLL = mixed-lineage leukemia; MRD = minimum residual disease; OPAL1 = outcome prediction for acute leukemia number 1; POG = Pediatric Oncology Group; RB = retinoblastoma; RFC = reduced folate carrier; TPMT = thiopurine methyltransferase; WHO = World Health Organization.