Recent Advances in Acute Lymphoblastic Leukemia

Epidemiology From data collected by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, it is estimated that there were 5330 cases of newly diagnosed ALL (3150 in males and 2180 in females) in 2010 in the United States, approximately 60% of which were diagnosed in patients younger than 20 years of age.[1] Hence, while the total number of cases of leukemia (including acute and chronic myeloid leukemia as well as chronic lymphocytic leukemia) is 10 times higher in adults than in children, ALL is predominantly a childhood disease. This difference in prevalence, together with the fact that most cases of childhood ALL, but only a very small proportion of adult cases, are treated in clinical trials, readily explains why most research advances in ALL are made in children. Molecular Genetics Standard genetic studies can identify specific genetic abnormalities with prognostic and therapeutic implications in only about 75% to 80% of childhood ALL cases.[2] Moreover, these studies cannot identify the full repertoire of genetic alterations in individual patients. Recent global genome-wide analyses have revealed many new “driver” mutations in ALL, including IKZF1 deletion, CRLF2 overexpression, JAK mutations, ERG deletion, and CREBBP mutations. These analyses have clearly showed that cooperative mutations are necessary for malignant transformation and progression, and that such mutations account for the development of drug resistance.[3-7] Virtually all childhood ALL cases can now be classified according to specific genetic abnormalities.[8] Importantly, the presence of JAK mutations in cases with IKZF1 deletion or CRLF2 overexpression has led to a phase I trial of JAK inhibitors in relapsed ALL, and the identification of CREBBP mutations that affect transcriptional and epigenetic regulation as a mechanism of drug resistance raises the possibility of epigenetic treatment with a histone deacetylase inhibitor.[7] Pharmacogenetics Rabin and Poplack mention that a deficiency of thiopurine methyltransferase can lead to myelosuppression and increase the risk of second malignancies induced by treatment with a “standard dose” of mercaptopurine. It should be noted that a so-called standard dose varies from 50 mg/m2 to 75 mg/m2 per day according to the specific clinical trial. While all patients who are homozygous for this deficiency (~1 in 180 to 1 in 2500 individuals) are at risk for life-threatening myelosuppression and require a 10-fold reduction in the dose of mercaptopurine, 30% to 60% of heterozygous patients (~3% to 14% of the population) are at risk for only moderate toxicity.[9] Thus, heterozygous patients should be started on a lower dose (eg, 50 mg/m2 per day), with subsequent doses adjusted according to the degree of myelosuppression. In this regard, in a Berlin-Frankfurt-Mnster (BFM) study featuring mercaptopurine at 60 mg/m2 per day, patients who were homozygous wild-type (normal enzyme activity) had higher minimal residual disease levels after treatment than did patients with enzyme deficiency, and they would have benefited from a higher dose of mercaptopurine.[10] The risk of mercaptopurine-induced second malignancy (mainly acute myeloid leukemia or myelodysplastic syndrome) depends not only on the enzyme activity but also on the dose intensity of antimetabolite treatment. Thus, lower enzyme activity was related to a relatively high risk of secondary acute myeloid malignancies in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 protocols, which featured intensive antimetabolite-based continuation treatment with a starting dose of mercaptopurine of 75 mg/m2