Acute Lymphoblastic Leukaemia (ALL), a malignant disorder of lymphoid progenitor cells, affects both children and adults, with peak incidence between the ages of 2 and 5 years, and a further peak in older age. While cure rates exceed 80%, relapsed B precursor ALL remains a leading cause of non-traumatic death in children and young adults. The outcome for older patients remains poor. Recent advances in genomic profiling have defined ALL as a heterogeneous disease with multiple subgroups characterized by distinct genetic alterations, with their own prognostic and therapeutic implications. A clinically important finding is the identification of a new subtype of high-risk ALL, termed Ph-like ALL, that exhibits a gene expression profile similar to BCR-ABL1 ALL and harbors a diverse range of genetic alterations activating tyrosine kinases, in addition to other genomic changes. The clinical importance of this finding is that these kinases provide therapeutic targets for which safe and active drugs are already available and in clinical use. We have developed rapid and accurate screening tests to identify these targetable genetic lesions in pre-B ALL patients to enhance the clinical application of rational anti-leukaemic agents in this setting. To date however, the evidence that such approaches will transform survival in this disease is limited to in vivo studies and anecdotal case reports. Furthermore the most efficacious therapeutic regimens are not established, and we have demonstrated in Ph+ ALL and CML that TKI monotherapy can result in resistance.
While there is no doubt that the use of rational therapies will transform outcomes for a large number of patients…there is also no doubt that we will be faced as researchers and clinicians with new challenges.