Acute Lymphoblastic Leukemia : Use of Tyrosine Kinase Inhibitors

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has historically been one of the most difficult to treat subsets of childhood ALL. Based on knowledge of the molecular genetics and biology of BCR-ABL1 fusion produced by the Ph+ in chronic myelogenous leukemia (CML) and Ph+ ALL, first (imatinib) and second (dasatinib and nilotinib) generation tyrosine kinase inhibitors (TKI) that target BCR-ABL1 were developed. These TKIs have revolutionized treatment of CML, and recent studies show that addition of imatinib to intensive chemotherapy leads to dramatic improvements in outcome of pediatric Ph+ ALL. These studies call for a reassessment of the routine use of stem cell transplantation (SCT) for all children with Ph+ ALL. The second generation TKIs have theoretical advantages over imatinib, but have not yet been used extensively in Ph+ ALL. In coming years, studies will define the optimal use of chemotherapy, SCT, and TKI in Ph+ ALL. New agents are being developed to circumvent resistance to first and second generation TKIs in Ph+ ALL and will likely be integrated into future treatment regimens for Ph+ ALL. Identification of the Philadelphia chromosome and BCR-ABL1 fusion The Philadelphia chromosome (Ph) was first recognized as a small chromosome present in two patients with CML by Nowell and Hungerford in 1960, and then shown by Janet Rowley in 1973 to be the reciprocal translocation t(9;22)(q34;q11.2). (1,2) In the early 1980s, molecular investigations revealed that the chromosome 9 gene involved in this translocation was ABL1, (3) the human homologue of the Abelson murine leukemia virus, and that chromosome 22 genomic breakpoints were clustered within a region of 5.8 kilobases (kb) in what was subsequently called the Breakpoint Cluster Region gene (BCR). (4) Subsequent studies showed that the t(9;22) created chimeric BCR-ABL1 transcripts that encoded for a fusion protein of 210 kD that had tyrosine kinase activity. (5) Transgenic mice that expressed BCR-ABL1 were generated and shown to have a myeloproliferative disorder similar to human CML. (6, 7) Critically, parallel studies established that the transforming potential of BCR-ABL1 was entirely dependent on an intact kinase domain. (8) Development of imatinib and early testing in CML Taken together, these observations suggested that agents that inhibited the tyrosine kinase activity of BCR-ABL1 might have therapeutic potential for CML. Brian Druker teamed with scientists at Ciba-Geigy (now Novartis) who were screening compounds to identify TKI. This collaboration eventually led to identification of STI571 (imatinib mesylate), which was found to be a potent and specific inhibitor of BCR-ABL1 that could kill CML cells in vitro. (9) A phase I dose escalation study of imatinib in patients with CML refractory to other therapies was begun in 1998. (10) Toxicity was mild in comparison to standard cytotoxic drugs and a maximally tolerated dose (MTD) was not identified when doses of up to 1000 mg/day were tested. The results of this trial were remarkable, with 98% (53/54) of patients with CML in chronic phase (CP) that were resistant/intolerant to interferon attaining a complete hematological response (CHR) when treated with at least 300 mg/day imatinib and 60% had a decrease of Ph+ metaphases to less than 35%. (10) This and other studies led to FDA approval of imatinib for the treatment of CML in 2000, and randomized trials showed imatinib to be the best available first line therapy for patients with CML-CP. (11)