The ABL tyrosine kinase inhibitor STI571 (Glivec) in Philadelphia positive acute lymphoblastic leukemia - promises, pitfalls and possibilities.

Selective targeting of neoplastic cells has long been an intriguing concept for treatment of malignant diseases, although its realization has proven elusive. Current therapy of malignant diseases thus still relies largely on cytotoxic drugs that may be potent but are quite nonspeci®c in their mechanisms of action. As a result, toxicity is frequent and clinical ecacy more often than not is limited. The recent clinical development of STI571, now also known as imatinib mesylate or Glivec, a signal transduction inhibitor which preferentially inhibits the tyrosine kinase (TK) activity of the ABL protooncogene, of c-kit and of the PDGF receptor, may therefore well be considered a breakthrough. It is an example of a rationally designed drug which, by successive chemical modi®cations of a promising lead compound resulted in a small, stable molecule that can be given orally and possesses selective activity against a small number of tyrosine kinases, the ABL TK having so far attracted the most attention. Conceptually, BCR-ABL positive leukemias are ideal models for molecularly targeted therapy, as the BCR-ABL translocation characteristic of these diseases is causally involved in leukemogenesis and ± more importantly ± is considered to be both sucient and essential for leukemic transformation. The pathophysiology of BCR-ABL positive leukemias and the rationale for treatment with STI571 have been reviewed extensively elsewhere. 6 The signi®cant hematologic and cytogenetic responses of patients with chronic phase CML to STI571 are in agreement with these theoretical premises and are responsible for the widespread attention this novel treatment modality has received. The results of the ®rst phase I study of STI571 which was initiated in 1998 and of subsequent phase II studies provided compelling evidence of the clinical ecacy of STI571 in CML, particularly in the chronic phase, leading in record time to FDA approval of the drug in May 2001. In Philadelphia chromosome (Ph) positive ALL, as in CML, the BCR-ABL translocation is considered the main transforming event, making it the second major hematologic malignancy known to be targeted by STI571. Ph/BCR-ABL+ ALL is a highly aggressive leukemia; it has the worst prognosis of all subsets of ALL, with overall survival rates of approximately 10 ± 15% and a median remission duration of less than six months when treated with chemotherapy. ± 9 The BCRABL translocation is the most frequent cytogenetic abnormality in adult ALL patients, with an incidence of 20 ± 30% of all cases but occurring exclusively in the subset of B-precursor ALL (c-ALL, pre-B-ALL). The speed of clinical progression of PhALL and its association with older age contribute to the fact that fewer than 30% of patients are able to undergo allogeneic transplantation (alloSCT). While this is the only potentially curative treatment, it retains a high risk of relapse and is additionally associated with substantial treatment related mortality. The need to improve current therapy is obvious. What is the role of STI571 in the treatment of advanced PhALL? In a recently published phase I study, 14 of 20 patients (70%) with lymphoid blast crisis or PhALL responded to treatment with STI571 at doses of 300 to 1000 mg, and four patients achieved a complete remission. The response duration was short, however, as 12 of 14 patients with LyBC relapsed after a median treatment duration of approximately two months. One patient underwent an allogeneic stem cell transplantation and another with extramedullary leukemia remained in a prolonged CR after eight months of treatment with STI571. *Correspondence: OG Ottmann, Medizinische Klinik III, Abteilung fuÈ r HaÈ matologie und Onkologie, Johann Wolfgang GoetheUniversitaÈ t, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany Tel: +49 69 6301 6365; Fax; +49 69 6301 7463; E-mail: [email protected] Received 18 October 2001; accepted 23 November 2001 The Hematology Journal (2002) 3, 2 ± 6 ã 2002 The European Haematology Association All rights reserved 1466 ± 4680/02 $25.00