CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
A little more than 3 years ago, a new drug, then called STI571, burst on to the medical scene, almost overnight establishing a new paradigm for the treatment of chronic myelogenous leukemia. This agent, subsequently named imatinib, proved to be a relatively selective inhibitor of the tyrosine kinase activity of Bcr-Abl. The discovery that most patients with chronic-phase chronic myelogenous leukemia (CML) achieved cytogenetic responses to imatinib was hugely important as a therapeutic advance.1 Additionally, the finding that inhibiting this one enzyme produced such profound responses confirmed the central importance of Bcr-Abl in producing the malignant phenotype. Not only were responses seen in patients with chronic-phase disease, but (to a lesser degree) patients with accelerated and even blastic-phase disease could achieve transient, clinically important responses.2 Curiously, in the studies of imatinib to treat blastic CML it was noted that myeloid blast crisis was somewhat more sensitive than lymphoid blast crisis, a surprising result given that, historically, patients with lymphoid disease had a slightly more favorable prognosis.
What then of the other Bcr-Abl leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)? This disease has traditionally been notoriously difficult to cure and has typically required the most aggressive available therapy (systemic multi-agent chemotherapy to induce a complete remission [CR] followed by allogeneic stem cell transplantation). In this patient population, imatinib has demonstrable activity, but compared with the chronic phase of CML, the single-agent activity in Ph+ ALL is disappointing, with responses seen in less than a third of patients and time to progression typically only 2 to 3 months.3
In this issue, Thomas and colleagues (page 4396) report on treating Ph+ ALL patients with imatinib combined with a standard ALL regimen, hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone). Though the number of patients treated was small (only 11 patients received this as their initial therapy), the comparison to a historic control group treated with hyper-CVAD alone appears promising. The authors treated an additional 9 patients who had previously received hyper-CVAD or other standard induction therapy without imatinib. Five of these patients were in CR when they enrolled in this study, and 4 entered with disease refractory to their initial induction regimen. All 4 patients who failed one cycle of standard induction therapy achieved CR when given combined imatinib-hyper-CVAD therapy.
The results of this trial are encouraging, but they must still be viewed as preliminary. The small number of patients treated, along with the relatively short follow-up (maximum 24 months) and the fact that most (7/11) of the de novo patients underwent stem cell transplantation in first CR, limits our ability to draw definite conclusions about the long-term efficacy of this regimen. Further study of this approach and other combinations of imatinib and chemotherapy will be required to assess the best way to incorporate imatinib into the treatment of patients with Ph+ ALL, and, until greater experience accumulates, it appears premature to abandon the use of allogeneic stem cell transplantation in first CR for these patients.
