Changing Paradigm of the Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

In the pre-imatinib era, the treatment outcome of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) was dismal. Complete remission was generally achieved only in about 50% to 60% of patients, and allogeneic hematopoietic stem cell transplantation (allo-HSCT), when feasible in younger patients, was virtually the sole curative modality. Imatinib has changed the situation dramatically, however, in combination with conventional chemotherapy or with corticosteroid alone, producing about 95% complete remission and thus increasing the number of patients undergoing allo-HSCT. Currently, the overall survival of patients who have undergone allo-HSCT exceeds 50%, and a considerable proportion of patients for whom allo-HSCT is not feasible are predictably curable. The next question is how to prevent relapse, which is observed not only in more than half of patients for whom allo-HSCT is not feasible but also in a considerable number of patients after allo-HSCT. Thus, improvement of postremission therapy is crucial. Whether intensive chemotherapy with currently available cytotoxic drugs contributes to the prevention of relapse is questionable, because intensive chemotherapy alone in the preimatinib era nearly always failed to cure this disease. Promising partners to be combined with imatinib or with a second-generation tyrosine kinase inhibitor (TKI) will be corticosteroids and vincristine. New TKIs such as dasatinib should be incorporated into the early phase of postremission therapy. Recognizing the small number of patients with Ph+ ALL, intergroup or international studies are necessary to develop the best postremission therapy. In the near future, it is hoped that Ph+ ALL will become one of the leukemias for which allo-HSCT is offered only for relapsed or extremely high-risk patients.