Emerging Strategies in the Management of Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a relatively rare disease, but its impact on the study and treatment of hematologic malignancies has been huge. The characteristic Philadelphia chromosome, the reciprocal translocation of bcr gene on chromosome 22 with the tyrosine kinase inhibitor (TKI) Abl from chromosome 9, has served as the target of understanding the genetics of leukemia transformation, molecular monitoring, and now, “targeted” therapy with the TKI. In the not-so-distant past, the only effective therapies for CML involved “immunotherapy,” either by interferon (IFN), which produced complete cytogenetic remission (CCyR) and increased survival in only a minority of cases, and stem cell transplantation, a procedure that trades good long-term outcomes for high short-term morbidity and mortality. The TKI imatinib revolutionized the treatment of CML. Imatinib is remarkably effective for patients treated in chronic phase because > 75% of patients exhibit a CCyR with 5-year survival > 90%. However, the response is relatively poor for patients in advanced phases of the disease. Although a small proportion of patients in chronic phase do not respond to therapy or experience relapse into chronic phase or progression on therapy, resistance is not futile in CML. Such resistance and relapse is unfortunately much more common in advanced phase disease. The challenges now are how to integrate new TKIs, molecular disease monitoring, and immunotherapy into a total package of therapy. This issue of Clinical Lymphoma & Myeloma addresses where we are in the therapy of CML and where we are heading. The article by Jabbour et al describes the current state of imatinib results. Results from the IRIS trial, now taken to 5 years of follow-up, reveal that 87% of chronic phase cases will achieve a CCyR. However, it should be noted that these are cumulative incidence figures and thus count all patients who had obtained a CCyR, even if it was very short. Approximately 70% of patients enrolled on the study are still on imatinib and in CCyR. The overall event-free survival is 83%, with only 6% of patients progressing to advanced-stage disease. Clearly, for newly diagnosed chronic phase CML, imatinib has set the bar quite high. The vast majority of patients in CCyR still have molecular evidence of disease if tested with sensitive polymerase chain reaction–based assays. Oehler et al review the rationale and clinical implications of monitoring patients on TKI therapy. In the IRIS trial, progressionfree survival was associated with the degree of cytogenetic and molecular response; thus, patients who enjoyed a CCyR and had a > 3-log reduction of the bcr-abl chimeric messenger RNA had a progression-free survival of 97%. In fact, the current Intergroup trial of CML uses the 12-month molecular response as the endpoint of the trial, a revolutionary use of the power of molecular monitoring. Moreover, careful molecular monitoring is useful in predicting which patients will experience relapse, especially those likely to have mutations in the Abl tyrosine kinase domains. This is especially important because patients who experience relapse with Abl point mutations can experience rapid progression to advanced-stage disease, especially those with the dreaded T315I mutation, which are resistant to imatinib as well as the next generation of TKIs. Before imatinib, IFN and transplantation were the most common treatment approaches in CML. Guillot et al review past experiences and future strategies for these and other immunologic approaches. Certainly, now, IFN has limited use as a solo first-line agent; transplantation, though it might bring long-term survival to > 80% of patients in chronic phase, has similarly been delegated to cases in which primary TKI therapy has failed. However, investigators are pursuing new ways of using IFN in concert with imatinib as first-line therapy or along with donor leukocyte infusions for patients who experience relapse after transplantation. New uses of immunotherapy include cellular therapy directed at antigens upregulated in CML (WT1 or PR3) or as multivalent vaccines that might be used in the future to eliminate residual cells left behind by TKIs.