Chronic myelogenous leukemia (CML) is caused by the constitutively active BCR-ABL fusion protein that results from t(9;22), the Philadelphia (Ph+) chromosome. Chronic myelogenous leukemia typically evolves through 3 clinical phases: an indolent chronic phase, an accelerated phase, and a terminal blast phase analogous to acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Fortunately, today more than 80% of patients are diagnosed in the chronic phase of the disease.1
Before the development of the tyrosine kinase inhibitor (TKI) imatinib, > 20% of the patients with chronic phase CML progressed to the blast phase every year.2 Based on data from 8 years of follow-up with imatinib therapy, the rate of progression to the advanced phases of CML is about 1% per year, with freedom from progression at 92%.3 For the majority of patients with chronic phase CML, due to advances in treatment, the disease does not affect mortality.
For those who progress to the terminal blast phase of CML, survival is typically measured in months unless allogeneic stem cell transplant (allo-SCT) is an option. This article will review one of the major remaining problems in CML: how to manage blast phase CML.
Definition and Diagnosis
Defining blast phase CML can be confusing, because different criteria have been proposed, none of which are biologically based. The most widely used definition is set forth by the European LeukemiaNet, recommending 30% blasts in the blood or bone marrow or the presence of extramedullary disease.1 Clinically, blast phase CML may present with constitutional symptoms, bone pain, or symptoms related to cytopenias (fatigue, dyspnea, bleeding, infections).
Diagnostic workup should include a complete blood cell count (CBC) with differential, bone marrow analysis with conventional cytogenetics, flow cytometry to determine whether the blast phase is of myeloid or lymphoid origin, and molecular mutational analysis of the BCR-ABL tyrosine kinase domain to help guide the choice of TKI. If age and performance status are favorable, a donor search for allo-SCT should be started promptly.
Chronic myelogenous leukemia cells that contain the BCR-ABL kinase protein are genetically unstable.4,5 Additional cytogenetic aberrations (ACAs) are seen in up to 80% of those with blast phase CML and are the most consistent predictor of blast transformation in those with chronic phase CML.6 Chromosomal changes are broken down into the nonrandom, “major route” ACAs (trisomy 8, additional Ph+ chromosome, isochromosome 17q, trisomy 19), considered likely to be involved in the evolution of CML, and the more random “minor route” ACAs, which may denote nothing more than the instability of the genome.5,7 Mutations of the BCR-ABL tyrosine kinase domain are also seen in the majority of those in blast phase CML and, depending on the specific mutation, can negatively predict the response to certain TKI therapies.4
Prognosis
The single most important prognostic indicator for patients with CML remains the length of response to initial BCR-ABL–specific TKI therapy. Only a very small minority of patients are refractory to TKIs from the beginning; these are the patients with the worst prognosis.8 If the response to treatment seems inadequate, then the health care professional should first verify with the patient that he or she is taking the medicine as prescribed.1 Lack of adherence continues to be the most common reason for less-than-ideal outcomes or fluctuations in response and plays a critical role in treatment with TKI therapy, with worse outcomes when < 90% of doses are taken.9
Other features associated with a poor prognosis include cytogenetic clonal evolution, > 50% blasts, and/or extramedullary disease.7,10,11 At the time of imatinib failure, detection of mutations of the BCR-ABL tyrosine kinase domain correlates to worse 4-year event-free survival.12 Showing the instability of the genome in CML, patients who harbor mutations of the BCR-ABL domain have a higher likelihood of relapse associated with further mutations and, therefore, potentially further TKI resistance.13 Once CML has progressed to the blast phase, life expectancy is, on average, less than a year.11
Treatment Strategy
Currently, the most effective treatment strategy in blast phase CML is to prevent the transformation from chronic phase from ever occurring. Management of blast phase CML depends on 2 factors: (1) previous therapies; and (2) type of blast phase—myeloid or lymphoid. The goal of treatment is to knock the disease back to a clinical remission and/or a chronic phase for a long enough period to get the patient to allo-SCT if age, performance status, and suitable donor allow for it.
Using single-agent imatinib for blast phase CML has been tried in patients who have never been on TKI therapy before. Hematologic responses were seen in the majority of patients, but any form of cytogenetic response was seen in fewer than 20% of patients. Median overall survival, although better than with previous conventional chemotherapies, was still measured in months.6 A patient with blast phase CML who has never been on BCR-ABL–specific TKIs is very rare now; at a minimum, the patient has usually tried at least 1 TKI previously.