Management of Patients With Resistant or Refractory Chronic Myelogenous Leukemia

In the absence of effective therapy, patients with chronic-phase chronic myeloid leukemia (CML) invariably progress to a more aggressive phase of the disease termed blastic phase, typically preceded by an accelerated phase of variable duration.[1] The hallmark of the accelerated phase and particularly of the blastic phase is an unregulated overproduction of cells of myeloid origin with an increasing representation of immature forms as the disease progresses. Thus, patients in blastic phase present with a peripheral blood or bone marrow blast percentage of 30% or higher.[1] The estimated risk of transformation to the blastic phase is 5% to 10% per year during the first 2 years after diagnosis and increases to up to 20%–25% per year thereafter.[1,2] Blastic-phase CML is usually resistant to standard chemotherapeutic agents. Prior to the introduction of targeted tyrosine kinase inhibitors (TKIs) for the treatment of CML, the median survival of patients in blastic phase was less than 6 months.

The hallmark genetic abnormality in CML is the balanced translocation t(9;22)(q34;q11.2), which results in the Philadelphia chromosome (Ph). The molecular surrogate of the Ph chromosome is the BCR-ABL hybrid oncogene,[3,4] which encodes for BCR-ABL, a tyrosine kinase with deregulated activity that has been shown to be both necessary and sufficient for the initiation and maintenance of CML.[5]

The addition of imatinib mesylate (Gleevec) to the therapeutic armamentarium for CML has dramatically changed the management and prognostic outlook of patients with this disease. Imatinib is a phenylamino pyrimidine TKI that specifically targets BCR-ABL, KIT, and platelet-derived growth factor receptor (PDGFR) kinases, has proven to be highly active and safe in patients with CML, and has become standard frontline therapy for patients with this disorder. Despite the outstanding results achieved with imatinib, approximately 20% to 30% of patients may either not respond to therapy or eventually develop resistance or intolerance to the drug. The occurrence of BCR-ABL kinase point mutations is the most frequently identified mechanism responsible for resistance to imatinib and other TKIs. In smaller subsets of patients, other mechanisms have been identified as responsible for imatinib resistance.

Clinical Resistance to Imatinib

Definitions

Resistance to imatinib therapy can be segregated into primary (or intrinsic), in which patients exhibit lack of efficacy to TKIs from the onset of therapy, and secondary (or acquired), in which patients experience an initial response to imatinib followed by loss of response after a period of time of variable length. Resistance can be further subdivided into hematologic (lack of normalization of peripheral blood counts), cytogenetic (persistence of Ph chromosome), and molecular resistance (persistence of BCR-ABL transcripts by reverse transcriptase polymerase chain reaction).



In 2006, on behalf of the European LeukemiaNet, a panel of experts put forth a set of recommendations for the definition of resistance to imatinib that has now become standard. According to this definition, the lack of achievement of a predefined level of response at specific temporal milestones or the loss of hematologic or cytogenetic response at any time defines imatinib failure (Table 1).[6] Patients who meet these definitions of failure to imatinib have an inferior outcome that mirrors that of patients in the pre-imatinib era.[7] Recognizing the importance of the time to achieve the therapeutic goals, this panel also included a group of patients who were defined as having a suboptimal response. These represent patients who cannot be considered to have failed therapy, but whose prognosis has been shown to be less favorable than that of patients with optimal response at the corresponding time points.

In addition, the panel issued a series of therapeutic recommendations for the management of patients who fail imatinib therapy. Although the definitions of imatinib failure provide a useful framework that facilitates the management of patients with CML, the proposals concerning therapeutic intervention have evolved significantly since the time of the issuance of the guidelines, particularly with the emergence of more data regarding the efficacy and safety of second-generation TKIs.