Treatment of Chronic Phase CML: A Decade of Progress

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Treatment of Chronic Phase CML: A Decade of Progress
Treatment of Chronic Phase CML: A Decade of Progress

Introduction

Chronic myelogenous leukemia (CML) is a myeloproliferative stem cell disease characterized by a shortened form of chromosome 22, known as the Philadelphia (Ph) chromosome, that results from a reciprocal translocation between chromosomes 9 and 22.1 The resulting BCR-ABL fusion gene encodes the bcr-abl protein  (also called p210), which is crucial to the development of CML.1 Nine of 10 patients are diagnosed in the earliest stage of CML, dubbed the “chronic phase” (hereafter, CML refers to chronic phase disease).2 Most of the genetic changes in CML progression occur in the transition between chronic and accelerated phases, making prevention of progression a key treatment goal.1

The identification of BCR-ABL presented an attractive target for development of tyrosine kinase inhibitors (TKIs), starting with imatinib.3 The discovery and clinical development of imatinib, first approved in 2001, revolutionized CML treatment.1 Today, the vast majority of the more than 5,000 Americans newly diagnosed annually with CML can expect to respond to oral TKI therapy and continue to live productive lives.1

Imatinib therapy validated the principle that TK inhibition of the bcr-abl protein substantially reduced progression of CML. As the standard of care, imatinib has demonstrated powerful and durable responses, with 8-year overall survival and event-free survival rates of 85% and 81%, respectively, from the landmark IRIS study in newly diagnosed CML.1,4 Long-term follow-up of patients from IRIS reveals that most progression events occur within a few years of diagnosis, with progressively diminishing risk over time in TKI-treated patients.4

Within 5 years of imatinib's arrival on the scene, two second-generation TKIs were being evaluated in clinical trials. Dasatinib and nilotinib gained another indication for treatment of newly diagnosed CML patients after their original FDA approvals as second-line therapy options. Another TKI, bosutinib, was approved in September 2012 for treatment of CML in patients resistant to or intolerant of other TKI therapy.1,5

Monitoring Response

With the advent of TKIs and widely available kits for quantitative measurement of BCR-ABL using reverse transcription polymerase chain reaction (RT-PCR, current guidelines from the National Comprehensive Cancer Network (NCCN) include cytogenetic and molecular response milestones (Table 1) for assessing patients' response to therapy.1

 Table 1. NCCN Response Criteria for Newly Diagnosed CML-CP Treated With TKIs1
Time (Months)
Optimal Response: Maintain Current Therapy
Failure: Consider Change in Therapy
3 BCR-ABL ≤10% (IS) or PCyR BCR-ABL ≥10% (IS) or <PCyR
12 CCyR <CCyR or cytogenetic relapse
18 CCyR PCyR* or cytogenetic relapse

Key: CCyR: complete cytogenetic response; CML-CP: CML in chronic phase; IS: International Scale; PCyR: partial cytogenetic response.
CCyR=0% Ph+ metaphases in bone marrow aspirate. PCyR=1%–35% of cells have Ph+ metaphases.

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