What is the role of TKIs in the treatment of chronic myelogenous leukemia (CML)?

Updated: Oct 23, 2019
  • Author: Rossa Khalaf, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Answer

Tyrosine kinase inhibitors (TKIs) are the drugs of choice for initial therapy of CML. [1] Imatinib was the first oral TKI approved for treatment of CML, in May 2001. Subsequently, second- and third-generation of TKIs (eg, dasatinib, nilotinib) were approved for first-line therapy. [2, 3]  

Treatment with TKIs significantly decreases the mortality rate in patients with CML. A study by Tang et al determined that long-term TKI therapy may reduce the abundance of leukemic stem cells in select patients. [4] A study by Gugliotta et al that examined the use of imatinib in patients aged 65 years or older found that the response to imatinib was not affected by age. [5]

In the IRIS (International Randomized Study of Interferon and STI571) study, imatinib produced a higher rate of complete cytogenetic response (CCyR) and major cytogenetic response (MCyR) compared with interferon alpha and cytarabinenal. [6] Additionally, a follow-up study showed significant improvement in 8-year event survival, freedom from progression to accelerated phase or blast phase, and overall survival. [7]

Several studies have evaluated the efficacy and safety of higher doses of imatinib (800 mg) in newly diagnosed CP-CML [7, 8, 9] In the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study, patients who had fewer treatment interruptions and who received higher imatinib doses had higher and faster response rates in the first year of treatment, but by 42 months the high- and low-dose arms showed similar rates of major molecular response (MMR) and no differences in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS). The authors concluded that adherence to the prescribed dose without interruption may be more important than starting therapy with higher doses. [9]

The CML-IV and SWOG 0325 studies reported higher rates of MMR with 800 mg of imatinib at 12 months; however, the higher dose was not associated with lower rate of progression to an advanced stage of CML. Also, grade III and IV adverse events and higher rates of interruptions, dose reduction, and even discontinuation were noted. [10]

The second-generation TKIs have shown superior efficacy and higher rates of CCyR and MMR when compared with imatinib. Lower rates of transformation to advanced phase were also seen. [2, 3]

In the DASISION (DASatinib versus Imatinib Study In treatment-Naive CML patients) trial, final 5-year analysis showed significantly higher MMR and molecular response with ≥4.5 log reduction of BCR-ABL on the International Scale (MR4.5) in patients with newly diagnosed CP-CML who received dasatinib, 100 mg once daily (n = 259), than in those who received imatinib, 400 mg once daily (n = 260). However, the estimated 5-year PFS and OS were similar in both groups. [2]

In the ENESTnd trial, which compared nilotinib with imatinib in patients with newly diagnosed CP-CML, by 5 years, more than half of all patients in the nilotinib arm achieved an MR(4.5) compared with less than a third of patients in the imatinib arm. In addition, patients receiving nilotinib demonstrated a lower rate of progression to the accelerated or blast stage of CML. Also in this study, the 5-year OS and PFS were similar in both groups. [3]

In patients who receive first-line therapy with TKIs, the rate of decline in BCR-ABL1 transcripts correlates with long-term response. [11, 12] The IRIS investigators reported that patients with BCR-ABL transcripts of >10% at 6 months and >1% at 12 months had inferior EFS and higher rate of progression to accelerated- or blast-phase CML, while those with an MMR (BCR-ABL1 ≤ 0.1%) by 18 months had no progression to advanced disease and 95% EFS at 7 years. Early cytogenetic response or molecular response to second-line and subsequent TKI therapy have also been found to be good predictors of OS and PFS. [13, 14, 15]


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