Relapse of CML after stopping tyrosine kinase inhibitor therapy – a review

This study reviewed evidence on relapsing after discontinuing TKI therapy for chronic myeloid leukemia (CML).

Major molecular response (MMR) is a response to treatment where hardly any genetic abnormalities can be found in the bone marrow. Treatment-free remission (sustained MMR) is often considered the main goal of CML treatment.

Many patients achieve this treatment goal with tyrosine kinase inhibitor (TKI) therapy, such as imatinib (Gleevec). TKIs are a type of targeted therapy that block enzymes called tyrosine kinases. However, many CML patients often have to continue TKI treatment throughout their lives. Many patients relapse once TKI therapy is stopped. Only about half of CML patients who achieve MMR may successfully stop therapy.

This study reviewed issues related to stopping TKI therapy, and how to treat patients who relapse.

Patients should be closely monitored after stopping TKI therapy with regular blood tests. A loss of MMR (molecular relapse) often occurs soon after discontinuation. 95% of molecular relapses occur within 6 to 12 months. It is recommended to carry out frequent blood tests during this period (every 4 to 6 weeks). After 12 months, blood tests should be carried out every 3 months.

While uncommon, it should be noted that relapses can also occur very late. Some relapses after over 5 years after stopping therapy have been reported. Long-term monitoring is therefore advisable during the treatment-free phase.

Patients experiencing relapse are generally restarted on the same TKI as the one used before treatment discontinuation. If the TKI caused unwanted side effects, another TKI can be tried. Most patients show good treatment response and regain MMR after restarting TKI therapy. Studies have reported that MMR was regained after as little as 2 to 3 months.

A long delay between relapse and restarting TKI therapy increases the risk of the treatment not working. This is because patients can develop a resistance (no longer respond to) standard TKI therapy over time. It is recommended that patients resume TKI therapy no later than 1 month after molecular relapse. Blood tests should monitor whether MMR has been regained every 3 months and then every 3 to 6 months. If a patient has developed a resistance to a TKI therapy, patients may be given a different TKI.

One study examined whether a second discontinuation attempt can be successful. The probability to remain treatment-free in MMR after the second stop was 35% at 36 months. More studies are needed to examine factors important in second discontinuation attempts. The type of TKI may play an important role.

This study reviewed current evidence on patients relapsing after TKI discontinuation. Whether therapy should be continued lifelong or whether a second discontinuation attempt is advisable is still under investigation.