Chronic Myeloid Leukemia: 5 Things to Know

Victoria Stern, MA


September 17, 2019

The prognosis for chronic myeloid leukemia (CML) has improved dramatically in recent years. A patient's life expectancy—which once hovered around 5 years post-diagnosis—now approaches that of the general population, thanks in large part to a handful of tyrosine kinase inhibitors (TKIs).[1] Still, these agents do not work for everyone. Approximately half of patients do not respond or become intolerant to their first-line TKI and require an alternative approach. Here are five things to know about treating CML.

1. TKIs do not cure CML.

Despite the success of TKIs, a cure for CML remains elusive. The ultimate goal is for patients to go off TKIs and stay in remission. But most patients need to continue drug therapy indefinitely to maintain a durable molecular response.

The BCR-ABL fusion oncogene, which encodes the BCR-ABL oncoprotein, is the molecular signature of CML. Although available TKIs effectively inhibit the kinase activity of BCR-ABL, the drugs do not eliminate leukemic stem cells.[2,3] In fact, research shows that the survival of these cells, which express BCR-ABL transcripts, is independent of BCR-ABL kinase activity.[4] In turn, the persistence of leukemic stem cells may fuel TKI resistance, promote relapse, or drive disease proliferation—all of which represent major roadblocks to a cure. Currently, researchers are exploring strategies to selectively target and wipe out these stem cells.[2]

2. Sustaining treatment-free remission poses a challenge.

A recent treatment goal for patients with CML is to stop TKIs for good. About 50% of patients who receive TKIs achieve a deep molecular response (BCR-ABL transcript level ≤ 0.01%, International Scale) and may be eligible to discontinue TKI therapy.[1] But a growing body of research shows that, of those patients, less than half—approximately 20%-25% overall—maintain treatment-free remission.[5,6,7]

Predicting which patients will remain in remission without TKIs is tricky. One key factor may be the duration of a patient's molecular response prior to stopping therapy. A 2019 analysis found that patients who had a durable molecular response for 6 years or longer before discontinuing their TKI had the lowest risk for relapse—7% versus 67% in patients with molecular responses for less than 6 years.[5] Patients with a low or intermediate Sokal risk score at diagnosis may also be more likely to maintain treatment-free remission.

Other potential relapse risks, however, are less clear-cut. The 2019 study[5] found, for instance, that the chance of relapse did not depend on whether patients had taken one TKI or had switched due to resistance or intolerance. However, a 2017 analysis reported that patients who had a poor response or resistance to a TKI faced an increased risk for relapse compared with those with intolerance to the TKI imatinib (Gleevec).[8]

Further research is needed to identify which patients are more likely to sustain treatment-free remission.[9] The upside is that almost all patients who relapse will regain their molecular response once they restart TKIs.[5]

Another bright spot for patients who relapse is that they could get a second shot at going off TKIs. Researchers are currently exploring whether a combination of a TKI and the JAK inhibitor ruxolitinib may allow patients to discontinue therapy even after an unsuccessful first attempt. In the phase 2 trial, patients with chronic-phase CML will receive the dual therapy for 12 treatment cycles (approximately 1 year). Those who meet the criteria for treatment-free remission will discontinue the drug regimen and be monitored closely over 36 months.


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