clinical topic updates

Chronic Myeloid Leukemia: Advances in Molecular Monitoring

by Neil P. Shah, MD, PhD

Overview

The use of quantitative real-time polymerase chain reaction (qRT-PCR) to test for BCR-ABL1 transcript levels in chronic myeloid leukemia (CML) is the gold standard for monitoring treatment response in the era of tyrosine kinase inhibitors.

Expert Commentary

Neil P. Shah, MD, PhD

Edward S. Ageno Distinguished Professorship in Hematology/Oncology
Professor, Department of Medicine
Program Leader, Hematopoietic Malignancies Program
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, CA 

“With respect to deepening the sensitivity of these detection tests, the extent to which improved sensitivity might help predict who is likely to succeed with therapy discontinuation is unclear."

Neil P. Shah, MD, PhD

The sensitivity of tests for the detection of BCR-ABL in CML is invariably limited by the fact that we can sample only a certain amount of blood from a single patient. Therefore, we can never say with 100% certainty that there is no detectable CML in a living person. But with respect to deepening the sensitivity of these detection tests, the extent to which improved sensitivity might help predict who is likely to succeed with therapy discontinuation is unclear. Although clinical trials have demonstrated that therapy discontinuation is possible in some patients, improvements in detection may lead to increased rates of success.

It may be possible that those patients who are destined to lose response upon stopping treatment in a deep remission have a quantifiable level of disease that can be detected, below the limit of detection of qRT-PCR. Digital droplet techniques that offer 1 to 2 logs greater sensitivity may better identify patients who have lower levels of disease burden and in whom therapy discontinuation may be more likely to be successful. However, the risks associated with therapy discontinuation are so low when National Comprehensive Cancer Network guidelines are followed and with adequate monitoring. I therefore do not believe that techniques with improved sensitivity will substantially impact decision making in this scenario.

Interestingly, there is a proportion of patients who are able to successfully stop therapy despite having a low but detectable amount of BCR-ABL1 by qRT-PCR. In some cases, the transcript level rises but plateaus below the threshold of 0.1% above which reinstitution of therapy is indicated.

In terms of mutation detection, resistance-conferring mutations in the kinase domain may primarily suggest that a patient might benefit from an alternative therapy. This is not a common issue in chronic-phase CML, as loss of response and the development of new mutations are quite rare. Thus, I do not think that there is currently a pressing need in this population to identify patients more quickly than we normally would by monitoring their transcript levels. However, disease can relapse very quickly in patients with advanced-phase CML, particularly those with blast phase CML. If we wait for clinical relapse, the disease burden will be very high. In addition, it is likely that the disease may have acquired a dominant mutation that confers resistance to the current therapy by that time. Even if that mutation is sensitive to a next-generation drug such as ponatinib, there is concern that there may be a low-level clone that has acquired a compound mutation that would confer resistance to ponatinib and ultimately become dominant.

Some of the next-generation sequencing technologies offer encouragingly greater detection sensitivity. In my opinion, one of the drawbacks of the most commonly used next-generation sequencing technologies is the short read lengths that are obtained, as they do not allow for the determination of whether 2 different detected mutations are on the same strand of DNA and therefore in the same cell, as opposed to being in 2 different cells. This information can have important prognostic value, including helping to determine whether a patient may respond to an agent such as ponatinib.

References

Izzo B, Gottardi EM, Errichiello S, Daraio F, Baratè C, Galimberti S. Monitoring chronic myeloid leukemia: how molecular tools may drive therapeutic approaches. Front Oncol. 2019;9:833. doi:10.3389/fonc.2019.00833

Radich J, Yeung C, Wu D. New approaches to molecular monitoring in CML (and other diseases). Blood. 2019;134(19):1578-1584. doi:10.1182/blood.2019000838

Soverini S, Bassan R, Lion T. Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges. J Hematol Oncol. 2019;12(1):39. doi:10.1186/s13045-019-0729-2

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