Molecular Diagnostics in CML Illustrate Ways to Enhance Well-Established Strategies

Maurie Markman, MD
Published: Friday, Jan 30, 2015
Maurie Markman, MD

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology

Cancer Treatment Centers of America, Eastern Regional Medical Center

Although there clearly are a number of worthy candidates for the single most influential event that unequivocally proclaimed the beginning of the modern era of precision cancer medicine, there would surely be many votes for the impact of imatinib on the course of the natural history of chronic myeloid leukemia (CML).1,2

The observation that this generally reasonably well-tolerated oral agent, targeted to the BCR-ABL tyrosine kinase, could substantially improve survival in this malignancy and make it a truly chronic condition helped revolutionize both the general paradigms for cancer drug development and the management of this malignant disease.

Another critical component strongly associated with this spectacular success story regarding the transformation of the survival outlook for CML has been the rapidly evolving ability to regularly analyze the effects of therapy at the molecular level.

Further, it has become possible to predict the future short- and longer-term course of the illness in individual patients based on the presence or absence of unique molecular abnormalities found in the blood or bone marrow. The commonly utilized strategy (real-time quantitative polymerase chain reaction) is able to detect the present of BCR-ABL1 with a remarkable sensitivity of at least 4.5 logs.

Clinical Relevance of Molecular Monitoring

In fact, such monitoring efforts have clearly demonstrated that, despite a highly clinically favorable response to imatinib, more than 50% of patients treated for longer than 5 years who remain in a clinical remission can be shown to persist in having cells with molecularly detectable abnormalities.3

This finding is of substantial clinical relevance for several reasons. First, it indicates that despite this number of years of effective therapy without clinical evidence of disease, the malignancy has not been cured. And second, it is realistically difficult to consider discontinuation of a reasonably well-tolerated therapy when it is known that persistent cancer is present.

However, the ability to monitor patients employing a molecular marker with such exquisite sensitivity permits an objectively rigorous exploration of alternative treatment strategies that have the potential to further optimize management of a cancer whose course has already been rather dramatically favorably altered.

A poignant example of the utility of molecular diagnostic testing is provided by a recent report describing an attempt to improve the negative BCR-ABL1 detection rate in CML patients with persistent abnormal findings following successful treatment with imatinib.3 Patients with CML treated with (and tolerating) imatinib for a minimum of 2 years and who had persistent molecular abnormalities were randomized to continuation of treatment with this agent or switched to nilotinib (a known effective alternative inhibitor of BCR-ABL1).

Not surprisingly, since one eligibility criteria for entry into this study was tolerability to imatinib therapy, there were more adverse events reported in the nilotinib treatment arm.3 However, at 1 or 2 years following initiation of disease management on this trial, the percentage of patients without any detectable molecular abnormalities (achieving a “deep molecular response”) was 12.5% versus 5.8% (P = .108) and 22.1% versus 8.7% (P = .0087) in the nilotinib versus imatinib treatment arms, respectively.

This near-tripling of the percentage of patients achieving the desired molecular state following the switch to nilotinib is clearly a clinically relevant finding. Of further interest, no patient who switched to nilotinib and achieved a deep molecular response reverted in subsequent follow-up testing to demonstrate the presence of molecular abnormalities.

These data raise the provocative issue of whether the next step in management of a patient in this setting might be the discontinuation of therapy after a period of time to determine whether the malignancy has actually been cured, or whether a state of long-term remission (measured in “many years”) is possible without active treatment.

Broader Implications

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