In CML, BCR-ABL monitoring takes on new importance

Anne Paxton

March 2020—Three decades ago, when Jerald Radich, MD, started doing BCR-ABL testing, the process was highly hands-on. In those days, “we used water baths to do PCR,” said Dr. Radich, an oncologist and director of the molecular oncology lab and member of the Clinical Research Division, Fred Hutchinson Cancer Research Center, in a recent CAP TODAY webinar.

BCR-ABL testing is much simplified and faster today. But more important, it is central to the strikingly successful diagnosis, treatment, and monitoring of chronic myeloid leukemia. Dr. Radich views the use of BCR-ABL for CML treatment and monitoring as “the poster child of what molecular medicine should really be about.”

CML patients treated in North America or Europe now have an average lifespan roughly the same as that of the normal population, he said, and thus “there has been a continued rise in the numbers of cases in the U.S.”

“We may only have roughly 5,000 cases a year in the U.S., but they’re now going to be living long lives.” That’s why understanding monitoring is going to become more and more important, he said. “As we get more patients, if we aren’t monitoring carefully, we are going to have failures go on to accelerated phase/blast crisis. And that would basically eliminate all of the progress we’ve made to date in getting people to a point of good response and potential discontinuation of the drug.”

With an incidence of roughly two per 100,000, CML is no public health menace, Dr. Radich said. But it has played a crucial role in translational research. “It really has taught us more about the bench to bedside than any other disease. It was the first disease where a specific genetic abnormality was found, the Philadelphia chromosome. It was the first molecular lesion where the genes involved in the translocation were discovered. It was the first disease where we could use that breakpoint as a way to monitor disease burden in patients.” And it was the first disease, he said, for which a targeted therapy to a chimeric tyrosine kinase was established, first with imatinib and then with other tyrosine kinase inhibitors.

The introduction of tyrosine kinases and targeted therapy marked a turning point, he noted. Before that, when patients would typically pre­sent in a chronic phase, without definitive therapy they would invariably progress to accelerated phase/blast crisis. Their median survival was roughly six years.

Targeted therapy with imatinib brought dramatic improvement. “There was an unbelievable change in outcomes in just a matter of a few years,” Dr. Radich said in the webinar, made possible by a special educational grant from Cepheid. Before imatinib, “we saw 70 percent of patients go into blast crisis in 10 years with various therapies.” Now, evolution of blast crisis is rare. “It’s really a heroic story of progression.”

Four FDA-approved front-line drugs and several second-line therapies are now available to treat CML. Clinical trials of the second-generation drugs nilotinib, dasatinib, and bosutinib show they all have a similar major molecular response (defined as a 3-log reduction in the BCR-ABL with therapy from time of diagnosis) and do it a little better than the first-generation drug, with better early response and fewer progressions. But all the drugs produce excellent survival rates, Dr. Radich noted.

Only about 60 percent of patients on imatinib therapy are still on it at five years, owing to a combination of poor early response in 10 to 20 percent of patients, toxicity, and resistance. The field has known since the 2003 IRIS trial (O’Brien SG, et al. N Engl J Med. 2003;348[11]:994–1004), which compared imatinib with interferon treatment, that monitoring molecular response with BCR-ABL from peripheral blood, not bone marrow, “pretty much predicts your long-term results,” Dr. Radich said.

Patients who have a BCR-ABL on the International Scale of less than or equal to one percent have excellent results, he said, while those with higher BCR-ABL are more likely to have an adverse event. As far as treatment of those with a BCR-ABL IS percent greater than 10 percent at the end of 12 months, “you have to think about plan B. This was our first indication that BCR-ABL monitoring with peripheral blood was going to make a difference in defining disease burden and predicting outcomes.”

Later studies have found that early response can indicate how patients will fare, he said. Patients who do worse at three months (>10 percent) have a dramatically lower probability of survival than those who have a better response at three months. So “even earlier monitoring can give us interesting and actionable information on how to treat patients.” A 2010 study found that patients who were above 10 percent at three months were likely to progress to accelerated phase/blast crisis (Hughes TP, et al. Blood. 2010;116[19]: 3758–3765).

However, an early suboptimal BCR-ABL level may occur for two reasons: bad biology or poor adherence to therapy. If bad biology is the culprit, “we have to consider changing therapy because of the risks involved with poor early molecular response,” including a greater than 10 percent risk of transformation, a greater than 10 percent risk of death due to transformation, and a greater than 90 percent risk of failing to achieve MR4.5 (a deep molecular response).

But resistance happens not infrequently, Dr. Radich said, often because of mutations in the ABL tyrosine kinase domain. People with such mutations have a lower probability of progression-free survival compared with those who don’t have the mutations. Before the second-generation drugs, patients who developed resistance progressed quickly to accelerated phase or blast phase CML. Now there is the option of salvage therapy, though it may not be curative. If a patient on imatinib had a mutation, for example, “you would want to change to dasatinib or bosutinib or nilotinib, based on the specific mutation.” After switching therapy, careful monitoring is warranted. “These patients especially need to be monitored carefully because if they don’t respond molecularly, they again have a higher risk of progression.” If they haven’t shown a response by PCR or cytogenetics at the end of three months, “at that time we move to a transplant.”

The National Comprehensive Cancer Network and the European LeukemiaNet have developed guidelines on monitoring and changes in therapies based on the response. “These are fairly easy guidelines, based now on PCR testing with peripheral blood.” They call for BCR-ABL testing every three months, so the average patient would have three or four tests per year. However, studies have shown that the medical community is falling short in following guidelines.

In a survey of 5,446 patients reported at ASCO in 2014, the annual testing rates were one test or fewer per year for more than 60 percent of those patients, which Dr. Radich called “spectacular underperformance.” A second survey of 40,000 patients looked at how often BCR-ABL mutations were tested for based on the NCCN guidelines, which say if you have two BCR-ABL tests three months apart and have a 1-log increase in level, you should get a BCR-ABL mutation test. Less than 10 percent with a rising BCR-ABL level were tested for mutations. In a third survey of 100 community oncologists, all said they believe the guidelines and that they follow them faithfully.

“So there seems to be a disconnect between what is out there as far as monitoring guidelines and what is actually done,” Dr. Radich said, suggesting that better communication with the medical community about the importance of these tests may be needed.

A study of people in two administrative health facilities, which looked at how adding BCR-ABL tests changed inpatient admissions, inpatient days, and ER visits, found that for every one extra test after a one-test year (so one to two tests a year), there was a large reduction in inpatient admissions and days and ER visits, he said (Latremouille-Viau D, et al. J Manag Care Spec Pharm. 2017;23[2]:214–224). “The testing does make a difference in patient care.”