Post-Study Paradigm Shift in CML Highlights Need for Accurate Molecular Monitoring

A retrospective study,¹published in October inClinical Lymphoma, Myeloma and Leukemia, claimed that a rarity of cytogenetic and molecular monitoring exists among patients with chronic myelogenous leukemia (CML) treated in a community setting; however, one researcher is challenging that claim.

The study found that only 24% of patients who received care through a community cancer network received both forms of diagnostic monitoring called for by guidelines, and only 60% of patients received a cytogenetic or a molecular response assessment every 3 months, as recommended by guidelines from the National Comprehensive Cancer Network²and the European Leukemia Network.³

The study, also found that second-generation tyrosine kinase inhibitors (TKIs) showed greater efficacy than first-generation TKIs in eliciting a genetic or molecular response in the newly-diagnosed, replicating findings in earlier clinical trials.

Treatment for CML has been in flux since TKIs were approved, starting with the licensure of imatinib in 2001. In 2010, dasatinib and nilotinib were approved as initial therapy of CML. Additionally, in 2011, it became possible to measure response of the disease to treatment using quantitative real-time polymerase chain reaction based on an international scale developed by experts.⁴Five-year survival has increased from 50% in 1999 to more than 95% today.

Drug Response in Community Setting Comparable to Clinical Trials

In the retrospective study, CA180-508, researchers conducted a review of electronic health record (EHR) data from 300 patients over 18 years of age with newly diagnosed CML. Of these patients, 222 were treated with imatinib, 34 with dasatinib, and 44 with nilotinib.

The patients received care at McKesson Specialty Health/US Oncology Network sites between July 2007 and March 2011. “Patients were followed for 18 months from the date of enrollment, and data [were] collected as of September 30, 2012,” the article said.

“It’s very encouraging that we’re seeing in the community the same results as in major academic clinical trials, because one of the critiques is that when you do a clinical trial for novel agents, the results are not going to be what happens in the community,” said Eunice S. Wang, MD, associate professor of oncology at Roswell Park Cancer Institute in Buffalo, who was not involved in the study.

However, monitoring in the community setting fell short of that recommended by the guidelines. Only 37% of patients received cytogenetic monitoring and 47% had molecular assessments at any time during the study. Only 23% of patients had molecular monitoring using the international scale, the article said. Within the first 3 months of their treatment, only 21% of patients had a molecular assessment, although the guidelines call for all patients to receive one, the article added.

Study’s Findings Criticized by Coauthor

However, a coauthor of the study has taken issue with the findings. “Some of these patients at the beginning of the study were enrolled in 2007, when some of these monitoring studies were not yet commercially widespread,” said Debra A. Patt, MD, MPH, an oncologist based in Austin, Texas, with The US Oncology Network, a network of private physician practices.

“The commercial availability of molecular monitoring has increased over time, and as more treatments become available, that becomes more attractive. In the past, if somebody didn’t respond to treatment, you couldn’t do anything but a bone marrow transplant,” explained Patt, who is also director of outcomes research at McKesson Specialty Health, which provides management and support to US Oncology.

“CML is a relatively rare disease, diagnosed in 5000 people annually across the country. Sometimes they may have gotten some of their molecular monitoring at a different institution, and the records just didn’t make it into the study. They may be in my notes in a verbal format, but not in a pathology or laboratory section of the EMR,” she added.

According to Elias J. Jabbour, MD, associate professor at MD Anderson Cancer Center in Houston, and a senior author on the study, “If the patient has the test done at a center of excellence, the results should be communicated to the community doctor, because if they are not responding very well, maybe the doctor can change the drug. But if the test results are not communicated, that means the physician cannot act. It doesn’t matter where the test is done, if the doctor is not acting on it. Monitoring in academic centers is great, but in the community, patients are not getting good monitoring,” Jabbour contended. “We need to have another study.”

Possible Post-Study Paradigm Shift

“It is possible that the electronic medical record system may not have incorporated outside test results being sent in from another center, but unlikely that we would miss 50% of patients being monitored by an outside facility,” said Wang, who was not involved in the study.

However, developments since the last patient initiated treatment may mean the findings do not describe current community practice. “The shift over the years has been for patients not necessarily to be referred to an academic center, but managed by a general hematologist/oncologist or, in some cases, even a primary care doctor,” Wang said.

In addition, the molecular monitoring process has become more standardized. “In the past, we used to use locally developed tests to conduct the molecular monitoring, and our center, MD Anderson, Sloan Kettering, and the Cleveland Clinic would all have [their] own test. Now, you can go and get the international standardized version of the same test done at any lab in the country. It costs several hundred dollars, but it is commonly available,” she noted.

What’s more, approval of second-generation TKIs as first-line therapy has opened up more options for patients with refractory disease.

It is important for physicians to conduct the monitoring tests on patients, not only to look for opportunities to improve patient compliance, but because patients with CML who do not respond to one form of TKI might have a resistant form of cancer that would respond to a different TKI, Wang explained.

“I sit down with my patient and try to tease out, ‘Are you having trouble taking this medicine? Are you having side effects? Is it inconvenient? Are you taking it regularly?’ This mutation is associated with 99% of CML cases. At 12 months you shouldn’t see any abnormal cells.

“But for some patients, their disease does not respond. The genetic mutation involved in CML can undergo different additional mutations, which make them insensitive to that drug,” Wang stated. But all three TKIs work by binding the mutation at different locations, Wang added.

The US Oncology Network has added an automated alert to the EHR system to improve adherence to the guidelines, the article said.

References

1. Di Bella N, Bhowmik D, Bhor M, et al. The effectiveness of tyrosine kinase inhibitors and molecular monitoring patterns in newly diagnosed patients with chronic myeloid leukemia in the community setting.Clin Lymphoma Myeloma Leuk. 2015;15(10):599-605. doi:10.1016/j.clml.2015.06.006.
2. National Comprehensive Cancer Network. NCCN Guidelines. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 12, 2014.
3. Baccarani M, Deininger M, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872-884.
4. Branford S, Cross N, Hocchaus A, et al. First results from a collaborative initiative to develop an international scale for the measurement of BCR-ABL by RQ-PCR based on deriving laboratory-specific conversion factors [abstract]. Paper presented at: American Society of Hematology, December 9-12, 2006; Orlando, Florida. Abstract 737.