Patients with chronic myeloid leukemia need regular BCR::ABL1 testing for the rest of their lives.
By Justin Brown, PhD
Progress in cancer is usually the result of a slow march of research and drug discovery efforts, with modest improvements in patient outcomes spread out over time. But in the case of chronic myeloid leukemia (CML), the advent of tyrosine kinase inhibitors (TKIs) rapidly and significantly changed expectations for patients.
The first TKI, imatinib, was approved for use in CML patients in 2001. Until that point, these patients had poor prognoses, with eight-year survival rates less than 15%.1 In the decade after 2001, survival rates rose higher than 75%.2 Since the approval of imatinib, dozens of other TKIs have been approved for clinical use, including at least four for CML.3 With additional refinements to the standard of care over time, including ultrasensitive molecular monitoring, patients are experiencing near-normal life expectancies.4
TKIs transformed not only what was possible for patients with CML, but also how clinical laboratories could help. The benefits of these treatments—and the possibility that patients may ultimately do so well they can even discontinue treatment—can only be realized through frequent molecular monitoring for the BCR::ABL1 fusion caused by a translocation between chromosomes 9 and 22.
Many clinical laboratories already perform BCR::ABL1 testing, either with FDA-cleared tests or laboratory-developed tests. But many of these tests may not be robust enough to meet rising demand. Patients with CML need regular BCR::ABL1 testing for the rest of their lives. With patients living decades longer, labs could see a significant increase in the need for BCR::ABL1 testing.
To meet this demand, clinical laboratory teams will do best with a scalable workflow that makes it possible to increase testing volume easily when needed, and without sacrificing valuable lab space to a high-throughput system that may sit idle for extended periods. A careful review of testing options can help clinical lab staff select the best one for the needs of their patient population.
How Much BCR::ABL1 Testing Is Needed?
An ongoing challenge in planning testing capacity is that there is no one-size-fits-all frequency for monitoring CML patients. As patients progress along the spectrum of treatment, molecular remission, and even treatment discontinuation, recommendations vary for how often BCR::ABL1 testing should be performed.
According to guidelines from the National Comprehensive Cancer Network (NCCN), patients on the standard TKI regimen should be tested every three months.4 That testing should continue until the patient has achieved a BCR::ABL1 result of ≤1%IS (equivalent to both ≥MR2 and complete cytogenetic response) for at least two years. At that point, patients and their physicians may choose to relax testing slightly, so long as tests are performed at least every six months.
In its latest guidelines, though, NCCN acknowledges that the optimal relaxed frequency for testing after achieving complete cytogenetic response remains unclear. The standard asserts that maintaining the three-month frequency even in this phase may be ideal because it can help spot non-adherence to treatment, which bears poorer prognosis. At this point in the cancer journey, and especially following the good news of achieving complete cytogenetic response, weary patients may temporarily stop treatment—usually without alerting their physicians. If the treatment holiday has caused patients to slip back into detectable levels of BCR::ABL1 analyte, identifying that problem as soon as possible is important for getting them back on track.
When all goes well for patients after reaching a stable molecular response of ≥MR4 (equivalent to ≤0.01%IS and sometimes called deep molecular response), they may work with their physicians to assess their eligibility to discontinue treatment indefinitely. This also requires documentation of at least four molecular test results showing deep molecular response. Frequent testing with an assay whose limit of detection is at least MR4.5 is crucial in this phase to ensure that treatment-free remission is durable. NCCN recommends molecular monitoring every month for the first six months, then every two months for another six months, and every three months thereafter. Even patients who continue to show no signs of molecular recurrence need to continue getting tested every three months for the rest of their lives.
For patients attempting treatment-free remission, if BCR::ABL1 levels increase ≤MR3 (equivalent to ≥0.1%IS), a return to treatment is indicated. In that case, testing is recommended every month until they regain major molecular response.
In addition to these scenarios and the uncertainty they offer clinical laboratories about how much testing volume to expect, there is another challenge. Recommendations about testing protocols have been evolving rapidly, making it difficult to keep up with the latest guidelines and to predict how they will affect demand for BCR::ABL1 testing. Just in the past year, the NCCN has updated its guidelines for CML treatment and testing three times.
Key Factors for BCR::ABL1 Testing
With so much uncertainty about BCR::ABL1 testing volumes in the context of longer-lived patients and those attempting treatment-free remission, clinical laboratories need scalable solutions that will make it easy to meet rising demand. But with so many test options available, there are several factors that should be considered to select the best one for each lab’s patient population.
Regulatory status. There are now four BCR::ABL1 tests, three of them commercially available, that have been cleared by the FDA. While many labs continue to use laboratory-developed tests (LDTs) using either their own designs or commercially available research-grade BCR::ABL1 reagents, this introduces an element of risk should regulatory guidelines change, as recent legislative efforts have indicated. While adopting an FDA-cleared test involves verification and implementation in the lab, it does reduce concerns about inviting regulatory scrutiny.
Complexity level. Among FDA-cleared tests, there are now high-complexity tests and moderate-complexity tests available. For labs already running high-complexity tests, either option would be fine; but for labs that are not equipped for this level, moderate-complexity approaches may be needed.
Footprint. Some test manufacturers are now able to achieve moderate complexity and higher throughput, but they do so at the cost of platform size. While most BCR::ABL1 testing can be performed on benchtop instruments, high-throughput platforms of reduced complexity are often large enough to need an entire section of the lab’s floor space, running several feet each in width, depth, and height.
Multiplexing capability. Some tests can detect BCR::ABL1 and control transcript ABL1 in the same well, making it possible to run far more samples per plate than tests that run them in separate wells. A test that incorporates multiplexing will be a more efficient option for labs that need to return more results.
Replication. Workflow efficiency can also be enhanced by using tests that are precise enough to be performed in singleton, meaning there is no need to run replicate wells for reliability. If the singleton reactions are also multiplexed, it provides even further scalability to the lab.
Test capacity. When evaluating test options, it’s important to understand exactly how many patient samples can be run at once. Factor in the calibrators, controls, and any replicates that must be run in order to get a clear understanding of the test’s capacity. Also consider workflow time: A test that takes less hands-on time per run but processes fewer samples at once might actually take more staff time to attain the same number of results as a higher-capacity test that requires more hands-on time per run.
The remarkable progress seen in CML patient outcomes is only possible with high-quality BCR::ABL1 testing from clinical laboratories. Lab teams should anticipate that demand could increase substantially as more patients benefit from TKI therapy and ultrasensitive molecular monitoring, gaining decades of life that would never have been possible before 2001.
ABOUT THE AUTHOR
Justin Brown, PhD, serves as principal scientist for diagnostics development at Asuragen, a Bio-Techne brand. He directed the team that developed the first FDA-cleared test for use in CML management.
- Kantarjian H, O’Brien S, Jabbour E, Garcia-Manero G, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood. 2012 Mar 1;119(9):1981-7. doi: 10.1182/blood-2011-08-358135. Epub 2012 Jan 6. PMID: 22228624; PMCID: PMC3311242.
- “Cancer Stat Facts: Leukemia — Chronic Myeloid Leukemia (CML).” National Cancer Institute. https://seer.cancer.gov/statfacts/html/cmyl.html. Accessed February 24, 2023.
- Jeon JY, Sparreboom A, Baker SD. Kinase Inhibitors: The Reality Behind the Success. Clin Pharmacol Ther. 2017 Nov;102(5):726-730. doi: 10.1002/cpt.815. PMID: 28795397; PMCID: PMC6069597.
- NCCN Guidelines: Chronic Myeloid Leukemia. Version 1.2023. National Comprehensive Care Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427. Accessed February 24, 2023.