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Evidence-Based Oncology January/February

Literature Review: Chronic Myeloid Leukemia

Recent reports have suggested that after 3 months of treatment with imatinib, patients with CML may experience inferior outcomes (in terms of both progression- free survival and overall survival [OS]) when they experience BCR-ABL/ ABLIS levels above 10%, or more than 1% after 6 months of imatinib therapy. Italian and German researchers have attempted to extend this finding by 1 step: to determine whether high levels of BCR-ABL transcripts found at the time of diagnosis would also be connected with an inadequate reaction to imatinib treatment.

The researchers analyzed BCR-ABL levels of 230 patients with newly diagnosed CML who were to receive imatinib /day. Either ABL or glucuronidasebeta (GUS) was used as reference genes for all molecular verifications.

The median follow-up time in the study population was 42 months. Cumulative incidences estimated at 5 years for complete hematologic responses, complete cytogenetic response (CCyR), and major molecular response were 98%, 89%, and 65%, respectively. Overall survival rate using 5-year probabilities was 93.8%, while a transformation-free survival rate, defined as survival without disease transformation to the accelerated phase or blast crisis, and failurefree survival (survival without imatinib failure as indicated in the 2009 European Leukemia Net recommendations) were 98% and 76%, respectively.

When GUS was used instead of ABL as a reference gene at diagnosis, connections between high BCR-ABL transcripts and the differential in inadequate IM responses were much greater. Both elevated BCR-ABL/GUSIS (P <.0001) and elevated BCR-ABL/ABLIS (P <.0001) levels were associated with a lower probability of optimal response. The investigators also indicated that after 12 months of imatinib therapy, a link existed between lower rates of cytogenetic response and higher BCR-ABL/ GUSIS measurements (P <.0001) but not higher BCR-ABL/ABLIS values (P = .18).

They noted that overall survival could not be predicted by levels of BCR-ABL/GUSIS or BCR-ABL/ABLIS at diagnosis. However, a more accurate connection between high levels of BCR-ABL/GUSIS and lower probabilities of failure-free survival (P <.0001) and transformationfree survival (P = .01) was found when compared with high levels of BCR-ABL/ABLIS (P = .02 and P = .36, respectively).

After subdividing the patient cohort into optimal responders, suboptimal responders, and subjects failing first-line therapy, based on the 2009 European Leukemia Net criteria, the authors discovered that elevated BCR-ABL/GUSIS (P <.0001) was a better determinant of patient outcome than elevated BCR-ABL/ ABLIS (P <.004). In addition, at diagnosis, the number of BCR-ABL/GUSIS transcripts was significantly different between the 3 patient groups (optimal vs suboptimal responses, P = .0002; optimal vs resistant responses, P <.0001; suboptimal vs resistant responses, P <.0001). At the time of diagnosis, BCR-ABL/ABLIS levels only discriminated optimal from resistant responders (P = .005). The researchers determined the threshold distinguishing those at low risk from patients at high risk as 16% BCR-ABL/GUSIS at diagnosis.

Patients with CML who would probably not benefit from imatinib treatment can be identified by high BCR-ABL transcripts when diagnosed, using GUS as a reference gene, the researchers concluded, and therefore should be given other TKIs as first-line treatment.

Source: Vigneri PG, Stagno F, Stella AS, et al. High BCR-ABL levels at diagnosis are associated with unfavorable responses to imatinib mesylate. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8-11, 2012.

Payer Perspective

Will Cytogenetic Testing Improve Value in CML Care?

Maria Lopes, MD, MS

As demonstrated in the presentation by Hermann and colleagues at the December 2012 American Society of Hematology meeting,1 it is clear that in practice, cytogenetic testing in patients with CML is not performed according to the latest NCCN guidelines, which now call for an evaluation at 3, 12, and 18 months to assess cytogenetic response. This affords the opportunity to assess whether the choice of therapy is effective, and if not, to evaluate patient compliance, drug-drug interactions, or mutations that may render current treatment ineffective. Given the guidelines, it would seem appropriate for testing to be a standard of care, and yet variability in testing still exists. At least 2 major issues may help explain why cytogenetic testing is not following NCCN recommendations.

One reason may be that although the NCCN guidelines call for cytogenetic testing at certain milestones, they do not sufficiently inform the decision-making process and recommend assessment and choice in second-line TKIs. For instance, once cytogenetic testing is done and resistance is apparent (in the form of mutations like T315I), it is unclear how to incorporate this information into a treatment decision and whether current therapy should be discontinued simply based on lab test results. It is also unclear whether a change in treatment ultimately affects overall survival and health outcomes. Furthermore, how does this influence what payers do to minimize waste and at what point should a payer require prescribers to change treatments that may be ineffective? How will testing impact shared decision making for patients of a specified age range, with comorbidities, specific mutations, and other considerations? As new therapies emerge that may induce fewer mutations or are the only agents that work in specific mutations, including T315I, this may become a more important consideration that minimizes waste and brings clinical utility to testing.

Second, NCCN guidelines do not factor cost into the treatment consideration. In other words, the guidelines are suggestive but are not sufficiently prescriptive for providers or payers to take action based on the results of cytogenetic testing. The updated guidelines offer a step in possibly identifying drug resistance and ineffective therapy, but new therapy options need to be incorporated for a more personalized approach to second-line therapy, defining which mutation is causing the resistance and which second-line treatment is appropriate to reduce waste and improve survival.

On a more practical level, the actual cytogenetic testing report may not always be easy to interpret, which leads to further ambiguity on how it should be incorporated into decision making. Payers, providers, and members need decision support tools to assist with patient assessment, compliance and adherence, and education on the clinical utility of cytogenetic testing, its implications for treatment considerations,

Given this level of ambiguity, it may be challenging for managed care organizations alone to take action at this time to promote or encourage the use of cytogenetic testing. Clear guidance is needed from NCCN on the implications of the results for treatment decisions and selection of therapy, and the approach to treatment.

The opportunity now exists, based on NCCN’s focus on cytogenetic testing, to discuss with providers ways to optimize value from the available TKIs. Payers worry about the cost of these agents and invite discussions on ways to mitigate waste and inappropriate use associated with ineffective treatment to ensure that these represent adequate value for the dollars being spent. This will become even more critical should the use of combination TKIs be incorporated into the CML guidelines. The increased costs will affect not only health plans and insurers, but patients and those bearing risk for total cost of care, such as accountable care organizations.

The concept of value in cancer care is gaining momentum among providers. In October 2012, executives from Memorial Sloan-Kettering Cancer Center wrote in the New York Times that they would not utilize an expensive colon cancer therapy because they did not believe it represented good value.2 This is a highly significant statement from a cancer center of excellence. In the past, providers did not generally consider cost of treatment a priority issue. With the trend toward accountable care organizations and using global or bundled forms of payment, this view may now be more common from the provider side.

As with many diseases, we often find significant variation in treatment and in the approach to patient management. Often, variability adds to cost, poor patient outcomes, and inefficient use of medical and financial resources. Evidence-based guidelines can help reduce this variation, but are often broad and too complex to implement. In a recent article in BMJ, the authors noted “unnecessary treatment in America accounts for 10% to 30% of health care spending, or up to $800 billion per year.”3 The US system can no longer sustain or afford such waste.

CML represents another example of where more can now be done to improve the dialogue between health plans, key opinion leaders, and community oncologists to formalize pathways, reduce unnecessary treatment variability, and maximize the value of treatments, particularly when it comes to combining TKIs. This is a cost benefit discussion that will be increasingly common among unusual partners.

Dr Lopes is chief medical officer at CDMI in Newport, RI.


1. Hermann R, Miller CB, Catchatorian R, et al. Understanding US treatment practices for the management of chronic myeloid leukemia (CML) in clinical practice: a US subgroup analysis of the WORLD CML Registry. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8-11, 2012.

2. Bach PB, Saltz LB, Wittes RE. In cancer care, cost matters (editorial). New York Times, October 14, 2012. Accessed December 11, 2012.

3. Lenzer J. Unnecessary care: are doctors in denial and is profit driven healthcare to blame? BMJ. 2012;345:e6230.

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