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Jennifer Klemm, PhD; and Stanton R. Mehr
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Chronic Myelogenous Leukemia

Jennifer Klemm, PhD; and Stanton R. Mehr
Chronic myelogenous leukemia (CML) is an acquired disorder in which the Philadelphia chromosome, a translocation between chromosomes 9 and 22, is acquired in hematopoietic stem cells, resulting in expression of the Bcr-Abl oncoprotein. Over 5000 Americans are diagnosed with CML each year.1 Fortunately, the advent of tyrosine kinase inhibitor (TKI) therapy has dramatically extended life expectancy, with only 270 Americans expected to die of CML in 2011.2 The introduction of TKI inhibitor therapy has effectively transformed CML into a chronic disease, and this contributes substantially to the economic burden associated with CML—the median survival of these patients exceeds 20 years.3 A recent study demonstrated that medical costs for a patient with CML averaged $78,334 for just 1 year of treatment,3 and TKI therapy must be given chronically or patients risk recurrence or progression to the advanced blast stage of CML, which can be life threatening.

Current Treatment Options

The primary front-line therapeutic option for CML is individual TKI treatment, specifically with imatinib, dasatinib, or nilotinib. Imatinib was the first TKI to be approved by the US Food and Drug Administration and is used primarily as first-line therapy—it is not approved for use after patients have tried dasatinib or nilotinib.4 In contrast, both nilotinib and dasatinib were initially improved as second-line therapy after development of imatinib resistance.5,6 However, recent trials have demonstrated that these agents may have advantages over imatinib as first-line therapy, particularly in patients with intermediate- or high-risk disease.7-10 Longer-term follow-up of these studies is necessary to determine if these “second-generation” TKIs should become standard first-line therapy. For now, they are approved for newly diagnosed and imatinib-resistant disease only.7,8

Patients achieving a complete cytogenetic response with a first-line TKI remain on that therapy as long as their disease is in chronic phase. If patients do not achieve a complete cytogenetic response after 12 months of treatment with imatinib, they may receive higherdose imatinib or switch to either nilotinib or dasatinib. For those receiving first-line nilotinib or dasatinib, treatment is often switched to the other second- generation TKI if their disease does not respond to initial therapy.

Some patients undergo mutational analysis of the Bcr-Abl kinase domain in order to choose the optimal second-line therapy, as both nilotinib and dasatinib are highly sensitive to specific mutations. In addition, mutational analysis can reveal the T315I mutation, which is resistant to all 3 TKIs; in patients with this mutation, allogeneic stem-cell transplantation is a reasonable option. Transplantation, which is the only curative treatment for CML, has lost favor as a first-line therapy with the advent of TKIs because of its high toxicity, including a 20% to 30% mortality rate,9 its limited feasibility (due to donor availability), and high cost.10

If a patient receiving front-line TKI therapy achieves an insufficient response to treatment (less than complete hematologic response at 3 months, no cytogenetic response at 6 months, minor or no cytogenetic response at 12 months, or a partial cytogenetic response at 18 months) or if the disease reaches accelerated phase, treatment may be switched to a different TKI or an allogeneic transplant may be considered. Once a patient reaches blast crisis, options are generally restricted to a clinical trial or an allogeneic transplant preceded by a TKI with or without concurrent chemotherapy.11,12


The management of CML is costly partially because patients continuously receive TKI therapy for many years. No clinical studies have yet shown that TKI therapy can be discontinued without patients experiencing relapse.

According to Medi-Span data as of December 2011, the wholesale acquisition cost per month of standard imatinib therapy is $5819, compared with $7882 for dasatinib and $8181 for nilotinib. The patent for imatinib expires in approximately 5 years, and a generic version could have a significant effect on pricing.

However, because some evidence suggests that nilotinib and dasatinib may have superior efficacy compared with imatinib in the front-line setting, these agents may be cost-effective in spite of their higher prices (in the present comparison). Further studies are needed to establish the cost-effectiveness of these second-generation agents relative to imatinib. Only retrospective health economic studies have examined the relative cost-effectiveness of nilotinib and dasatinib. For instance, a recent examination of claims from 521 patients with CML receiving second-line TKI therapy (452 receiving dasatinib, 69 receiving nilotinib) showed that patients taking dasatinib had nearly twice as many inpatient admissions (incidence rate ratio, 1.99; P = .047) and more than twice as many inpatient days (incidence rate ratio, 2.44; P <.001) compared with patients receiving nilotinib.3 In addition, patients given dasatinib therapy had $8288 more medical service costs (P <.001), which were primarily associated with inpatient care. Finally, those taking dasatinib were found to be 13% less adherent to their medication than patients taking nilotinib (P = .009), despite the fact that nilotinib is taken twice daily and dasatinib is taken only once daily. Caution must be used when interpreting retrospective studies, but these data are intriguing. They are also consistent with another study of 267 patients, which demonstrated that patients with lower adherence to TKI therapy (in this case, imatinib) incurred higher annual medical costs.13 In this study, patients with a medication possession ratio (MPR) of 75% incurred an additional $4072 in medical costs in 1 year compared with patients having an MPR of just 10% higher, or 85%.

An interesting issue involving these TKIs is that they are oral drugs rather than injectable oncology agents, and are covered sometimes as part of the medical benefit versus the pharmacy benefit. In fact, since they are given on a continuing basis, many payers utilizing the pharmacy benefit elect to purchase and supply these agents through specialty pharmacy providers, who may have greater leverage with manufacturers (which results in somewhat lower prices).

Additional Drivers of the Cost of Care and Value

As expected, drug costs for patients with CML is the main driver of the cost of care, accounting for 42% of the total cost in one study examining costs incurred in the first year of care.3 This is true not only because TKIs are expensive drugs, but also because they are given indefinitely, until patients reach advanced phase disease, which may take many years. For example, 55% of patients receiving imatinib as part of the pivotal IRIS trial were still taking the drug after 8 years.14

Aside from drug costs, both outpatient costs and inpatient costs are substantial as well, accounting for 27% and 26% of the total cost, respectively (Figure).3 Examples of outpatient costs include both disease monitoring and mutational analysis. Although patients may receive TKI therapy and remain clinically stable for years, their response to therapy requires frequent monitoring. The National Comprehensive Cancer Network recommends that patients achieving a complete cytogenetic response to TKI therapy should receive Bcr-Abl transcript monitoring every 3 months for 3 years and every 3 to 6 months thereafter. The cost of this monitoring ranges from $375 to $1500 for each test.15 However, since this type of monitoring is necessary to determine when therapy should be switched, this represents a necessary cost. Mutational analysis, which is often performed before choosing a specific TKI, is over $500.16 Although this test is not absolutely necessary, it represents a good value for 2 reasons. First, it can provide a rationale for using imatinib over the more expensive second-generation TKIs if none of the mutations that are highly sensitive to either nilotinib or dasatinib are found. Second, if the patient is found to have the T315I mutation, no TKI therapy should be used, since that mutation is associated with poor response to all current TKI therapeutic agents.

Payer Perspective

Interview with Allan Jay Kogan, MD

EBO: In the majority of patients, chronic myelogenous leukemia (CML) is highly treatable with today’s therapeutic agents. What has been the value of targeted treatment on value for the payer and the patient with CML?

Dr Kogan: The introductions of the targeted tyrosine kinase inhibitors, such as imatinib, have made a great difference in terms of outcomes to patients with CML. As a health plan, we support the appropriate use of targeted treatment with biomarker testing.

EBO: Considering the state of the art in CML treatment today, what are your objectives in setting medical benefit policy to ensure optimal treatment?

Dr Kogan: We use prior authorization to ensure that biomarker testing has been done, according to the prescribing information, before targeted treatment is undertaken.

EBO: What would you characterize as the determinants of good value in treating patients with CML today?

Dr Kogan: We feel that the best value should be attained if we can achieve a remission with the fewest side effects. We would also prefer therapies with easy, convenient dosing to enhance compliance, especially since compliance seems to be a strong factor in averting recurrence. We also believe we can achieve greatest value if the regimen results in minimal interactions with other drugs the patient may be taking.

EBO: What are the key objectives as a payer when managing patients with CML?

Dr Kogan: Obtaining a cure or remission with the fewest side effects would be the first objective. We want to avoid blast crisis, but it is difficult to determine who may be at higher risk for progression to blast crisis. It would be nice to have a biomarker to help in this respect. Stem-cell transplant is the most expensive treatment for CML. If we can avoid (not simply delay) the need for stem-cell transplant, that would create a very beneficial cost offset.

EBO: Does your plan contract with any major cancer treatment networks?

Dr Kogan: Although we don’t contract with major cancer networks, we do have preferred contracts with centers of excellence. The major benefits of these contracts are quality assurance and documentation of best outcomes. Most cancer networks want exclusive contracts, which would limit network negotiations with other needed providers geographically as a national health plan.

EBO: Does your health plan collaborate with any organizations to encourage members to participate in clinical trials in cancer treatment?

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